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Changing the Management of Paracetamol Poisoning
Clinical Therapeutics/Volume ], Number ], 2015
Changing the Management of Paracetamol Poisoning D. Nicholas Bateman, BSc, MBBS, MD Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom ABSTRACT Purpose: The management of paracetamol poisoning was revolutionized after use of acetylcysteine in the 1970s. The protocol used, 3 weight-related infusions, requires almost 24 hours in hospital. It is associated with adverse events in treated patients, particularly anaphylactoid reactions and vomiting. Present treatment nomograms were based on a small series of untreated patients: only 5 of 22 (23%) and 6 of 25 (24%) between the 100 to 200 mg/L and 200 to 300 mg/L nomogram lines, respectively, developed liver injury (alanine transaminase 41000 IU/L). Many patients treated today are unlikely to be at actual risk for major hepatotoxicity. This article discusses the background to future prospects in this area. Methods: The history behind approaches to the use of acetylcysteine is presented briefly. The rationale for, and key findings of, a new 12-hour antidote regimen for paracetamol poisoning are detailed. Newer markers of hepatotoxicity, such as miR-122, HMGB1, and necrosis K18, which predict patients at risk more reliably and earlier than existing tests, are discussed. Findings: A 2-phase 12-hour acetylcysteine infusion protocol (100 mg/kg over 2 hours: 200 mg/kg over 10 hours) was studied in a formal factorial design against the traditional 3-phase 20.25-hour infusion protocol, with and without pretreatment with ondansetron or placebo. The 12-hour regimen was associated with very significant reductions in anaphylactoid reactions (odds ratio ¼ 0.23; 95% CI, 0.120.43; P o 0.0001) and vomiting (odds ratio ¼ 0.37; 95% CI, 0.180.79; P ¼ .003) compared with the 20.25-hour infusion protocol. There were few withdrawals from the clinical trial, indicating the feasibility of conducting such studies in Europe. Implications: Novel proteomic markers are better than existing standard tests (alanine transaminase and international normalized ratio) early in the course of paracetamol poisoning. Together with these new biomarkers of hepatotoxicity, a 12-hour acetylcysteine
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protocol offers clinicians and patients the possibility for better targeting of therapy, fewer adverse effects, a simpler dosing regimen, and shorter hospital stay. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: paracetamol overdose, antidotes, risk assessment.
BACKGROUND Paracetamol was introduced into medical practice in the United States in 1955 and in the United Kingdom in 1956. Poisoning was first described in humans in Scotland in 1966.1,2 Subsequently, the mechanism of paracetamol toxicity, production of a reactive benzoquinoneimine metabolite (N-acetyl-para-benzoquinoneimine), was understood after work by Mitchell et al in the United States.3 This led to the development of antidotes that were designed to replace the naturally occurring antioxidant glutathione consumed by binding and neutralizing N-acetyl-para-benzoquinoneimine. Availability of glutathione is influenced by environmental factors, particularly nutritional status. Production of N-acetyl-para-benzoquinoneimine from paracetamol, primarily by CYP2E1, is potentially inducible, and can also be inhibited by acute ingestion of ethanol. These different factors might be difficult to assess in poisoned patients.4,5 The lead candidate antidote in the 1970s soon became acetylcysteine, given intravenously in a 3-step regimen. This is known in the United Kingdom as the “Prescott” regimen, and consists of weight-related dosages of acetylcysteine given in 3 infusions, initially 150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, and finally 100 mg/kg over 16 hours.6,7 Accepted for publication July 14, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.07.012 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics Methods of risk assessment were also derived in Edinburgh based on patients not treated with antidote, and using paracetamol concentrations at presentation to derive nomograms. A nomogram was published by Rumack and Matthew8 in 1975, although the article has no patient data included. Subsequently, further risk analyses were derived from the Edinburgh patient population by Prescott.9 The case data extracted from the Prescott publication are shown in the Table, and are based on an alanine transaminase (ALT) of 4 1000 IU/L as the marker of hepatotoxicity. This is a relatively poor indicator of prognosis, even though it is a sensitive measure of liver injury, as judged by its noninclusion in the Kings College criteria of prognosis.4 However, it is clear from the data in the Table that only one quarter of patients at concentrations below the 300 mg/L line and above the 100 mg/kg line developed important liver injury. There was no gradation in the proportion developing an ALT 41000 IU/L in those lying between the 100 to 200 mg/L and 200 to 300 mg/L lines, even though liver failure and renal injury were seen in those above the 200 mg/L line only. In untreated paracetamol poisoning cases in which the liver is damaged, the clearance of paracetamol is reduced and half-life is prolonged in proportion to the degree of liver injury.10 Without liver damage, paracetamol has a half-life of about 2 hours.11 Because treatment is not commenced until at least 4 hours after ingestion, it is clear that with a half-life of 2 hours, paracetamol will be undetectable in the blood of patients not at risk many hours before the end of
Table. Patients with untreated paracetamol overdose who developed liver injury (ALT 41000 IU/L), renal failure, or death stratified by paracetamol nomogram lines. Data are given as n (%) unless otherwise noted and are derived from Prescott.9 Paracetamol Line (mg/L) o100 100200 200300 4300
2
No. of Patients 9 22 25 27
Liver Injury 0 5 6 25
(0) (23) (24) (93)
Renal Failure Death 0 0 1 (4) 5 (20)
0 0 0 3 (12)
the current 21-hour antidote infusion. This means that many patients are likely to be kept in hospital well after their risk of paracetamol-induced liver injury could be excluded. Based on these data, clearance of paracetamol combined with other tests could be used as an indicator of good prognosis, but is rarely applied in this way.
Problems with the Paracetamol Nomograms The nomogram lines derived in the 1970s were drawn by eye rather than by using any statistical derivation. They are lines drawn from a 4-hour postoverdose time point, commencing at 300, 200, 150, or 100 mg/L (1.98, 1.32, 0.99, and 0.66 mmol/L respectively), and all have a half-life of decline of 4 hours, despite the known variability of paracetamol clearance in poisoned patients.10 In the United Kingdom, the Prescott article9 supported a 200-mg line, which was adopted in the late 1970s. In the United States, Rumack and Matthew’s8 original suggestion of a 200mg line was modified by the US Food and Drug Administration to the 150-mg line. The rationale was that 150 mg was half the concentration of 300 mg/L, which at that time was believed to cause death.12 Subsequent reports have found that deaths can occur in untreated patients at concentrations below the 200 mg/L line and, in very rare patients who are fasting, even below 100 mg/L.5,13,14 In the 1990s, the United Kingdom changed its policy to include a risk assessment in those patients with paracetamol concentrations between the 100 and 200 mg/L nomograms.15 The risk factors used to influence a treatment decision included malnutrition, debilitating disease (including AIDS), chronic high ethanol consumption, and enzymeinducing drugs.4 This was subsequently changed after a review by the UK regulator (The Medicines and Healthcare Products Regulatory Agency [MHRA]) to a single decision tool in 2012, the 100-mg/L nomogram line, after the death of a young woman with a presentation concentration just over the 100-mg line but who was not treated, as risk factors were reportedly not apparent at presentation.5 The impact of these changes on clinical practice in the United Kingdom was reported subsequently, with many additional hospital presentations and admissions, at an estimated cost of £17.3 m (95% CI, £13.4 m£21.5 m) (€21.2 m, $29 m) to prevent one death.16 Few modern health care systems would find such costs justifiable. Volume ] Number ]
D.N. Bateman Despite the availability of an antidote, failure to present early to hospital remains the major risk factor for poorer outcomes,17,18 and paracetamol is still the most common cause of listing for liver transplant after drug overdose; it is involved in 96% of such cases in Europe.19 Risk of liver injury in patients treated with acetylcysteine depends on time to presentation and mode of ingestion. Larger series of patients treated indicate that acute single overdoses have better outcomes than multiple ingestions and therapeutic excess. Patients who present after 24 hours have the worst prognoses.20 In a recent large UK series, only 10 of 2743 patients with acute single ingestion and 1 of 202 therapeutic excess treated with acetylcysteine developed hepatotoxicity (ALT 41000 IU/L). However, 10 of 452 delayed single (424 hours) and 13 of 426 staggered (repeated) overdoses developed hepatotoxicity.21 Because there is little evidence that acetylcysteine is effective after 24 hours from ingestion, other than in treatment of hepatic encephalopathy,22 these figures emphasize the fact, as first shown by Prescott in 1978, that a large proportion of patients who do not receive treatment do not develop hepatic failure (Table). A key issue for managing patients with paracetamol poisoning more efficiently is correct identification of patients at risk who would benefit from treatment with acetylcysteine. The present cutoffs of 150 mg/L (in the United States and Australia) or 100 mg/L (in the United Kingdom and Ireland) will include a large proportion of patients who are not at risk of serious liver damage. Indeed, just taking all untreated patients above the 200-mg nomogram line, 50% of patients did not get an ALT rise above 1000 IU/L (Table).9 This means that many patients are being treated to protect the proportion of the population who are at greater risk. As treatment lines have been lowered over the years, this proportion is likely to have increased. Paracetamol overdose, therefore, remains a very significant public health issue, and although steps to reduce pack size have had some impact in the United Kingdom, the overall decline in paracetamol mortality has been disappointingly small, probably because most patients who develop problems in Europe present too late for therapy.21,23 The focus going forward is therefore better identification of patients who need antidotal therapy and optimizing this therapy to reduce adverse events.
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Problems with Acetylcysteine Although effective as an antidote, use of acetylcysteine was soon recognized to be associated with adverse effects, in particular anaphylactoid reactions, nausea, and vomiting.24–26 Anaphylactoid reactions in particular result in discontinuation of antidote (in almost 30% of patients treated in one clinical trial),27 sometimes refusal by the patient to have more treatment, and rarely treatment with acetylcysteine being declined by physicians because of concern about the risk of anaphylactoid response in those who have suffered this previously.4 The frequency of adverse drug reactions depends on the methods used to collect data,26 but is highest in studies done prospectively. In one clinical trial, nausea and vomiting occurred in almost 70% of patients treated with the 15-minute initial NAC infusion protocol,27 whereas retrospective studies report rates nearer to 20%.26 Some have suggested the nausea is due to paracetamol, but a recent study showed no relationship between paracetamol concentration and use of antiemetic drugs for vomiting in those receiving acetylcysteine.16 A further confounder is likely to be the concentration of paracetamol in patients who develop anaphylactoid responses. A number of studies indicate that although nausea is unaffected by paracetamol concentration,16,28,29 anaphylactoid reactions are much more frequent at paracetamol concentrations o100 mg/L. For example, in patients with concentrations 4100 mg/L, paracetamol rates of anaphylactoid reactions are approximately 5 times less than in those below this concentration (odds ratio = 0.19; 95% CI, 0.100.37; P o 0.001).16 This is an important finding because, as discussed, patients with lower concentrations of paracetamol are also at lower risk of liver injury. In the 1980s, we showed that patients who experienced anaphylactoid reactions were more susceptible to wheal and flare response from intradermal injection of acetylcysteine at the concentration present in the initial infusion of the Prescott regimen than controls.24 The reactions appear to be due in part to the release of histamine, and higher concentrations of histamine are found in the plasma of patients who have had an allergic-like (nonimmunologic) response.30 It was also increasingly recognized that these adverse reactions were more frequent in patients who have lower concentrations of paracetamol in their blood.28,29
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Clinical Therapeutics In addition, the 3-stage infusion is associated with medication error secondary to the complexity of the dosage regimen.31 This led the MHRA to include specific guidance in 2012 on acetylcysteine administration as part of their review of antidote use in paracetamol overdose.5 It has been the practice for some years in North America and Australia to give the initial acetylcysteine infusion over 1 hour rather than the 15 minutes used in the initial Prescott protocol. In 2012, the UK MHRA also changed its guidance to recommend a 1-hour infusion to try and reduce adverse effects of acetylcysteine. This was because of an Australian study that suggested a nonsignificant benefit from this approach, but was underpowered to show a difference based on the numbers recruited.32 Observational data subsequently obtained after the change by the MHRA in the United Kingdom has shown that adverse reaction rates appear unaffected by the lengthening of the initial infusion to 1 hour from 15 minutes.16 Although it seems logical that pretreatment with an antihistamine might reduce anaphylactoid reactions,29 there are no formal studies to assess the impact of this approach. However, treatment interruption and therapy with antihistamines is standard in those who suffer adverse effects due to anaphylactoid reactions. Some clinicians use pretreatment with antihistamines in patients who have had reactions with acetylcysteine previously. In contrast, corticosteroids are not part of the standard UK protocol for initial management of allergic-type reactions, as the reaction settles quickly (ie, before the action of corticosteroids can take effect), and is nonimmunologic. Treatment in the United Kingdom includes interrupting the acetylcysteine, an intravenous antihistamine, and inhaled salbutamol in those with wheeze.4 Adrenaline is rarely indicated clinically. Finally, since its introduction, intravenous acetylcysteine has been given in a dose related to patient weight, not ingested dose of paracetamol. The dose of acetylcysteine is likely to be excessive as a glutathione replacement for all but the largest of paracetamol overdoses, that is, with concentrations 4500 or 600 mg/L.12 Some have suggested it might be possible to model acetylcysteine requirements based on estimated paracetamol dose, but this has yet to be tested in practice.33
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A New Approach to Paracetamol Poisoning Based on this discussion, there are now several reasons to consider revision of the way in which paracetamol poisoning is both assessed and treated. The nomograms used to predict treatment are based on a conservative estimate of risk and a significant proportion of patients with paracetamol overdose who are treated are not at risk of severe liver injury. Although current strategies are very effective in reducing the risk of toxicity in the population as a whole, this is at the cost of treating many patients who are unlikely to develop major hepatic injury. Traditional markers of liver injury, such as ALT, rise relatively slowly, generally after 24 hours, and in proportion to the extent of liver injury.34 Although a normal ALT at presentation seems to predict a good outcome in patients treated with acetylcysteine,35 it is not a screening test that can exclude the need for therapy. A high product of paracetamol concentration and concurrent ALT might also predict hepatic injury in those who are treated with acetylcysteine, but its utility in defining need for therapy has not been tested.36 Changes in international normalized ratio are a more sensitive measure of hepatic injury, but changes in international normalized ratio follow liver injury, and they are useful in estimating recovery from liver injury rather than predicting risk earlier.4 Renal failure is rare, so it is not useful as a screening measure, but at presentation it predicts poor outcome.20 Recent work evaluating new biomarkers of hepatotoxicity suggests that it should be possible to determine who is going to develop significant liver injury earlier in the course of the disease, either at presentation to hospital or soon after.37,38 These include miR-122, HMGB1, and necrosis K18, which are all more specific than ALT,38 which is a relatively poor marker of actual prognosis once elevated.4 A case report confirms that these markers may well be elevated in patients who subsequently develop toxicity, opening the possibility of more specific, earlier markers than are currently used.39 If this can be reproduced in a larger series of cases, it would be theoretically possible to predict those at risk of hepatic injury far earlier, and to better target therapy. A second target for improvement is the way in which acetylcysteine is given. This would aim to reduce the incidence of adverse effects in patients treated with acetylcysteine and, assuming it will be
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D.N. Bateman possible to stratify hepatotoxic risk earlier and more accurately, shortening of the duration of treatment for many patients. A key step in reducing adverse effects and duration of treatment is, therefore, to redesign the antidote regimen used. In the 1980s, Prescott et al measured the concentrations of acetylcysteine in blood with his 3-dose regimen.40 As expected, concentrations were initially high, but fell quickly once the rate of infusion had dropped during the second and third phases of antidote administration. Because we believe that the anaphylactoid reactions are related to the initial infusion, and most occur in a time window compatible with this hypothesis16—within 1 hour of a 15-minute infusion and 2 hours of commencement of a 1-hour initial infusion—it seemed logical to concentrate protocol redesign of the way in which the antidote is given during the initial infusion. In addition, because the dose of acetylcysteine currently used is probably excessive for the requirements of most patients, we believed this was unlikely to reduce patient benefit from the antidote.12 We undertook Monte Carlo modeling to design a simpler and shorter protocol for giving acetylcysteine. The object was to achieve concentrations above the original Prescott values of acetylcysteine concentration within about 1 hour of commencement. The eventual regimen we designed consists of 2 infusion periods, 100 mg/kg in 200 mL in 5% dextrose over 2 hours, followed by 200 mg/kg in 1 L 5% dextrose over 10 hours. It had originally been intended to study the 12hour regime in a noninferiority design, testing it against the standard 20.25-hour regimen. Because hepatotoxicity is rare when patients have received acetylcysteine, large numbers of patients would need to be included in such a trial. Our funders were uncertain whether it was possible to recruit overdose patients into clinical trials in Europe. Power calculations suggested we would require many more patients than the funding body were prepared to underwrite in our grant application. We, therefore, tested the efficacy of our regimen in reducing adverse events in a factorial study using ondansetron as “positive control” treatment for emesis. The trial had 4 arms, conventional 20.25-hour acetylcysteine or our novel 12-hour protocol both with and without ondansetron pretreatment.27,41 The outcomes of this study clearly showed that the new 12-hour regimen significantly reduced anaphylactoid reactions that required interruption of treatment or
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specific drug therapy and vomiting. Importantly, the effect on anaphylactic reactions was to reduce these from almost 30% to 6% (odds ratio = 0.23; 95% CI, 0.120.43; P o 0.0001) and to reduce vomiting from 66% to 33% (odds ratio = 0.37; 95% CI, 0.180.79; P = 0.003).27 It is important to note that this study was not designed to prove comparative efficacy, but there was no signal that either ALT, using a 1.5-fold increase as a marker of incipient liver injury, or the newer marker miR-122, was elevated in the treated group compared with control. The completion of this study in patients with paracetamol poisoning in Europe is important, as such large studies have not been conducted previously in poisoned patients in this environment. Indeed, the consent (85%) and dropout (2%) rates in this trial were similar to those seen in other clinical trials of more standard medical problems. Poisoning is a large problem for many health care systems, and paracetamol poisoning is the most common form of poisoning in the United Kingdom and United States.4,42 It is, therefore, important to develop methodologies to test the most effective and cost-efficient therapies in this large patient group. Additional studies of the 12-hour acetylcysteine regimen are now required to prove efficacy and, in particular, better define whether all patient groups benefit equally, even though there was no signal of any increased risk of hepatotoxicity in the clinical trial.27 It seems clear, however, that this advance is stimulating research internationally on the way antidotes are given in paracetamol overdose.43,44
DISCUSSION In paracetamol poisoning, there are better ways to give acetylcysteine that will reduce adverse reactions, patient discomfort, and, hopefully, medication error. A shorter duration for giving acetylcysteine, combined with better methods of detecting those patients at risk of paracetamol toxicity, also has the possibility of reducing hospital stay for many patients, and freeing hospital beds in burdened health care facilities. Clinicians should be evaluating better markers of liver injury to avoid treating patients who are not at risk, while identifying earlier those who might benefit from more intensive therapy, as shown in animals.45 Finally, clinical trials can and should be done in patients with
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Clinical Therapeutics poisoning in Europe, despite the complexities of the European Clinical Trial Regulations.
ACKNOWLEDGMENTS This article was written as a background to the award to the author of the European Association for Clinical Pharmacology and Therapeutics Clinical Trial Prize 2015 for the article, “Reduction of Adverse Effects From Intravenous Acetylcysteine Treatment for Paracetamol Poisoning: A Randomised Controlled Trial” published in The Lancet in 2014. The author is grateful to the European Association for Clinical Pharmacology and Therapeutics for this opportunity to publish reference to this work, and wishes to acknowledge the assistance and support of all the coauthors of the original trial. The trial was funded by the Chief Scientist Office of the Scottish Government.
CONFLICTS OF INTEREST The author has indicated that there are no conflicts of interest regarding the content of this article.
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11. Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982;7:93–107. 12. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol. 2012;50:91–98. 13. Beer C, Pakravan N, Hudson M, et al. Liver unit admission following paracetamol overdose with concentrations below current UK treatment thresholds. QJM. 2007;100:93–96. 14. Bateman DN, Dear J. Medicine, poison, and mystic potion: a personal perspective on paracetamol Louis Roche lecture, Stockholm, 2009. Clin Toxicol. 2010;48:97–103. 15. Routledge P, Vale JA, Bateman DN, et al. Paracetamol (acetaminophen) poisoning. No need to change current guidelines to accident departments. BMJ. 1998;317:1609–1610. 16. Bateman DN, Carroll R, Pettie J, et al. Effect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol. 2014;78:610–618. 17. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319:1557–1562. 18. Waring WS. Criteria for acetylcysteine treatment and clinical outcomes after paracetamol poisoning. Expert Rev Clin Pharmacol. 2012;5:311–318. 19. Gulmez SE, Larrey D, Pageaux G-P, et al. Liver transplant associated with paracetamol overdose: results from the seven-country SALT study. Br J Clin Pharmacol. 2015. May 27, http://dx.doi.org/10.1111/bcp.12635. [Epub ahead of print]. 20. Pakravan N, Simpson KJ, Waring WS, et al. Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit. Eur J Clin Pharmacol. 2009;65:163–168. 21. Wong A, Sivilotti ML, Dargan PI, et al. External validation of the paracetamolaminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose. Clin Toxicol. 2015;53:353. 22. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303:1026– 1029. 23. Bateman DN. Pack size and paracetamol overdose: 16 years later. Clin Toxicol. 2014;52:821–823. 24. Bateman DN, Woodhouse KW, Rawlins MD. Adverse reactions to N-acetylcysteine. Hum Toxicol. 1984;3: 393–398. 25. Sandilands EA, Bateman DN. Adverse reactions associated with acetylcysteine. Clin Toxicol. 2009;47:81–88. 26. Koppen A, van Reil A, de Vreis I, Meulenbelt J. Recommendations for the paracetamol treatment nomogram and side effects of N-acetylcysteine. Neth J Med. 2014; 72:251–257.
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D.N. Bateman 27. Bateman DN, Dear JW, Thanacoody HK, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet. 2014;383:697–704. 28. Waring WS, Pettie JM, Dow MA, Bateman DN. Paracetamol appears to protect against N-acetylcysteineinduced anaphylactoid reactions. Clin Toxicol. 2006;44:441–442. 29. Schmidt LE. Identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment of paracetamol overdose. Clin Toxicol. 2013;51:467–472. 30. Pakravan N, Waring WS, Bateman DN. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol. 2008;46: 697–702. 31. Ferner RE, Langford NJ, Anton C, et al. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example. Br J Clin Pharmacol. 2001;52:573–577. 32. Kerr F, Dawson A, Whyte IM, et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2005;45:402–408. 33. Duffull SB, Isbister GK. Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose. Clin Toxicol. 2013;51:772–776. 34. Green TJ, Sivilotti MLA, Langmann C, et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol. 2010;48:787–792. 35. Al-Hourani K, Mansi R, Pettie J, et al. The predictive value of hospital admission serum alanine transaminase activity in patients treated for paracetamol overdose. QJM. 2013;106:541–546. 36. Sivilotti MLA, Green TJ, Langmann C, et al. Multiplying the serum aminotransferase by the acetaminophen
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concentration to predict toxicity following overdose. Clin Toxicol. 2010;48: 793–799. Antoine DJ, Dear JW, Lewis PS, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology. 2013;58: 777–787. Dear JW, Antoine DJ. Stratification of paracetamol overdose patients using new toxicity biomarkers: current candidates and future challenges. Expert Rev Clin Pharmacol. 2014;7:181–189. Dear JW, Antoine DJ, StarkeyLewis P, et al. Early detection of paracetamol toxicity using circulating liver microRNA and markers of cell necrosis. B J Clin Pharm. 2013;77:904–905. Prescott LF, Donovan JW, Jarvie DR, Proudfoot AT. The disposition and kinetics of intravenous Nacetylcysteine in patients with paracetamol overdosage. Eur J Clin Pharmacol. 1989;37:501–506.
41. Thanacoody HK, Gray A, Dear JW, et al. Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP). BMC Pharmacol Toxicol. 2013;14:20. 42. Mowry JB, Spyker DA, Cantilena LR, et al. 2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol. 2014;52:1032–1283. 43. Graudins A, Harper A. Comparison of adverse drug reaction rates using a two-bag to a standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning. Clin Toxicol. 2015;53:249. 44. Isbister GK, Downes MA, Mcnamara K, et al. A novel infusion protocol for the administration of acetylcysteine. Clin Toxicol. 2015;53: 249–250. 45. Dear JW, Simpson KJ, Nicolai MP, et al. Cyclophilin A is a damageassociated molecular pattern molecule that mediates acetaminopheninduced liver injury. J Immunol. 2011;187:3347–3352.
Address correspondence to: D. Nicholas Bateman, BSc, MBBS, MD, University of Edinburgh, Edinburgh, UK, EH16 4TJ. E-mail: nbateman@ staffmail.ed.ac.uk
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Changing the Management of Paracetamol Poisoning D. Nicholas Bateman, BSc, MBBS, MD Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom ABSTRACT Purpose: The management of paracetamol poisoning was revolutionized after use of acetylcysteine in the 1970s. The protocol used, 3 weight-related infusions, requires almost 24 hours in hospital. It is associated with adverse events in treated patients, particularly anaphylactoid reactions and vomiting. Present treatment nomograms were based on a small series of untreated patients: only 5 of 22 (23%) and 6 of 25 (24%) between the 100 to 200 mg/L and 200 to 300 mg/L nomogram lines, respectively, developed liver injury (alanine transaminase 41000 IU/L). Many patients treated today are unlikely to be at actual risk for major hepatotoxicity. This article discusses the background to future prospects in this area. Methods: The history behind approaches to the use of acetylcysteine is presented briefly. The rationale for, and key findings of, a new 12-hour antidote regimen for paracetamol poisoning are detailed. Newer markers of hepatotoxicity, such as miR-122, HMGB1, and necrosis K18, which predict patients at risk more reliably and earlier than existing tests, are discussed. Findings: A 2-phase 12-hour acetylcysteine infusion protocol (100 mg/kg over 2 hours: 200 mg/kg over 10 hours) was studied in a formal factorial design against the traditional 3-phase 20.25-hour infusion protocol, with and without pretreatment with ondansetron or placebo. The 12-hour regimen was associated with very significant reductions in anaphylactoid reactions (odds ratio ¼ 0.23; 95% CI, 0.120.43; P o 0.0001) and vomiting (odds ratio ¼ 0.37; 95% CI, 0.180.79; P ¼ .003) compared with the 20.25-hour infusion protocol. There were few withdrawals from the clinical trial, indicating the feasibility of conducting such studies in Europe. Implications: Novel proteomic markers are better than existing standard tests (alanine transaminase and international normalized ratio) early in the course of paracetamol poisoning. Together with these new biomarkers of hepatotoxicity, a 12-hour acetylcysteine
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protocol offers clinicians and patients the possibility for better targeting of therapy, fewer adverse effects, a simpler dosing regimen, and shorter hospital stay. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: paracetamol overdose, antidotes, risk assessment.
BACKGROUND Paracetamol was introduced into medical practice in the United States in 1955 and in the United Kingdom in 1956. Poisoning was first described in humans in Scotland in 1966.1,2 Subsequently, the mechanism of paracetamol toxicity, production of a reactive benzoquinoneimine metabolite (N-acetyl-para-benzoquinoneimine), was understood after work by Mitchell et al in the United States.3 This led to the development of antidotes that were designed to replace the naturally occurring antioxidant glutathione consumed by binding and neutralizing N-acetyl-para-benzoquinoneimine. Availability of glutathione is influenced by environmental factors, particularly nutritional status. Production of N-acetyl-para-benzoquinoneimine from paracetamol, primarily by CYP2E1, is potentially inducible, and can also be inhibited by acute ingestion of ethanol. These different factors might be difficult to assess in poisoned patients.4,5 The lead candidate antidote in the 1970s soon became acetylcysteine, given intravenously in a 3-step regimen. This is known in the United Kingdom as the “Prescott” regimen, and consists of weight-related dosages of acetylcysteine given in 3 infusions, initially 150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, and finally 100 mg/kg over 16 hours.6,7 Accepted for publication July 14, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.07.012 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics Methods of risk assessment were also derived in Edinburgh based on patients not treated with antidote, and using paracetamol concentrations at presentation to derive nomograms. A nomogram was published by Rumack and Matthew8 in 1975, although the article has no patient data included. Subsequently, further risk analyses were derived from the Edinburgh patient population by Prescott.9 The case data extracted from the Prescott publication are shown in the Table, and are based on an alanine transaminase (ALT) of 4 1000 IU/L as the marker of hepatotoxicity. This is a relatively poor indicator of prognosis, even though it is a sensitive measure of liver injury, as judged by its noninclusion in the Kings College criteria of prognosis.4 However, it is clear from the data in the Table that only one quarter of patients at concentrations below the 300 mg/L line and above the 100 mg/kg line developed important liver injury. There was no gradation in the proportion developing an ALT 41000 IU/L in those lying between the 100 to 200 mg/L and 200 to 300 mg/L lines, even though liver failure and renal injury were seen in those above the 200 mg/L line only. In untreated paracetamol poisoning cases in which the liver is damaged, the clearance of paracetamol is reduced and half-life is prolonged in proportion to the degree of liver injury.10 Without liver damage, paracetamol has a half-life of about 2 hours.11 Because treatment is not commenced until at least 4 hours after ingestion, it is clear that with a half-life of 2 hours, paracetamol will be undetectable in the blood of patients not at risk many hours before the end of
Table. Patients with untreated paracetamol overdose who developed liver injury (ALT 41000 IU/L), renal failure, or death stratified by paracetamol nomogram lines. Data are given as n (%) unless otherwise noted and are derived from Prescott.9 Paracetamol Line (mg/L) o100 100200 200300 4300
2
No. of Patients 9 22 25 27
Liver Injury 0 5 6 25
(0) (23) (24) (93)
Renal Failure Death 0 0 1 (4) 5 (20)
0 0 0 3 (12)
the current 21-hour antidote infusion. This means that many patients are likely to be kept in hospital well after their risk of paracetamol-induced liver injury could be excluded. Based on these data, clearance of paracetamol combined with other tests could be used as an indicator of good prognosis, but is rarely applied in this way.
Problems with the Paracetamol Nomograms The nomogram lines derived in the 1970s were drawn by eye rather than by using any statistical derivation. They are lines drawn from a 4-hour postoverdose time point, commencing at 300, 200, 150, or 100 mg/L (1.98, 1.32, 0.99, and 0.66 mmol/L respectively), and all have a half-life of decline of 4 hours, despite the known variability of paracetamol clearance in poisoned patients.10 In the United Kingdom, the Prescott article9 supported a 200-mg line, which was adopted in the late 1970s. In the United States, Rumack and Matthew’s8 original suggestion of a 200mg line was modified by the US Food and Drug Administration to the 150-mg line. The rationale was that 150 mg was half the concentration of 300 mg/L, which at that time was believed to cause death.12 Subsequent reports have found that deaths can occur in untreated patients at concentrations below the 200 mg/L line and, in very rare patients who are fasting, even below 100 mg/L.5,13,14 In the 1990s, the United Kingdom changed its policy to include a risk assessment in those patients with paracetamol concentrations between the 100 and 200 mg/L nomograms.15 The risk factors used to influence a treatment decision included malnutrition, debilitating disease (including AIDS), chronic high ethanol consumption, and enzymeinducing drugs.4 This was subsequently changed after a review by the UK regulator (The Medicines and Healthcare Products Regulatory Agency [MHRA]) to a single decision tool in 2012, the 100-mg/L nomogram line, after the death of a young woman with a presentation concentration just over the 100-mg line but who was not treated, as risk factors were reportedly not apparent at presentation.5 The impact of these changes on clinical practice in the United Kingdom was reported subsequently, with many additional hospital presentations and admissions, at an estimated cost of £17.3 m (95% CI, £13.4 m£21.5 m) (€21.2 m, $29 m) to prevent one death.16 Few modern health care systems would find such costs justifiable. Volume ] Number ]
D.N. Bateman Despite the availability of an antidote, failure to present early to hospital remains the major risk factor for poorer outcomes,17,18 and paracetamol is still the most common cause of listing for liver transplant after drug overdose; it is involved in 96% of such cases in Europe.19 Risk of liver injury in patients treated with acetylcysteine depends on time to presentation and mode of ingestion. Larger series of patients treated indicate that acute single overdoses have better outcomes than multiple ingestions and therapeutic excess. Patients who present after 24 hours have the worst prognoses.20 In a recent large UK series, only 10 of 2743 patients with acute single ingestion and 1 of 202 therapeutic excess treated with acetylcysteine developed hepatotoxicity (ALT 41000 IU/L). However, 10 of 452 delayed single (424 hours) and 13 of 426 staggered (repeated) overdoses developed hepatotoxicity.21 Because there is little evidence that acetylcysteine is effective after 24 hours from ingestion, other than in treatment of hepatic encephalopathy,22 these figures emphasize the fact, as first shown by Prescott in 1978, that a large proportion of patients who do not receive treatment do not develop hepatic failure (Table). A key issue for managing patients with paracetamol poisoning more efficiently is correct identification of patients at risk who would benefit from treatment with acetylcysteine. The present cutoffs of 150 mg/L (in the United States and Australia) or 100 mg/L (in the United Kingdom and Ireland) will include a large proportion of patients who are not at risk of serious liver damage. Indeed, just taking all untreated patients above the 200-mg nomogram line, 50% of patients did not get an ALT rise above 1000 IU/L (Table).9 This means that many patients are being treated to protect the proportion of the population who are at greater risk. As treatment lines have been lowered over the years, this proportion is likely to have increased. Paracetamol overdose, therefore, remains a very significant public health issue, and although steps to reduce pack size have had some impact in the United Kingdom, the overall decline in paracetamol mortality has been disappointingly small, probably because most patients who develop problems in Europe present too late for therapy.21,23 The focus going forward is therefore better identification of patients who need antidotal therapy and optimizing this therapy to reduce adverse events.
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Problems with Acetylcysteine Although effective as an antidote, use of acetylcysteine was soon recognized to be associated with adverse effects, in particular anaphylactoid reactions, nausea, and vomiting.24–26 Anaphylactoid reactions in particular result in discontinuation of antidote (in almost 30% of patients treated in one clinical trial),27 sometimes refusal by the patient to have more treatment, and rarely treatment with acetylcysteine being declined by physicians because of concern about the risk of anaphylactoid response in those who have suffered this previously.4 The frequency of adverse drug reactions depends on the methods used to collect data,26 but is highest in studies done prospectively. In one clinical trial, nausea and vomiting occurred in almost 70% of patients treated with the 15-minute initial NAC infusion protocol,27 whereas retrospective studies report rates nearer to 20%.26 Some have suggested the nausea is due to paracetamol, but a recent study showed no relationship between paracetamol concentration and use of antiemetic drugs for vomiting in those receiving acetylcysteine.16 A further confounder is likely to be the concentration of paracetamol in patients who develop anaphylactoid responses. A number of studies indicate that although nausea is unaffected by paracetamol concentration,16,28,29 anaphylactoid reactions are much more frequent at paracetamol concentrations o100 mg/L. For example, in patients with concentrations 4100 mg/L, paracetamol rates of anaphylactoid reactions are approximately 5 times less than in those below this concentration (odds ratio = 0.19; 95% CI, 0.100.37; P o 0.001).16 This is an important finding because, as discussed, patients with lower concentrations of paracetamol are also at lower risk of liver injury. In the 1980s, we showed that patients who experienced anaphylactoid reactions were more susceptible to wheal and flare response from intradermal injection of acetylcysteine at the concentration present in the initial infusion of the Prescott regimen than controls.24 The reactions appear to be due in part to the release of histamine, and higher concentrations of histamine are found in the plasma of patients who have had an allergic-like (nonimmunologic) response.30 It was also increasingly recognized that these adverse reactions were more frequent in patients who have lower concentrations of paracetamol in their blood.28,29
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Clinical Therapeutics In addition, the 3-stage infusion is associated with medication error secondary to the complexity of the dosage regimen.31 This led the MHRA to include specific guidance in 2012 on acetylcysteine administration as part of their review of antidote use in paracetamol overdose.5 It has been the practice for some years in North America and Australia to give the initial acetylcysteine infusion over 1 hour rather than the 15 minutes used in the initial Prescott protocol. In 2012, the UK MHRA also changed its guidance to recommend a 1-hour infusion to try and reduce adverse effects of acetylcysteine. This was because of an Australian study that suggested a nonsignificant benefit from this approach, but was underpowered to show a difference based on the numbers recruited.32 Observational data subsequently obtained after the change by the MHRA in the United Kingdom has shown that adverse reaction rates appear unaffected by the lengthening of the initial infusion to 1 hour from 15 minutes.16 Although it seems logical that pretreatment with an antihistamine might reduce anaphylactoid reactions,29 there are no formal studies to assess the impact of this approach. However, treatment interruption and therapy with antihistamines is standard in those who suffer adverse effects due to anaphylactoid reactions. Some clinicians use pretreatment with antihistamines in patients who have had reactions with acetylcysteine previously. In contrast, corticosteroids are not part of the standard UK protocol for initial management of allergic-type reactions, as the reaction settles quickly (ie, before the action of corticosteroids can take effect), and is nonimmunologic. Treatment in the United Kingdom includes interrupting the acetylcysteine, an intravenous antihistamine, and inhaled salbutamol in those with wheeze.4 Adrenaline is rarely indicated clinically. Finally, since its introduction, intravenous acetylcysteine has been given in a dose related to patient weight, not ingested dose of paracetamol. The dose of acetylcysteine is likely to be excessive as a glutathione replacement for all but the largest of paracetamol overdoses, that is, with concentrations 4500 or 600 mg/L.12 Some have suggested it might be possible to model acetylcysteine requirements based on estimated paracetamol dose, but this has yet to be tested in practice.33
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A New Approach to Paracetamol Poisoning Based on this discussion, there are now several reasons to consider revision of the way in which paracetamol poisoning is both assessed and treated. The nomograms used to predict treatment are based on a conservative estimate of risk and a significant proportion of patients with paracetamol overdose who are treated are not at risk of severe liver injury. Although current strategies are very effective in reducing the risk of toxicity in the population as a whole, this is at the cost of treating many patients who are unlikely to develop major hepatic injury. Traditional markers of liver injury, such as ALT, rise relatively slowly, generally after 24 hours, and in proportion to the extent of liver injury.34 Although a normal ALT at presentation seems to predict a good outcome in patients treated with acetylcysteine,35 it is not a screening test that can exclude the need for therapy. A high product of paracetamol concentration and concurrent ALT might also predict hepatic injury in those who are treated with acetylcysteine, but its utility in defining need for therapy has not been tested.36 Changes in international normalized ratio are a more sensitive measure of hepatic injury, but changes in international normalized ratio follow liver injury, and they are useful in estimating recovery from liver injury rather than predicting risk earlier.4 Renal failure is rare, so it is not useful as a screening measure, but at presentation it predicts poor outcome.20 Recent work evaluating new biomarkers of hepatotoxicity suggests that it should be possible to determine who is going to develop significant liver injury earlier in the course of the disease, either at presentation to hospital or soon after.37,38 These include miR-122, HMGB1, and necrosis K18, which are all more specific than ALT,38 which is a relatively poor marker of actual prognosis once elevated.4 A case report confirms that these markers may well be elevated in patients who subsequently develop toxicity, opening the possibility of more specific, earlier markers than are currently used.39 If this can be reproduced in a larger series of cases, it would be theoretically possible to predict those at risk of hepatic injury far earlier, and to better target therapy. A second target for improvement is the way in which acetylcysteine is given. This would aim to reduce the incidence of adverse effects in patients treated with acetylcysteine and, assuming it will be
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D.N. Bateman possible to stratify hepatotoxic risk earlier and more accurately, shortening of the duration of treatment for many patients. A key step in reducing adverse effects and duration of treatment is, therefore, to redesign the antidote regimen used. In the 1980s, Prescott et al measured the concentrations of acetylcysteine in blood with his 3-dose regimen.40 As expected, concentrations were initially high, but fell quickly once the rate of infusion had dropped during the second and third phases of antidote administration. Because we believe that the anaphylactoid reactions are related to the initial infusion, and most occur in a time window compatible with this hypothesis16—within 1 hour of a 15-minute infusion and 2 hours of commencement of a 1-hour initial infusion—it seemed logical to concentrate protocol redesign of the way in which the antidote is given during the initial infusion. In addition, because the dose of acetylcysteine currently used is probably excessive for the requirements of most patients, we believed this was unlikely to reduce patient benefit from the antidote.12 We undertook Monte Carlo modeling to design a simpler and shorter protocol for giving acetylcysteine. The object was to achieve concentrations above the original Prescott values of acetylcysteine concentration within about 1 hour of commencement. The eventual regimen we designed consists of 2 infusion periods, 100 mg/kg in 200 mL in 5% dextrose over 2 hours, followed by 200 mg/kg in 1 L 5% dextrose over 10 hours. It had originally been intended to study the 12hour regime in a noninferiority design, testing it against the standard 20.25-hour regimen. Because hepatotoxicity is rare when patients have received acetylcysteine, large numbers of patients would need to be included in such a trial. Our funders were uncertain whether it was possible to recruit overdose patients into clinical trials in Europe. Power calculations suggested we would require many more patients than the funding body were prepared to underwrite in our grant application. We, therefore, tested the efficacy of our regimen in reducing adverse events in a factorial study using ondansetron as “positive control” treatment for emesis. The trial had 4 arms, conventional 20.25-hour acetylcysteine or our novel 12-hour protocol both with and without ondansetron pretreatment.27,41 The outcomes of this study clearly showed that the new 12-hour regimen significantly reduced anaphylactoid reactions that required interruption of treatment or
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specific drug therapy and vomiting. Importantly, the effect on anaphylactic reactions was to reduce these from almost 30% to 6% (odds ratio = 0.23; 95% CI, 0.120.43; P o 0.0001) and to reduce vomiting from 66% to 33% (odds ratio = 0.37; 95% CI, 0.180.79; P = 0.003).27 It is important to note that this study was not designed to prove comparative efficacy, but there was no signal that either ALT, using a 1.5-fold increase as a marker of incipient liver injury, or the newer marker miR-122, was elevated in the treated group compared with control. The completion of this study in patients with paracetamol poisoning in Europe is important, as such large studies have not been conducted previously in poisoned patients in this environment. Indeed, the consent (85%) and dropout (2%) rates in this trial were similar to those seen in other clinical trials of more standard medical problems. Poisoning is a large problem for many health care systems, and paracetamol poisoning is the most common form of poisoning in the United Kingdom and United States.4,42 It is, therefore, important to develop methodologies to test the most effective and cost-efficient therapies in this large patient group. Additional studies of the 12-hour acetylcysteine regimen are now required to prove efficacy and, in particular, better define whether all patient groups benefit equally, even though there was no signal of any increased risk of hepatotoxicity in the clinical trial.27 It seems clear, however, that this advance is stimulating research internationally on the way antidotes are given in paracetamol overdose.43,44
DISCUSSION In paracetamol poisoning, there are better ways to give acetylcysteine that will reduce adverse reactions, patient discomfort, and, hopefully, medication error. A shorter duration for giving acetylcysteine, combined with better methods of detecting those patients at risk of paracetamol toxicity, also has the possibility of reducing hospital stay for many patients, and freeing hospital beds in burdened health care facilities. Clinicians should be evaluating better markers of liver injury to avoid treating patients who are not at risk, while identifying earlier those who might benefit from more intensive therapy, as shown in animals.45 Finally, clinical trials can and should be done in patients with
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Clinical Therapeutics poisoning in Europe, despite the complexities of the European Clinical Trial Regulations.
ACKNOWLEDGMENTS This article was written as a background to the award to the author of the European Association for Clinical Pharmacology and Therapeutics Clinical Trial Prize 2015 for the article, “Reduction of Adverse Effects From Intravenous Acetylcysteine Treatment for Paracetamol Poisoning: A Randomised Controlled Trial” published in The Lancet in 2014. The author is grateful to the European Association for Clinical Pharmacology and Therapeutics for this opportunity to publish reference to this work, and wishes to acknowledge the assistance and support of all the coauthors of the original trial. The trial was funded by the Chief Scientist Office of the Scottish Government.
CONFLICTS OF INTEREST The author has indicated that there are no conflicts of interest regarding the content of this article.
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41. Thanacoody HK, Gray A, Dear JW, et al. Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP). BMC Pharmacol Toxicol. 2013;14:20. 42. Mowry JB, Spyker DA, Cantilena LR, et al. 2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol. 2014;52:1032–1283. 43. Graudins A, Harper A. Comparison of adverse drug reaction rates using a two-bag to a standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning. Clin Toxicol. 2015;53:249. 44. Isbister GK, Downes MA, Mcnamara K, et al. A novel infusion protocol for the administration of acetylcysteine. Clin Toxicol. 2015;53: 249–250. 45. Dear JW, Simpson KJ, Nicolai MP, et al. Cyclophilin A is a damageassociated molecular pattern molecule that mediates acetaminopheninduced liver injury. J Immunol. 2011;187:3347–3352.
Address correspondence to: D. Nicholas Bateman, BSc, MBBS, MD, University of Edinburgh, Edinburgh, UK, EH16 4TJ. E-mail: nbateman@ staffmail.ed.ac.uk
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