INTRODUCTION:Antipsychotic medications are often associated with QT interval prolongation, which can lead to ventricular dysrhythmias, including torsade de pointes. However, unstable or significant dysrhythmic events are rare. Evidence-based recommendations on the assessment and management of poisoned patients at risk for QT interval prolongation are lacking. Current practice often involves costly and lengthy cardiac monitoring, leading to delayed disposition of the patient from emergency departments or prolonged monitoring times in other hospital units. To address this issue, the QT Interval Prolongation in Clinical Toxicology Workgroup was formed by the Clinical Toxicology Recommendations Collaborative to develop evidence-based recommendations for the management and treatment of QT interval prolongation in acute overdose patients. This article reports our findings on patients with antipsychotic poisoning. METHODS:A systematic review of the literature regarding QT interval prolongation in all acute overdoses was undertaken, and the evidence was summarized for antipsychotic medication overdose. Voting statements were drafted using a predetermined format for monitoring the QT interval and use of continuous cardiac monitoring. A two-round modified Delphi method was used to reach a consensus. The strength of consensus was measured using the disagreement index as defined by the RAND/UCLA Appropriateness Method. RESULTS:From the 327 articles that were included in the systematic review of QT interval prolongation in all acute overdoses, a total of 55 articles were relevant to antipsychotic medication-induced QT prolongation in acute overdose. Medications with more than three articles were reviewed individually for recommendations, whilst medications with less than three were grouped together for discussion as miscellaneous. Individual medication recommendations were made for amisulpride (15 articles), thioridazine (11 articles), ziprasidone (eight articles) and quetiapine (13 articles), whilst consensus statements based on limited data were made for acute ingestions of clozapine, haloperidol, iloperidone, pimozide, pipamperone, olanzapine and risperidone (14 articles in total). The electrocardiogram is suggested as a risk assessment tool for ingestion of all antipsychotic medication. We recommend continuous cardiac monitoring for patients ingesting more than amisulpride 2 g, thioridazine 1 g, and ziprasidone 3 g. We suggest continuous cardiac monitoring for the above-mentioned medications for lower dose ingestions as well as for ingestions of haloperidol, iloperidone, pimozide and pipamperone. We do not suggest continuous cardiac monitoring for acute clozapine and risperidone poisoning, and do not recommend continuous cardiac monitoring for the QT interval in acute olanzapine or quetiapine poisoning. The need for ongoing cardiac monitoring should be guided by an individual risk assessment considering the medication and dose ingested, the time since ingestion, as well as other factors such as heart rate or co-ingestions. DISCUSSION:The quality of evidence for the risk of QT interval prolongation and torsade de pointes is heterogeneous among different antipsychotics and inherently constrains the recommendations. Available data suggest that amisulpride, thioridazine and ziprasidone are associated with QT interval prolongation and torsade de pointes, while the risk is likely overstated for quetiapine, olanzapine and risperidone. Ongoing research is needed to improve management strategies for acute antipsychotic overdose-induced QT interval prolongation and dysrhythmias. CONCLUSIONS:The QT Interval Prolongation in Clinical Toxicology Workgroup recommends the use of screening electrocardiograms in all patients with acute antipsychotic medication overdose and cardiac monitoring in patients with at-risk overdoses from thioridazine, amisulpride, and ziprasidone. The QT Interval Prolongation in Clinical Toxicology Workgroup suggests the same approach for patients with overdoses of haloperidol, iloperidone, pipamperone and pimozide. The risk of torsade de pointes is likely overstated for acute antipsychotic medication overdose as a general class group, and concern should rather focus on a few specific medications.

Introduction Cannabis is the most common recreational drug worldwide and synthetic cannabinoid receptor agonists are currently the largest group of new psychoactive substances. The aim of this study was to compare the clinical features and outcomes of lone acute cannabis toxicity with lone acute synthetic cannabinoid receptor agonist toxicity in a large series of presentations to European emergency departments between 2013-2020. Methods Self-reported drug exposure, clinical, and outcome data were extracted from the European Drug Emergencies Network Plus which is a surveillance network that records data on drug-related emergency department presentations to 36 centres in 24 European countries. Cannabis exposure was considered the control in all analyses. To compare the lone cannabis and lone synthetic cannabinoid receptor agonist groups, univariate analysis using chi squared testing was used for categorical variables and non-parametric Mann-Whitney U- testing for continuous variables. Statistical significance was defined as a P value of < 0.05. Results Between 2013-2020 there were 54,314 drug related presentations of which 2,657 were lone cannabis exposures and 503 lone synthetic cannabinoid receptor agonist exposures. Synthetic cannabinoid receptor agonist presentations had statistically significantly higher rates of drowsiness, coma, agitation, seizures and bradycardia at the time of presentation. Cannabis presentations were significantly more likely to have palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting and headache. Discussion Emergency department presentations involving lone synthetic cannabinoid receptor agonist exposures were more likely to have neuropsychiatric features and be admitted to a psychiatric ward, and lone cannabis exposures were more likely to have cardiovascular features. Previous studies have shown variability in the acute toxicity of synthetic cannabinoid receptor agonists compared with cannabis but there is little comparative data available on lone exposures. There is limited direct comparison in the current literature between lone synthetic cannabinoid receptor agonist and lone cannabis exposure, with only two previous poison centre series and two clinical series. Whilst this study is limited by self-report being used to identify the drug(s) involved in the presentations, previous studies have demonstrated that self-report is reliable in emergency department presentations with acute drug toxicity. Conclusion This study directly compares presentations with acute drug toxicity related to the lone use of cannabis or synthetic cannabinoid receptor agonists. It supports previous findings of increased neuropsychiatric toxicity from synthetic cannabinoid receptor agonists compared to cannabis and provides further data on cardiovascular toxicity in lone cannabis use.

Objective To analyse the relative percentage of acute recreational drug toxicity emergency department (ED) presentations involving the main drug groups according to age and sex and investigate different patterns based on sex and age strata. Methods We analysed all patients with acute recreational drug toxicity included by the Euro-DEN Plus dataset (22 EDs in 14 European countries) between October 2013 and December 2016 (39 months). Drugs were grouped as: opioids, cocaine, cannabis, amphetamines, gamma-hydroxybutyrate (GHB), hallucinogens, new psychoactive substances (NPS), benzodiazepines and ketamine. Descriptive data by age and sex are presented and compared among age/sex categories and among drug families. Results Of 17,371 patients were included during the 39-month period, 17,198 (99.0%) had taken at least one of the investigated drugs (median age: 31 years; 23.9% female; ethanol co-ingestion recorded in 41.5%, unknown in 31.2%; multiple drug use in 37.9%). Opioids (in 31.4% of patients) and amphetamines (23.3%) were the most frequently involved and hallucinogens (1.9%) and ketamine (1.7%) the least. Overall, female patients were younger than males, both in the whole cohort (median age 29 vs. 32 years; p < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years; p = 0.83). The relative proportion of each drug group was different at every age strata and some patterns could be clearly described: cannabis, NPS and hallucinogens were the most common in patients <20 years; amphetamines, ketamine and cocaine in the 20- to 39-year group; GHB/GBL in the 30- to 39-year group; and opioids and benzodiazepines in patients >= 40 years. Ethanol and other drug co-ingestion was more frequent at middle-ages, and multidrug co-ingestion was more common in females than males. Conclusion Differences in the drugs involved in acute drug toxicity presentations according to age and sex may be relevant for developing drug-prevention and education programs for some particular subgroups of the population based on the increased risk of adverse events in specific sex and/or age strata.

Objective: Ethanol intake can increase the sedative effects of gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL), although the real clinical impact is unknown. We studied the clinical impact of the co-ingestion of ethanol in patients presenting to the Emergency Department (ED) with acute toxicity related to GHB/GBL use. Method: We performed a secondary analysis of the Euro-DEN Plus Registry (14 countries, 22 EDs) which includes 17,371 consecutive patients presenting to the ED with acute recreational drug toxicity over 39 consecutive months (October 2013 - December 2016). We compared the epidemiological and clinical characteristics and ED management of patients identified as presenting with acute toxicity related to lone GHB/GBL (Group A) or GHB/GBL combined with ethanol (Group B) without other concomitant drugs. Results: A total of 609 patients were included (age 32 (8) years; 116 women (19%); Group A: 183 patients and Group B: 426). The most common features were reduction in consciousness (defined as Glasgow Coma Score < 13 points: 56.1%) and agitation/aggressiveness (33.6%). Those with ethanol co-ingestion were younger patients (Group A/B: 31.5/33.1 years, p = 0.029) and ethanol co-ingestion was associated with a lower frequency of bradycardia (23.5%/15.7%, p = 0.027) and more frequent arrival at the ED by ambulance (68.3/86.6%; p < 0.001), reduction in consciousness (58.9%/49.1%; p = 0.031), need for treatment in the ED (49.2%/60.4%; p = 0.011), use of sedatives (20.1%/12.8%; p = 0.034), admission to critical care units (22.4%/55.3%; p < 0.001), and longer hospital stay (stay longer than 6 h: 16.9%/28.4%; p = 0.003). Conclusions: Co-ingestion of ethanol increases the adverse effects of patients intoxicated by GHB/GBL, leading to greater depression of consciousness, need for treatment, admission to the ICU and longer hospital stay.

Background: Methanol poisoning is an important cause of mortality and morbidity worldwide. Although it often occurs as smaller sporadic events, epidemic outbreaks are not uncommon due to the illicit manufacture and sale of alcoholic beverages.Objective: We aimed to define methanol poisoning outbreak (MPO), outline an approach to triaging an MPO, and define criteria for prioritizing antidotes, extracorporeal elimination treatments (i.e., dialysis), and indications for transferring patients in the context of an MPO.Methods: We convened a group of experts from across the world to explore geographical, socio-cultural and clinical considerations in the management of an MPO. The experts answered specific open-ended questions based on themes aligned to the goals of this project. This project used a modified Delphi process. The discussion continued until there was condensation of themes.Results: We defined MPO as a sudden increase in the number of cases of methanol poisoning during a short period of time above what is normally expected in the population in that specific geographic area. Prompt initiation of an antidote is necessary in MPOs. Scarce hemodialysis resources require triage to identify patients most likely to benefit from this treatment. The sickest patients should not be transferred unless the time for transfer is very short. Transporting extracorporeal treatment equipment and antidotes may be more efficient.Conclusion: We have developed consensus statements on the response to a methanol poisoning outbreak. These can be used in any country and will be most effective when they are discussed by health authorities and clinicians prior to an outbreak.

Editor’s note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication.

Objective: To analyse the epidemiology, clinical picture and emergency department (ED) management of a large series of patients who presented to European EDs after cocaine consumption, comparing data from powder (C-1 group) and crack (C-2 group) consumers. Methods: Between October 2013 and December 2016, the Euro-DEN Plus Registry recorded 17,371 consecutive acute recreational drug toxicity presentations to 22 EDs in 14 European countries. Epidemiological and demographic data, co-ingestion of alcohol and other drugs, clinical features, ED management and outcome (death) were analysed for cocaine cases, and comparison of clinical picture in C-1 and C-2 patients were performed adjusting for alcohol and other drug co-ingestion. Results: We included 3002 cases (C-1: 2600; C-2: 376; mixed consumption: 26): mean age 32(9) years, 23% female. The proportion of presentations involving cocaine varied significantly between countries (>30% in Malta, Spain, France, Denmark) and only centres in France, United Kingdom, Poland, Ireland and Malta recorded crack-related cases. Cocaine was frequently used with ethanol (74.3%, C-1>C-2) and other drugs (56.8%, C-2>C-1), the most frequent amphetamine (19.4%, C-1>C-2) and opioids (18.9%, C-2>C-1). C-2 patients were more likely to have clinically significant episodes of hypotension (adjusted OR = 2.35; 95%CI = 1.42-3.89), and bradypnea (1.81; 1.03-3.16) and systolic blood pressure >180 mmHg on ED arrival (2.59; 1.28-5.25); while less likely anxiety (0.51; 0.38-0.70), chest pain (0.47; 0.31-0.70), palpitations (0.57; 0.38-0.84), vomiting (0.54; 0.32-0.90), and tachycardia on ED arrival (0.52; 0.39-0.67). Sedative drugs were given in 29.3%. The median length of hospital stay was 4:02 h, 22.1% patients were hospitalized, and 0.4% (n = 12) died. Conclusion: Cocaine is commonly involved in European ED presentations with acute recreational drug toxicity, but there is variation across Europe not just in the involvement of cocaine but in the proportion related to powder versus crack. Some differences in clinical picture and ED management exist between powder cocaine and crack consumers.

Seizures are a recognized and potentially serious complication of recreational drug use. This study examined a large international data set of presentations to Emergency Departments with acute recreational drug toxicity, the European Drug Emergencies Plus (Euro-DEN Plus) Network, to compare presentations with and without seizures and estimate incidence and associated drugs. Amongst 23,947 presentations between January 2014 and December 2017, there were 1013 (4.2%) with reported seizures. Clinical and demographic features were similar between individuals who had a seizure and those who did not, although rates of coma, cardiac arrest, intubation, intensive care admission, and death were significantly higher in those with seizures. There was a significant association between specific drugs and a higher seizure incidence, including fentanyl (odds ratio 2.63, 95% confidence interval 1.20-5.80), and synthetic cannabinoids (OR 2.90, 95% CI 2.19-3,84). Other drugs were associated with a lower seizure incidence, including heroin (OR 0.46, 95% CI 0.35-0.61), clonazepam (OR 0.22, 95% CI 0.06-0.91), and cannabis (OR 0.65, 95% CI 0.50-0.86). This substantiates observations that the synthetic cannabinoids as a group of novel psychoactive substances are clinically different in consequence of intoxication than cannabis, and that individuals who suffer a seizure in the context of recreational drug intoxication are likely to have worse outcomes overall. Utilising this information of what substances have a greater risk of seizures, could provide tailored harm reduction and education strategies to users to reduce the risk of seizures and their associated complications.

Background: Methanol poisoning is an important cause of mortality and morbidity worldwide. Although it often occurs as smaller sporadic events, epidemic outbreaks are not uncommon due to the illicit manufacture and sale of alcoholic beverages. Objective: We aimed to define methanol poisoning outbreak (MPO), outline an approach to triaging an MPO, and define criteria for prioritizing antidotes, extracorporeal elimination treatments (i.e., dialysis), and indications for transferring patients in the context of an MPO. Methods: We convened a group of experts from across the world to explore geographical, socio-cultural and clinical considerations in the management of an MPO. The experts answered specific open-ended questions based on themes aligned to the goals of this project. This project used a modified Delphi process. The discussion continued until there was condensation of themes. Results: We defined MPO as a sudden increase in the number of cases of methanol poisoning during a short period of time above what is normally expected in the population in that specific geographic area. Prompt initiation of an antidote is necessary in MPOs. Scarce hemodialysis resources require triage to identify patients most likely to benefit from this treatment. The sickest patients should not be transferred unless the time for transfer is very short. Transporting extracorporeal treatment equipment and antidotes may be more efficient. Conclusion: We have developed consensus statements on the response to a methanol poisoning outbreak. These can be used in any country and will be most effective when they are discussed by health authorities and clinicians prior to an outbreak.

Objetivo: Analizar algunas caracteristicas epidemiologicas, clinicas y asistenciales de los pacientes atendidos por sintomatologia directamente derivada del consumo de drogas de abuso en dos servicios de urgencias (SU) espanoles y compararlas con las observadas en otras regiones de Europa. Metodo: Analisis secundario del Registro Euro-DEN Plus (14 paises europeos, 20 SU) que incluyo todos los pacientes atendidos por sintomatologia derivada del consumo de drogas (excepto etanol aislado) durante 39 meses consecutivos (octubre 2013 a diciembre 2016). Se comparan los casos de los 2 centros espanoles (Barcelona, Palma) con los de 5 centros de Reino Unido e Irlanda (Islas Britanicas -IB-), 6 del Norte de Europa (NE) y 7 de Europa Central (EC). Resultados: Se recogieron 17.103 pacientes: Espana 1166, IB 6652, NE 6097 y EC 3168. En Espana, hubo mas urgencias por cocaina (48,4%) ý menos por opiaceos (12,4%) que en el resto de zonas; los pacientes eran mas jovenes (32,2 anos) que en NE y mayores que en IB y EC; menos frecuentemente mujeres (21,9%) que en NE y CE; llegaron menos frecuentemente en ambulancia (70,0%) que en IB y NE; y en el SU se registro escasamente la temperatura (29,8%) y frecuencia respiratoria (30,3%). Las manifestaciones clinicas difirieron entre zonas por la distinta prevalencia de cada tipo de droga. Naloxona (9,6%) se utilizo menos que en IB y NE, y flumazenilo (5,6%) mas que en las otras zonas, y los porcentajes de ingresos (4,6%) y fugas del SU (6,2%) fueron los menores de todas las regiones. La mortalidad, en urgencias (0,4%) y global (0,7%), fue significativamente superior que en NE. Conclusiones: Las caracteristicas de las urgencias generadas por drogas de abuso son diferentes en Espana respecto a otras zonas europeas, debido a un diferente patron de consumo. Su manejo en el SU, en terminos de exploraciones realizadas, tratamientos empleados y disposicion tras la asistencia tambien son diferentes. Palabras clave: Drogas, urgencias, sintomas, evolucion, epidemiologia.

Objectives. To analyze epidemiologic, clinical, and care characteristics in cases in which patients came to 2 Spanish emergency departments (EDs) with symptoms caused by recreational drug abuse. To compare the characteristics with those reported for other areas of Europe. Methods. Secondary analysis of the registry of the European Drug Emergencies Network (Euro-DEN Plus), which collects cases in 14 European countries and 20 EDs. The registry included all patients attending EDs with symptoms of recreational drug abuse (excepting cases involving alcohol alone) over a period of 39 consecutive months (October 2013 to December 2016). We compared the cases from the 2 Spanish EDs (in Barcelona and Palma de Mallorca) to those from the 5 EDs in Ireland and the UK, 6 in northern Europe, and 7 in central Europe. Results. A total of 17 104 patients' cases were included: Spain, 1186; UK and Ireland, 6653; northern Europe, 6097; and central Europe, 3168. Spain saw more emergencies related to cocaine (48.4%) and fewer related to opioids (12.4%) than the other areas. The Spanish patients were younger (32.2 years) on average than those in northern Europe and older than those in the UK and Ireland and central Europe. Fewer patients were women in Spain (21.9%) than in northern or central Europe. Fewer arrived in ambulances in Spain (70.0%) than in the UK and Ireland or northern Europe. The Spanish EDs recorded the temperature and respiratory frequency of fewer patients (29.8% and 30.3%, respectively). Clinical signs differed between geographical areas attributable to differences in drug-use patterns. In Spain, naloxone was used by fewer patients (9.6%) than in the UK and Ireland and northern Europe, and flumazenil was used by more patients (5.6%) than in other areas. Spain saw lower percentages of admissions (4.6%) and patients who left without an ED discharge (6.2%) in comparison with other areas. Mortality rates in the Spanish EDs (0.4%) and after discharge from them (0.7%) were higher than in northern Europe. Conclusions. The characteristics of emergencies related to recreational drug abuse registered by the Spanish EDs were differed from those registered in other parts of Europe due to different patterns of drug use. We also detected differences between the Spanish and other European EDs with respect to examinations or tests performed, treatment given, and discharge disposition.

OBJECTIVE:To study the profile of European gamma-hydroxybutyrate (GHB) and gammabutyrolactone (GBL) intoxication and analyse the differences in the clinical manifestations produced by intoxication by GHB/GBL alone and in combination with other substances of abuse. METHOD:We prospectively collected data on all the patients attended in the Emergency Departments (ED) of the centres participating in the Euro-DEN network over 12 months (October 2013 to September 2014) with a primary presenting complaint of drug intoxication (excluding ethanol alone) and registered the epidemiological and clinical data and outcomes. RESULTS:We included 710 cases (83% males, mean age 31 years), representing 12.6% of the total cases attended for drug intoxication. Of these, 73.5% arrived at the ED by ambulance, predominantly during weekend, and 71.7% consumed GHB/GBL in combination with other substances of abuse, the most frequent additional agents being ethanol (50%), amphetamine derivatives (36%), cocaine (12%) and cannabis (8%). Among 15 clinical features pre-defined in the project database, the 3 most frequently identified were altered behaviour (39%), reduced consciousness (34%) and anxiety (14%). The severity ranged from mild cases requiring no treatment (308 cases, 43.4%) to severe cases requiring admission to intensive care (103 cases, 14.6%) and mechanical ventilation (49 cases, 6.9%). No deaths were reported. In comparison with only GHB/GBL consumption, patients consuming GHB/GBL with co-intoxicants presented more vomiting (15% vs. 3%, p<0.001) and cardiovascular symptoms (5.3% vs. 1.5%, p<0.05), a greater need for treatment (59.8% vs. 48.3%, p<0.01) and a longer ED stay (11.3% vs. 3.6% patients with ED stay >12h, p<0.01). CONCLUSIONS:The profile of the typical GHB/GBL-intoxicated European is a young male, requiring care for altered behaviour and reduced level of consciousness, mainly during the weekend. The clinical features are more severe when GHB is consumed in combination with other substances of abuse.

[This corrects the article DOI: 10.1371/journal.pone.0152676.].

Aims: The initial management of acute recreational drug and new psychoactive substance (NPS) toxicity is often by non-specialists working in the night-time economy. The aim was as part of the European Drug Emergencies Network (Euro-DEN) project to pilot training of these workers in multiple European countries. Methods: Following evaluation of training needs, guidelines and training package were developed. Night-time economy workers in London, UK; Parnu/Tallinn, Estonia; and Oslo, Norway participated in a 1- to 2-h interactive case-based training session. Participants completed a questionnaire pre-/post-training to assess confidence in managing acute recreational drug/NPS toxicity and evaluate the training package/guidelines. Findings: 98 (London: 42; Oslo: 39; Parnu/Tallinn: 17) completed both pre-/post-training questionnaires. Participants felt significantly more confident in managing someone unwell following classical recreational drug use compared to NPS (5.6 +/- 2.9 vs. 4.3 +/- 2.7, p<0.001); this difference persisted after the training (7.6 +/- 1.9 vs. 6.9 +/- 2.0, p<0.001). 147 (London: 42; Oslo: 88; Parnu/Tallinn: 17) completed the post-training evaluation; the training session and the guidelines were rated 8.2 +/- 1.4 and 8.7 +/- 1.7, respectively (out of 10). Conclusions: The guidelines and training were well received by night-time economy workers in three European countries and improved confidence in managing acute recreational drug/NPS toxicity. Appropriate national and European bodies need to look at wider dissemination of this work.