Methoxyflurane Toxicity: Historical Determination and Lessons For

REVIEW ARTICLE

Methoxyflurane toxicity: historical determination and lessons for modern patient and occupational exposure Serah J Allison, Paul D Docherty, Dirk Pons, J Geoffrey Chase

ABSTRACT AIM: Historically methoxyflurane was used for anaesthesia. Evidence of nephrotoxicity led to abandonment of this application. Subsequently, methoxyflurane, in lower doses, has re-emerged as an analgesic agent, typically used via the Penthrox inhaler in the ambulance setting. We review the literature to consider patient and occupational risks for methoxyflurane. METHOD: Articles were located via PubMed, ScienceDirect, Google Scholar, Anesthesiology journal and the Cochrane Library. RESULTS: Early studies investigated pharmacokinetics and considered the resulting effects to pose minimal risk. Pre-clinical rodent studies utilised a species not vulnerable to the nephrotoxic fluoride metabolite of methoxyflurane, so nephrotoxicity was not identified until almost a decade after its introduction, and was initially met with scepticism. Further evidence of nephrotoxicity led to abandonment of methoxyflurane use for anaesthesia. Subsequent research suggested there are additional risks potentially relevant to recurrent patient or occupational exposure. Specifically, greater than expected fluoride production after repeated low-dose exposure, increased fluoride production due to medication-caused hepatic enzyme induction, fluoride deposition in bone potentially acting as a slow-release fluoride compartment, which suggests a risk of skeletal fluorosis, and hepatotoxicity. Gestational risk is unclear. CONCLUSIONS: Methoxyflurane poses a potentially substantial health risk in high (anaesthetic) doses, and there are a number of pathways whereby repeated exposure to methoxyflurane in lower doses may pose a risk. Single analgesic doses in modern use generally appear safe for patients. However, the safety of recurrent patient or occupational healthcare-worker exposure has not been confirmed, and merits further investigation.

ethoxyflurane is a volatile organic Renal failure was identified in some patients liquid,1 a fluorinated hydrocarbon, anaesthetised with methoxyflurane.10,11 Mthat vaporises readily2 and has Methoxyflurane is estimated to have been historically been used as an anaesthetic responsible for clinical nephrotoxicity in agent from 1958.3 A decade after discovery, approximately 100 patients worldwide, and methoxyflurane was used frequently, mak- death in approximately 20 cases, before its ing up 10% of annual purchases of inhaled near universal discontinuation since the anaesthetics in the USA.3 Sedative and 1970s.12 4,5 analgesic effects were described, which However, methoxyflurane has been prompted an extension of its use outside reintroduced into the contemporary arma- of the operating room for indications such mentarium as an analgesic for emergency or 6–8 9 as labour pain and dressing changes. short procedures. Australasia,13,14 Europe,15

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Canada,16 South Africa17 and, more recently, the following sections of this paper. Only numerous other countries18 allow methoxy- English-language material was reviewed. flurane administration via the Penthrox Reference sections of relevant articles inhaler. This device has been manufactured were examined to identify further relevant by Medical Developments International material for inclusion. Documents included (formerly Medical Developments Australia) in this review range across case reports, since 1978, specifically for analgesic use,19 animal and human prospective observa- and Penthrox is currently the only widely tional studies, experimental trials and other commercially available methoxyflurane literature reviews. administration device. The Penthrox inhaler is a tube into which the methoxyflurane Historic use of medication is poured to soak a wick, with a whistle-like mouthpiece through which the methoxyflurane patient inhales methoxyflurane vapour.20 Early published animal studies were The device features a ‘dilution hole’, which conducted on dogs and determined allows the patient to control the concen- that, with regards to incidence of lethal tration delivered18,21 and can incorporate arrhythmias,29,30 electrolyte disturbances an activated carbon (AC) filter through or liver dysfunction,31 methoxyflurane which the patient is encouraged to exhale. compared favourably with alternative Methoxyflurane has an estimated atmo- inhaled anaesthetic agents. Reports were spheric lifetime of 54 days and a 100-year conflicted with regards to cardiovascular global warming potential four times that and respiratory effects,31–33 although these of carbon dioxide, although it compares risks are not generally discussed in later favourably in that regard against other investigations. Researchers of canine inhalational anaesthetics.22 Administration models noted a slow recovery from anaes- of methoxyflurane via the Penthrox inhaler thesia, with the dogs appearing sluggish has been demonstrated as more effective at until the next day.31 Anaesthetised human relieving pain than placebos and alternative subjects also exhibited slow onset and analgesia in a variety of settings including emergence from anaesthesia.4 Arterial pre-hospital,23,24 clinic,25 and emergency methoxyflurane was approximately double department.26,27 the venous level during early anaesthesia We reviewed the historic literature to (2 to 15 minutes), equilibrating after 100 34 describe the evolution in the understanding minutes. This suggests ready uptake into of the health risks associated with anaes- tissue, confirming laboratory studies that thetic methoxyflurane. Thus we identify had suggested methoxyflurane would have the potential patient and occupational risks high solubility in blood and high uptake in 28 of methoxyflurane in the modern setting, adipose tissue. Methoxyflurane concen- in order to help guide policymakers and tration in subcutaneous fat rose slowly, clinicians who might consider making peaking 5–8 hours after commencement methoxyflurane available in their clinical of anaesthesia and remaining elevated 34 environments. beyond 30 hours after cessation. Overall, these studies suggested that methoxyflurane had a large volume of distribution and Search strategy consequent delayed equilibration between To gain a comprehensive overview of the compartments. historical literature, we sought to locate As methoxyflurane was a new anaes- research and commentary on methoxy- thetic agent, a significant proportion of the flurane administration in any setting for historical animal and human research was any indication by any method other than dedicated to investigating the rate of onset the modern Penthrox inhaler. Articles were of and emergence from anaesthesia,4,31,35,36 located using PubMed, ScienceDirect and the concentration required to achieve Google Scholar and by searching the Anes- adequate anaesthesia1,20,37 and the threshold thesiology journal and Cochrane Library of sedation.36 Early medication safety investi- databases with the term ‘methoxyflurane’. gations included effects on respiration2,4,31,35,38 Articles were selected based on rele- and cardiovascular stability,4,35,38,39 with vance to health effects, as categorised in

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methoxyflurane demonstrating reasonable of methoxyflurane into fluoride. Only safety with regards to these concerns. Fischer 344 rats demonstrated biochemical Although many of these historical anaes- and pathological renal changes following thesia studies might not meet modern methoxyflurane anaesthesia.51 In susceptible scientific standards due to the poor quality rats, elevated fluoride was associated with and quantity of data, examination of this dose-related high-output renal failure.43,52,53 literature nonetheless allows identification Therefore, due to the use of a non-sus- and extraction of worthwhile findings. ceptible rat type, preclinical trials had Fluoride-associated health effects unfortunately failed to identify the nephrotoxic potential of methoxyflurane. Methoxyflurane is metabolised by lung and liver tissue into a variety of products,40 Early observations of anaesthetised including fluoride and oxalic acid.20 human subjects also suggested no renal Some medications are known to increase toxicity.35 Nephrotoxicity in clinical use (‘induce’) metabolism pathways in the liver. was suggested by a 1966 case series of 17 Pre-treatment of rat hepatic microsomes patients,10 although unfortunately this first in vitro with phenobarbital, an anticon- report of human methoxyflurane anaes- vulsant therapy,41 caused a 7- to 10-fold thesia-associated nephrotoxicity was met increase in fluoride production in response with scepticism.12 It was a further five to methoxyflurane exposure.40,42 Similarly, years until further incidents of high-output in vivo pre-treatment of rats with pheno- failure were described,54–56 at which time a barbital increased methoxyflurane uptake relationship was identified between serum and fluoride production.43–45 A patient fluoride following methoxyflurane anaes- who had secobarbital prior to receiving thesia and the degree of renal toxicity. In methoxyflurane had peak serum fluoride 1973, strong correlations were identified that was three times that of patients who between methoxyflurane anaesthetic dose, did not receive secobarbital, and the patient increased serum inorganic fluoride concen- subsequently exhibited a decrease in renal tration and the degree of nephrotoxicity,11 function. This suggests increased risk of with further biochemical evidence of renal elevated serum fluoride, and possibly dysfunction emerging the following year increased susceptibility to health effects from patients receiving methoxyflurane associated with elevated fluoride levels, for anaesthesia.39,60 Two types of methoxy- exposed individuals concomitantly using flurane-induced renal pathology were medications that affect methoxyflurane identified: low output failure exhibited metabolism. calcium oxalate crystals in the tubules of the renal cortex and the collecting tubules Prolonged exposure to methoxyflurane of the medulla, with cortex tubular inflam- also causes enzyme induction, altering matory changes;61 whereas high output methoxyflurane metabolism.46 Rat hepatic failure exhibited tubular necrosis,51 wide- microsomes in vitro exposed to low-dose spread tubular dilatation and calcium and methoxyflurane produced proportionally calcium oxalate crystals in the tubular more fluoride than with high-dose epithelium.62 In combination, these exposure,42 and the susceptible Fischer 344 findings provided “compelling scientific rat strain demonstrated prolonged low-dose evidence [which] led practitioners and exposure also resulting in increased fluoride the manufacturer to abandon methoxy- production.47 This nonlinear response flurane.”12 Methoxyflurane administration suggests extrapolation from single high-dose to human patients for both anaesthesia outcomes to repeated low-dose use or occu- and analgesia was generally discontinued pational exposure 48–50 cannot be undertaken around 1974.19,63 with simple linear assumptions. There appears to be inter-person variation Renal toxicity in response to serum fluoride resulting from Although preclinical trials conducted in methoxyflurane, with some studies demon- Sprague-Dawley rats found no evidence of strating serum fluoride levels above the 51 nephrotoxicity, over a decade later it was toxic threshold11 without identifying renal determined that different rat types exhibited dysfunction.65,66 This variability may be different degrees of hepatic conversion partially explained by additive nephrotox-

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icity from medications, such as tetracycline skeletal fluorosis risk,80,81 suggesting the or other antibiotics,67,68 that can alter typical potential for skeletal fluorosis in exposed methoxyflurane dose-responses, although persons or the foetuses of exposed pregnant variable susceptibility to the effects of persons. However, the quantity of risk is fluoride and/or other metabolites is also a unclear in the context of modern analgesic possibility. use and occupational exposure, and further Interestingly, the renal toxic serum study is needed. fluoride threshold is not necessarily Gestational effects consistent across fluorinated anaesthetic In rats, recurrent subanaesthetic methoxy- 71–73 agents. For example, sevoflurane, which flurane exposure does not appear to undergoes minimal renal defluorination significantly alter foetal loss, but it does compared with methoxyflurane, some- decrease foetal weight.82 In mice, recurrent times produces serum fluoride ≥50µmol/L low-dose exposure to methoxyflurane 71 without apparent renal dysfunction. provokes increased rates of foetal devel- Transient changes in renal function have opment variation, and frequent higher-dose been observed in some studies using rats (though still subanaesthetic) exposure and human subjects following sevoflurane causes decreased birth weight and increased anaesthesia. The renal changes are believed rates of death in utero.79 These findings to be due to a different compound that is suggest that there are potentially gestational formed by sevoflurane and unrelated to effects consequent of recurrent maternal 74 fluoride formation. However, differences exposure, although large human cohort in renal function following sevoflurane studies are needed to examine whether such are not statistically significant on meta- effects occur with modern use. analysis.75 It has been suggested that Women in labour receiving methoxy- the more pronounced renal metabolism flurane analgesia during labour produce exhibited by methoxyflurane is responsible fluoride that appears in their urine and for its comparatively greater renal toxic the urine of their newborns.83,84 The effect.70,71 Direct comparison between agents biological effect of maternal methoxy- is challenging. flurane analgesia on newborns has not Fluoride bone deposition been studied in humans. Likewise, human A 1973 study of mice and Wistar rats antenatal methoxyflurane use does not found 4.7–6.7% of the fluoride in methoxy- appear to have been explicitly studied.85 flurane was deposited in bone. Washout Furthermore, there appears to be an of bone fluoride was slow, returning to absence of research of the occupational control after 40–60 days. In concert with the safety of pregnant healthcare workers findings of enzyme induction studies,40,42 exposed to methoxyflurane. phenobarbital increased the amount of Hepatotoxicity fluoride deposited in bone.77 Subsequent Researchers in 1962 noted no clinical research confirmed fluoride deposition in indications of liver toxicity in two patient rat bone following methoxyflurane anaes- cohorts anaesthetised with methoxy- thesia, with preferential deposition in foetal flurane.35,38 However, subsequent case bone in the third trimester of pregnancy.78 reports of hepatitis emerged, which were Similarly, recurrent high-dose exposure associated with anaesthesia,86 delivery7,8 appears to cause decreased foetal ossifi- and medication abuse.87 The majority cation and minor skeletal abnormalities in of these reports occurred as or after mice.79 methoxyflurane was becoming used less These findings suggest that bone has the frequently worldwide. A further study in potential to act as a long-acting storage 1980 identified changes in hepatic function compartment of fluoride metabolite, which biomarkers following occupational exposure raises the possibility of fluoride accumu- of delivery-ward personnel.88 Hepatotox- lation with repeated exposure within an icity appears to have been an infrequent extended clearance time frame. Elevated but important effect that was unpredictably fluoride intake is associated with both associated with single or multiple doses of elevated serum fluoride and increased methoxyflurane.

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Summary of historical use a control group, but nonetheless it is highly In the 1960s, methoxyflurane was a new unlikely that anaesthetic methoxyflurane anaesthetic agent. Research focused on studies will ever be repeated to ensure determining its pharmacokinetics, utility scientific rigour. as an anaesthetic agent, respiratory effects Methoxyflurane is experiencing a revival and cardiovascular changes. None of these in lower-dose analgesic use. The historical factors were ultimately determined to be experience has provided some insight into areas of significant risk. Methoxyflurane risk in the modern setting, with researchers appeared to be a useful agent for providing specifically investigating the possibility and stable anaesthesia with gradual emergence. finding no evidence of patient nephrotox- 27,89 Nephrotoxicity was only identified after icity and hepatotoxicity in current use. approximately a decade of use and was not However, the literature suggests some unre- formally associated as a methoxyflurane solved safety concerns. dose-response until approximately 15 years The Australian Therapeutic Goods Admin- after its introduction. Individual variation istration (TGA) reported 25 cases of adverse in nephrotoxic threshold added further reaction associated with Penthrox between complication, and it is possible scepticism 1971 and 19 July 2020. These cases included may have impeded research into toxic two deaths and one report of adverse effect effects. Hepatotoxicity occurred infre- due to occupational exposure.90 The New quently enough that it was not identified as Zealand Medicines and Medical Devices an important risk of methoxyflurane, and Safety Authority (Medsafe) reported six the combination of circumstances under cases of adverse reaction associated with which methoxyflurane causes hepatitis are Penthrox between 2000 and 19 October still unclear. 2020, with no deaths.91 These reports are Studies of hepatic induction of methoxy- aggregated in Table 1. The earliest report in flurane metabolism suggest that frequent the Australian TGA database is November low-dose uses or exposures, or some medica- 2005, and the earliest report in the New tions taken concomitantly, have the potential Zealand Medsafe database is January 2012. to produce proportionally greater toxicity Hence it is possible that any earlier events 90,91 than historical one-off high dose exposures. were unreported. It is important to Bone fluoride deposition as a result of acknowledge that association with adverse methoxyflurane exposure has been mini- events does not necessarily imply methoxy- mally studied. A small but not irrelevant flurane caused the event. However, these teratogenic risk is suggested by two animal reports suggest a non-zero risk requiring studies undertaken after methoxyflurane surveillance and investigation. use had generally ceased. In contemporary use in Australasia, patients are administered up to 6mL Relevance to the methoxyflurane per day and up to 15mL per week.13,14 Each 3mL dose lasts between 20 modern setting and 60 minutes depending on how intensely This review was undertaken with the goal the patient inhales.92 Methoxyflurane is used of including the widest possible range of by Australian and New Zealand ambulance historical literature in order to describe the services,23,24,48,89,92–99 by at least one Australian evolution of understanding of the health emergency department100 and in Austral- risks associated with methoxyflurane. asian in-hospital and clinic settings.25,101–108 Literature was located non-systematically, It has been administered to five million including extensive use of locating citations patients in Australia18 and a further one and a wide range of search terms. Thus, the million patients outside of Australia.112 Given review search is not completely systematic, this extensive use, the number of adverse but it is nonetheless comprehensive. Equally, events reported is reassuringly low, and due to near-global abandonment of studies suggests that modern use of methoxyflurane in the 1970s, research was restricted until may be safe for short-term administration. recently, which limits numbers and avail- Furthermore, the low rate of adverse effects ability of prior publications. Much of the implies relative safety for those who are historical data utilise small samples and lack occupationally exposed to methoxyflurane.

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Table 1: Aggregated reports of adverse events involving methoxyflurane from the Australian Therapeutic Goods Administration (TGA)90 and the New Zealand Medicines and Medical Devices Safety Authority (Medsafe).91

Month Year Country Gender Age Adverse Other Other con- effects suspected comitant/not medications suspected medications Apr 1985 Australia Male 20 Hepatitis Chlorproma- None reported zine, fentanyl, halothane, flucoxacillin, pancuronium, suxamethoni- um, pethidine, thiopentone

Dec 2000 Australia Male 30 Malignant hy- Suxamethoni- None reported perthermia um, sevoflurane, propofol

Nov 2005 Australia Male 57 Hypoxia, medi- None reported None reported cation error

Dec 2005 Australia Female 34 Confusion, diz- None reported None reported ziness, hypoxia, somnolence

Jun 2006 Australia Female 20 Jaundice, None reported None reported abnormal liver function test result, vomiting

Mar 2008 Australia Male 26 Blood pressure None reported None reported fluctuation

Feb 2010 Australia Female 33 Hepatitis, None reported Sodium tetra- hepatomegaly, decyl sulphate, jaundice, liver fexofenadine, injury paracetamol

Feb 2010 Australia Female Not reported Hepatic failure, None reported None reported renal failure

Jul 2010 Australia Male 19 Affect lability, None reported None reported amnesia

May 2011 Australia Female 12 Lipase Box jellyfish Paracetamol, increased, antivenom, prednisolone pancreatitis morphine, fentanyl

Nov 2011 Australia Female 75 Altered state Morphine Not suspected of consciousness, nausea, vomiting

Jan 2012 New Zealand Male 64 Hepatic failure None reported None reported

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Month Year Country Gender Age Adverse Other Other con- effects suspected comitant/not medications suspected medications May 2014 Australia Female 86 Anaphylactic Fentanyl, tel- None reported reaction misartan

Apr 2015 Australia Female Not reported Liver function None reported None reported test increased

May 2015 Australia Male 64 Cardiac arrest, None reported None reported hypotension, nausea, syn- cope

Apr 2016 Australia Male 30 Depressed None reported None reported mood, feeling abnormal, nightmare

Jul 2016 Australia Female 10 Vomiting Oxycodone, Metronidazole, fentanyl, ampi- Augmentin, cillin paracetamol

Sep 2017 New Zealand Male 36 Dizziness, mal- None reported None reported aise, nausea

May 2018 Australia Female 47 Dizziness, None reported None reported muscle rigidity, nausea, un- responsive to stimuli

Aug 2018 Australia Male Not reported Depressed level None reported None reported of consciousness

Aug 2018 New Zealand Male 11 Abnormal None reported Morphine behaviour, depressed level of consciousness, dysphemia, hyperaesthesia, myoclonus

Oct 2018 Australia Male Not reported Drug abuse, None reported None reported hepatitis

Feb 2019 Australia Female Not reported Dizziness, None reported Not reported occupational exposure to product

May 2019 Australia Female 48 Aggression, None reported None reported amnesia

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Month Year Country Gender Age Adverse Other Other con- effects suspected comitant/not medications suspected medications Jun 2019 Australia Female 36 Abdominal None reported None reported pain, hepatitis, liver function test increased, malaise

Jul 2019 Australia Female Not reported Intentional None reported None reported product misuse

Aug 2019 Australia Female 75 Aphasia None reported None reported

Aug 2019 New Zealand Female 29 Anaphylactic Ibuprofen, None reported reaction paracetamol

Sep 2019 Australia Male Not reported Nephropathy None reported None reported

Feb 2020 New Zealand Female 44 Anaphylactic None reported Ethinylestradi- reaction ol, felodipine, enalapril, citalopram

May 2020 New Zealand Female 63 Hepatitis, hy- None reported Pantoprazole perbilirubinae- mia, myocardi- al infarction

However, absence of evidence does not use or exposure. Skeletal fluorosis, gesta- necessarily mean an absence of harm, and it tional and hepatotoxic risk should be may be difficult to identify the true risk. The further investigated. Workplaces where identification of potential nephrotoxic and methoxyflurane vapour is present could other risks, combined with the low numbers institute monitoring of at-risk healthcare and high age of prior studies, provides workers’ urine fluoride against published a basis for consideration of research of guidelines114,115 as a general health measure. methoxyflurane safety in the modern Although the historical literature associates setting. The literature illustrates a paucity serum fluoride level with renal toxicity, Safe of clinical trials confirming the safety of Work Australia does not recommend work- methoxyflurane in cases other than one-off places institute serum fluoride testing, due analgesic administration. Therefore, despite to practical complexities.115 the apparent relative safety in modern use Although there has been some thus far, there is good cause for further primary108,116 and secondary48 reporting research to be undertaken to ensure the of occupational exposure ranges with the safety of patients and healthcare workers. Penthrox inhaler, the degree to which In summary, the risks of patient and patients exhale methoxyflurane into the occupational methoxyflurane exposure local environment beyond the duration of have been identified. The degree of risk for their treatment could be explained further patients and healthcare workers appears as this might cause exposure for other low, but nonetheless remains unquantified healthcare workers who subsequently in the following domains: receive and care for the patient. A recent • renal toxicity study supported by the Penthrox manufacturer derived an eight-hour Maximum • enzyme induction due to concomitant Exposure Limit by estimating the level medication use or repeated methoxy- at which there is a 10% increased risk of flurane exposure kidney toxicity from historical single-ex- • a possibility of fluoride bone depo- posure anaesthetic data.48 This provides a sition with unknown skeletal fluorosis useful measure against which to compare risk reported or predicted exposures. However, • hepatotoxicity. independent confirmation of this Maximum Additionally, there is a notable dearth of Exposure Limit would be ideal.48,117,118 research of gestational effects relating to Finally, the only recently published deter- repeated methoxyflurane exposure. Because minations of occupational health risk have of these currently unquantified risks, it been theoretical models and extrapolation to may be prudent for healthcare workers compare with a single-exposure nephrotoxic to minimise exposure through adequate threshold.48–50 Further research to determine environment ventilation and by directing the nephrotoxic and other health effect risk patients to exhale through the AC filter of associated with recurrent exposure would the Penthrox device. be valuable. The historical literature has been examined and the evolution of under- A number of areas for future research standing of health risks associated with are suggested. For example, prolonged methoxyflurane described. This stands as a compartmental equilibration28,34 suggests a case study of a medication enthusiastically potential for healthcare workers to accu- put into clinical practice without sufficient mulate methoxyflurane and metabolites confirmation of occupational safety. Policy- with repeated exposure over prolonged makers should take heed of the persistent periods. Whether such an effect occurs need for scientific confirmation of the has been investigated only by one pilot occupational safety of methoxyflurane study,113 and further research is warranted. administration, and also of the potential for The rate of use among both patients and similar oversights that could occur with the healthcare workers of relevant enzyme-in- utilisation of new medications or medica- ducing and nephrotoxic medications could tions with controversial characteristics. be considered in the context of the increased risk posed by concomitant methoxyflurane

Competing interests: Ms Allison reports a grant from the NZ National Science Challenge, and a grant from the NZ Tertiary Education Commission, during the conduct of the study, and is a paramedic who utilises methoxyflurane for patient analgesia. Acknowledgements: Funding for the overall study was provided by the NZ National Science Challenge 7, Science for Technology and Innovation [grant number 2019-S3-CRS]; and the NZ Tertiary Education Com- mission (TEC) fund MedTech CoRE (Centre of Research Excellence) [grant number 3705718]. Author information: Serah J Allison: PhD candidate, Department of Mechanical Engineering, University of Canterbury, New Zealand and Intensive Care Paramedic, Wellington Free Ambulance, New Zealand. Paul D Docherty: Associate Professor, Department of Mechanical Engineering, University of Canterbury, New Zealand; Institute of Technical Medicine, Furtwangen University, Germany. Dirk Pons: Associate Professor, Department of Mechanical Engineering, University of Canterbury, New Zealand. J Geoffrey Chase: Distinguished Professor, Department of Mechanical Engineering, University of Canterbury, New Zealand. Corresponding author: Paul D Docherty, Department of Mechanical Engineering, Private bag 4800, Christchurch 8041, New Zealand [email protected] URL: www.nzma.org.nz/journal-articles/methoxyflurane-toxicity-historical-determination-and-lessons-for-modern-patient-and-occupational-exposure

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