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.

A stitch in time saves nine: timely use of N-acetyl cysteine (NAC) for chemotherapy-induced veno-occlusive disease (VOD)-is it a cost-effective alternative?

Chemotherapy-induced veno-occlusive disease (VOD) is a rare liver dysfunction seen among pediatric cancer patients which could lead to severe morbidity and mortality. Defibrotide is the commonly used antidote in the management of both stem cell transplant and chemotherapy-associated VOD along with liver supportive measures. Defibrotide is costly and generally not accessible to majority of patients treated at resource poor settings. In this report, we describe the successful management of chemotherapy-induced VOD with timely administration of N-acetyl cysteine.

Electrophysiological assessment and pharmacological treatment of blast-induced tinnitus.

Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the "central gain theory" posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N-acetylcysteine (NAC) and disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.

Informe diário de evidências COVID-19: busca realizada em 28 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 28, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 18 artigos e 3 protocolos.

Informe diário de evidências COVID-19: busca realizada entre 6 e 8 de junho de 2020 / COVID-19 daily evidence report: search conducted between 6 and 8 June 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 13 artigos.

Variation in contrast-associated acute kidney injury prophylaxis for percutaneous coronary intervention: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) program.

BACKGROUND: Contrast-Associated Acute Kidney Injury (CA-AKI) is a serious complication associated with percutaneous coronary intervention (PCI). Patients with chronic kidney disease (CKD) have an elevated risk for developing this complication. Although CA-AKI prophylactic measures are available, the supporting literature is variable and inconsistent for periprocedural hydration and N-acetylcysteine (NAC), but is stronger for contrast minimization. METHODS: We assessed the prevalence and variability of CA-AKI prophylaxis among CKD patients undergoing PCI between October 2007 and September 2015 in any cardiac catheterization laboratory in the VA Healthcare System. Prophylaxis included periprocedural hydration with normal saline or sodium bicarbonate, NAC, and contrast minimization (contrast volume to glomerular filtration rate ratio ≤ 3). Multivariable hierarchical logistic regression models quantified site-specific prophylaxis variability. As secondary analyses, we also assessed CA-AKI prophylaxis measures in all PCI patients regardless of kidney function, periprocedural hydration in patients with comorbid CHF, and temporal trends in CA-AKI prophylaxis. RESULTS: From 2007 to 2015, 15,729 patients with CKD underwent PCI. 6928 (44.0%) received periprocedural hydration (practice-level median rate 45.3%, interquartile range (IQR) 35.5-56.7), 5107 (32.5%) received NAC (practice-level median rate 28.3%, IQR 22.8-36.9), and 4656 (36.0%) received contrast minimization (practice-level median rate 34.5, IQR 22.6-53.9). After adjustment for patient characteristics, there was significant site variability with a median odds ratio (MOR) of 1.80 (CI 1.56-2.08) for periprocedural hydration, 1.95 (CI 1.66-2.29) for periprocedural hydration or NAC, and 2.68 (CI 2.23-3.15) for contrast minimization. These trends were similar among all patients (with and without CKD) undergoing PCI. Among patients with comorbid CHF (n = 5893), 2629 (44.6%) received periprocedural hydration, and overall had less variability in hydration (MOR of 1.56 (CI 1.38-1.76)) compared to patients without comorbid CHF (1.89 (CI 1.65-2.18)). Temporal trend analysis showed a significant and clinically relevant decrease in NAC use (64.1% of cases in 2008 (N = 1059), 6.2% of cases in 2015 (N = 128, p = < 0.0001)) and no significant change in contrast-minimization (p = 0.3907). CONCLUSIONS: Among patients with CKD undergoing PCI, there was low utilization and significant site-level variability for periprocedural hydration and NAC independent of patient-specific risk. This low utilization and high variability, however, was also present for contrast minimization, a well-established measure. These findings suggest that a standardized approach to CA-AKI prophylaxis, along with continued development of the evidence base, is needed.

Low-cost management of mushroom poisoning in a limited-resource area: a 12-year retrospective study.

Amatoxin poisoning is the main cause of death from accidental ingestion of poisonous mushrooms and a mortality rate of 27.3% has been reported in Thailand. Symptoms of mushroom ingestion are often confused with food poisoning; thus, gastroenteritis is not recognised as the first phase of poisoning. Our study assessed the efficacy of N-acetylcysteine (NAC) as a treatment for amatoxin poisoning. We retrospectively analysed 74 medical records over 12 years. The majority (70/74) were treated successfully with NAC; death in the remaining 4 (5.4%) patients was attributed to late presentation in three and advanced alcoholic cirrhosis in one.

Clinical Trial Assessment of Intermittent and Continuous Infusion Dose of N-Acetylcysteine on Redox Status of the Body in Patients with Sepsis Admitted to the ICU.

PURPOSE: Conflicting results exist regarding the efficacy of N-acetyl cysteine (NAC) in sepsis treatment. A pivotal factor affecting the therapeutic potency of NAC in sepsis is timing and dosing of its infusion. We aimed to assess the effect of NAC on redox status of patients with sepsis and to compare its efficacy in intermittent and continuous infusion with the objective of developing the infusion regimen and optimizing the timing. MATERIALS AND METHODS: A prospective, randomized clinical trial was designed to compare the antioxidative effect of NAC in intermittent infusion group (IV: 25 mg/kg bolus and then 25 mg/kg/8 hours 3 times) and continuous infusion group (IV: 25 mg/kg bolus and then 75 mg/kg over 24 hours) in 60 critically ill patients with sepsis (20 patients in each group). Blood samples were collected immediately before and after intervention for total antioxidant capacity (TAC) and malondialdehyde (MDA) assessment. RESULTS: N-acetyl cysteine considerably increased TAC levels in both intermittent (0.68 ± 0.60; P value = .036) and continuous (0.69 ± 0.64; P value = .015) infusion groups when compared to placebo (0.61 ± 0.10); however, the difference in TAC levels between the intermittent and the continuous infusion did not reach statistical significance (P value = .942). Likewise, NAC treatment decreased MDA levels in both intermittent (19.45 ± 4.18; P value = 0.001) and continuous (22.47 ± 6.68; P value = .002) infusion groups when compared to placebo (31.76 ± 11.06), while the difference in MDA levels between the intermittent and the continuous infusion did not reach statistical significance (P value = .481). CONCLUSION: Our data confirmed the antioxidative effect of NAC treatment in patients with sepsis, with no significant difference in intermittent and continuous infusion.

[Improved and harmonised laboratory analysis of paracetamol provides safer assessment of poisoning cases]. / Bättre labbanalys av paracetamol ger säkrare bedömning av förgiftningsfall - Bestämning av koncentrationen är grunden för rätt behandling.

Toxicological analysis is an important part of the acute treatment of various intoxications. Rapid laboratory responses are important for the patient to be assessed and treated correctly, and also to exclude poisoning and thus avoid unjustified and costly overtreatment. In Sweden, paracetamol (acetaminophen) is one of the most common pharmaceuticals in drug poisoning. Paracetamol overdose can cause severe liver damage unless treated early with the antidote acetylcysteine. A nation-wide initiative for improved laboratory measurement of paracetamol in plasma/serum samples has resulted in a marked reduction in the inter-laboratory coefficient of variation to generally below 10%. The introduction of a harmonized national reporting range for plasma/serum paracetamol covering at least 50-5 000 µmol/l was also recommended. This initiative will hopefully contribute to better healthcare from both a patient and health resource perspective in cases of paracetamol poisoning.

Victims of chemical terrorism, a family of four who were exposed to sulfur mustard.

Sulfur mustard (SM) was responsible for more than 80% of all documented chemical casualties during the Great War. Recent literature on clinic picture of SM exposure remained so limited with the sporadic cases who were accidentally exposed to SM especially either in Western Europe or China. We reported a Syrian family of four who became victims of chemical terrorism due to SM exposure and we described the detailed clinical course of the family including the medical history, initial symptomatology, clinical examination, hematological data, and initial treatment in the first 48 hours after exposure at Kilis State Hospital, Turkey. The principles of our therapeutic approaches were designed according to the total affected body surface area, severity of cutaneous and respiratory lesions, and existing hematological disorders. SM is still considered as a critical vesicant agent and a current threat because of its ease of synthesis. Chemical terrorist attacks of non-state actors or terrorist organizations with "home-made" SM is likely such a threat which is targeting health systems of developed and developing countries. Except sarin attacks in Japan, the literature depends on real incidents of chemical terrorism is so rare and for this reason we have gaps and challanges in the prepardness of medical response system against chemical terrorism. Medical management could be performed adequetly only if the response system is well planned, well equipped, and well prepared for overburdened medical facilities filled with SM contaminated casualties after a chemical terrorist attack.

Assessment and treatment of trichotillomania (hair pulling disorder) and excoriation (skin picking) disorder.

Recommendations are provided for the assessment and treatment of trichotillomania (hair pulling disorder, or HPD) and excoriation disorder (skin picking disorder, or SPD), two body-focused repetitive behavior (BFRB) disorders, based on their severity, comorbidities, and behavioral style. Habit reversal training (HRT) and stimulus control are first-line behavioral treatments that can be used in cases of all severity levels and may be particularly helpful when pulling or picking is performed with lowered awareness/intention. Acceptance and commitment therapy (ACT) and dialectical behavior therapy (DBT) are behavioral treatments that can be employed to augment HRT/stimulus control, especially when negative emotions trigger the pulling or picking. There are currently no FDA-approved pharmacologic treatments for HPD or SPD, though certain medications/supplements have shown varying degrees of efficacy in trials. N-acetylcysteine (NAC) should be considered for all severity levels and styles given its moderate gain/low side effect profile. Other pharmacologic interventions, including selective serotonin reuptake inhibitors (SSRIs), should be considered in cases with significant comorbidities or previous behavioral/NAC treatment failure.

Assessment of N-acetylcysteine as a therapy for phosgene-induced acute lung injury.

The toxic industrial chemical (TIC1) phosgene remains an important chemical intermediate in many industrial processes. Inhalation of phosgene can cause an acute lung injury (ALI) which, in severe cases may result in death. There are currently no effective pharmacological therapies or evidence-based treatment guidelines for managing exposed individuals. N-acetylcysteine (NAC) is a commercially available drug licensed in the UK and elsewhere for the treatment of paracetamol (acetaminophen) overdose. It has a number of mechanisms of action which may provide therapeutic benefit for the treatment of phosgene-induced ALI. It has previously been shown to provide therapeutic efficacy against the lung damaging effects of sulfur mustard vapour exposure, when given by the inhaled route, in the pig (Jugg et al., 2013). Our research objective was to determine whether inhaled NAC might also be therapeutic for other chemicals, in this case, phosgene. This study has demonstrated that multiple nebulised doses, administered from 30 min after exposure of terminally anaesthetised pigs to phosgene, is not an effective therapy when administered at the times and doses employed in this study. There remains no pharmacological treatment for phosgene-induced lung injury.

The effect of N-acetylcysteine and working memory training on cocaine use, craving and inhibition in regular cocaine users: correspondence of lab assessments and Ecological Momentary Assessment.

INTRODUCTION: Effective treatment for cocaine use disorder should dampen hypersensitive cue-induced motivational processes and/or strengthen executive control. Using a randomized, double-blind, placebo-controlled intervention, the primary aim of this study was to investigate the effect of N-Acetylcysteine (NAC) and working memory (WM)-training to reduce cocaine use and craving and to improve inhibition assessed in the laboratory and during Ecological Momentary Assessment (EMA). The second aim was to examine correspondence between laboratory and EMA data. METHODS: Twenty-four of 38 cocaine-using men completed a 25-day intervention with 2400mg/day NAC or placebo and WM-training as well as two lab-visits assessing cocaine use, craving and inhibition (Stop Signal task). Additionally, cocaine use, craving and cognition (Stroop task) were assessed using EMA during treatment, with 26 participants completing 819 assessments. RESULTS: Cocaine problems according to the Drug Use Disorder Identification Test (DUDIT) decreased more after NAC than after placebo, and the proportion of cocaine-positive urines at lab-visit 2 was lower in the NAC group. No NAC effects were found on craving. For cocaine use and craving, results from the lab data were generally similar to EMA results. NAC also showed some effects on cognitive control: improved inhibition assessed with the Stop Signal task in the lab, and decreased classic Stroop performance during EMA. There were no significant effects of number of completed WM-training sessions. CONCLUSIONS: Overall this study revealed mixed findings regarding the treatment of cocaine use disorders with NAC and WM-training. The effect of NAC on inhibition should be further investigated.

Evaluation of a Food and Drug Administration Mandate to Limit Acetaminophen in Prescription Combination Products.

INTRODUCTION: In 2014, the US Food and Drug Administration limited the production of prescription acetaminophen-opioid combination products to 325 mg per dose unit. The goal of this mandate was to decrease the likelihood of unintentional acetaminophen hepatotoxicity. This study was designed to determine if this federal regulation has succeeded in reducing unintentional acetaminophen-induced hepatotoxicity from opioid combination products. METHODS: Using data from the National Poison Data System (NPDS), we analyzed all calls to US Poison Control Centers in the years 2013 and 2015 for acetaminophen-opioid combination product exposures. We then excluded cases that were classified as intentional and those aged 12 years and younger. We used a primary endpoint of N-acetylcysteine administration; secondary endpoints included evidence of hepatotoxicity as aspartate aminotransferase elevation, opioid antagonist administration and severity of overall medical outcome. RESULTS: A total of 18,259 calls between the two yearlong periods met inclusion criteria. 5.16 and 5.01% of calls resulted in N-acetylcysteine administration in 2013 and 2015, respectively. 3.63 and 4.02% received naloxone in 2013 and 2015, respectively, and 0.9% in each year developed hepatotoxicity. Rates of N-acetylcysteine administration, naloxone administration, and hepatotoxicity did not differ significantly between 2013 and 2015. Severity of medical outcome was worse in 2015 as compared to 2013 with more cases being categorized as "major effect" and fewer cases being categorized as "no effect." CONCLUSIONS: The Food and Drug Administration limitation on acetaminophen content per dose unit in opioid combination products did not reduce the occurrence of unintentional acetaminophen-induced hepatotoxicity or N-acetylcysteine administration as reported to NPDS.

A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK.

BACKGROUND: International guidelines recommend nintedanib (OFEV®) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS: A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS: Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS: Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.

The changing face of liver transplantation for acute liver failure: Assessment of current status and implications for future practice.

The etiology and outcomes of acute liver failure (ALF) have changed since the definition of this disease entity in the 1970s. In particular, the role of emergency liver transplantation has evolved over time, with the development of prognostic scoring systems to facilitate listing of appropriate patients, and a better understanding of transplant benefit in patients with ALF. This review examines the changing etiology of ALF, transplant benefit, outcomes following transplantation, and future alternatives to emergency liver transplantation in this devastating condition.

Epidemiology, management and outcome of paracetamol poisoning in an inner city emergency department.

BACKGROUND: Paracetamol poisoning accounts for just under half of all self-poisoning cases that present to hospitals in England. Treatment with acetylcysteine is routine, yet recommendations regarding its use vary internationally and have recently been revised in England and Wales. METHODS: Data on all cases of paracetamol poisoning presenting to an adult inner city emergency department between May 2011 and April 2012 were prospectively collected using the Bristol Self-harm Surveillance Register. RESULTS: Paracetamol overdoses accounted for 44% of adult self-poisoning cases. A quarter (26.9%) of patients required treatment with acetylcysteine and it was estimated that recent changes in treatment guidelines would increase that proportion to 32.6%. Paracetamol concentration was positively associated with the risk of any adverse reaction to acetylcysteine. 22.5% of patients experienced anaphylactoid reactions to acetylcysteine. There was no clear evidence of an association between risk of anaphylactoid reaction and blood paracetamol levels. Patients presenting with blood paracetamol levels greater than 200 mg/L at 4 h post-ingestion were at greater risk of repeat self-harm (HR 2.17, 95% CI 1.11 to 4.21, p=0.033). DISCUSSION: The recent changes in UK treatment guidelines are expected to increase the proportion of our population requiring acetylcysteine by 5.7%. We found no clear evidence that risk of anaphylactoid or more general adverse reaction to acetylcysteine was increased in patients presenting with lower blood paracetamol concentrations. Blood paracetamol level was highlighted as a potentially useful clinical indicator for risk of repeat self-harm.

Paracetamol toxicity: what would be the implications of a change in Australian treatment guidelines?

OBJECTIVES: The present study aims to study the implications for resource utilisation if Australia adopted recent revised UK treatment guidelines for paracetamol poisoning. METHODS: Retrospective database review of paracetamol toxicity presentations and calls from the Victorian Poisons Information Centre (VPIC) and Austin Hospital, Victoria, Australia, from 1 January 2010 to 31 December 2011. There were 200 presentations at the Austin Hospital, and the VPIC received 4272 calls regarding paracetamol toxicity. An analytical model was designed to estimate the cost of this additional treatment and referral to hospital. The main outcome measures were the potential increase in number of admissions requiring treatment with N-acetylcysteine (NAC), costs involved and increased number of referrals to hospitals by the VPIC. RESULTS: Twenty-five (12.5%, 95% confidence interval 8.4-17.6%, P < 0.01) patients in our study who did not qualify for NAC therapy based upon the current Australasian paracetamol treatment guideline would have received it if the revised UK guideline was followed. Eighteen (72%) of these presented with acute single ingestions of paracetamol. No patients re-presented to our hospital with acute liver injury or required admission to the liver transplant unit. CONCLUSIONS: Alignment of current Australian paracetamol treatment guidelines with those in the UK would result in an increase in ED attendances as directed by Poisons Information Centres and hospital admissions for antidotal treatment. This would be associated with increased health expenditure and inpatient bed utilisation. The present study does not support the clinical need for adoption of UK paracetamol treatment guidelines in Australia.

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.

O impacto de reúso de dialisadores nos marcadores de estresse oxidativo e inflamatórios em pacientes em hemodiálise / Evaluation of oxidative stress and inflamatory markers on hemodialysis patients with and without dialysers reuse

A morbimortalidade dos pacientes em hemodiálise permanece alta apesar da evolução tecnológica do procedimento, sendo que os eventos cardiovasculares são a sua principal causa. Estes desencadeados pela alta prevalência de fatores de risco tradicionais, fatores relacionados ao procedimento dialítico e estresse oxidativo. Considerando o procedimento dialítico e o estresse oxidativo, foi avaliado o quanto a habitual prática de reuso de dialisadores/RD (difundida nas Américas e amparada principalmente por questões econômicas) e uso único de dialisadores, influenciam nos marcadores inflamatórios e de estresse oxidativo. Para isto, foram utilizados como marcadores laboratoriais as medidas de PCR ultrassensível (u PCR), interleucina 6 (IL6), a determinação de substâncias reativas ao ácido tiobarbitúrico (TBARS), superóxido dismutase (SOD), glutationa (GSH) e albumina, em 29 pacientes em tratamento de hemodiálise. Estes pacientes encontravam-se em tratamento com dialisadores de alto fluxo do tipo polieterssulfona e reuso manual, e ao iniciar este estudo foram programados 3 ciclos sequenciais com duração de 6 semanas com as seguintes características: primeiro ciclo (uso único de dialisadores;); segundo ciclo (reuso de dialisadores); terceiro ciclo (reuso de dialisadores e administração de N-acetilcisteína/NAC, na dose de 1200 mg/dia). Foram coletadas amostras de sangue de cada paciente no início e final da última sessão de hemodiálise anteriormente ao início dos ciclos (denominado Período 1) e no início e final da última sessão de hemodiálise de cada ciclo (denominados Períodos 2, 3 e 4 respectivamente). O TBARS aumentou no período de uso único. Todas as demais variáveis não apresentaram diferença significativa. Os resultados indicaram que o RD pode proporcionar uma melhora no estresse oxidativo. O uso único foi associado com maior estresse oxidativo. Não foi encontrado nenhum benefício adicional com NAC.

The morbidity and mortality of patients undergoing hemodialysis remains high despite the technological development of this procedure, and cardiovascular events are the main causes of morbidity and mortality. These cardiovascular events are triggered by the high prevalence of traditional risk factors, factors associated with dialysis procedures, and oxidative stress. Considering the factors associated with dialysis procedures and oxidative stress, we assessed how dialyzer reuse (DR; widespread in the Americas, especially because of economic issues) and use of single-use dialyzers influence oxidative stress and inflammatory markers. We used ultrasensitive PCR (u-PCR) to measure levels of the laboratory markers interleukin-6 (IL6), thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), glutathione (GSH), and albumin in 29 patients undergoing hemodialysis treatment. These patients were receiving treatment with polyethersulfone high-flux dialyzers and manual reuse. In the initial phase of this study, the 3 following sequential cycles, each lasting 6 weeks, were scheduled: first cycle (single-use dialyzers); second cycle (DR); and third cycle (DR and administration of N-acetylcysteine [NAC] at a dose of 1200 mg/day). Blood samples were collected from each patient at the beginning and end of the last hemodialysis session that preceded the start of the cycles (termed Period 1), and at the beginning and end of the last hemodialysis session of each cycle (termed Periods 2, 3, and 4, respectively). The levels of TBARS increased during the single-use period. The remaining variables did not show significant differences. The results indicated that DR may ameliorate oxidative stress. Single-use dialyzers were associated with higher oxidative stress. No additional benefit was found with use of NAC.