Methoxyflurane

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Methoxyflurane
Methoxyflurane.svg
Methoxyflurane-3D-balls.png
Clinical data
Trade names Penthrox, Penthrane, Metofane, others
Other names2,2-dichloro-1,1-difluoroethyl methyl ether
AHFS/Drugs.com Consumer Drug Information
Pregnancy
category
  • AU:C
Routes of
administration 		Inhalation
Drug class Volatile anesthetic
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism 70%
Onset of action Rapid [4]
Duration of action Several minutes [4]
Identifiers
  • 2,2-dichloro-1,1-difluoro-1-methoxyethane
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.870 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C3H4Cl2F2O
Molar mass 164.96 g·mol−1
3D model (JSmol)
  • ClC(Cl)C(F)(F)OC
  • InChI=1S/C3H4Cl2F2O/c1-8-3(6,7)2(4)5/h2H,1H3 Yes check.svgY
  • Key:RFKMCNOHBTXSMU-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. [5] [6] It may also be used for short episodes of pain as a result of medical procedures. [4] Onset of pain relief is rapid and of a short duration. [4] Use is only recommended with direct medical supervision. [5]

Contents

Common side effects include anxiety, headache, sleepiness, cough, and nausea. [5] Serious side effects may include kidney problems, liver problems, low blood pressure, and malignant hyperthermia. [5] [4] It is unclear if it is safe in either pregnancy or breastfeeding. [5] It is only recommended in those who have a normal level of consciousness and stable blood pressure and heart rate. [4] It is classified as a volatile anaesthetic. [4]

It was first made in 1948 by William T. Miller and came into medical use in the 1960s. [7] It was used as a general anesthetic from its introduction in 1960 until the late 1970s. [8] In 1999, the manufacturer discontinued methoxyflurane in the United States, and in 2005 the Food and Drug Administration withdrew it from the market. [8] It is still used in New Zealand, Australia, Ireland, and the United Kingdom for pain. [9] [4] [10] [5] [11]

Medical use

Patient self-administering penthrox at the Royal Melbourne Hospital (hospital, medication, painkillers) Green Whistle.jpg
Patient self-administering penthrox at the Royal Melbourne Hospital

Methoxyflurane is used for relief of moderate or severe pain as a result of trauma. [6] [5] It may also be used for short episodes of pain as a result of procedures. [4]

Each dose lasts approximately 30 minutes. [12] Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation. [13] The maximum recommended dose is 6 milliliters per day or 15 milliliters per week because of the risk of kidney problems, and it is not recommended to be used on consecutive days. [4] Despite the potential for kidney problems when used at anesthetic doses, no significant adverse effects have been reported when it is used at the lower doses (up to 6 milliliters) used for pain relief. [14] [15] [16] Due to the risk of kidney toxicity, methoxyflurane is contraindicated in people with pre-existing kidney disease or diabetes mellitus, and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or enzyme-inducing drugs. [15]

It is self-administered to children and adults using a hand-held inhaler device. [17] [14] [18] [15] A non-opioid alternative to morphine, it is also easier to use than nitrous oxide. [4] A portable, disposable, single-use inhaler device, along with a single 3 milliliter brown glass vial of methoxyflurane allows people who are conscious and hemodynamically stable (including children over the age of 5 years) to self-administer the medication, under supervision. [4]

In prehospital care Penthrox offers an alternative to Entonox, it being smaller, lighter and not contraindicated with chest injuries. [19]

Side effects

The consensus is that the use of methoxyflurane should be restricted only to healthy individuals, in situations where it offers specific advantages and even then, only at dosages less than 2.5 MAC hours. [20] [21] The National Institute for Occupational Safety and Health maintains a recommended exposure limit for methoxyflurane as waste anesthetic gas of 2 ppm (13.5 mg/m3) over 60 minutes. [22]

Kidney

The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute kidney injury, two of whom were found to have calcium oxalate crystals in the renal tubules at autopsy. [23] In 1966, Crandell and colleagues reported a series in which 17/95 (18%) of patients developed an unusual type of nephropathy after operations in which methoxyflurane was used as a general anesthetic. This particular type of chronic kidney disease was characterized by vasopressin-resistant high-output kidney failure (production of large volumes of poorly concentrated urine) with a negative fluid balance, pronounced weight loss, elevation of serum sodium, chloride, osmolality and blood urea nitrogen. The urine of these patients was of a relatively fixed specific gravity and an osmolality very similar to that of the serum. Furthermore, the high urine output persisted a challenge test of fluid deprivation. Most cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted for more than one year in 3 of these 17 cases (18%), and more than two years in one case (6%). [24]

Compared with halothane, methoxyflurane produces dose-dependent abnormalities in kidney function. The authors showed that subclinical nephrotoxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3 hours (2.5 to 3 MAC hours), while overt toxicity was present in all patients at dosages greater than five MAC hours. [20] This study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades. [25] Furthermore, the concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity. [26]

Liver

Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966.

Mechanism

The biodegradation of methoxyflurane begins immediately. The kidney and liver toxicity observed after anesthetic doses is attributable to one or more metabolites produced by O-demethylation of methoxyflurane. Products of this catabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. [21] Methoxyflurane nephrotoxicity is dose dependent [24] [27] [28] and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA. [4] It is not entirely clear whether the fluoride itself is toxic—it may simply be a surrogate measure for some other toxic metabolite. [29] The concurrent formation of inorganic fluoride and DCAA is unique to methoxyflurane biotransformation compared with other volatile anesthetics, and this combination is more toxic than fluoride alone. This may explain why fluoride formation from methoxyflurane is associated with nephrotoxicity, while fluoride formation from other volatile anesthetics (such as enflurane and sevoflurane) is not. [30]

Pharmacokinetics

Methoxyflurane has a very high lipid solubility (oil:gas partition coefficient of around 950), which gives it very slow pharmacokinetics [ citation needed ] (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that in unpremedicated healthy individuals, induction of general anesthesia with methoxyflurane-oxygen alone or with nitrous oxide was difficult or even impossible using the vaporizers available at that time. It was found to be necessary to administer an intravenous anesthetic agent such as sodium thiopental to ensure a smooth and rapid induction. It was further found that after thiopental induction, it was necessary to administer nitrous oxide for at least ten minutes before a sufficient amount of methoxyflurane could accumulate in the bloodstream to ensure an adequate level of anesthesia. This was despite using high flow (litres per minute) of nitrous oxide and oxygen, and with the vaporizers delivering the maximum possible concentration of methoxyflurane. [31]

Similar to its induction pharmacokinetics, methoxyflurane has very slow and somewhat unpredictable emergence characteristics. During initial clinical studies in 1961, the average time to emergence after discontinuation of methoxyflurane was 59 minutes after administration of methoxyflurane for an average duration of 87 minutes. The longest time to emergence was 285 minutes, after 165 minutes of methoxyflurane administration. [31]

Pharmacodynamics

Heart

The effects of methoxyflurane on the circulatory system resemble those of diethyl ether. [32] In dogs, methoxyflurane anesthesia causes a moderate decrease in blood pressure with minimal changes in heart rate, and no significant effect on blood sugar, epinephrine, or norepinephrine. Bleeding and increased arterial partial pressure of carbon dioxide (PaCO2) both induce further decreases in blood pressure, as well as increases in blood glucose, epinephrine and norepinephrine. [33] In humans, methoxyflurane produces some decrease in blood pressure, but cardiac output, stroke volume, and total peripheral resistance are only minimally depressed. Its effect on the pulmonary circulation is negligible, and it does not predispose the heart to cardiac dysrhythmias. [31] [34] [35] [36]

Lungs

Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a dose-dependent decrease in respiratory rate and a marked decrease in respiratory minute volume, with a relatively mild decrease in tidal volume. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant. [32] The net effect of these changes is profound respiratory depression, as evidenced by CO2 retention with a concomitant decrease in arterial pH (this is referred to as a respiratory acidosis) when anesthetized subjects are allowed to breathe spontaneously for any length of time. [31]

Pain

Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the lipid compartment of the body for a long time, providing sedation and analgesia well into the postoperative period. [37] [32] There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses. [17] [14] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] Supervised self-administration of methoxyflurane in children and adults can briefly lead to deep sedation, [14] and it has been used as a patient controlled analgesic for painful procedures in children in hospital emergency departments. [18] During childbirth, administration of methoxyflurane produces significantly better analgesia, less psychomotor agitation, and only slightly more somnolence than trichloroethylene. [40]

Penthrox, commonly known as the "green whistle", has been offered in hospital to women for painful intrauterine device procedures (insertion and removal). [49]

Central nervous system

Similar to other inhalational anesthetics, the exact mechanism of action is not clearly defined and likely involves multiple molecular targets in the brain and spinal cord. [50] [51] Methoxyflurane is a positive allosteric modulator of GABAA and glycine receptors as demonstrated in electrophysiology studies. [52] [53] This mechanism is shared with alcohols that produce general anesthesia. [54]

Chemical properties

Space-filling model (three-dimensional molecular structure) of methoxyflurane Methoxyflurane-3D-vdW.png
Space-filling model (three-dimensional molecular structure) of methoxyflurane

With a molecular formula of C3H4Cl2F2O and a condensed structural formula of CHCl2CF2OCH3, the International Union of Pure and Applied Chemistry (IUPAC) name for methoxyflurane is 2,2-dichloro-1,1-difluoro-1-methoxyethane. It is a halogenated ether in form of a clear, colorless liquid, and its vapor has a strong fruity aroma. It is miscible with ethanol, acetone, chloroform, diethyl ether, and fixed oils. It is soluble in rubber. [12]

With a minimum alveolar concentration (MAC) of 0.16%, [55] methoxyflurane is an extremely potent anesthetic agent. It is a powerful analgesic agent at well below full anesthetic concentrations. [18] [56] [57] [58] [37] Because of its low volatility and very high boiling point (104.8 °C at 1 atmosphere), methoxyflurane has a low vapor pressure at ambient temperature and atmospheric pressure. It is therefore quite difficult to vaporize methoxyflurane using conventional anesthetic vaporizers.

PropertyValue [12] [31] [59]
Boiling point (at 1  atmosphere)104.8 °C
Minimum alveolar concentration (MAC)0.16% [55]
Vapor pressure (mmHg at 20 °C)22.5
Partition coefficient (Blood:Gas)12
Partition coefficient (Oil:Gas)950
Partition coefficient (Oil:Water)400
Specific gravity at 25 °C1.42
Flash point 63 °C
Molecular weight (g mol−1)164.97
Vapor-liquid equilibrium (mL)208
Flammability limits7% in air
Chemical stabilizer necessaryYes

The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest chemical bond in organic chemistry. [60] Furthermore, this bond becomes shorter and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this, fluoroalkanes are some of the most chemically stable organic compounds.

History

Methoxyflurane has been used since the 1970s in Australia as an emergency analgesic for short-term use by the Australian Defence Force and New Zealand Defence Force, [17] the Australian ambulance services, [14] [38] [39] and both St John Ambulance [61] and Wellington Free Ambulance [62] in New Zealand. Since 2018, it has also been used by some emergency medical services in Germany. [63] Methoxyflurane inhalers are nicknamed 'green whistles' due to the green colour of their casing. [64]

All of the currently used volatile anesthetic agents are organofluorine compounds. Aside from the synthesis of Freon (Thomas Midgley Jr. and Charles F. Kettering, 1928) [65] and the discovery of Teflon (Roy J. Plunkett, 1938), [66] the field of organofluorine chemistry had not attracted a great deal of attention up to 1940 because of the extreme reactivity of elemental fluorine, which had to be produced in situ for use in chemical reactions. The development of organofluorine chemistry was a spin-off from the World War 2 nuclear Manhattan Project, during which elemental fluorine was produced on an industrial scale for the first time.

The need for fluorine arose from the need to separate the isotope uranium-235 (235U) from uranium-238 (238U) because the former, present in natural uranium at a concentration of less than 1% is fissile (capable of sustaining a nuclear chain reaction of nuclear fission with thermal neutrons), [67] whereas the latter is not. Members of the MAUD Committee (especially Francis Simon and Nicholas Kurti) proposed the use of gaseous diffusion for isotope separation, since, according to Graham's law the rate of diffusion is inversely proportional to molecular mass. [68] After an extensive search, uranium hexafluoride (UF6) was determined to be the most suitable compound of uranium to be used for the gaseous diffusion process. [69] Elemental fluorine is needed in the production of UF6.

Obstacles had to be overcome in the handling of both fluorine and UF6. Before the K-25 gaseous diffusion enrichment plant could be built, it was first necessary to develop non-reactive chemical compounds that could be used as coatings, lubricants and gaskets for the surfaces which would come into contact with the UF6 gas (a highly reactive and corrosive substance). William T. Miller, [70] professor of organic chemistry at Cornell University, was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactive chlorofluorocarbon polymers that were used in this application.

Miller and his team continued to develop organofluorine chemistry after the end of World War II and methoxyflurane was made in 1948. [71]

In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia. [72] The Analgizer consisted of a polyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled wick of polypropylene felt which held 15  milliliters of methoxyflurane. Because of the simplicity of the Analgizer and the pharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of conscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly amnesic to the sense of pain; the device could be refilled if necessary. [43] The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with bone fractures and joint dislocations, [43] and for dressing changes on burn patients. [42] When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect on Apgar scores. [43] All vital signs remain normal in obstetric patients, newborns, and injured patients. [43] The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today. [40] [41] [44] [45] The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the Penthrox inhaler. [17] [14] [18] [15] During 2020 trials of methoxyflurane as an analgesic in emergency medicine were held in the UK. [73]

Notes

  1. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. ↑ "Regulatory Decision Summary for Penthrox". 23 October 2014.
  3. ↑ "List of nationally authorised medicinal products : Active substance: methoxyflurane : Procedure no. PSUSA/00010484/202005" (PDF). Ema.europa.eu. Retrieved 12 March 2022.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 National Prescribing Service (2010). "Methoxyflurane (Penthrox) for analgesia (doctor's bag listing)". NPS RADAR. Canberra, Australia: National Prescribing Service, Department of Health and Ageing. Archived from the original on 27 July 2011. Retrieved 12 June 2011.
  5. 1 2 3 4 5 6 7 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. X. ISBN   9780857113382.
  6. 1 2 Jephcott C, Grummet J, Nguyen N, Spruyt O (May 2018). "A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures". British Journal of Anaesthesia. 120 (5): 1040–1048. doi: 10.1016/j.bja.2018.01.011 . PMID   29661381.
  7. ↑ Hardman JG, Hopkins PM, Struys MM (2017). Oxford Textbook of Anaesthesia. Oxford University Press. p. 553. ISBN   9780199642045.
  8. 1 2 Mazze RI (October 2006). "Methoxyflurane revisited: tale of an anesthetic from cradle to grave". Anesthesiology. 105 (4): 843–846. doi: 10.1097/00000542-200610000-00031 . PMID   17006084.
  9. ↑ "NZ Medsafe Datasheet" (PDF). Medsafe.govt.nz. Retrieved 12 March 2022.
  10. ↑ PHECC Clinical Practice Guidelines (6 ed.). Pre-Hospital Emergency Care Council. March 2017. p. 100. ISBN   978-0-9929363-6-5 . Retrieved 7 January 2019.
  11. ↑ Porter KM, Siddiqui MK, Sharma I, Dickerson S, Eberhardt A (2018). "Management of trauma pain in the emergency setting: low-dose methoxyflurane or nitrous oxide? A systematic review and indirect treatment comparison". Journal of Pain Research. 11: 11–21. doi: 10.2147/JPR.S150600 . PMC   5741984 . PMID   29302193.
  12. 1 2 3 Medical Developments International Pty. Ltd. (2009). "Penthrox (methoxyflurane) inhalation: product information" (PDF). Springvale, Victoria, Australia: Medical Developments International Limited. Archived from the original (PDF) on 15 March 2012. Retrieved 12 June 2011.
  13. ↑ Wellness on Wellington (2010). "The green whistle" (PDF). Wellnews. 12 (2): 1. Archived from the original (PDF) on 29 March 2011.
  14. 1 2 3 4 5 6 Babl FE, Jamison SR, Spicer M, Bernard S (August 2006). "Inhaled methoxyflurane as a prehospital analgesic in children". Emergency Medicine Australasia. 18 (4): 404–410. doi:10.1111/j.1742-6723.2006.00874.x. PMID   16842312. S2CID   1619160.
  15. 1 2 3 4 Grindlay J, Babl FE (February 2009). "Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting". Emergency Medicine Australasia. 21 (1): 4–11. doi: 10.1111/j.1742-6723.2009.01153.x . PMID   19254307. S2CID   40158248.
  16. ↑ Rossi S, ed. (2009). Australian Medicines Handbook (10th ed.). Adelaide: Australian Medicines Handbook Pty, Ltd. ISBN   978-0-9757919-9-8.
  17. 1 2 3 4 McLennan JV (June 2007). "Is methoxyflurane a suitable battlefield analgesic?" (PDF). Journal of the Royal Army Medical Corps. 153 (2): 111–113. doi:10.1136/jramc-153-02-08. PMID   17896540. S2CID   38517296. Archived from the original (PDF) on 15 July 2011.
  18. 1 2 3 4 Babl F, Barnett P, Palmer G, Oakley E, Davidson A (February 2007). "A pilot study of inhaled methoxyflurane for procedural analgesia in children". Pediatric Anesthesia. 17 (2): 148–153. doi:10.1111/j.1460-9592.2006.02037.x. PMID   17238886. S2CID   30105092.
  19. ↑ Boyle M, Mallinson T, Worral M, Pearce L, Duff L, Price R (May 2022). "Use of Penthrox® as a Prehospital Analgesic within a Scottish Responder Service".
  20. 1 2 Cousins MJ, Mazze RI (September 1973). "Methoxyflurane nephrotoxicity. A study of dose response in man". JAMA. 225 (13): 1611–1616. doi:10.1001/jama.1973.03220410023005. PMID   4740737.
  21. 1 2 Gottlieb LS, Trey C (1974). "The effects of fluorinated anesthetics on the liver and kidneys". Annual Review of Medicine. 25: 411–429. doi:10.1146/annurev.me.25.020174.002211. PMID   4596236.
  22. ↑ "CDC - NIOSH Pocket Guide to Chemical Hazards - Methoxyflurane". www.cdc.gov. Retrieved 19 November 2015.
  23. ↑ Paddock RB, Parker JW, Guadagni NP (1964). "The Effects of Methoxyflurane on Renal Function". Anesthesiology. 25: 707–708. PMID   14211499.
  24. 1 2 Crandell WB, Pappas SG, Macdonald A (1966). "Nephrotoxicity associated with methoxyflurane anesthesia". Anesthesiology. 27 (5): 591–607. doi: 10.1097/00000542-196609000-00010 . PMID   5918999. S2CID   39661400.
  25. ↑ Barash, Cullen and Stoelting (2009), Ebert and Schmid, Chapter 17: Inhaled Anesthetics, pp. 413–43
  26. ↑ Helsinn Birex Therapeutics Ltd (2009). "By-Mycin 50mg capsules". medicines.ie: Medicines information online. Dublin, Ireland: Irish Pharmaceutical Healthcare Association Ltd. Archived from the original on 21 July 2011. Retrieved 12 June 2011.
  27. ↑ Jones NO (March 1972). "Methoxyflurane nephrotoxicity--a review and a case report". Canadian Anaesthetists' Society Journal. 19 (2): 152–159. doi: 10.1007/BF03005045 . PMID   5029469.
  28. ↑ Mazze RI (June 1976). "Methoxyflurane nephropathy". Environmental Health Perspectives. 15: 111–119. Bibcode:1976EnvHP..15..111M. doi:10.1289/ehp.7615111. JSTOR   3428393. PMC   1475154 . PMID   1001288.
  29. ↑ Kharasch ED, Schroeder JL, Liggitt HD, Park SB, Whittington D, Sheffels P (October 2006). "New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway". Anesthesiology. 105 (4): 726–736. doi: 10.1097/00000542-200610000-00019 . PMID   17006072. S2CID   25900511.
  30. ↑ Kharasch ED, Schroeder JL, Liggitt HD, Ensign D, Whittington D (October 2006). "New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites". Anesthesiology. 105 (4): 737–745. doi: 10.1097/00000542-200610000-00020 . PMID   17006073. S2CID   21609274.
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  32. 1 2 3 Siebecker KL, James M, Bamforth BJ, Orth OS (1961). "The respiratory effect of methoxyflurane on dog and man". Anesthesiology. 22 (1): 143. doi: 10.1097/00000542-196101000-00044 .
  33. ↑ Millar RA, Morris ME (May 1961). "A study of methoxyflurane anaesthesia". Canadian Anaesthetists' Society Journal. 8 (3): 210–215. doi: 10.1007/BF03028110 . PMID   13770698.
  34. ↑ Artusio JF, Van Poznak A, Hunt RE, Tiers RM, Alexander M (1960). "A clinical evaluation of methoxyflurane in man". Anesthesiology. 21 (5): 512–517. doi:10.1097/00000542-196009000-00009. PMID   13794589. S2CID   45338415.
  35. ↑ Van Poznak A, Artusio JF (July 1960). "Anesthetic properties of a series of fluorinated compounds. I. Fluorinated hydrocarbons". Toxicology and Applied Pharmacology. 2 (4): 363–373. Bibcode:1960ToxAP...2..363P. doi:10.1016/0041-008X(60)90002-8. PMID   13841124.
  36. ↑ Van Poznak A, Artusio JF (July 1960). "Anesthetic properties of a series of fluorinated compounds. II. Fluorinated ethers". Toxicology and Applied Pharmacology. 2 (4): 374–378. Bibcode:1960ToxAP...2..374V. doi:10.1016/0041-008X(60)90003-X. PMID   13841125.
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  39. 1 2 Johnston S, Wilkes GJ, Thompson JA, Ziman M, Brightwell R (January 2011). "Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service". Emergency Medicine Journal. 28 (1): 57–63. doi:10.1136/emj.2009.078717. PMID   20466829. S2CID   24955345.
  40. 1 2 3 Major V, Rosen M, Mushin WW (December 1966). "Methoxyflurane as an obstetric analgesic: a comparison with trichloroethylene". British Medical Journal. 2 (5529): 1554–1561. doi:10.1136/bmj.2.5529.1554. PMC   1944957 . PMID   5926260.
  41. 1 2 Dragon A, Goldstein I (November 1967). "Methoxyflurane: preliminary report on analgesic and mood-modifying properties in dentistry". Journal of the American Dental Association. 75 (5): 1176–1181. doi:10.14219/jada.archive.1967.0358. PMID   5233333.
  42. 1 2 Packer KJ, Titel JH (December 1969). "Methoxyflurane analgesia for burns dressings: experience with the analgizer". British Journal of Anaesthesia. 41 (12): 1080–1085. CiteSeerX   10.1.1.1028.6601 . doi:10.1093/bja/41.12.1080. PMID   4903969.
  43. 1 2 3 4 5 Romagnoli A, Busque L, Power DJ (May 1970). "The "analgizer" in a general hospital: a preliminary report". Canadian Anaesthetists' Society Journal. 17 (3): 275–278. doi: 10.1007/BF03004607 . PMID   5512851.
  44. 1 2 Firn S (May 1972). "Methoxyflurane analgesia for burns dressings and other painful ward procedures in children". British Journal of Anaesthesia. 44 (5): 517–522. doi: 10.1093/bja/44.5.517 . PMID   5044082. S2CID   35308189.
  45. 1 2 Josephson CA, Schwartz W (February 1974). "The Cardiff inhaler and penthrane. A method of sedation-analgesia in routine dentistry". The Journal of the Dental Association of South Africa = die Tydskrif van die Tandheelkundige Vereniging van Suid-Afrika. 29 (2): 77–80. PMID   4534883.
  46. ↑ Lewis LA (February 1984). "Methoxyflurane analgesia for office surgery. Surgical gem". The Journal of Dermatologic Surgery and Oncology. 10 (2): 85–86. doi:10.1111/j.1524-4725.1984.tb01191.x. PMID   6693612.
  47. ↑ Komesaroff D (1995). "Pre-hospital pain relief: Penthrane or Entonox". Australian Journal of Emergency Care. 2 (2): 28–9. ISSN   1322-3127.
  48. ↑ Chin R, McCaskill M, Browne G, Lam L (2002). "A randomised controlled trial of inhaled methoxyflurane pain relief in children with upper limb fracture (abstract)". Journal of Paediatrics and Child Health. 38 (5): A13–4. doi:10.1046/j.1440-1754.2002.00385.x. ISSN   1034-4810.
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Related Research Articles

<span class="mw-page-title-main">Anesthesia</span> State of medically-controlled temporary loss of sensation or awareness

Anesthesia or anaesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia, paralysis, amnesia, and unconsciousness. An individual under the effects of anesthetic drugs is referred to as being anesthetized.

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

Awareness under anesthesia, also referred to as intraoperative awareness or accidental awareness during general anesthesia (AAGA), is a rare complication of general anesthesia where patients regain varying levels of consciousness during their surgical procedures. While anesthesia awareness is possible without resulting in any long-term memory of the experience, it is also possible for victims to have awareness with explicit recall, where they can remember the events related to their surgery.

<span class="mw-page-title-main">Nitrous oxide (medication)</span> Gas used as anesthetic and for pain relief

Nitrous oxide, as medical gas supply, is an inhaled gas used as pain medication, and is typically administered with 50% oxygen mix. It is often used together with other medications for anesthesia. Common uses include during childbirth, following trauma, and as part of end-of-life care. Onset of effect is typically within half a minute, and the effect lasts for about a minute.

<span class="mw-page-title-main">Epidural administration</span> Medication injected into the epidural space of the spine

Epidural administration is a method of medication administration in which a medicine is injected into the epidural space around the spinal cord. The epidural route is used by physicians and nurse anesthetists to administer local anesthetic agents, analgesics, diagnostic medicines such as radiocontrast agents, and other medicines such as glucocorticoids. Epidural administration involves the placement of a catheter into the epidural space, which may remain in place for the duration of the treatment. The technique of intentional epidural administration of medication was first described in 1921 by Spanish military surgeon Fidel Pagés.

Fluoride toxicity is a condition in which there are elevated levels of the fluoride ion in the body. Although fluoride is safe for dental health at low concentrations, sustained consumption of large amounts of soluble fluoride salts is dangerous. Referring to a common salt of fluoride, sodium fluoride (NaF), the lethal dose for most adult humans is estimated at 5 to 10 g. Ingestion of fluoride can produce gastrointestinal discomfort at doses at least 15 to 20 times lower than lethal doses. Although it is helpful topically for dental health in low dosage, chronic ingestion of fluoride in large amounts interferes with bone formation. In this way, the most widespread examples of fluoride poisoning arise from consumption of ground water that is abnormally fluoride-rich.

<span class="mw-page-title-main">Remifentanil</span> Synthetic opioid analgesic

Remifentanil, marketed under the brand name Ultiva is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia. The use of remifentanil has made possible the use of high-dose opioid and low-dose hypnotic anesthesia, due to synergism between remifentanil and various hypnotic drugs and volatile anesthetics.

<span class="mw-page-title-main">Enflurane</span> Chemical compound

Enflurane is a halogenated ether. Developed by Ross Terrell in 1963, it was first used clinically in 1966. It was increasingly used for inhalational anesthesia during the 1970s and 1980s but is no longer in common use.

<span class="mw-page-title-main">Inhalational anesthetic</span> Volatile or gaseous anesthetic compound delivered by inhalation

An inhalational anesthetic is a chemical compound possessing general anesthetic properties that is delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporiser and an anesthetic delivery system. Agents of significant contemporary clinical interest include volatile anesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anesthetic gases such as nitrous oxide and xenon.

<span class="mw-page-title-main">Inhaler</span> Medical device used to deliver medicines into lungs

An inhaler is a medical device used for delivering medicines into the lungs through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with asthma and chronic obstructive pulmonary disease (COPD) being among the most notable.

Minimum alveolar concentration or MAC is the concentration, often expressed as a percentage by volume, of a vapour in the alveoli of the lungs that is needed to prevent movement in 50% of subjects in response to surgical (pain) stimulus. MAC is used to compare the strengths, or potency, of anaesthetic vapours. The concept of MAC was first introduced in 1965.

<span class="mw-page-title-main">Patient-controlled analgesia</span> Administration of pain relief medication by a patient

Patient-controlled analgesia (PCA) is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber. If it is programmed and functioning as intended, the machine is unlikely to deliver an overdose of medication. Providers must always observe the first administration of any PCA medication which has not already been administered by the provider to respond to allergic reactions.

<span class="mw-page-title-main">History of general anesthesia</span>

Throughout recorded history, attempts at producing a state of general anesthesia can be traced back to the writings of ancient Sumerians, Babylonians, Assyrians, Egyptians, Indians, and Chinese. Despite significant advances in anatomy and surgical technique during the Renaissance, surgery remained a last-resort treatment largely due to the pain associated with it. However, scientific discoveries in the late 18th and early 19th centuries paved the way for the development of modern anesthetic techniques.

<span class="mw-page-title-main">History of neuraxial anesthesia</span>

The history of neuraxial anaesthesia dates back to the late 1800s and is closely intertwined with the development of anaesthesia in general. Neuraxial anaesthesia, in particular, is a form of regional analgesia placed in or around the Central Nervous System, used for pain management and anaesthesia for certain surgeries and procedures.

Obstetric anesthesia or obstetric anesthesiology, also known as ob-gyn anesthesia or ob-gyn anesthesiology, is a sub-specialty of anesthesiology that provides peripartum pain relief (analgesia) for labor and anesthesia for cesarean deliveries ('C-sections').

Balanced anesthesia, also known as multimodal anesthesia, is a technique used to induce and maintain anesthesia in patients undergoing surgery or certain medical procedures. This method employs a combination of anesthetic agents and other drugs – and techniques – to selectively target various aspects of the central nervous system, allowing for a tailored anesthetic experience based on the individual patient's needs and the specific requirements of the procedure.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

References

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