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Cyanide is a prevalent, lethal chemical. Possible sources of exposure include products of combustion, plant material, industry, chemical warfare and terrorism.Retrospective review of UK Poisons Information Database of telephone enquiries to the National Poisons Information Service between 1A total of 1,252 cases of suspected cyanide poisoning were identified, 239 (19%) involved children under 10 years. The commonest sources of exposure were ingestion of plant material (437 cases; 35%) and smoke inhalation (399; 32%). Smoke inhalation caused the majority of severe and fatal cases (139; 71%). Clinical features associated with fatal outcomes were cardiac arrest (OR 36.4; 95% CI 14.4-92.2), hypotension (15.8; 7.0-35.9), coma (10.8; 5.6-21.0) and lactic acidosis (7.8; 4.1-14.8). 110 patients (9%) were given an antidote and 40 patients (3%) died.Lactate concentrations correlate with Poisoning Severity Score category (Most cases of ingestion of plant material involved children under five years and resulted in no or mild symptoms. In adults smoke inhalation was associated with the most severe poisoning. The lactate cut-off values associated with each severity score calculated in this study are lower than the values used by NPIS on TOXBASE. Analytical conformation of cyanide exposure was unavailable in the majority of case, limiting the strength of these conclusions.

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.

Introduction. Snakebite is recognised as a neglected tropical disease and a cause of substantial morbidity and mortality. Whilst the most medically important snakes are typically native of Asia, Africa, Latin America and Oceania, the possibility of encountering these snakes is no longer limited by geography due to an increasing number of exotic (non-native) snakes being held in captivity. Methods. A retrospective review of snakebite enquiries to the UK National Poisons Information Service (NPIS) between 2009 and 2020. Enquiries about the European adder (Vipera berus) or where the identity of the snake was unknown were excluded. Results. There were 321 exotic snakebites in 300 patients involving 68 different species during this period. Ten patients were bitten on more than one occasion. The majority of patients (64.5%) were male. Most bites were inflicted by snakes of the family Colubridae (184/321, 57.3%); seventeen bites resulted in moderate symptoms (predominantly swelling of the bitten limb). There were 30 (9.3%) bites by Viperidae and 14 (4.3%) bites by Elapidae. All severe cases (n=15) resulted from bites by either Viperidae (n=10) or Elapidae (n=5). Antivenom was given in 17 cases. One fatality was recorded. Conclusions. Despite their low incidence, exotic snakebites present a substantial challenge for UK healthcare professionals. Although rare, these bites typically occur in individuals (usually male) who keep snakes as part of their occupation or hobby and are therefore at risk of multiple bites. Bites can result in venom hypersensitisation and the risk of venom-induced anaphylaxis. Rapid access to expert clinical advice is available in the UK on a 24-hour basis through the National Poisons Information Service and is strongly recommended in all cases of exotic snakebite.

Background Unintentional carbon monoxide (CO) poisoning poses a public health challenge. The UK National Poisons Information Service (NPIS) provides advice to healthcare professionals via the online database, TOXBASE®, and a 24-hour telephone line. Our aim was to analyse all CO-related enquiries to the NPIS. Methods We analysed enquiries regarding unintentional CO exposure (1st July 2015-30th June 2019). Information on patient demographics, CO source and location, clinical features and poisoning severity was collected from telephone enquiries and TOXBASE accesses. Results 2970 unintentional non-fire-related CO exposures were reported. Exposures occurred commonly in the home (60%) with faulty boilers frequently implicated (27.4%). Although five fatalities were reported, 68.7% of patients experienced no or minor symptoms only (headache most frequently reported). Despite being the gold standard measurement, blood carboxyhaemoglobin concentration was only recorded in 25.6% patients, with no statistically significant correlation with severity. Conclusions Unintentional CO exposures in the UK commonly occur in domestic settings and although are generally of low severity, fatalities continue to occur. Carboxyhaemoglobin measurement is important to confirm exposure but further work is required to assess its validity as a prognostic indicator in CO exposure. Public health policy should continue to focus on raising awareness of the dangers of CO.

It would be challenging for all doctors to have a detailed knowledge of every poison they may meet in their career and so it is important to become proficient in the general principles of the management of poisoned patients. This chapter aims to guide the reader through the initial approach and general principles to consider when managing a poisoned patient.

Introduction: Automatic dishwashing rinse aids are drying aids which contain non-ionic surfactants, usually ethoxylated alcohols, typically at concentrations of ≤30%. Objective: To assess the reported toxicity of rinse aids. Methods: Telephone enquiries to the UK National Poisons Information Service were analysed from January 2008 to June 2019. Results: Ingestion: Ingestion was involved in 976 cases and produced gastrointestinal features, coughing and central nervous system depression, particularly in young children. In those in whom the amount ingested was known, the majority (56%) of children Conclusions: Overall, clinical features developed in 47% of patients exposed to rinse aids, but more severe features (PSS ≥ 2) were rare (

Introduction:Detergents used in automatic dishwashing machines are of two main types: traditional tablets that require removal from an external wrapper and newer soluble film tablets.Objective:To determine the toxicity of automatic dishwashing tablets.Methods:Telephone enquiries to the UK National Poisons Information Service were analysed for the period January 2008 to June 2019.Results:Ingestion: Ingestion was involved in 798 traditional tablet exposures and 725 soluble film exposures. Clinical features (Poisoning Severity Score ≥ 1) developed in 22.2% of patients ingesting traditional tablets and in 28.8% ingesting soluble film tablets; moderate or severe toxicity was rare (Conclusions:Children (≤5 years) significantly more often developed features following ingestion of soluble film than traditional tablets, although the likelihood of a child developing features was relatively low (

Objective A recent study has shown that the averaged time tabled teaching for a medical student across 5 years in the UK was 4629 hours. Radiology has been demonstrated to be an excellent teaching source, yet the number of hours allocated to this has never been calculated. The aims of this study were to evaluate and quantify the hours allocated to radiology teaching in Scottish Medical Schools and to evaluate if they can fulfil requirements expected from other Clinical disciplines and the upcoming General Medical Council Medical Licensing Assessment (GMC MLA). Methods Data pertaining to timetabled teaching for Radiology in Scottish Universities were obtained from the authors of the Analysis of Teaching of Medical Schools (AToMS) survey. In addition, University Lead Clinician Teachers were surveyed on the radiological investigations and skills medical students should have at graduation. Results Medical students in Scottish Universities were allocated 59 h in Radiology (0.3%) out of a total 19,325 h of timetabled teaching. Hospital-based teaching was variable and ranged from 0 to 31 h. Almost half (15 of 31) of Clinician Teachers felt that there was insufficient radiology teaching in their specialty. Thirteen of 30 conditions included in the GMC MLA were listed by Clinician Teachers, while 23 others not listed by the GMC were considered important and cited by them. Conclusion This study demonstrates that medical students do not receive enough radiology teaching. This needs to be addressed by Universities in collaboration with the NHS in an effort to bring up this up to line with other developed countries and prepare students for the GMC MLA. Advances in knowledge (1) There is insufficient time allocated in Medical Students’ curriculum to Radiology. (2) Radiology teaching in medical schools fall short of University Lead Clinician Teachers’ and GMC expectations of medical students at graduation.

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.

This project has been funded by the EU’s INTERREG VA programme, managed by the special EU Programmes Body (SEUPB) Background and Aims N-acetyl-L-cysteine (NAC) has been proposed as a prophylactic for the prevention of contrast induced nephropathy (CIN), a serious, adverse complication following administration of contrast media in patients with diabetes and chronic kidney disease (CKD). However, clinical trial results have failed to demonstrate consistently the beneficial qualities of NAC in this setting. The suggested mechanism by which NAC has been proposed to be effective is via antioxidant activity, but NAC itself appears not to be a powerful antioxidant; intracellular conversion of NAC to glutathione (GSH) is essential for antioxidant effects. We tested the hypothesis that oral or intravenous NAC fails to increase antioxidant activity in the plasma of healthy volunteers or CKD stage III patients undergoing elective coronary angiography. Method 16 healthy volunteers (8 receiving contrast media) and 8 patients with chronic renal failure were recruited to 3 separate groups as a part of a crossover design study. 66 patients with CKD stage III undergoing elective coronary angiography were recruited to a parallel group randomized controlled trial. Each volunteer or patient was randomised to receive NAC (i.v.; 50 mg/kg/hr infusion for 2 h, followed by 20 mg/kg/hr infusion for a further 5 h), or NAC (oral; 1200 mg twice daily, commencing the day before the study visit) or placebo. Participants attended the Clinical Research Facility on three occasions for the crossover groups, but only once in the parallel group trial. Patients were infused with para-aminohippurate (PAH) and inulin to enable measurement of renal function parameters. Plasma and paired buffy coat samples were collected at several time points for 2 hours before contrast infusion and for 6 hours after. Samples were used to measure various clinical parameters, along with intracellular and plasma thiol concentrations and the plasma antioxidant capacity (oxygen radical antioxidant capacity; ORAC). Results Plasma NAC concentrations peaked at 222 µM (healthy volunteers), 354 µM (CKD patients), 271 µM (healthy volunteers receiving contrast) and 348 µM (CKD patients undergoing elective coronary angiography) following infusion of NAC. The corresponding peak concentrations were ∼2 µM following oral NAC across all groups. No comparable increase in the plasma compartment ORAC antioxidant capacity was measured in any of the treatment groups. Equally, contrast infusion itself did not significantly reduce antioxidant capacity in plasma, even in the placebo group. Buffy coat measures showed that there was a significant increase of intracellular GSH in some patients. Also, no clear additional benefit was witnessed by increasing plasma NAC ∼100-fold through infusion of NAC over oral administration. Conclusion NAC fails to influence ORAC antioxidant capacity in the plasma compartment of CKD stage III patients receiving contrast media. Our results question the importance of oxidative stress in contrast-induced nephropathy. Furthermore, the findings fail to demonstrate a direct antioxidant impact of NAC in the plasma compartment and question the antioxidant hypothesis related to contrast-induced nephropathy and NAC.

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 CONCLUSION: Single-agent iron exposures reported from UK hospitals were most common in children

Clozapine is a potent antipsychotic commonly used for refractory schizophrenia. Adverse effects are well recognised including constipation, intestinal obstruction, agranulocytosis and cardiomyopathy. We present a case of paradoxical refractory hypotension following epinephrine administration in a patient taking clozapine. A psychiatric inpatient who had been taking clozapine for many years developed paralytic ileus and obstruction requiring surgical intervention. Following initiation of epinephrine administration intraoperatively he developed refractory hypotension which improved only when epinephrine was weaned off. This effect is likely due to uninterrupted β2-agonist activity in the presence of clozapine-induced α-blockade. Clinicians need to have greater awareness of this serious interaction and avoid the use of epinephrine in patients taking clozapine.

OBJECTIVE To determine the toxicity of rinse aids which are used as drying aids to remove water from crockery. METHODS Enquiries to the UK National Poisons Information Service (NPIS) were analysed retrospectively for the period January 2008 to December 2016. RESULTS There were 855 enquiries relating to 828 patients; children aged 5 years or less accounted for 91.1%. Most exposures occurred from ingestion alone (n = 778, 94.0%), but 26 involved ingestion and other routes: 21 with skin contact, 3 with eye contact, and two with both skin and eye contact. There were a further 24 cases of eye contact alone (n = 20, 2.4%) or skin contact alone (n = 3, 0.4%) and a single case of inhalation alone. The World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists (WHO/IPCS/EC/EAPCCT) Poisoning severity score [PSS] was known in 824 of the 828 exposures: 425 of 824 (51.6%) patients did not develop clinical features, 381 (46.2%) had a PSS of 1 (minor toxicity), 15 (1.8%) developed moderate (PSS 2) and 3 (0.4%) severe (PSS 3) toxicity. Vomiting was the most common feature, occurring in over a third of all ingestions (n = 286, 35.8%), followed by coughing (n = 73, 9.1%). A higher proportion of adults than children developed clinical features (72.7% of 33 vs 46.0% of 767, p = .0026), although vomiting occurred significantly more frequently amongst children (p = .0315). Of the 25 eye contact cases, eye pain (n = 8) and/or eye irritation (n = 8) were reported, with or without abnormal vision (n = 7); there were two cases of corneal abrasion. Dermal contact rarely produced features; only 4 of 26 patients reported symptoms including skin rash or burning or numbness at the contact site. CONCLUSIONS Severe clinical features were uncommon following rinse aid exposure; vomiting was the most frequently reported symptom following ingestion.

Background: Suspected poisoning is a common cause of hospital admission internationally. In the United Kingdom, the National Poisons Information Service (NPIS), a network of four poisons units, provides specialist advice to health professionals on the management of poisoning by telephone and via its online poisoning information and management database, TOXBASE®. Objective: To demonstrate the impact of NPIS telephone advice and TOXBASE® guidance on poisoning-related referrals to emergency departments (ED) from primary healthcare settings. Methods: A telephone survey of primary healthcare providers calling the NPIS and an online survey of TOXBASE® primary care users were conducted to evaluate the effect of these services on poisoning-related ED referrals. Enquirers were asked to indicate whether referral was needed before and after using these information sources. Results: The number of cases considered by enquirers appropriate for ED referral was reduced from 1178 (58.1%) before to 819 (40.4%) after the provision of telephone advice for 2028 cases (absolute reduction 17.7%, 95% CI 14.6, 20.7%) and from 410 (48.2%) before to 341 (40.1%) after consideration of TOXBASE® guidance for 851 cases (absolute reduction 8.1%, 95% CI 3.3, 12.9%). By extrapolating these figures over a full year, it is estimated that these services prevent approximately 41,000 ED referrals annually. Conclusions: The use of NPIS services significantly reduced ED referrals from primary healthcare services with resulting avoided healthcare costs exceeding the current annual NPIS budget. Further studies are needed to evaluate other potential benefits of accessing NPIS services.

Oven cleaning products contain corrosive substances, typically sodium or potassium hydroxide.To determine the reported toxicity from exposure to oven cleaning products.Telephone enquiries to the UK National Poisons Information Service regarding oven cleaning products were analysed retrospectively for the period January 2009 to December 2015.There were 796 enquiries relating to 780 patients. Ninety-six percent of the products involved in the reported exposures contained sodium hydroxide and/or potassium hydroxide. Ingestion alone (n = 285) or skin contact alone (n = 208) accounted for the majority of cases; inhalation alone (n = 101), eye contact alone (n = 97), and multiple routes of exposure (n = 89) accounted for the remainder. Ninety-five percent of patients exposed by inhalation, 94% exposed dermally and 85% reporting eye exposure, developed features of toxicity. Patients exposed by multiple routes developed symptoms in 70% of cases. Only 103 of the 285 patients ingested oven cleaner directly, whereas 182 patients ingested food they considered to have been contaminated with oven cleaner. In 100 of the 103 direct ingestions where the features and World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists Poisoning Severity Score were known, 56 reported symptoms which were minor in 51 cases. The most common features following ingestion were vomiting (n = 26), abdominal pain (n = 22) or pharyngitis (n = 15). Skin burns (n = 91) predominantly involving the hands or arms, occurred in 44% of dermal exposures. Following inhalation, patients frequently developed respiratory features (n = 52) including coughing and chest pain/tightness. Eye pain (n = 43) and conjunctivitis (n = 33) commonly occurred following ocular exposure.Most (71%) patients exposed to an oven cleaner irrespective of the route of exposure developed features of toxicity, though in most cases only minor features developed; moderate or severe features ensued in ∼4%. Those patients exposed dermally, ophthalmically or by inhalation developed features more frequently (≥85%) than those who ingested a product directly (56%).

Grout, tile and floor stone sealants contain a solvent, a water-repelling agent and in the case of aerosols a propellant. The water-repelling agent used is typically a fluoropolymer resin, a silicon-based resin, or a combination of both.To report the clinical course in patients exposed to fluoropolymer-containing sealants referred to the United Kingdom National Poisons Information Service.A retrospective analysis was performed of telephone enquiries received between 2009 and 2015.101 enquiries involving 96 exposures were received. The majority of the exposures (n = 88) occurred when the sealant was delivered from an aerosol. Twelve patients were exposed occupationally and the remainder were exposed while using the product at home. Eighty-nine exposures were as a result of inhalation alone, two followed ingestion, three skin contact and one eye contact; one involved inhalation and eye contact. All 90 patients exposed by inhalation developed clinical features: 31 had a World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists Poisoning Severity Score of 1 (minor toxicity), 51 patients had features of moderate toxicity (PSS 2) and eight were graded PSS 3 (severe poisoning). The most common features were dyspnea (n = 52; 57.8%; 95% CI = 47.0-68.5), chest pain/tightness (n = 34; 37.8%; 95% CI = 27.2-48.4), coughing (n = 27; 30.0%; 95% CI = 20.0-40.0) and sinus tachycardia (n = 11; 12.2%; 95% CI = 4.1-18.2); hypoxemia was present in 20 (22.2%; 95% CI = 13.1-31.4). At the time of the enquiry a chest X-ray had been performed on 15 patients: in eight patients (all of whom were PSS 3) the X-ray was reported as being abnormal and showed bilateral shadowing.This study demonstrates that if fluoropolymer-containing sealants are inhaled then clinical features may occur and in a small proportion (9%) these features may be severe.

Background: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen. Methods: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge. Findings: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference −0.7%, 95% CI −2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)). Interpretation: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions. Keywords: Acute liver failure, Paracetamol, NAC, Clinical practice, Drug-induced liver injury

Introduction N-acetyl-l-cysteine (NAC) has been proposed as a prophylactic for the prevention of contrast induced nephropathy (CIN), a severe, undesirable consequence following angiography that accounts for ∼12% of all hospital-acquired acute renal injury. However, results from clinical trials of NAC in this setting to date have been inconclusive. The potential benefits of NAC in CIN have been attributed to its antioxidant potential, but NAC itself is a very weak antioxidant; intracellular conversion to the detoxifying agent, glutathione (GSH) is a pre-requisite for antioxidant benefits.1 We tested the hypothesis that neither oral nor intravenous NAC conveys antioxidant activity in the plasma of healthy volunteers or patients with chronic renal disease (CKD), but that intracellular conversion to GSH was achieved in those patients depleted of intracellular GSH. Materials and methods 8 healthy volunteers and 8 patients with chronic renal failure were recruited to separate studies conducted in parallel. Each volunteer or patient was randomised to receive NAC (i.v.; 50 mg/kg/hr infusion for 2 hour, followed by 20 mg/kg/hr infusion for a further 5 hour), or NAC (oral; 1200 mg twice daily, commencing the day before the study visit) or placebo on each of three visits to the Clinical Research Facility. On study days, volunteers were infused with inulin and PAH to facilitate a number of renal function measures.2 Plasma samples and matched buffy coat samples were obtained at intervals throughout the study for measurement of clinical parameters, together with plasma antioxidant capacity, plasma and intracellular thiol concentrations. Results Plasma NAC concentrations peaked at 187 µM (healthy volunteers) and 280 µM (CKD patients) when infused with NAC; the equivalent peak concentrations were 2 µM in both groups after oral administration of NAC. There was no equivalent increase in plasma antioxidant capacity in any of the treatment groups. Intracellular measures from buffy coat cells indicated that there was a significant increase in GSH in some healthy volunteers and some patients, but the effect was variable. In addition, there was no added benefit of increasing plasma NAC ∼10 fold through the i.v. delivery route over oral administration. Conclusion NAC is ineffective in altering antioxidant capacity in the plasma compartment, but can be converted to GSH in the intracellular environment in subjects with low intracellular GSH at baseline. Subsequent studies will determine the impact of contrast medium on both plasma and intracellular thiol concentrations and antioxidant capacity, as well as the extent of the capability of NAC to protect against the effects. Our results, however, call into question whether NAC could be effective in this setting and highlight the complexity of the concept of antioxidant capacity in vivo. This project has been funded by the EU’s INTERREG VA programme, managed by the Special EU Programmes Body (SEUPB). References Sandilands, E. A., S. Cameron, F. Paterson, S. Donaldson, L. Briody, J. Crowe, J. Donnelly, A. Thompson, N. R. Johnston, I. Mackenzie, N. Uren, J. Goddard, D. J. Webb, I. L. Megson, N. Bateman and M. Eddleston (2012). ‘Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.’ BMC Clin Pharmacol12:3. Treweeke, A. T., T. J. Winterburn, I. Mackenzie, F. Barrett, C. Barr, G. F. Rushworth, I. Dransfield, S. M. MacRury and I. L. Megson (2012). ‘N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial.’Diabetologia55(11):2920–2928.

Introduction: Liquid laundry detergent capsules contain concentrated liquid laundry detergent in a water-soluble polyvinyl alcohol membrane.Objective: To review 4652 exposures reported to the Unite...

Dear EditorWe are grateful for an opportunity to reply to the comments of Grewal et al. from North America. They make three points which we are pleased to respond to.The first puzzles us, an allega...

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.

AIMSIn 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.METHODSData 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.RESULTSThere 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 CONCLUSIONSThe 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.

SummaryBackgroundParacetamol 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.MethodsWe 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).FindingsOf 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

Aim To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. Methods Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose–response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1- and H2-receptor antagonists. Flare and itch were assessed in all studies. Results Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min−1) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min−1 100 ml−1; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2-receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min−1 histamine: −11.9 ml min−1 100 ml−1 (−4.0, −19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: −403.7 cm2 (−231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1-receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. Conclusion Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2-receptors are important in this process. Our results support further exploration of combined H1- and H2-receptor antagonist therapy in acute allergic syndromes.

A 28-year-old woman was admitted in a comatose state following ingestion of 5 g of amitriptyline. On arrival, there was intermittent seizure activity and a broad complex tachycardia on the ECG. Immediate resuscitation included 8 mg lorazepam, 2 L crystalloid fluid, 100 mL 8.4% sodium bicarbonate, 2 g of magnesium sulphate and lipid emulsion infusion. Despite this, the broad complex tachycardia persisted with haemodynamic instability. The case was discussed with the National Poisons Information Service, which advised further 8.4% sodium bicarbonate to achieve serum alkalinisation. Following this, the QRS duration reduced and haemodynamic stability was achieved. Serum alkalinisation continued in the intensive treatment unit before the patient was successfully extubated on day 5 and discharged on day 7 with no neurological sequelae. To our knowledge, this case is the largest recorded overdose of amitriptyline to have survived to discharge. The importance of serum alkalinisation in the management of tricyclic antidepressant poisoning is highlighted.

The epidemiology of poisoning can be studied from different perspectives. These include overall mortality, hospital admission rates, and enquiries to Poisons Information Services. Accidental poisoning is most common in children, but deliberate self-harm becomes predominant in teenage years and early adulthood. Understanding the patterns of poisoning assists in developing suicide prevention strategies and reducing the risks of accidental poisoning.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Medication errors, and particularly prescribing errors, are common in UK hospitals. • Junior doctors make the majority of prescribing errors. • Deficiencies in prescribing education and training have been closely linked to the high frequency of medication errors. WHAT THIS STUDY ADDS • Focussed prescribing teaching can lead to an improvement in prescribing ability. • Prescribing confidence can be significantly improved through education. • Education is insufficient alone in eradicating prescribing errors. AIM To assess the impact of prescribing teaching on final year medical students. METHODS Students randomly allocated to two hospitals completed a prescribing assessment. Prescribing teaching was delivered to the intervention group while no additional teaching was provided for the control group. All students then completed a second prescribing assessment. RESULTS Teaching improved the assessment score: mean assessment 2 vs. 1, 70% vs. 62%, P= 0.007; allergy documentation: 98% vs. 74%, P= 0.0001; and confidence. However, 30% of prescriptions continued to include prescribing errors. CONCLUSION Medical students make significant errors in prescribing. Teaching improves ability and confidence but is insufficient alone in eradicating errors.

Non-steroidal anti-inflammatory drugs are widely available and a common component of overdose. Toxic effects are principally renal. At high doses, coma and hepatic injury are rarely reported. Mefenamic acid is notable as it causes convulsions, although these are usually short-lived. Treatment is to a large extent supportive.

Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.

Background Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen. Methods/Design We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course. Discussion This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk. Trial registration EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270

Henry Fok, David Webb, and Euan Sandilands explain the work of clinical toxicologists and how to get a foothold in this research oriented career

Background Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease. Methods/Design We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance. Discussion Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials. Trial registration Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.

We report a case that involves the use of intravenous lipid emulsion as an antidote for a drug overdose involving a 20-month-old girl who had ingested a potentially lethal amount of the tricyclic antidepressant (TCA) dothiepin. The patient's condition continued to deteriorate despite implementation of standard pediatric treatment recommendations for TCA toxicity. Administration of intravenous lipid emulsion in addition to standard therapy (including sodium bicarbonate) and direct-current cardioversion for ventricular arrhythmia led to a successful outcome. The case report is followed by a review of the current evidence underlying this novel therapy and the background on its use. TCA toxicity is addressed specifically.

Editor - We read with interest and concern Jones et al 's case report of yew tree poisoning in which they appear to advise induced emesis in the management of overdose ( Clin Med April 2011 pp 173–5), a therapy not advised by the UK National Poisons Information Service (NPIS) for over 20 years.

Dextropropoxyphene, widely used in combination with paracetamol, is a weak opioid unique among its class in its propensity to block two receptor groups, opioid and sodium channels. It achieved popu...

This review examines the potential use of nerve agents by a terrorist organisation against a civilian population, which has become an increasingly apparent threat in the UK. Present guidelines for the use of atropine, particularly in children, following such an event are unclear. No precise agreement exists on the most appropriate dose of atropine, or the frequency with which it should be administered. This uncertainty leaves children vulnerable as potentially life-saving treatment may be crucially delayed. Guidelines must be standardised to allow rapid antidotal delivery and maximise the potential for survivors. This review examines the issues currently surrounding the use of atropine in children following a nerve agent attack and propose strategies for treating exposed children.

To determine what effect the withdrawal of co-proxamol from the UK market has had on mortality from poisoning in Scotland.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.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%); P0.0001]. The most significant reduction was seen in male out-of-hospital deaths [mean 2000-2004, 17 (21.8%); 2006, two (2.9%); P0.0001]. 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).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.

A 19-year-old man with a history of eczema was admitted to the emergency department following collapsing at home. The paramedics found him unresponsive with poor respiratory effort and a widespread erythematous rash. Anaphylaxis, thought to be secondary to flucloxacillin he had recently been prescribed, was diagnosed. Epinephrine, steroids and antihistamines were administered without clinical improvement. On arrival to hospital, constricted pupils were noted prompting the emergency physicians to consider opiate toxicity. Intravenous naloxone brought about an immediate recovery. His father subsequently disclosed that he had given his son one of his own fentanyl patches to alleviate the distressing symptoms of eczema. Although the patient had removed the patch prior to collapsing, he had suffered life-threatening opioid toxicity likely due to enhanced opiate absorption through eczematous skin. This case highlights the risks associated with fentanyl patches in patients with chronic skin conditions.

Objectives & Background Paracetamol poisoning is common worldwide. Standard intravenous N-acetylcysteine (NAC) therapy is complex, and commonly associated with concentration-related adverse effects and the potential for administration errors. We aimed to determine whether adverse effect incidence could be reduced by antiemetic pre-treatment and/or a simpler and shorter intravenous N-acetylcysteine regimen. Methods We delivered, in 3 centres, a randomised factorial trial comparing a modified 12 h (100 mg/kg over 2 h, 200 mg/kg over 10 h) with a standard 20.25 h NAC regimen (150 mg/kg 15 min, 50 mg/kg 4 h, 100 mg/kg 16 h) with and without pre-treatment with ondansetron (4 mg IV). The primary endpoint was absence of retching, vomiting or need for rescue antiemetic at 2 h; secondary endpoints included the incidence of anaphylactoid reactions, the need for medication or treatment interruption, and hepatic toxicity (ALT, INR). Results In 217 participants, retching and vomiting were less common with ondansetron than placebo (OR 0.406, 97.5% CI 0.205–0.803, p=0.0031) and with the modified compared to the conventional acetylcysteine regimen (OR 0.260, 97.5% CI 0.130–0.518, p Conclusion In patients with paracetamol poisoning requiring acetylcysteine, adverse effects were substantially reduced by ondansetron pre-treatment and by using a modified, shorter treatment regimen. Ondansetron, but not the modified regimen, increased the frequency of liver function abnormalities. If large effectiveness studies confirm the modified regimen is non-inferior to conventional then shorter and safer treatment would be possible for this common poisoning.

ncreasing public safety by limiting the availability of drugs that are only toxic in overdose sets an interesting and challenging problem for drug regulators and physicians alike. The prescription-only combination analgesic coproxamol (paracetamol 325mg and dextropropoxyphene 32.5mg) was previously one of the most commonly used medications in the UK for the treatment of mild to moderate pain. Concerns regarding the risks of co-proxamol were first raised in the 1980s and, although this led to strengthened warnings in the product information, no reduction was observed in deaths from co-proxamol poisoning as it continued to be widely available, particularly in primary care. Excess mortality More recently, co-proxamol had been shown to cause excess mortality in overdose compared to other paracetamol-opioid combination analgesics, with an estimated 39 excess deaths each year in Scotland being due to co-proxamol poisoning. 1