Publications by authors named "Michael Eddleston"

208 Publications

Detection of flubromazolam in patients with suspected non-medical drug use attending emergency departments in the United Kingdom.

Clin Toxicol (Phila) 2021 Jun 3:1-5. Epub 2021 Jun 3.

Clinical Toxicology, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK.

Introduction: Non-medical use of novel benzodiazepines has recently become common. Here, we describe the recent frequent detection of flubromazolam in patients attending United Kingdom emergency departments.

Methods: Adults presenting to participating hospitals with toxicity after suspected drug misuse were studied between March 2015 and January 2021. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry.

Results: Flubromazolam and/or its mono-hydroxylated metabolite were detected in samples from 14 of 957 patients, all presenting since July 2020. Reported clinical features included reduced level of consciousness (10), confusion/agitation (6) and acidosis (5) but multiple other substances were detected in all patients. All patients survived to discharge (length of hospital stay 3.0 to 213 h, median 24.1 h). There was no correlation between admission blood/serum flubromazolam concentrations (range 1.7-480.5 ng/ml, median 7.4 ng/ml) and Glasgow Coma Scale or length of hospital stay. In one patient who needed intubation and ventilation for five days, there was an exponential decline in flubromazolam concentrations with time (calculated half-life 39.8 h). Hydroxyl-flubromazolam was also identified at all time points.

Conclusions: Flubromazolam has been detected frequently in drug users presenting to UK emergency departments since July 2020. Prolonged toxicity may occur as a result of the long half-life of flubromazolam and the production of metabolites likely to be active.
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http://dx.doi.org/10.1080/15563650.2021.1931692DOI Listing
June 2021

Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure.

Clin Toxicol (Phila) 2021 May 14:1-20. Epub 2021 May 14.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Background: Ingestion of agricultural organophosphorus insecticides is a significant cause of death in rural Asia. Patients often show acute respiratory failure and/or delayed, unexplained signs of neuromuscular paralysis, sometimes diagnosed as "Intermediate Syndrome". We tested the hypothesis that omethoate and cyclohexanol, circulating metabolites of one agricultural formulation, cause muscle weakness and paralysis.

Methods: Acetylcholinesterase activity of insecticide components and metabolites was measured using purified enzyme from eel electroplaque or muscle homogenates. Mechanomyographic recording of pelvic limb responses to nerve stimulation was made in anaesthetized pigs and isometric force was recorded from isolated nerve-muscle preparations from mice. Omethoate and cyclohexanol were administered intravenously or added to physiological saline bathing isolated muscle. We also assessed the effect of MgSO and cooling on neuromuscular function.

Results: Omethoate caused tetanic fade in pig muscles and long-lasting contractions of the motor innervation zone in mouse muscle. Both effects were mitigated, either by i.v. administration of MgSO or by adding 5 mM Mg to the medium bathing isolated preparations. Combination of omethoate and cyclohexanol initially potentiated muscle contractions but then rapidly blocked them. Cyclohexanol alone caused fade and block of muscle contractions in pigs and in isolated preparations. Similar effects were observed with cyclohexanone and xylene. Cyclohexanol-induced neuromuscular block was temperature-sensitive and rapidly reversible.

Conclusions: The data indicate a crucial role for organophosphorus and solvent metabolites in muscle weakness following ingestion of agricultural OP insecticide formulations. The metabolites omethoate and cyclohexanol acted conjointly to impair neuromuscular function but their effects were mitigated by elevating extracellular Mg and decreasing core temperature, respectively. Clinical studies of MgSO therapy and targeted temperature management in insecticide-poisoned patients are required to determine whether they may be effective adjuncts to treatment.
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http://dx.doi.org/10.1080/15563650.2021.1916519DOI Listing
May 2021

Acute phenthoate self-poisoning: a prospective case series.

Clin Toxicol (Phila) 2021 May 7:1-7. Epub 2021 May 7.

Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh, UK.

Background: The clinical characteristics following self-poisoning with organophosphorus (OP) insecticides differs according to the insecticide ingested. Phenthoate is a dimethoxy WHO Hazard Class II OP pesticide with limited literature on its clinical characteristics and outcome. We aimed to better understand its clinical characteristics by studying patients with phenthoate self-poisoning in Sri Lanka.

Methods: We conducted a prospective cohort study of patients presenting with phenthoate self-poisoning to eight hospitals in Sri Lanka between 2002 and 2018. Clinical outcomes were recorded for each patient. Blood samples for measuring plasma phenthoate concentration, cholinesterase activity, and response to oximes were available for a very small number of patients recruited to a clinical trial.

Results: Two hundred and ninety-two patients who ingested agricultural phenthoate formulations were included in the study. Median time to admission was 3.9 (IQR 2.4 - 6.8) h. Forty-two (14.4%) patients were intubated, mostly (30/37, 81%) within 24 h of ingestion (median time to intubation 7.2 [IQR 2.6-20.9] h). Median duration of intubation was 74.8 (IQR 26.8-232.5) h; the longest duration in a survivor was 592 h. Nineteen died (case fatality 6.5%, 95% CI 4.0-10.0); median time to death was 37 (IQR 16 - 101.7) h. Median plasma phenthoate concentration in patients with samples ( = 81) was 135 (IQR 62.7-356.5) ng/mL (0.42 µmol/mL [0.2 to 1.1 µmol/mL]). Five of six patients receiving pralidoxime chloride 2 g showed an initial increase in AChE and BuChE activity that was not sustained despite an infusion of pralidoxime.

Conclusion: Phenthoate self-poisoning has a 6.5% case fatality rate. Most patients who experience respiratory failure undergo early intubation; most deaths occurred among those patients who were intubated less than 24 h after ingestion. There was a non-sustained increase in cholinesterase activity with pralidoxime, but further studies are required to analyse the extent to which oximes are clinically effective in phenthoate self-poisoning.
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http://dx.doi.org/10.1080/15563650.2021.1917596DOI Listing
May 2021

Acute phenthoate self-poisoning: a prospective case series.

Clin Toxicol (Phila) 2021 May 7:1-7. Epub 2021 May 7.

Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh, UK.

Background: The clinical characteristics following self-poisoning with organophosphorus (OP) insecticides differs according to the insecticide ingested. Phenthoate is a dimethoxy WHO Hazard Class II OP pesticide with limited literature on its clinical characteristics and outcome. We aimed to better understand its clinical characteristics by studying patients with phenthoate self-poisoning in Sri Lanka.

Methods: We conducted a prospective cohort study of patients presenting with phenthoate self-poisoning to eight hospitals in Sri Lanka between 2002 and 2018. Clinical outcomes were recorded for each patient. Blood samples for measuring plasma phenthoate concentration, cholinesterase activity, and response to oximes were available for a very small number of patients recruited to a clinical trial.

Results: Two hundred and ninety-two patients who ingested agricultural phenthoate formulations were included in the study. Median time to admission was 3.9 (IQR 2.4 - 6.8) h. Forty-two (14.4%) patients were intubated, mostly (30/37, 81%) within 24 h of ingestion (median time to intubation 7.2 [IQR 2.6-20.9] h). Median duration of intubation was 74.8 (IQR 26.8-232.5) h; the longest duration in a survivor was 592 h. Nineteen died (case fatality 6.5%, 95% CI 4.0-10.0); median time to death was 37 (IQR 16 - 101.7) h. Median plasma phenthoate concentration in patients with samples ( = 81) was 135 (IQR 62.7-356.5) ng/mL (0.42 µmol/mL [0.2 to 1.1 µmol/mL]). Five of six patients receiving pralidoxime chloride 2 g showed an initial increase in AChE and BuChE activity that was not sustained despite an infusion of pralidoxime.

Conclusion: Phenthoate self-poisoning has a 6.5% case fatality rate. Most patients who experience respiratory failure undergo early intubation; most deaths occurred among those patients who were intubated less than 24 h after ingestion. There was a non-sustained increase in cholinesterase activity with pralidoxime, but further studies are required to analyse the extent to which oximes are clinically effective in phenthoate self-poisoning.
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http://dx.doi.org/10.1080/15563650.2021.1917596DOI Listing
May 2021

Acute toxicity from the synthetic cathinone -ethylpentylone (ephylone) in the United Kingdom.

Clin Toxicol (Phila) 2021 Apr 15:1-4. Epub 2021 Apr 15.

NIHR Health Protection Research Unit for Chemical Threats and Hazards, Newcastle University, Newcastle, UK.

Introduction: Acute toxicity caused by New Psychoactive Substances (NPS) has created a significant burden for Emergency Departments (EDs). Here we report characteristics of people presenting with toxicity after exposure to the synthetic cathinone -ethylpentylone (NEP).

Methods: Adults presenting to hospital with severe acute toxicity after suspected NPS use were recruited between March 2015 and October 2020. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry.

Results: NEP was detected in at least one sample from 9 of 893 patients recruited during the period of study, all presenting between 2016 and 2019 and 8 presenting in southern England. Commonly reported clinical features included tachycardia (6), agitation (6), confusion (6), mydriasis (5), hallucinations (4), acidosis (3) and elevated creatine kinase (3). Co-used drugs, detected in 6 patients, may have contributed to these features, but agitation and hallucinations were also reported in all 3 patients without analytical evidence of co-use.

Conclusions: NEP was detected infrequently in episodes of drug toxicity in the UK between 2016 and 2019, especially in southern England. Clinical characteristics of toxicity are similar to those of other cathinones, although co-use of other drugs is common and may contribute to the features observed.
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http://dx.doi.org/10.1080/15563650.2021.1909730DOI Listing
April 2021

Moderate-to-severe envenoming requiring ViperaTAb antivenom therapy in the UK.

Clin Toxicol (Phila) 2021 Mar 15:1-10. Epub 2021 Mar 15.

National Poisons Information Service - Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: Bites by the European adder () in the UK are uncommon but potentially life threatening, and can be associated with marked limb swelling and disability. Following an interruption in Zagreb Imunološki zavod antivenom supply around 2012, the UK changed its national choice of antivenom for to ViperaTAb, an ovine Fab monospecific antivenom. In the absence of randomised controlled trials, we established an audit to review its use in clinical practice.

Methods: A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom for envenoming were invited to discuss the case with the on-call clinical toxicology consultant. Information was collected prospectively on indications, administration, adverse reactions and outcome of patients administered ViperaTAb antivenom.

Results: One hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2-87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5-4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9-3.6) h. A minority of patients presented to hospital more than 12 h after being bitten ( = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital ( = 17, 10.0%). Features of systemic envenoming were present in 64/170 (37.6%) patients, including 23 (13.5%) with anaphylaxis and 26 (15.3%) with hypotension (nine with both). Clinician assessment considered the initial antivenom to have been effective in 122/169 (72.2%) patients. Repeated dosing was common, occurring in 55/169 (32.5%), predominantly due to persisting or worsening local effects (46/51, 90.2%). There were three cases of probable early adverse reaction. No deaths occurred during the study. Complications of envenoming were rare but included four patients that underwent surgery, three patients each with acute kidney injury, mild coagulopathy, or thrombocytopenia (one severe). The median duration of hospital stay was 43.7 (IQR 22.5-66.5) h, longer for children than adults (52.5 vs 41.3 h).

Conclusion: ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.
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http://dx.doi.org/10.1080/15563650.2021.1891245DOI Listing
March 2021

Moderate-to-severe envenoming requiring ViperaTAb antivenom therapy in the UK.

Clin Toxicol (Phila) 2021 Mar 15:1-10. Epub 2021 Mar 15.

National Poisons Information Service - Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: Bites by the European adder () in the UK are uncommon but potentially life threatening, and can be associated with marked limb swelling and disability. Following an interruption in Zagreb Imunološki zavod antivenom supply around 2012, the UK changed its national choice of antivenom for to ViperaTAb, an ovine Fab monospecific antivenom. In the absence of randomised controlled trials, we established an audit to review its use in clinical practice.

Methods: A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom for envenoming were invited to discuss the case with the on-call clinical toxicology consultant. Information was collected prospectively on indications, administration, adverse reactions and outcome of patients administered ViperaTAb antivenom.

Results: One hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2-87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5-4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9-3.6) h. A minority of patients presented to hospital more than 12 h after being bitten ( = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital ( = 17, 10.0%). Features of systemic envenoming were present in 64/170 (37.6%) patients, including 23 (13.5%) with anaphylaxis and 26 (15.3%) with hypotension (nine with both). Clinician assessment considered the initial antivenom to have been effective in 122/169 (72.2%) patients. Repeated dosing was common, occurring in 55/169 (32.5%), predominantly due to persisting or worsening local effects (46/51, 90.2%). There were three cases of probable early adverse reaction. No deaths occurred during the study. Complications of envenoming were rare but included four patients that underwent surgery, three patients each with acute kidney injury, mild coagulopathy, or thrombocytopenia (one severe). The median duration of hospital stay was 43.7 (IQR 22.5-66.5) h, longer for children than adults (52.5 vs 41.3 h).

Conclusion: ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.
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http://dx.doi.org/10.1080/15563650.2021.1891245DOI Listing
March 2021

Factors associated with purchasing pesticide from shops for intentional self-poisoning in Sri Lanka.

Trop Med Int Health 2020 10 5;25(10):1198-1204. Epub 2020 Aug 5.

Department of Community Medicine, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Anuradhapura, Sri Lanka.

Objective: In South Asia, up to one in five individuals who ingest pesticides for self-poisoning and survive purchased them from a shop immediately prior to the event. Thus far, no research has taken place to determine whether interventions implemented through the pesticide sellers might be acceptable or effective, despite the hundreds of thousands of such risk purchases each year. We aimed to investigate factors associated with purchasing pesticides for self-poisoning in Sri Lanka.

Methods: We used a case-control study. Cases (n = 50) were individuals who ingested pesticides after purchasing them for the act, and controls (n = 200) were customers who bought pesticides but did not use them for self-harm. Logistic regression analysis was used to assess socio-demographic and purchase-specific risk factors.

Results: Alcohol intoxication (adjusted odds ratios [AOR] 36.5, 95% confidence intervals [CI] 1.7-783.4) and being a non-farmer AOR 13.3, 95% CI 1.8-99.6 were the main distinguishing factors when purchasing pesticides for self-poisoning. The positive predictive values were 93.3% (95% CI 68.0-99.8%) and 88.2% (95% CI 72.5-96.7%), respectively. One and/or other of these factors characterised 72.0% of cases but only 2.5% controls.

Conclusion: While results need to be interpreted cautiously, sales restrictions to prevent alcohol-intoxicated persons and non-farmers purchasing pesticides for self-poisoning may be effective.
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http://dx.doi.org/10.1111/tmi.13469DOI Listing
October 2020

Organophosphorus poisoning: the wet opioid toxidrome.

Lancet 2021 01 23;397(10270):175-177. Epub 2020 Dec 23.

Department of Internal Medicine, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh; Toxicology Society of Bangladesh, Dhaka, Bangladesh.

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http://dx.doi.org/10.1016/S0140-6736(20)32749-5DOI Listing
January 2021

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

J Am Coll Emerg Physicians Open 2020 Oct 13;1(5):1078-1089. Epub 2020 Jun 13.

Pharmacology, Toxicology & Therapeutics University/BHFCentre for Cardiovascular Research, University of Edinburgh Edinburgh UK.

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, < 0.0001; England and Wales excluding London, < 0.0001; London, < 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%] [ = 0.032]; London, -1.02% [-1.53%, -0.50%] [ < 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%] [ = 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%] [ = 0.036]; England and Wales excluding London, -0.18% [-0.30%, -0.06%] [ = 0.001]) but higher admissions in London (+0.52% [+0.03%, +1.01%] [ = 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.
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http://dx.doi.org/10.1002/emp2.12116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593423PMC
October 2020

Diagnosis of COVID-19 by analysis of breath with gas chromatography-ion mobility spectrometry - a feasibility study.

EClinicalMedicine 2020 Dec 24;29:100609. Epub 2020 Oct 24.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, United Kingdom.

Background: There is an urgent need to rapidly distinguish COVID-19 from other respiratory conditions, including influenza, at first-presentation. Point-of-care tests not requiring laboratory- support will speed diagnosis and protect health-care staff. We studied the feasibility of using breath-analysis to distinguish these conditions with near-patient gas chromatography-ion mobility spectrometry (GC-IMS).

Methods: Independent observational prevalence studies at Edinburgh, UK, and Dortmund, Germany, recruited adult patients with possible COVID-19 at hospital presentation. Participants gave a single breath-sample for VOC analysis by GC-IMS. COVID-19 infection was identified by transcription polymerase chain reaction (RT- qPCR) of oral/nasal swabs together with clinical-review. Following correction for environmental contaminants, potential COVID-19 breath-biomarkers were identified by multi-variate analysis and comparison to GC-IMS databases. A COVID-19 breath-score based on the relative abundance of a panel of volatile organic compounds was proposed and tested against the cohort data.

Findings: Ninety-eight patients were recruited, of whom 21/33 (63.6%) and 10/65 (15.4%) had COVID-19 in Edinburgh and Dortmund, respectively. Other diagnoses included asthma, COPD, bacterial pneumonia, and cardiac conditions. Multivariate analysis identified aldehydes (ethanal, octanal), ketones (acetone, butanone), and methanol that discriminated COVID-19 from other conditions. An unidentified-feature with significant predictive power for severity/death was isolated in Edinburgh, while heptanal was identified in Dortmund. Differentiation of patients with definite diagnosis (25 and 65) of COVID-19 from non-COVID-19 was possible with 80% and 81.5% accuracy in Edinburgh and Dortmund respectively (sensitivity/specificity 82.4%/75%; area-under-the-receiver- operator-characteristic [AUROC] 0.87 95% CI 0.67 to 1) and Dortmund (sensitivity / specificity 90%/80%; AUROC 0.91 95% CI 0.87 to 1).

Interpretation: These two studies independently indicate that patients with COVID-19 can be rapidly distinguished from patients with other conditions at first healthcare contact. The identity of the marker compounds is consistent with COVID-19 derangement of breath-biochemistry by ketosis, gastrointestinal effects, and inflammatory processes. Development and validation of this approach may allow rapid diagnosis of COVID-19 in the coming endemic flu seasons.

Funding: MR was supported by an NHS Research Scotland Career Researcher Clinician award. DMR was supported by the University of Edinburgh ref COV_29.
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http://dx.doi.org/10.1016/j.eclinm.2020.100609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585499PMC
December 2020

Breath markers for therapeutic radiation.

J Breath Res 2020 10 24;15(1):016004. Epub 2020 Oct 24.

Centre for Analytical Science, Chemistry, Loughborough University, Loughborough, United Kingdom.

Radiation dose is important in radiotherapy. Too little, and the treatment is not effective, too much causes radiation toxicity. A biochemical measurement of the effect of radiotherapy would be useful in personalisation of this treatment. This study evaluated changes in exhaled breath volatile organic compounds (VOC) associated with radiotherapy with thermal desorption gas chromatography mass-spectrometry followed by data processing and multivariate statistical analysis. Further the feasibility of adopting gas chromatography ion mobility spectrometry for radiotherapy point-of-care breath was assessed. A total of 62 participants provided 240 end-tidal 1 dm breath samples before radiotherapy and at 1, 3, and 6 h post-exposure, that were analysed by thermal-desorption/gas-chromatography/quadrupole mass-spectrometry. Data were registered by retention-index and mass-spectra before multivariate statistical analyses identified candidate markers. A panel of sulfur containing compounds (thio-VOC) were observed to increase in concentration over the 6 h following irradiation. 3-methylthiophene (80 ng.m to 790 ng.m) had the lowest abundance while 2-thiophenecarbaldehyde(380 ng.m to 3.85 μg.m) the highest; note, exhaled 2-thiophenecarbaldehyde has not been observed previously. The putative tumour metabolite 2,4-dimethyl-1-heptene concentration reduced by an average of 73% over the same time. Statistical scoring based on the signal intensities thio-VOC and 3-methylthiophene appears to reflect individuals' responses to radiation exposure from radiotherapy. The thio-VOC are hypothesised to derive from glutathione and Maillard-based reactions and these are of interest as they are associated with radio-sensitivity. Further studies with continuous monitoring are needed to define the development of the breath biochemistry response to irradiation and to determine the optimum time to monitor breath for radiotherapy markers. Consequently, a single 0.5 cm breath-sample gas chromatography-ion mobility approach was evaluated. The calibrated limit of detection for 3-methylthiophene was 10 μg.m with a lower limit of the detector's response estimated to be 210 fg.s; the potential for a point-of-care radiation exposure study exists.
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http://dx.doi.org/10.1088/1752-7163/aba816DOI Listing
October 2020

Development of a histopathology scoring system for the pulmonary complications of organophosphorus insecticide poisoning in a pig model.

PLoS One 2020 14;15(10):e0240563. Epub 2020 Oct 14.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556475PMC
December 2020

Development of a histopathology scoring system for the pulmonary complications of organophosphorus insecticide poisoning in a pig model.

PLoS One 2020 14;15(10):e0240563. Epub 2020 Oct 14.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556475PMC
December 2020

Development of a histopathology scoring system for the pulmonary complications of organophosphorus insecticide poisoning in a pig model.

PLoS One 2020 14;15(10):e0240563. Epub 2020 Oct 14.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556475PMC
December 2020

Development of a histopathology scoring system for the pulmonary complications of organophosphorus insecticide poisoning in a pig model.

PLoS One 2020 14;15(10):e0240563. Epub 2020 Oct 14.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556475PMC
December 2020

Development of a histopathology scoring system for the pulmonary complications of organophosphorus insecticide poisoning in a pig model.

PLoS One 2020 14;15(10):e0240563. Epub 2020 Oct 14.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556475PMC
December 2020

Does oxidative stress contribute to toxicity in acute organophosphorus poisoning? - a systematic review of the evidence.

Clin Toxicol (Phila) 2020 06 6;58(6):437-452. Epub 2019 Dec 6.

Department of Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science and Centre for Pesticide Suicide Prevention, University of Edinburgh, Edinburgh, UK.

Organophosphorus (OP) insecticide self-poisoning is a global problem, killing tens of thousands of people every year. Oxidative stress has been proposed to play a pathological role in OP poisoning, but whether it plays a direct toxic role is currently unclear. To determine whether there is consistent evidence of oxidative stress in patients with acute OP insecticide self-poisoning, and whether there are animal or human trial data that indicate that treatment of oxidative stress provides clinical benefit, which would suggest a direct toxic effect of oxidative stress. We conducted a systematic review using the PubMed, EMBASE and MEDLINE databases, and the Cochrane Database of Systematic reviews, based upon the following search terms and keywords: "organophosphate poisoning", "oxidative stress" and "antioxidant". All articles relevant to the aims of the study were included. Articles related to chronic OP poisoning, to use of medicines without antioxidant benefits, or to subjects other than oxidative stress were excluded. The search returned 256 results of which 17 studies were considered relevant and grouped under the following categories: observational human studies ( = 11) and intervention studies in animals ( = 4) and humans ( = 2). Oxidative damage to lipids and proteins was reported in all eleven human studies. Eight of nine studies reported variable increases in a weak marker of lipid peroxidation, malondialdehyde. In two case-control studies, erythrocyte membrane malondialdehyde concentrations were 380% and 160% higher in cases than controls, while plasma malondialdehyde concentrations were ∼63% higher in cases than controls in three case-control studies. In a prospective study, plasma malondialdehyde did not increase significantly from baseline in moderate or severely poisoned patients. Five case-control studies measured thiol residues as markers of protein oxidative damage and found variable changes after poisoning. No evidence of oxidative DNA damage was found in the one study that investigated it. After treatment with an antioxidant, all four studies showed an improvement in either markers of oxidative damage or antioxidant activity. One mouse study with a relatively low risk of bias showed that administration of acetylcysteine 200 mg/kg reduced malondialdehyde by 35% and increased survival by more than 60%. We found two small randomised controlled trials reporting the use of acetylcysteine as an adjunct to standard treatment in acute OP poisoning. The trials found that acetylcysteine reduced atropine requirements by 77% and 55%, but did not affect clinically relevant outcomes. Several studies showed evidence of OP insecticide-induced oxidative damage and antioxidant activity, suggesting that endogenous antioxidant defences are triggered in acute OP poisoning. However, the markers of lipid peroxidation used were weak, there was high inter-individual variability between studies in results and quality, and marked variation between the OP insecticides involved. Animal data provide some evidence that antioxidants alleviate adverse effects of acute poisoning, suggesting that oxidative stress may directly cause clinical harm. Acetylcysteine appeared beneficial in animal studies, but this could be mediated increased synthesis of the endogenous detoxifying agent, glutathione, rather than through a direct antioxidant effect. The two human clinical studies were too small to provide any clear evidence to support the use of acetylcysteine in OP poisoning. Further research into the mechanisms of oxidative stress in acute OP poisoning, combined with large unambiguous clinical trials of antioxidants, are required before they can be used routinely in treatment.
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http://dx.doi.org/10.1080/15563650.2019.1693589DOI Listing
June 2020

VOCCluster: Untargeted Metabolomics Feature Clustering Approach for Clinical Breath Gas Chromatography/Mass Spectrometry Data.

Anal Chem 2020 02 5;92(4):2937-2945. Epub 2020 Feb 5.

Pharmacology, Toxicology and Therapeutics Unit , University of Edinburgh , Edinburgh EH8 9YL , U.K.

Metabolic profiling of breath analysis involves processing, alignment, scaling, and clustering of thousands of features extracted from gas chromatography/mass spectrometry (GC/MS) data from hundreds of participants. The multistep data processing is complicated, operator error-prone, and time-consuming. Automated algorithmic clustering methods that are able to cluster features in a fast and reliable way are necessary. These accelerate metabolic profiling and discovery platforms for next-generation medical diagnostic tools. Our unsupervised clustering technique, VOCCluster, prototyped in Python, handles features of deconvolved GC/MS breath data. VOCCluster was created from a heuristic ontology based on the observation of experts undertaking data processing with a suite of software packages. VOCCluster identifies and clusters groups of volatile organic compounds (VOCs) from deconvolved GC/MS breath with similar mass spectra and retention index profiles. VOCCluster was used to cluster more than 15 000 features extracted from 74 GC/MS clinical breath samples obtained from participants with cancer before and after a radiation therapy. Results were evaluated against a panel of ground truth compounds and compared to other clustering methods (DBSCAN and OPTICS) that were used in previous metabolomics studies. VOCCluster was able to cluster those features into 1081 groups (including endogenous and exogenous compounds and instrumental artifacts) with an accuracy rate of 96% (±0.04 at 95% confidence interval).
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http://dx.doi.org/10.1021/acs.analchem.9b03084DOI Listing
February 2020

VOCCluster: Untargeted Metabolomics Feature Clustering Approach for Clinical Breath Gas Chromatography/Mass Spectrometry Data.

Anal Chem 2020 02 5;92(4):2937-2945. Epub 2020 Feb 5.

Pharmacology, Toxicology and Therapeutics Unit , University of Edinburgh , Edinburgh EH8 9YL , U.K.

Metabolic profiling of breath analysis involves processing, alignment, scaling, and clustering of thousands of features extracted from gas chromatography/mass spectrometry (GC/MS) data from hundreds of participants. The multistep data processing is complicated, operator error-prone, and time-consuming. Automated algorithmic clustering methods that are able to cluster features in a fast and reliable way are necessary. These accelerate metabolic profiling and discovery platforms for next-generation medical diagnostic tools. Our unsupervised clustering technique, VOCCluster, prototyped in Python, handles features of deconvolved GC/MS breath data. VOCCluster was created from a heuristic ontology based on the observation of experts undertaking data processing with a suite of software packages. VOCCluster identifies and clusters groups of volatile organic compounds (VOCs) from deconvolved GC/MS breath with similar mass spectra and retention index profiles. VOCCluster was used to cluster more than 15 000 features extracted from 74 GC/MS clinical breath samples obtained from participants with cancer before and after a radiation therapy. Results were evaluated against a panel of ground truth compounds and compared to other clustering methods (DBSCAN and OPTICS) that were used in previous metabolomics studies. VOCCluster was able to cluster those features into 1081 groups (including endogenous and exogenous compounds and instrumental artifacts) with an accuracy rate of 96% (±0.04 at 95% confidence interval).
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http://dx.doi.org/10.1021/acs.analchem.9b03084DOI Listing
February 2020

Response to the letter from Wong

EClinicalMedicine 2019 Sep 27;14:13. Epub 2019 Sep 27.

Medical Toxicology Centre, Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK.

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http://dx.doi.org/10.1016/j.eclinm.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833363PMC
September 2019

Response to the letter from Wong

EClinicalMedicine 2019 Sep 27;14:13. Epub 2019 Sep 27.

Medical Toxicology Centre, Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK.

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http://dx.doi.org/10.1016/j.eclinm.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833363PMC
September 2019

Efficacy of an organophosphorus hydrolase enzyme (OpdA) in human serum and minipig models of organophosphorus insecticide poisoning.

Clin Toxicol (Phila) 2020 05 27;58(5):397-405. Epub 2019 Aug 27.

CSIRO Biocatalysis & Synthetic Biology Team, Black Mountain Science and Innovation Park, Canberra, Australia.

Current therapeutic options for organophosphorus (OP) insecticide self-poisoning including atropine and oximes are inadequate and case fatality may exceed 20%. An OP hydrolase enzyme, OpdA, has been used for environmental cleansing of OP insecticides and prevented death in rat and non-human primate models of OP insecticide poisoning if given very quickly after exposure. We here tested OpdA's ability to break down OP insecticides in human serum and in clinically relevant minipig models of OP insecticide poisoning. Human serum was spiked with seven diverse WHO Class II OP insecticides (chlorpyrifos, quinalphos, diazinon, dimethoate, fenthion, phenthoate, and profenofos) and the effect of OpdA on degradation measured. The pharmacodynamic and clinical effects of OpdA treatment were studied in Gottingen minipigs orally poisoned with agricultural formulations of dimethoate EC40 or methyl parathion EC60; pharmacodynamic effects were also assessed in profenofos EC50-poisoned pigs. OpdA effectively hydrolysed OP insecticides in human serum, with rates varying from 856 (SD 44) down to 0.107 (SD 0.01) moles of substrate hydrolysed/mole of enzyme/sec (k) for quinalphos and phenthoate, respectively, although at rates 2-3 log orders less than found in buffered solution. It showed clinical benefit in minipig models, reducing the dose of noradrenaline required to sustain an adequate mean arterial pressure after dimethoate (mean 0.149 [SD 0.10] μg/kg/h vs. 1.07 [SD 0.77] μg/kg/h,  < .0001) and methyl parathion (mean 0.077 [SD 0.08] μg/kg/h vs. 0.707 [SD 0.49] μg/kg/h,  < .0001) poisoning. OpdA reduced blood OP insecticide concentration and acetylcholinesterase inhibition after poisoning by dimethoate, methyl parathion, and profenofos insecticides. incubation of OpdA in human serum showed hydrolysis of diverse OP insecticides, although at lower rates than found in buffer solutions. This activity results in clinical and pharmacodynamic efficacy against several OP insecticides. These results support the testing of OpdA in further animal models before considering human trials to determine whether it may become an urgently required novel therapeutic agent for OP insecticide self-poisoning.
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http://dx.doi.org/10.1080/15563650.2019.1655149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114914PMC
May 2020

Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning.

Clin Toxicol (Phila) 2020 03 7;58(3):190-200. Epub 2019 Aug 7.

Department of Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment. We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured. Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics. In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.
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http://dx.doi.org/10.1080/15563650.2019.1628969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034532PMC
March 2020

A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning.

Clin Toxicol (Phila) 2020 04 31;58(4):254-261. Epub 2019 Jul 31.

South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.

A common manifestation of organophosphorus insecticide self-poisoning is prolonged respiratory failure due to neuromuscular junction dysfunction and likely nicotinic receptor overstimulation. We aimed at collecting preliminary data on whether addition of the competitive nicotinic antagonist rocuronium to standard early therapy might be clinically feasible and associated with reduced duration of ventilation. A pilot three-arm dose-response phase II trial was set up to compare bolus doses of rocuronium bromide titrated to produce initial >95% or 50% inhibition of neuromuscular function, measured using acceleromyography, plus standard treatment, versus standard treatment alone. After attaining inhibition, patients receiving bolus rocuronium then received rocuronium infusions for a maximum of 120 h. Primary outcome was duration of intubation; secondary outcome was case fatality. Plasma butyrylcholinesterase activity was measured throughout the inpatient stay. Blood was analysed to confirm the organophosphorus insecticide ingested. Forty-five patients were randomised to receive: rocuronium to initially attain 95% inhibition (Roc>95,  = 15), rocuronium to initially attain 50% inhibition (Roc50,  = 14), or no rocuronium (control,  = 16). The most commonly ingested pesticide was profenofos (29/45, 64.4%). Butyrylcholinesterase activity remained severely inhibited for the duration of the study for most patients. Case fatality was 9/45 (20%) and similar across study arms: control 3/16 (18.8%), Roc50 4/14 (28.6%) and Roc>95 2/15 (13.3%) ( = .5842). When excluding patients who died, median [IQR] duration of intubation was significantly longer in the Roc50 (259.5 [176-385] h) and Roc>95 (226.8 [186-355] h) groups compared to controls (88.5 [47-160] h,  = .0162 and  = .0016, respectively). In this pilot dose-response study, we found no evidence that rocuronium in addition to standard therapy reduced the duration of intubation. It is possible that it worsened neuromuscular junction function. Further clinical research, including testing of shorter duration regimens, needs to be performed before nicotinic antagonists can be used in the clinical management of OP poisoning.
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http://dx.doi.org/10.1080/15563650.2019.1643467DOI Listing
April 2020

Consensus statements on the approach to patients in a methanol poisoning outbreak.

Clin Toxicol (Phila) 2019 12 22;57(12):1129-1136. Epub 2019 Jul 22.

The Norwegian CBRNE Centre of Medicine, Department of Acute Medicine, Oslo University Hospital, Oslo, Norway.

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. 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. 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. 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. 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.
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http://dx.doi.org/10.1080/15563650.2019.1636992DOI Listing
December 2019

Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.

EClinicalMedicine 2019 May-Jun;11:11-17. Epub 2019 May 2.

Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, UK.

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.
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http://dx.doi.org/10.1016/j.eclinm.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610779PMC
May 2019

Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.

EClinicalMedicine 2019 May-Jun;11:11-17. Epub 2019 May 2.

Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, UK.

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.
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http://dx.doi.org/10.1016/j.eclinm.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610779PMC
May 2019