D. Nicholas Bateman

Mechanistic biomarkers provide early and sensitive detection of acetaminophen‐induced acute liver injury at first presentation to hospital

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient‐individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen‐induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA‐122 (miR‐122; high liver specificity), high mobility group box‐1 (HMGB1; marker of necrosis), full‐length and caspase‐cleaved keratin‐18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR‐122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR‐122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision‐making, both in the treatment of ALI and the design/execution of patient‐individualized treatment strategies. (Hepatology 2013;58:777–787)

Management of paracetamol poisoning

#### Summary points Paracetamol (acetaminophen) is an effective oral analgesic, with few adverse effects when used at the recommended dose. Nevertheless, paracetamol poisoning is common and potentially fatal.1 It is a leading cause of acute liver failure in the United Kingdom2 and the United States.3 Potential liver damage, predicted from blood paracetamol concentration and time from ingestion, can be prevented by prompt treatment with antidote. However, young and otherwise healthy patients still risk serious liver injury, especially if they present more than a few hours after overdose or take staggered overdoses over hours or days.4 #### Sources and selection criteria We based our review on a PubMed search for articles on paracetamol (or acetaminophen) and acetylcysteine or ( N- acetylcysteine) published between 1 January 1990 and 31 December 2010, without language limits. The search was limited to human clinical trials, meta-analyses, randomised controlled trials, reviews, and case reports. We also searched a newspaper database for reports published after 1988 of coroners’ inquests and procurators’ fiscal inquiries into fatal cases of paracetamol poisoning. In addition, we used a bibliography and our own collections of relevant references.5 The …

Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial

BACKGROUND Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. METHODS We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270). FINDINGS Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024). INTERPRETATION In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen. FUNDING Chief Scientist Office of the Scottish Government.

Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose

Background. Adverse effects to N-acetylcysteine (NAC) are well recognized, but their etiology and incidence are unclear. Methods. The nature and severity of adverse effects were prospectively studied in 169 patients and potential reaction mediators studied in 22 patients. Results. Adverse effects were minimal in 101 (59.8%), moderate in 51 (30.2%), and severe in 17 (10.1%). Features were nausea (70.4%), vomiting (60.4%), flushing (24.9%), pruritus (20.1%), dyspnea (13.6%), chest pain (7.1%), dizziness (7.7%), fever (4.7%), wheeze and bronchospasm (7.1%), and rash and urticaria (3.6%). Serum acetaminophen concentration was lower in patients with severe adverse effects: median (IQR) 46 mg/L (0 to 101 mg/L), moderate 108 mg/L (54 to 178 mg/L), and minimal 119 mg/L (77 to 174 mg/L), p = 0.002. Family history of allergy and female gender were independent risk factors for adverse effects. Severity of adverse effects was associated with histamine release: AUC for change from baseline histamine was −6 ng/mL min (−60 to 11 ng/mL min) in the minimal group, 26 ng/mL min (3–129 ng/mL min) in the moderate group, and 49 ng/mL min (21–68 ng/mL min) in the severe group (p = 0.01). There was no increase in tryptase and no differences between groups for NAC concentrations or hemostatic and inflammatory variables (factors II, VII, IX, X, vWF, tPA, IL6, and CRP). Conclusion. Severity of adverse effects correlates with the extent of histamine release. Histamine release appears independent of tryptase suggesting a non-mast cell source. Acetaminophen is protective against adverse effects of NAC, and mechanisms by which acetaminophen might lessen histamine release require further attention.

Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment

Aims In September 2012 the UK’s Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single ‘100 mg l−1’ nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning. Methods Data were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose. Results There were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI –4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million–10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million–21.5 million). Conclusions The changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.

Acetaminophen and acetylcysteine dose and duration: Past, present and future

Abstract Acetylcysteine has been utilized successfully in the treatment of acetaminophen overdose since the 1970s. Although prospective trials as to efficacy and safety of acetylcysteine were conducted, there were no randomized controlled trials. This commentary addresses the reasons for this, and the background to choice of dose of acetylcysteine utilized in the oral and IV dosing regimens. Nomograms to predict possible hepatotoxicity based upon time of ingestion of acetaminophen were developed from a relatively arbitrary definition of toxicity as an aspartate aminotransferase/alanine aminotransferase (ALT/AST) greater than 1000 IU/L. While these have proved generally useful, patients still continue to develop hepatic damage after acetaminophen overdose, particularly if they present late after ingestion. The optimum management of these patients remains unclear, and one area of uncertainty is the dose and duration of acetylcysteine in various circumstances. This article discusses the issues that need to be elucidated to better target changes in acetylcysteine dose. The potential for measurements of other markers to improve treatment selection is the subject of further research.

Evaluation of a QT nomogram for risk assessment after antidepressant overdose.

AIMS A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia. METHODS A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT(c) (QT corrected by Bazetts formula) greater than ≥440 ms and QT(c) ≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals. RESULTS There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT(c) was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QT(c) was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT(c) ≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013). CONCLUSIONS The QT nomogram was associated with a lower false positive rate than widely accepted QT(c) criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT(c) criteria and merits further investigation in a clinical setting.

Paracetamol (acetaminophen) poisoning: no need to change current guidelines to accident departments

income differentials. Income differentials vary over time and from place to place, suggesting that they are not just a fact of life. It could be argued that wide income differentials are an economic manifestation of people taking advantage of each other, and that it is the latter that causes premature mortality—through the emotional distress it generates. Solutions to apparently intractable public health problems like inequalities in health and unhealthy lifestyles may therefore lie in research into emotional wellbeing. A broad range of studies is needed to test the hypothesis that emotional distress creates susceptibility to physical illness and a further range is to research interventions which can prevent emotional distress and promote mental and social health. Two of the most promising approaches depend on a further body of research which shows that unresolved emotional distress in childhood is an important cause of emotional distress in adulthood. 14 These approaches are parenting programmes and mental health promotion programmes in schools. The evidence showing that parenting programmes can both reverse emotional and behavioural problems and prevent their emergence is robust. Several school mental health promotion programmes have been subject to controlled trials which show a positive impact on emotional wellbeing. Through developing empathy and respect, both types of programmes improve self esteem in children and parents and increase their ability to give and receive social and emotional support. Long term follow up studies are needed to test the hypothesis that these programmes affect adult physical and mental health, but the epidemiological evidence suggesting that they could is strong. Successful implementation of the agenda defined in Our Healthier Nation will depend on research and development of such programmes. For this to happen doctors, and others who determine the allocation of NHS funds, will need to believe that emotional and social wellbeing are at least as important for health as physical wellbeing and invest both development and research funds accordingly.

Exposure to liquid detergent capsules: A study undertaken by the UK National Poisons Information Service

Objective. To ascertain the reported toxicity of liquid detergent capsules. Methods. Between 1 March 2008 and 30 April 2009 the UK National Poisons Information Service collected prospectively 647 telephone enquiries relating to liquid detergent capsules. Results. The majority of enquiries (96.1%) concerned children of 5 years of age or less. Exposure to these products occurred mainly as a result of ingestion alone (n = 518; 80.1%), with eye contact alone (n = 61; 9.4%), and skin contact alone (n = 7; 1.1%) being less common; multiple routes of exposure were involved in 61 (9.4%) enquiries. Following ocular exposure, conjunctivitis with or without eye pain (n = 61), eye pain alone (n = 11) and keratitis (n = 4) developed; in one case the keratitis persisted for nine days, though recovery occurred in all cases as far as is known. The most common features reported following ingestion alone were nausea and vomiting (n = 143), followed by coughing (n = 21). Eleven children less than 2 years of age also developed drowsiness. A rash occurred in nine patients where ingestion was considered to be the route of exposure, probably due to topical contact with the capsule. Seven children aged 3 or less were exposed via the dermal route alone and developed rash (n = 4), irritation (n = 2), chemical burn (n = 2), and paresthesia (n = 1). Conclusions. Ocular exposure may lead to conjunctivitis and keratitis; recovery is to be expected in all cases within 7–10 days. Ingestion may also result in drowsiness. Greater consumer awareness is required to reduce injury from liquid detergent capsules, particularly that involving the eye. Parents have a vital role to play in ensuring that these products are stored safely at all times.

Co‐proxamol withdrawal has reduced suicide from drugs in Scotland

AIM To determine what effect the withdrawal of co-proxamol from the UK market has had on mortality from poisoning in Scotland. METHODS This was a retrospective, observational study of mortality relating to poisoning by single agents in Scotland for the period 2000-2006. Mortality data were obtained from the General Register Office Scotland, and primary care prescribing data from the Information and Statistics Division of the Scottish Executive Health Department. RESULTS A significant reduction in the proportion of poisoning deaths due to co-proxamol was observed following legislation [mean 2000-2004, 37 deaths (21.8% of total poisoning deaths); 2006, 10 (7.8%); P < 0.0001]. The most significant reduction was seen in male out-of-hospital deaths [mean 2000-2004, 17 (21.8%); 2006, two (2.9%); P < 0.0001]. This was associated with a decline in prescriptions by 60% within 6 months of legislation. The total number of poisoning deaths also fell, slightly earlier than the full impact on co-proxamol deaths (mean 2000-2004, 171.2; mean 2005-2006, 129.5; P = 0.005). CONCLUSIONS Legislation has resulted in a major reduction in the number of deaths associated with co-proxamol poisoning in Scotland, with no compensatory rise in mortality from poisonings from other common analgesics. We estimate from this study that a minimum of 300 lives across the UK will have been saved by the withdrawal of co-proxamol.