Developing new antidotes for poisons with existing effective treatments: a case study of fomepizole in paracetamol poisoning.

INTRODUCTION: Acetylcysteine is the only effective and licensed therapy for paracetamol poisoning. However, acetylcysteine loses efficacy if treatment is delayed 8-12 hours after paracetamol ingestion, and there is also uncertainty as to whether the dose should be increased in high-risk paracetamol ingestions. Studies have identified potential therapeutic targets, including enzymes that metabolize paracetamol; the pathways causing mitochondrial toxicity via c-Jun N-terminal kinases or superoxide generation; and other specific targets, such as nuclear factor-erythroid factor 2-dependent gene induction and autophagy. With this range of potential additional therapies, how should the speciality of clinical toxicology approach the development of new antidotes for this common poisoning? HISTORICAL BACKGROUND: When the first treatments for paracetamol toxicity were developed, the clinical trial and ethical basis of practice were different from today. Acetylcysteine was never subjected to placebo-controlled studies, even by the United States Food and Drug Administration, as it was presumed that the toxicity of high paracetamol concentrations was so evident that placebo-controlled studies were unethical. Thus, the absolute benefit of acetylcysteine remains unknown. In addition, no dose-ranging studies of acetylcysteine in patients were ever done. The weakness of assessing the efficacy of additional antidotes in small groups of patients with moderate poisoning is illustrated by the use of cimetidine in paracetamol poisoning. CURRENT APPROACHES TO DRUG (AND ANTIDOTE) DEVELOPMENT: The approach required by regulatory authorities today relies on several important steps. First, a clear target for therapeutic effect is sought, normally in a laboratory model. Next, a 'proof of principle' study is required to demonstrate that the target is 'druggable'. Finally, clinical studies to confirm proof of principle applies in humans, followed by a controlled trial with matched patient groups with sufficient power to demonstrate the clinical outcome being sought. Such patient studies can be expensive to conduct, and non-commercial groups suffer the risk of not being funded. FOMEPIZOLE: Fomepizole prevents paracetamol-induced hepatic toxicity in mice by inhibiting cytochrome P4502E1, thereby preventing the conversion of paracetamol to its toxic metabolite. Fomepizole also inhibits c-Jun N-terminal kinases, a key pathway in the downstream toxicity on the mitochondria. The present evidence of efficacy in humans is based on small case series with no control groups. The availability of a licensed indication has facilitated off-label use of fomepizole in an unproven indication. CONCLUSIONS: Paracetamol poisoning is common, and randomized, controlled clinical trials are possible. The benefit of fomepizole can only be shown by such a study. As clinical trials using fomepizole as an added therapy to acetylcysteine are recruiting in the United States, these should be supported by all clinical toxicologists. In the interim, the publication of small case series using fomepizole should be discouraged by journals.

Large paracetamol overdose-Higher dose acetylcysteine is required.

Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

Fifty years of paracetamol (acetaminophen) poisoning: the development of risk assessment and treatment 1973-2023 with particular focus on contributions published from Edinburgh and Denver.

INTRODUCTION: Fifty years ago, basic scientific studies and the availability of assay methods made the assessment of risk in paracetamol (acetaminophen) poisoning possible. The use of the antidote acetylcysteine linked to new methods of risk assessment transformed the treatment of this poisoning. This review will describe the way in which risk assessment and treatments have developed over the last 50 years and highlight the remaining areas of uncertainty. METHODS: A search of PubMed and its subsidiary databases revealed 1,166 references published in the period 1963-2023 using the combined terms "paracetamol", "poisoning", and "acetylcysteine". Focused searches then identified 170 papers dealing with risk assessment of paracetamol poisoning, 141 with adverse reactions to acetylcysteine and 114 describing different acetylcysteine regimens. To manage the extensive literature, we focused mainly on contributions made by the authors during their time in Edinburgh and Denver. DOSE AND CONCENTRATION RESPONSE: The key relationship between paracetamol dose and toxicity risk was established in 1971 and led to the development of the Rumack-Matthew nomogram from data collected in Edinburgh. MECHANISMS OF TOXICITY: A series of papers on the mechanisms of toxicity were published in 1973, and these showed that paracetamol hepatotoxicity was caused by the formation of a toxic intermediate epoxide metabolite normally detoxified by glutathione but which, in excess, was bound covalently to hepatic enzymes and proteins. An understanding of the relationship between the rate of paracetamol metabolism, paracetamol concentration, and toxic hazard in humans soon followed. ANTIDOTE DEVELOPMENT AND EFFICACY IN PATIENTS: These discoveries were followed by the testing of a range of sulfhydryl-donors in animals and "at risk" patients. Acetylcysteine was developed as the lead intravenous antidote in the United Kingdom. The license holder in the United States refused to make an intravenous formulation. Thus, oral acetylcysteine became the antidote trialed in the United States National Multicenter Study. Intravenous acetylcysteine regimens used initially in the United Kingdom and subsequently in the United States used loading doses of 150 mg/kg over 15 minutes or one hour, 50 mg/kg over four hours, and 100 mg/kg over 16 hours. These regimens were associated with adverse drug reactions (nausea, vomiting and anaphylactoid reactions) and hence, treatment interruption. Newer dosing regimens now give loading doses more slowly. One, the Scottish and Newcastle Anti-emetic Pretreatment protocol, using an acetylcysteine regimen of 100 mg/kg over two hours followed by 200 mg/kg over 10 hours, has been widely adopted in the United Kingdom. A cohort comparison study suggests this regimen has comparable efficacy to standard regimens and offers opportunities for selective higher acetylcysteine dosing. RISK ASSESSMENT AT PRESENTATION: No dose-ranging studies with acetylcysteine were done, and no placebo-controlled studies were performed. Thus, there is uncertainty regarding the optimal dose of acetylcysteine, particularly in patients ingesting very large overdoses of paracetamol. The choice of intervention concentration on the Rumack-Matthew nomogram has important consequences for the proportion of patients treated. The United States National Multicenter Study used a "treatment" line starting at 150 mg/L (992 µmol/L) at 4 hours post overdose, extending to 24 hours with a half-life of 4 hours, now standard there, and subsequently adopted in Australia and New Zealand. In the United Kingdom, the treatment line was initially 200 mg/L (1,323 µmol/L) at 4 hours (the Rumack-Matthew "risk" line). In 2012, the United Kingdom Medicines and Healthcare products Regulatory Agency lowered the treatment line to 100 mg/L (662 µmol/L) at 4 hours for all patients, increasing the number of patients admitted and treated at a high cost. Risk assessment is a key issue for ongoing study, particularly following the development of potential new antidotes that may act in those at greatest risk. The development of biomarkers to assess risk is ongoing but has yet to reach clinical trials. CONCLUSION: Even after 50 years, there are still areas of uncertainty. These include appropriate acetylcysteine doses in patients who ingest different paracetamol doses or multiple (staggered) ingestions, early identification of at-risk patients, and optimal treatment of late presenters.

Toxicity of phosphate enemas - an updated review.

INTRODUCTION: Enemas containing phosphate are widely prescribed and may cause important adverse effects. A systemic review published in 2007 reported the literature on the adverse effects of phosphate enemas from January 1957 to March 2007 and identified 12 deaths. These were thought due to electrolyte disturbances, heart failure and kidney injury. These data raised concerns about the use of phosphate enemas in routine practice. Newer osmotic-based enema alternatives are now available that do not contain absorbable ions. We sought to review the literature since this review and evaluate the latest data on the toxicity of phosphate-containing enemas. To gain a fuller picture we included case series and larger studies as well as case reports. OBJECTIVES: To review the toxicity of phosphate enemas, particularly with respect to acute metabolic consequences and their associated clinical features. To identify risk factors for metabolic toxicity and consider whether phosphate enemas should be relatively contra-indicated in specific patient groups. METHODS: A systematic literature review was conducted in PubMed, Google Scholar, and Cochrane Reviews (2005-2021) using the search terms 'phosphate enema or sodium phosphate enema' or 'phosphate-based enema' or (phosphate AND enema) or (Fleet AND enema) or 'sodium phosphate laxatives' or 'sodium phosphate catharsis' or 'sodium phosphate cathartic'. Relevant papers were read, and data were extracted. RESULTS: The searches identified 489 papers of which 25 were relevant: seven papers were case reports or small case series of metabolic abnormalities from the use of phosphate enemas in nine children, six were case reports on 16 adults. Nine papers were large case series or clinical studies that included data on systemic metabolic effects, of varying size from 24 healthy volunteers to a cohort of 70,499 patients. Case reports identified seven adult deaths but none in children. Children most often presented with decreased consciousness (6/9), and tetany (4/9). In adults overall only five cases had clinical features reported, hypotension was seen in four and QT prolongation in two. Treatment was generally symptomatic, with intravenous fluid and calcium salts for electrolyte changes and hypocalcaemia, and vasopressors for severe hypotension. Haemodialysis was used in three children and peritoneal dialysis in one, all of whom survived. In adults, haemodialysis did not prevent death in two of four cases in whom it was used. Common factors underlying toxicity were inappropriately high phosphate dose, or enema retention, both resulting in greater absorption of phosphate. Associated pre-disposing conditions included Hirschsprung disease in children and co-morbidity and renal impairment (2/5) in older adults. Absolute reported changes in serum phosphate or calcium were not accurate indicators of outcome. Larger case series and clinical trials confirm an acute effect of phosphate enemas on serum phosphate, which was related to both dose and retention time. These effects were not seen with non-phosphate preparations. In these cases series, adverse events were rarely reported. CONCLUSION: Phosphate enemas are potentially toxic, particularly in young children with Hirschsprung disease and in the elderly with co-morbidity. Raised awareness of the risk of phosphate enemas is still required. Other less toxic enema preparations are available and should be considered in patients at extremes of age. If phosphate enemas are the only clinical option careful monitoring of biochemical sequelae should be undertaken.

Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

A metabolomic analysis of thiol response for standard and modified N-acetyl cysteine treatment regimens in patients with acetaminophen overdose.

N-acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol-APAP)-induced acute liver injury (ALI). The 3-bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post-start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post-infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP-metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP-metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP-induced ALI.

Use of the online poisons information database TOXBASE and admissions rates for poisoned patients from emergency departments in England and Wales during 2008 to 2015.

BACKGROUND: The impact of poison information services on patient care in hospital, particularly decisions on whether to admit patients after initial attendance at an emergency department (ED), is unclear. In the United Kingdom, the vast majority of poisons information is provided by use of the online poisons information database, TOXBASE. We investigated the relationship between rates of hospital access to TOXBASE and rates of poisoning admissions from EDs in England and Wales to begin to address the interactions between use of poisons information and patient management as reflected by hospital activity. METHODS: Data were obtained on attendances and admissions due to poisoning for individual National Health Service (NHS) Trusts in both England and Wales, together with data on the overall number of accesses to TOXBASE for drugs (pharmaceuticals and drugs of abuse), from 2008 to 2015. Rates of TOXBASE access and admissions per poisoning attendance in London were clearly different to the rest of England and Wales; London was therefore analyzed separately. Negative binomial generalized additive models were fit, incorporating an interaction effect, for accesses, attendances and admissions to check for variability according to hospital size. Additional models were then fit to assess whether there was any variation in association of overall TOXBASE use with rates of admission for 6 key drug subgroups: antidepressants, paracetamol, antipsychotics, opioids (including all medicines, but excluding heroin), heroin and non-opioid drugs of abuse. RESULTS: Rates of TOXBASE use per Trust increased across the study period by 39.3% (95% confidence interval [CI] = 34.1%, 44.8%) in England and 76.9% (24.7%, 151.0%) in Wales, showing an increase in TOXBASE use which was substantially greater than the increase in poisoning attendances. Admission rates exhibited seasonality, with lower rates in January and February, increasing by 2.0% (1.0%, 3.1%) in England and 5.8% (5.5%, 5.9%) in Wales toward the middle of the year. The initial model fit indicated that the average proportion of poisoning patients admitted increased with both increasing attendances and increasing TOXBASE use (England and Wales overall, P < 0.0001; England and Wales excluding London, P < 0.0001; London, P < 0.0001). In England and Wales overall, and in London alone, increased TOXBASE access to non-opioid drugs of abuse advice was associated with a significant decrease in admissions (England and Wales, -0.15% [-0.29%, -0.01%] [P = 0.032]; London, -1.02% [-1.53%, -0.50%] [P < 0.0001]). In contrast, increased access to heroin advice was associated with a significant increase in admissions in London (+2.03% [+0.11%, +3.99%] [P = 0.034]). Increasing access to TOXBASE for paracetamol advice was associated with lower admissions in England and Wales (England and Wales, -0.11% [-0.23%, -0.01%] [P = 0.036]; England and Wales excluding London, -0.18% [-0.30%, -0.06%] [P = 0.001]) but higher admissions in London (+0.52% [+0.03%, +1.01%] [P = 0.035]). CONCLUSIONS: We have shown that greater overall use of TOXBASE by hospitals is associated with a higher proportion of poisoning attendances being admitted. Interestingly, looking at particular drug groups, we found significant associations in both directions between overall TOXBASE use and rates of admission for some drug groups. The current methodology is unable to determine whether such decisions might be appropriate or not. Mixed-methods research is now required to gain a better understanding of how provision of poisons information affects decisions within the ED.

Acetylcysteine in paracetamol poisoning: a perspective of 45 years of use.

Paracetamol poisoning was first reported in 1966. The development of antidotes followed within 10 years, and by 1980 acetylcysteine (NAC) was acknowledged as the optimal therapy available. This article examines the history of the development of NAC and recent developments in its use. We offer suggestions for improvements in the way NAC may be administered and outline new developments that should have major impacts on the way we manage paracetamol poisoning in the near future.

Iron overdose epidemiology, clinical features and iron concentration-effect relationships: the UK experience 2008-2017.

Background: Iron poisoning is potentially serious, but mortality has fallen worldwide since implementation of pack size and packaging restrictions, and changes in iron use during pregnancy. The management of individual cases of overdose remains problematic due to uncertainty about indications for antidote. We examine the epidemiology of iron overdose in hospital cases referred to the UK National Poisons Information Service (NPIS) and evaluate the toxicokinetics of iron in patients ingesting only iron preparations. Methods: Anonymized hospital referral patient data from the NPIS database were collated for the period 1 January 2008 to 31 July 2017. Information was extracted, where recorded, on type of ingestion [iron alone (single), or combined with other agents (mixed)], reported dose, iron salt, timed iron concentrations and symptoms. In single-agent ingestions, the relationships between reported elemental iron dose, early concentrations (4-6 h), and symptoms were evaluated in teenagers and adults (≥13 years) and children (≤12 years) using standard statistical techniques (correlation and unpaired nonparametric comparisons). In those patients with sufficient sample points (three or more), a simple kinetic analysis was conducted. Results: Of 2708 patients with iron overdoses referred by UK hospitals for advice during the 9.7 years study period, 1839 were single-agent ingestions. There were two peaks in age incidence in single-agent exposures; 539/1839 (28.4%) were <6 years (54.1% males) while 675/1839 (36.7%) were between 13 and 20 years (91% females), the latter a substantial excess over the proportion in the totality of hospital referrals to the NPIS in the same period (13-20 years: 23,776/144,268 16.5%; 67.5% female) (p < .0001 overall and for female %). In 475 teenagers and adults and 86 children, with at least one-timed iron concentration available, there was no correlation between stated dose and iron concentration measured 4-6 h post-ingestion. Observed peak iron concentrations were not related to reported symptoms in adults. Initial iron concentrations were significantly higher in 30 patients (25 adults, 5 children) who received desferrioxamine (DFO) compared to those that did not [no DFO: mean 63.8 µmol/L (95% CI 62.1-65.6), median 64; DFO: mean 78.5 µmol/L (95% CI 69.2-87.7), median 78.1; Mann-Whitney p < .0018). No significant differences in symptoms were observed pre-treatment between DFO-treated and untreated groups. No patients died in this cohort. Conclusion: Single-agent iron exposures reported from UK hospitals were most common in children <5 years and young people aged 13-20 years. Poisoning with organ failure was not identified and there were no fatalities. No correlations were observed between reported iron doses and early concentrations, or between iron concentrations and symptoms in this cohort of mild-to-moderate poisoning.

Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine.

CONTEXT: Paracetamol (acetaminophen) overdose is a common reason for emergency hospital admission in the UK and the leading cause of acute liver failure in the Western world. Currently, the antidote acetylcysteine (NAC) is administered at a dose determined only by body weight without regard for the body burden of paracetamol. OBJECTIVE: To determine whether higher plasma paracetamol concentrations are associated with increased risk of liver injury despite prompt treatment with intravenous NAC. METHODS: Patients admitted to hospital for treatment with intravenous NAC following a single acute paracetamol overdose entered the study if NAC was commenced within 24 h of drug ingestion (N = 727 hospital presentations). Based on the plasma paracetamol concentration at first presentation to hospital, a series of nomograms were created: 0-100, 101-150, 151-200, 201-300, 301-500 and over 501 mg/L. The primary endpoints were acute liver injury (ALI - peak serum ALT activity >150 U/L and double the admission value) and hepatotoxicity (peak ALT >1000 U/L). RESULTS: ALI and hepatotoxicity were more common in patients with higher admission plasma paracetamol concentrations despite NAC treatment (ALI: nomogram 0-100: 6%, 101-150: 3%, 151-200: 3%, 201-300: 9%, 301-500: 13%, over 501 mg/dL: 27%. p < 0.0001). This dose-response relationship between paracetamol concentration and ALI persisted even in patients treated with NAC within 8 h of overdose (nomogram 0-100: 0%, 101-150: 0.8%, 151-200: 2%, 201-300: 3.6%, 301-500: 12.5%, over 501mg/L: 33%. p < 0.0001) and in patients with normal ALT activity at first presentation (nomogram: 0-100: 0%, 101-150: 1.2%, 151-200: 1.5%, 201-300: 5.3%, 301-500: 10.8% p < 0.0001). DISCUSSION: Patients with increased concentrations of plasma paracetamol at hospital presentation are at higher risk of liver injury even when intravenous NAC is promptly administered before there is biochemical evidence of toxicity. CONCLUSION: This study supports theoretical concerns that the current intravenous dose of NAC may be too low in the setting of higher paracetamol exposure.

Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes.

Some toxins cause their effects by affecting physiological processes that are fundamental to cell function or cause systemic effects as a result of cellular interaction. This review focuses on four examples, coumarin anticoagulants, isoniazid, methotrexate and thyroxine from the context of management of overdose as seen in acute general hospitals. The current basic clinical pharmacology of the toxin, the clinical features in overdose and evidence base for specific antidotes are discussed. The treatment for this group is based on an understanding of the toxic mechanism, but studies to determine the optimum dose of antidote are still required in all these toxins except thyroxine, where treatment dose is based on symptoms resulting from the overdose.

New regimens for intravenous acetylcysteine, where are we now?

Acetylcysteine has been used as a treatment for paracetamol overdose as a 20.25- or 21-h infusion for nearly 40 years. These regimens give 50% of the dose in the first 15 min or 1 h, and are associated with high rates of adverse reactions. A randomised controlled trial has demonstrated that a shorter (12 h) and simpler (two infusions) acetylcysteine regimen using a slower initial infusion rate produces lower rates of adverse events than the original 20.25-h regimen. However, this study was not sufficiently large to show therapeutic equivalence as a hepatoprotective therapy in paracetamol overdose. Two further studies are now reported, which also suggest lower rates of adverse reactions with lower initial rates of acetylcysteine administration. These modified regimens can now be accepted as better tolerated, but it is unlikely that a randomised study of sufficient size to demonstrate non-inferiority of any novel regimen would ever be funded. Against this background we suggest what can be done to establish the efficacy of these less toxic and potentially shorter alternative acetylcysteine regimens and to establish them into routine clinical use.

Disproportionate effect on child admissions of the change in Medicines and Healthcare Products Regulatory Agency guidance for management of paracetamol poisoning: an analysis of hospital admissions for paracetamol overdose in England and Scotland.

OBJECTIVE: The aim of the present study was to assess the effects of the changes in the management of paracetamol overdose recommended by the UK Commission for Human Medicines on rates of hospital admission. METHODS: An interrupted time series analysis was carried out on data for hospital admissions for paracetamol poisoning for England between January 2010 and June 2014, and for Scotland between January 2010 and Sept. 2014. The main outcome measure was admissions to hospital with paracetamol poisoning (T39.1), as defined by first position coding in children and adults. RESULTS: The time series analysis (Jan 2010 to June 2014) showed that admission rates for paracetamol poisoning were steady from 2010 to the date of change (September 2012), with an estimated 269 [95% confidence interval (CI) 252.5, 285.5] child (0-14 years) and 3541 (95% CI 3454, 3628) adult admissions per month. In September 2013, 12 months after the change, there were an estimated additional 116 [37.3% (95% CI 17.2-67.4)] child and 426 [12.5% (95% CI 4.5-19.6)] adult admissions. Thus, in the year before the change (September 2011 to August 2012) there were 45,181 (3500 child and 41,681 adult) admissions, and in the year after (September 2012 to August 2013) there were 50,198 (4779 child and 45,419 adult) admissions. The overall proportion of child admissions was significantly greater after the change (Chi-square 32.486, P < 0.001), emphasizing the disproportionate effect in children. CONCLUSIONS: Changes to the management guidelines for paracetamol poisoning in September 2012 were rapidly implemented but have particularly increased paediatric hospital admissions for paracetamol poisoning. This impact in children, who are at low risk of mortality from paracetamol toxicity, appears excessive.

Changing the Management of Paracetamol Poisoning.

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 >1000 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 = 0.23; 95% CI, 0.12-0.43; P < 0.0001) and vomiting (odds ratio = 0.37; 95% CI, 0.18-0.79; P = .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 protocol offers clinicians and patients the possibility for better targeting of therapy, fewer adverse effects, a simpler dosing regimen, and shorter hospital stay.