Toxicology

To the Editor: Chan and colleagues1 recently reported a case of putative e‐cigarette or vaping product use‐associated lung injury (EVALI) in a 15 year‐old girl who was a low level user of vaporised nicotine (without adulterants). We believe that, rather than EVALI, her presentation is better explained by urosepsis‐related acute lung injury. Current guidance from the United States Centers for Disease Control and Prevention (CDC)2 emphasises the role of adulterants, especially vitamin E acetate, in EVALI. In a US study completed before the widespread adoption of e‐cigarettes, the incidence of acute lung injury in 15–19‐year‐olds was 16 per 100 000 patient‐years, with many cases stemming from non‐pulmonary sepsis.3 In February 2020, only 2807 cases of vaping lung injury had been reported in the US, representing an incidence of well under one case per 100 000 patient‐years.1 Given these rates, as well as the patient’s prominent dysuria, polyuria, back pain and worsening pyrexia, we think urosepsis triggered the acute lung injury in this case. The authors say that sepsis was ruled out due to negative blood and urine cultures. However, if samples were collected after the initiation of antibiotics, false negative cultures are common in sepsis. The patient met the accepted criteria for sepsis, with suspected infection, a systemic inflammatory response syndrome and acute end‐organ failure,4 and was treated for this condition with antibiotics and corticosteroids for the acute lung injury. The CDC criteria for EVALI emphasise that the diagnosis should only be made where there is “no evidence in [the] medical record of alternative plausible diagnoses”.5 Dysuria, polyuria and back pain are not known symptoms of EVALI, and the authors have not explained how EVALI could account for this aspect of her presentation nor why these symptoms preceded the respiratory symptoms. In conclusion, the evidence to support a diagnosis of EVALI is insufficient in this case, and an alternative explanation is far more likely. Therefore, this case report should not be regarded as evidence for a case of EVALI occurring in Australia.

Cameron RL McKenzie · Joshua Davis · Adrian J Dunlop

Suicide prevention requires ensuring that social media are responsible and accountable, and that poisoning surveillance systems are adequately supported

Bridin P Murnion · Darren M Roberts

Knowledge about the composition and physiological effects of e-liquids is essential for assessing their effects on health

Ira N Advani · Mario Perez · Laura E Crotty Alexander

A 15-year-old girl presented with a 4-day history of dysuria, urinary frequency and back pain followed by 2 days of vomiting and rigors

Betty S Chan · Alexander Kiss · Nathan McIntosh · Vicky Sheppeard · Andrew H Dawson

A public health unit in Sydney was notified of two unrelated patients who presented on the previous day with methaemoglobinaemia

Caitlin O’Neill · Zeina Najjar · Andrew Ingleton · Alan Edwards · Andrew Dawson · Leena Gupta

Collaboration and education are critical to understanding and managing this mounting public health problem

Elliot Freeman · Stuart K Roberts

To the Editor: Published evidence recognises that the recreational misuse of nitrous oxide (N2O) can be associated with vitamin B12 deficiency and subacute combined degeneration of the spinal cord.1 Misuse of N2O is increasing,2 with canisters (known as “nangs” or “whippits”) readily available for legal purchase in convenience stores and online ostensibly for the purpose of whipping cream. In recent years, an increase in the number of emergency presentations and acute hospital admissions related to N2O misuse has been recorded in Australia.3,4 We have also seen an increase in the number of patients requiring specialist multidisciplinary rehabilitation for severe impairments, including proprioceptive deficits, ataxia, disabling lower limb weakness and persistent gait abnormalities. Over recent years, a growing number of patients have been admitted to our inpatient metropolitan Sydney rehabilitation unit with serious disabilities related to N2O misuse. In line with published reports, our experience confirmed that patients are often university students (typically aged < 30 years).3,4 As acute medical specialties recognise the significance of these presentations,3,4 we highlight that the resulting disabilities can remain for months or years at functional, vocational and emotional levels, and many will be lifelong. This will impose a significant disability burden that will require ongoing management by specialist rehabilitation and disability services and will have an impact on the wider health care utilisation and cost. As long as N2O remains legal and accessible and is perceived by many as seemingly innocuous, users will remain largely unaware of the severity and risk presented by its long term use. Compared with messaging surrounding other “hard drugs”, most of the literature and the public health messaging in Australia do not appear to emphasise the potential for catastrophic, permanent injury associated with the misuse of N2O. Given the emerging disability burden resulting from recreational N2O misuse, we recommend enhancing existing public awareness campaigns.5 We suggest that educational resources place greater emphasis on the potential for serious, long term impairments and that education campaigns be targeted to most susceptible people via tertiary and/or secondary education establishments. Widespread restrictions on N2O purchase should also be considered. Such measures may help prevent permanent and devastating disabilities resulting from the misuse of this easily accessible substance.

Simon Mosalski · Anne Tanner · Christine T Shiner

Objective: To compare the characteristics and outcomes of drug‐induced liver injury (DILI) caused by paracetamol and non‐paracetamol medications, particularly herbal and dietary supplements. Design: Retrospective electronic medical record data analysis. Setting, participants: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009–2020. Main outcome measures: 90‐day transplant‐free survival; drugs implicated as causal agents in DILI. Results: A total of 115 patients with paracetamol‐related DILI and 69 with non‐paracetamol DILI were admitted to our centre. The most frequently implicated non‐paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti‐tuberculosis medications (six, 9%), and anti‐cancer medications (five, 7%). The number of non‐paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009–11 to 9 of 19 (47%) during 2018–20 (linear trend: P = 0.011). Despite higher median baseline model for end‐stage liver disease (MELD) scores, 90‐day transplant‐free survival for patients with paracetamol‐related DILI was higher than for patients with non‐paracetamol DILI (86%; 95% CI, 79–93% v 71%; 95% CI, 60–82%) and herbal and dietary supplement‐related cases (59%; 95% CI, 34–85%). MELD score was an independent predictor of poorer 90‐day transplant‐free survival in both paracetamol‐related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09–3.74) and non‐paracetamol DILI (aHR, 1.24; 95% CI, 1.14–1.36). Conclusion: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety‐day transplant‐free survival for patients with non‐paracetamol DILI, especially those with supplement‐related DILI, is poorer than for those with paracetamol‐related DILI.

Emily Nash · Abdul‐Hamid Sabih · John Chetwood · Georgette Wood · Keval Pandya · Terry Yip · Avik Majumdar · Geoffrey W McCaughan · Simone I Strasser · Ken Liu

To the Editor: We identified a geographic and temporal cluster of four patients with drug poisoning occurring within one week in February 2020 from two addresses less than 1 km apart. All patients presented with typical features of opiate poisoning but had no history of opiate use. There was one death, with the three other cases having significant morbidity, which required escalating bolus doses of naloxone. Rapid sample analysis by the New South Wales Pathology Forensic and Analytical Science Service (FASS) using liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC‐Q‐TOF‐MS) found acetyl fentanyl — a synthetic fentanyl non‐pharmaceutical designer drug — in all cases within 3 days. The identification and subsequent response were coordinated by the Prescription, Recreational and Illicit Substance Evaluation (PRISE) program, a collaboration between the NSW Ministry of Health, the NSW Poisons Information Centre and FASS. The analytical confirmation and public health response, involving data collection, risk assessment with a health expert committee and customised clinical and public health response, occurred within 15 days of notification to PRISE. Two further cases were identified by the NSW Ministry of Health in other hospitals in the 2 months prior and 2 months subsequent to our cases. In October 2020, a further cluster of five cases occurred in regional NSW. Ethics approval was granted by the Sydney Local Health District Research Ethics and Governance Office, HREC 2020/ETH01380. The presence of fentanyl analogues as an adulterant in recreational drugs has become common globally but only one case of poisoning by acetyl fentanyl has been reported in the literature in Australia.1,2 This poses a significant risk to unassuming users, particularly users whose primary recreational use is stimulants, as they are likely to be opioid naïve and have worse clinical outcomes. Cases of toxicity from fentanyl and its analogues are often under‐reported because of issues with detection. Synthetic opioids do not test positive on urine drug screen immunoassays; mass spectrometry is required to confirm the diagnosis.3 Acetyl fentanyl is a non‐pharmaceutical designer analogue of fentanyl first described in 2013 after an outbreak with reported mortality in Rhode Island.4 Pharmacokinetic data for acetyl fentanyl are limited, but the drug is 15 times more potent than heroin and has an ED50 (median effective dose) and LD50 (median lethal dose) ten times narrower than morphine.5 The purpose of PRISE is to detect atypical substances in the community, focusing on presentations that are unexpected, severe and/or clusters, and coordinate an appropriate response. Rapid detection and toxicosurveillance allowed for prompt dissemination of information to clinicians and the public. Information directed to user groups is a particularly important harm minimisation strategy. Rapid detection and early dissemination of information may have limited further outbreaks. Clinicians should be informed that atypical presentations in recreational drug use may be due to substitution or contamination by other substances. Notification of cases to Poisons Information Centres can provide treatment advice and facilitate rapid identification and response by providing an access pathway, such as the NSW Ministry of Health PRISE Program.

Varan Perananthan · Chris Tremonti · Emily Nash · Thanjira Jiranantakan · Andrew H Dawson

A 74-year-old Vietnamese man presented with a 1-year history of pruritic nodules on his feet

Kajal Patel · Alexander Gin · Laura Scardamaglia

A 52-year-old fireman presented to the hospital after being bitten by a white snake when demonstrating a snake handling technique to his colleagues

Kuang‐Ting Chen · Chien‐Ming Chiu

To the Editor: We read the perspective by Weinstein and colleagues1 with interest and agree that treatment of snake envenoming in Australia is complex, and that clinicians should seek expert advice in cases of severe or unusual envenoming. There is 24‐hour specialist clinical toxicologist support available through the national Poisons Information Centre network (13 11 26), which takes 300 calls annually regarding snakebite. However, we are concerned that the authors argue for just one non‐evidenced‐based solution — higher doses of antivenom — despite the extensive evidence that this historical approach does not lead to better outcomes. They suggest that the reduction in antivenom doses is based on a study of snakebite data in Australia from 2005 to 2015,2 which concluded that as “the usual antivenom dose for all major snake groups has decreased to one vial, with no evidence of adverse consequences, this approach should be retained” (emphasis added).2 However, the evidence supporting the move to lower doses of antivenom was based on a series of around 15 earlier studies.2 Serial measurement of venom concentrations using enzyme immunoassays in patients with snake envenoming demonstrated complete neutralisation after any dose,2 and the time course of recovery was unaltered by antivenom dose. The evidence suggests benefits from earlier antivenom but not from higher doses.3 Weinstein and colleagues cite a study by O'Leary and colleagues4 when they state that using “samples from rodents injected with venom … inaccurately determines a true neutralising dose”. However, the cited study measured venom–antivenom complexes in vitro to determine the antivenom concentration at which every venom molecule is bound to at least one antivenom molecule, as a measure of efficacy.4 It showed that this was similar to the manufacturer's original recommendation of a dose of a single vial of antivenom. Weinstein and colleagues criticise the use of data from the large multicentre prospective cohort, the Australian Snakebite Project, which reports both clinical and laboratory outcomes and measures venom concentrations. They provide no citations to support their contentions, other than single cases and opinion (often citing their own previous views). A coroner's case in which a person died after three vials of antivenom is strangely cited as highlighting concerns that a single vial of antivenom is insufficient. They suggest two vials may be sufficient, or even larger doses, but offer no research or studies to support this, and no guidance as to when larger doses are required. They also do not provide a useful or practical alternative approach to the treatment of snake envenoming. Current national evidence‐based guidelines and Poisons Information Centres recommend that one vial of brown snake antivenom and one vial of tiger snake antivenom be given as soon as possible in most snake envenoming cases in Australia.5 This ensures that the most common snakes are covered, as snake venom detection kits are unreliable.2 It also means an equivalent of two vials of antivenom is administered, because Australian “monovalent” antivenoms are in fact polyvalent.6 Evidence‐based guidelines continuously evolve, and we believe the key to better outcomes is early identification of envenomed patients and prompt access to the latest evidence‐based advice by consulting a clinical toxicologist through the Poisons Information Centre.

Geoffrey K Isbister · Nicholas A Buckley

To the Editor: Rising obesity rates in high income countries have resulted in a growing demand for weight‐loss products.1 Unfortunately, drugs that increase energy expenditure often have severe adverse effects. 2,4‐Dinitrophenol (DNP) uncouples oxidative phosphorylation, inducing a hyper‐metabolic state. It was first used for weight loss in the 1930s but was banned due to deaths.2 It has recently had a resurgence in popularity in the body building/body sculpting arena as a “fat burner” and “pre‐event shredder”, and is available online and as an undeclared ingredient in supplements.1 DNP was up‐scheduled in Australia in 2017 to Schedule 10 (“substances of such danger to health as to warrant prohibition of sale, supply and use”).3 We used data from the New South Wales Poisons Information Centre (NSWPIC) and the National Coronial Information System (NCIS) to evaluate effects of up‐scheduling. Ethics approval was granted from the Sydney Children's Hospitals Network (LNR/16/SCHN/44) and from the Victorian Department of Justice (CF/15/18367) human research ethics committees. There were 24 DNP exposures reported to NSWPIC between 2004 and 2018, with an increasing trend (Box). Most patients (71%, n = 17) were male, 83% (n = 20) were adults aged 20–74 years, and 92% (n = 22) were in hospital or were referred to hospital by NSWPIC. The NSWPIC database showed one death — an adult man who had a cardiac arrest after taking four DNP capsules — and NCIS recorded three more deaths from DNP. All deaths occurred since 2015, with two occurring since the 2017 rescheduling. Despite up‐scheduling, we have identified rapidly increasing harms from DNP, which suggest a resurgence of DNP use. Increasing use and deaths have also been reported in the United Kingdom4 and the United States.5 This highlights the need for urgent action by state and federal law enforcement agencies and awareness campaigns targeting high risk groups. It is important to note that the Therapeutic Goods Administration makes scheduling changes but does not enforce non‐medicinal product restrictions, which is the role of police and Fair Trading. It is likely that DNP is frequently obtained online and often disguised for shipping (eg, labelled as turmeric), thus complicating detection.1 Increased incoming mail screening and awareness and education at gyms may be an option to restrain the use of DNP. Medical practitioners should warn patients of the dangers of illicit weight‐loss supplements. Box – Time trends in 2,4‐dinitrophenol exposures reported to the New South Wales Poisons Information Centre (NSWPIC) in 2004–2018. Up‐scheduling to Schedule 10 was announced in September 2016 and implemented in February 2017. The timing of deaths is censored due to low numbers; however, all deaths occurred since 2015, including two since the 2017 scheduling

Rose Cairns · Jacques Raubenheimer · Jared A Brown · Kylie McArdle · Nicholas A Buckley

Ongoing population- level strategies are needed to further reduce lead exposure

Mark P Taylor · Bruce P Lanphear

To the Editor: Currie and colleagues highlight the important topic of animal vaccines as occupational hazards and the need for improved clinician advice to manage patients safely.1 The article title describes “high pressure” injections, yet the oil emulsion vaccine of most concern, against ovine Johne's disease, is delivered via a standard needle injection. All accidental mineral oil injections are of concern (as are all high pressure injections). Appropriate identification and advice can be obtained by contacting a Poisons Information Centre (PIC). This was not discussed by Currie and colleagues, although it was recommended in a reference they cited.2 Unlike some vaccine manufacturers, the publicly funded PIC service provides 24‐hour emergency medical advice (131 126) for the public and health professionals. PICs access the Australian National Poisons Register, which allows rapid identification of the dozens of oil‐containing vaccines. Currently in Australia, oil adjuvant vaccines lack clear labelling to identify the presence of oil on the front packaging. Increased prominence would aid recognition, similar to initiatives for active ingredients within human therapeutic products. Indeed, review of the unscheduled status of most animal vaccines is required as they possess a risk assessment profile at odds with the Scheduling Policy Framework.3 Improved pharmacovigilance of veterinary products (and agrochemicals) is urgently required, particularly regarding the risks posed to human health. Unpublished analysis of data from Australian PIC annual reports identified about 2000 cases annually of human exposures to veterinary pharmaceuticals. We recently reported on human exposures to veterinary pharmaceuticals from New South Wales PIC calls from 2014 to 2016, with 30 exposures to Johne's disease vaccine alone.4 Collectively, PICs have over 20 times the number of reports to the designated authority for post‐market surveillance; the Australian Adverse Experience Reporting Program run by the Australian Pesticides and Veterinary Medicines Authority received 91 reports for human effects from registered veterinary medicines and agricultural chemical products combined in 2015.5 There is an opportunity for PICs to be engaged more efficiently in surveillance, which would allow the collection of additional information through follow‐up calls to understand risk factors, evaluate outcomes and recommend interventions to prevent future injuries. This would facilitate improvements in management of human exposures to veterinary pharmaceuticals to protect occupational health.

Jared A Brown · Nicholas A Buckley · Rose Cairns · Claire E Wylie

Essential oil exposures are frequent in Australia, and more than half involve children

Kristenbella AYR Lee · Joanna E Harnett · Rose Cairns

Since the publication of the previous guidelines in 2015, further evidence has emerged that has led to a change in management of paracetamol poisoning

Angela L Chiew · David Reith · Adam Pomerleau · Anselm Wong · Katherine Z Isoardi · Jessamine Soderstrom · Nicholas A Buckley

The decline in codeine-related presentations was not associated with a rise in alternative opioid-related presentations

Keith Harris · Andrew Jiang · Robert Knoeckel · Katherine Z Isoardi

Despite harm reduction being a pillar of the Australian National Drug Strategy, current governments are shying away from pill-testing as a viable strategy

Jody Morgan · Alison Jones

To the Editor: Recreational misuse of nitrous oxide remains a significant public health problem,1 sustained in part by the ready availability online of gas‐containing canisters intended for use in the catering industry. Known as “nangs” or “whippits” and usually purchased in bulk, each canister contains 8 g of nitrous oxide. When inhaled, this gives a seconds‐long “high”, which is typically prolonged by using several “nangs” in a single session. Some individuals can consume hundreds each day. Prolonged exposure to nitrous oxide leads to the oxidisation of vitamin B12, rendering it unusable in key enzymatic reactions necessary for normal myelin synthesis.2 Over time, this leads to a potentially devastating neuropsychiatric syndrome that commonly presents with ataxia.3 Notably, the culprit shortage of vitamin B12 is a qualitative one and can be purely so, meaning that marked clinical deficits emerge in the presence of serum B12 levels that appear normal on standard laboratory assays. Furthermore, with continued exposure to nitrous oxide, these deficits will respond poorly to vitamin B12 supplementation. In a year‐long clinical audit at Royal Prince Alfred Hospital (2017–2018), seven nitrous oxide users, all aged between 20 and 30 years, presented with ataxia that ranged from mild to severe (Box 1). Most patients also had psychiatric symptoms. Nearly every patient estimated using 100 or more canisters of nitrous oxide per day in the months before being seen. Four patients also reported engaging in B12 supplementation (both oral and parenteral), aiming to circumvent the harmful sequelae of prolonged nitrous oxide misuse. Laboratory studies showed that all seven patients had accumulated homocysteine, as is usually seen when vitamin B12 is in short supply in the body.2 Individuals who reported taking supplements had serum B12 levels that were either normal or in excess of normal, implicating a qualitative deficiency of metabolically useful B12. Evidence of demyelination was seen on spinal cord imaging in six patients, including all those who used supplements, with the “inverted V” sign4 visible on T2‐weighted magnetic resonance imaging sequences (Box 2). Despite treatment according to best practice guidelines, all patients left hospital with persistent symptoms, and most were unable to walk or to attend to their bodily needs without the assistance of family members (modified Rankin score, 4). Sadly, one of the least affected individuals re‐presented to hospital with worsened symptoms because of continued nitrous oxide misuse. At every opportunity nitrous oxide users should be reminded of the futility of B12 supplementation, as one of many reasons why they should choose to avoid this profoundly destructive drug. Box 1 – Patients presenting with symptoms due to nitrous oxide misuse Age (years) Sex Canister use Duration of use B12 supplementation Ataxia severity* Psychiatric symptoms† Homocysteine level Serum B12 (active) MRI: “inverted V” sign‡ mRS: Day 1 mRS: discharge 20 Female 250/day 1 year No Severe Yes High Low (low) Yes 4 4 30 Male 60/day 1 year No Moderate Yes High Low (low) Yes 1 1 30 Male 100/day 6 months No Mild No High Low (normal) No 1 1 21 Male 200/day 1 year Yes Severe Yes High Normal (normal) Yes 4 4 23 Female 300/day 2 months Yes Severe Yes High Normal (high) Yes 4 4 23 Female 200/day 2 months Yes Severe Yes High High (high) Yes 4 4 28 Male 300/day 1 year Yes Mild No High Normal (normal) Yes 1 1 MRI = magnetic resonance imaging; mRS = modified Rankin score of neurological disability. * Ataxia: mild = visible gait disturbance; moderate = frequent falls; severe = inability to walk without assistance. † Psychiatric symptoms included mood disturbance, memory impairment and psychosis. ‡ MRI findings: “inverted V” sign on T2‐weighted MRI spinal cord imaging (Box 2). mRS: 0 = no symptoms; 1 = no significant disability despite symptoms; 2 = slight disability; 3 = moderate disability; 4 = moderately severe disability, unable to walk or attend to bodily needs without assistance; 5 = severe disability, bedridden; 6 = dead. Box 2 – T2‐weighted magnetic resonance imaging sequence showing “inverted V” sign, indicating the presence of dorsal column demyelination

Christopher Blair · Chris Tremonti · Leon Edwards · Paul S Haber · G Michael Halmagyi

Paracetamol remains one of the drugs most frequently implicated in deliberate self- poisoning overdoses in Australia

Andis Graudins · Anselm Wong

The availability of paracetamol needs to be restricted to stem the increasing number of overdoses

Rose Cairns · Jared A Brown · Claire E Wylie · Andrew H Dawson · Geoffrey K Isbister · Nicholas A Buckley