Christopher Yates

Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement.

Objective:Methanol poisoning can induce death and disability. Treatment includes the administration of antidotes (ethanol or fomepizole and folic/folinic acid) and consideration of extracorporeal treatment for correction of acidemia and/or enhanced elimination. The Extracorporeal Treatments in Poisoning workgroup aimed to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning. Design and Methods:Utilizing predetermined methods, we conducted a systematic review of the literature. Two hundred seventy-two relevant publications were identified but publication and selection biases were noted. Data on clinical outcomes and dialyzability were collated and a two-round modified Delphi process was used to reach a consensus. Results:Recommended indications for extracorporeal treatment: Severe methanol poisoning including any of the following being attributed to methanol: coma, seizures, new vision deficits, metabolic acidosis with blood pH ⩽7.15, persistent metabolic acidosis despite adequate supportive measures and antidotes, serum anion gap higher than 24 mmol/L; or, serum methanol concentration 1) greater than 700 mg/L (21.8 mmol/L) in the context of fomepizole therapy, 2) greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment, 3) greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase blocker; in the absence of a methanol concentration, the osmolal/osmolar gap may be informative; or, in the context of impaired kidney function. Intermittent hemodialysis is the modality of choice and continuous modalities are acceptable alternatives. Extracorporeal treatment can be terminated when the methanol concentration is <200 mg/L or 6.2 mmol/L and a clinical improvement is observed. Extracorporeal Treatments in Poisoning inhibitors and folic/folinic acid should be continued during extracorporeal treatment. General considerations: Antidotes and extracorporeal treatment should be initiated urgently in the context of severe poisoning. The duration of extracorporeal treatment extracorporeal treatment depends on the type of extracorporeal treatment used and the methanol exposure. Indications for extracorporeal treatment are based on risk factors for poor outcomes. The relative importance of individual indications for the triaging of patients for extracorporeal treatment, in the context of an epidemic when need exceeds resources, is unknown. In the absence of severe poisoning but if the methanol concentration is elevated and there is adequate alcohol dehydrogenase blockade, extracorporeal treatment is not immediately required. Systemic anticoagulation should be avoided during extracorporeal treatment because it may increase the development or severity of intracerebral hemorrhage. Conclusion:Extracorporeal treatment has a valuable role in the treatment of patients with methanol poisoning. A range of clinical indications for extracorporeal treatment is provided and duration of therapy can be guided through the careful monitoring of biomarkers of exposure and toxicity. In the absence of severe poisoning, the decision to use extracorporeal treatment is determined by balancing the cost and complications of extracorporeal treatment to that of fomepizole or ethanol. Given regional differences in cost and availability of fomepizole and extracorporeal treatment, these decisions must be made at a local level.

The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology

Abstract Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1–9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.

Acute recreational drug and new psychoactive substance toxicity in Europe: 12 months data collection from the European Drug Emergencies Network (Euro-DEN).

Context. Despite the potential for recreational drugs and new psychoactive substances (NPSs) to cause significant morbidity and mortality, there is limited collection of systematic data on acute drug/NPS toxicity in Europe. Objective. To report data on acute drug/NPS toxicity collected by a network of sentinel centres across Europe with a specialist clinical and research interest in the acute toxicity of recreational drugs and NPS to address this knowledge gap. Methods. Sixteen sentinel centres in 10 European countries (Denmark, Estonia, France, Germany, Ireland, Norway, Poland, Spain, Switzerland and the UK) collected data on all acute drug toxicity presentations to their Emergency Rooms (ERs) for 12 months (October 2013–September 2014); information on the drug(s) involved in the presentations was on the basis of patient self-reporting. Results. Data were collected on a total of 5529 presentations involving 8709 drugs (median (interquartile range [IQR]): 1 (1–2) drugs per presentation), a median of 0.3% of all ER attendances. Classical recreational drugs were most common (64.6%) followed by prescription drugs (26.5%) and NPS (5.6%). The ‘top five’ drugs recorded were heroin (1345 reports), cocaine (957), cannabis (904), GHB/GBL (711) and amphetamine (593). 69.5% of individuals went to hospital by ambulance (peak time between 19:00 and 02:00 at weekends); the median (IQR) age was 31 (24–39) years and 75.4% were male. Although serious clinical features were not seen in most presentations and 56.9% were medically discharged from the ER (median length of stay: 4.6 hours), a significant number (26.5%) was agitated, in 10.5% the GCS was 8 or less and 35 presented in cardiac arrest. There were 27 fatalities with opioids implicated in 13. Conclusion. The Euro-DEN dataset provides a unique insight into the drugs involved in and clinical pattern of toxicity/outcome of acute recreational drug toxicity presentations to hospitals around Europe. This is complimentary to other indicators of drug-related harm and helps to build a fuller picture of the public health implications of drug use in Europe.

Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup

Abstract Background: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, we present our results for digoxin. Methods: After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations. Results: Out of 435 articles screened, 77 met inclusion criteria. Only in-vitro, animal studies, case reports and case series were identified yielding a very low quality of evidence for all recommendations. Based on data from 84 patients, including six fatalities, it was concluded that digoxin is slightly dialyzable (level of evidence = B), and that ECTR is unlikely to improve the outcome of digoxin-toxic patients whether or not digoxin immune Fab (Fab) is administered. Despite the lack of robust clinical evidence, the workgroup recommended against the use of ECTR in cases of severe digoxin poisoning when Fab was available (1D) and also suggested against the use of ECTR when Fab was unavailable (2D). Conclusion: ECTR, in any form, is not indicated for either suspected or proven digoxin toxicity, regardless of the clinical context, and is not indicated for removal of digoxin-Fab complex.

Current European data collection on emergency department presentations with acute recreational drug toxicity: Gaps and national variations

Abstract Background. The number of new (novel) psychoactive substances (NPS) available in the illegal market is increasing; however, current monitoring of the drug situation in Europe focuses mainly on classical drugs of abuse, with limited emphasis on clinical presentation in the emergency department (ED). The European Drug Emergencies Network (Euro-DEN) is a European Commission-funded project that aims to improve the knowledge of acute drug toxicity of both classical recreational drugs and NPS. As a baseline for this project, we performed a study to establish which data are currently being collected and reported in Europe on ED presentations with acute toxicity related to NPS and classical drugs of abuse. Methods. We used a three-pronged approach to identify any systematic collection of data on NPS toxicity in Europe by i) performing a literature search, ii) utilising an online survey of the European Monitoring Centre for Drugs and Drug Addiction Re seau Europe en d’Information sur les Drogues et les Toxicomanies national focal points and iii) exploiting the knowledge and resources of the Euro-DEN network members. Results. The literature search revealed 21 papers appropriate for assessment, but only one described a systematic collection of clinical data on NPS. Twenty-seven of thirty countries responded to the online survey. More than half of all the countries (52%) did not perform any registration at all of such data, 37% collected systematic clinical data on NPS at a national level, while 44% collected data on classical drugs. A few examples for good practice of systematic collection of clinical data on ED presentations due to acute toxicity were identified. Conclusion. The systematic collection of data on ED presentation of toxicity related to NPS and classical drugs in Europe is scarce; the existing collection is limited to single centres, single countries, groups of patients or not focused on novel drugs; the collection of data is highly variable between the different countries. Euro-DEN, a European Commission funded project, aims at closing some of these gaps.

Extracorporeal Treatment for Tricyclic Antidepressant Poisoning: Recommendations from the EXTRIP Workgroup

The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two‐round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy‐seven articles met inclusion criteria. Only case reports, case series, and one poor‐quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.

Acute intoxication caused by synthetic cannabinoids 5F-ADB and MMB-2201: A case series

Synthetic cannabinoids are relatively new substances of abuse. Recently, abuse of synthetic cannabinoids has been increasingly reported in the lay press and medical literature. When new compounds are introduced, their use is initially not restricted by prohibition therefore their consumption cannot be verified by standard drug tests. The use of these compounds among adolescents and young adults is constantly growing, making it important for emergency services to be familiar with the signs and symptoms of intoxication present. Overdose and chronic use of these substances can cause adverse effects including altered mental status, tachycardia, and loss of consciousness. Here, we report five cases of acute intoxication by synthetic cannabinoids 5F-ADB and MMB-2201 with analytical confirmation.

Intoxication by gamma hydroxybutyrate and related analogues: Clinical characteristics and comparison between pure intoxication and that combined with other substances of abuse

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.

Elimination half-life of alpha-pyrrolidinovalerophenone in an acute non-fatal intoxication

Alpha-pyrrolidinovalerophenone (a-PVP, a-pyrrolidinopentiophenone or flakka) is a synthetic stimulant drug that belongs to the cathinone family.[1] We present a non-fatal a-PVP intoxication with drug quantification and a pharmacokinetic profile. A 19-year-old male was admitted to the hospital after presumed consumption of alcohol and drugs. During transport 15 mg of intravenous midazolam was administered to control agitation and tachycardia (174 bpm). On admission, the patient was agitated with persecutory delusions, bruxism, mydriasis, blood pressure (BP) 135/63 mmHg, and heart rate (HR) 157 bpm. The ECG revealed sinus tachycardia without signs of sodium channel blockade. Another 15 mg of midazolam, repeated doses of intravenous diazepam (total dose 175 mg during 33 h) and physical restraints were required. At eight hours post-admission (BP: 155/85 mmHg; HR: 137 bpm), the temperature reached 38 C and was controlled with physical cooling and paracetamol (1 g). At 32 h psychotic symptoms ceased and he admitted ethanol and ecstasy consumption (administration route, dose, and time at consumption were unknown). At 40 h, vital signs were normalized and he was discharged at 57 h post-admission. The poisoning severity score was 2 (moderate). Laboratory results on admission revealed leukocytosis (15.300/lL) and elevation of serum creatine kinase (1759 U/L) and myoglobin (611 ng/mL). Toxicological analyses involved: serum ethanol, that was undetectable (<0.10 g/L) by an enzymatic method (Abbott Diagnostics; Abbott Laboratories, Irving, TX), urine drug screening by immunoassay (DRIR , Abbott Diagnostics; Abbott Laboratories, Irving, TX) for amfetamine, ecstasy, cannabinoids, cocaine metabolite and opiates, that was also negative, and urine drug screen by gas chromatography coupled to mass spectrometry (Agilent 5975/6890R ; Agilent Technologies, Barcelona, Spain), that was positive for a-PVP and its metabolite a-(200-oxo-pyrrolidino)valerophenone. The following drugs were specifically ruled out: methylone, mephedrone, 3,4methylenedioxypyrovalerone (MDPV), para-methoxymethamfetamine, ketamine, and methoxetamine. At admission, a-PVP serum and urine levels were 23 ng/mL and 4451 ng/mg related to creatinine (mg), respectively. Eight serum samples were obtained between 4 and 42 h post-admission to describe a-PVP pharmacokinetic profile using non-compartmental methods. a-PVP peak concentration was 39 ng/mL, measured at 12 h post-admission. The terminal elimination half-life (t1/2) was 4.29 h, calculated using the formula t1=2 1⁄4 ln 2=k, where the elimination rate constant (k) was obtained from the slope of the terminal portion of the semi-logarithmic serum concentration vs. time curve (Figure 1). The area under the curve was 570.72 ng h/mL from 4 to 42 h post-admission. Data available on a-PVP serum concentrations in non-fatal cases are limited.[1,2] Serial concentrations and t1/2 have not been previously reported. The estimated a-PVP t1/2 is comparable to those published for close related drugs such as cathinone [3] (4.33 ± 1.7 h) and synthetic derivatives as MDPV [4] (1.88 h). These values are lower than those reported for classical drugs [5] as metilendioxymethamfetamine (8–9 h), methoxymethamfetamine (10–12 h), or amfetamine (12–15 h), suggesting a faster elimination for cathinones. Our study has limitations which should be considered. The estimated pharmacokinetic parameters are based on one patient and the toxicological screening cannot exclude all drugs. In conclusion, the calculated t1/2 might represent a first guidance to estimate the duration of symptoms, however further cases are essential to reinforce these data.

Review of European-Drug Emergencies Network (Euro-DEN) training package for non-specialist workers to assess acute recreational drug and new psychoactive substance toxicity in night-time economy environments

Abstract 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; Pärnu/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; Pärnu/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; Pärnu/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.