The Use of Trifluoroethyl Vinyl Ether (Fluoromar®) in Anaesthesia For

THE USE OF TRIFLUOROETHYL VINYL ETHER (FLUOROMAR| IN ANAESTHESIA FOR DENTISTRY**

HARRY M. SLATER, M.D. * ~ *

THE quest for an agent which will ,completely fulfil the requirements ofI patient, surgeon, and anaesthetist will never end. Pharmac61ogists and chemists are constantly studying and testing chemacals in the hope 0f discovenng a drug winch is safe and simple to administer to patients of all ages, is pleasant to the mdlwdual and permits a rapid uncomplicated recovery. /gxantz (1) and his co-workers had for some lame been examining the anaesthetic possibilities of certain hydrocarbons and ethers. In 1947, he reported his k,boratory studies of ethyl vinyl ether (Vinanaar| an agent winch has since been proven to have definite merits for induction and maintenance of anaesthesia in children (2). The chemical propertaes desigmated Vinamar as a hybrid of diethyl and divinyl ethers, exhibiting many of the good features of both agents. Vinamar possesses excellent analgesic propertie,~ and, together with nitrous oxide and ox)'gen, becomes a useful tool for anaesthesia of the ambulatory patient.

TABLE I (SADOVE, BALAGOT AND LINDE)(5)

Dmthyl D1vmyl Ethyl-vinyl Tnfluoroethyl Property ether ether ether wnyl ether "Ether .... Vmethene"' 'Vlntmar .... Fluoromar" Bolhng point 34 6 ~ C 28 4 ~ C 35 b ~ C. 42 7 ~ C. Vapour pressure mm of Hg at 20 ~ C 442 553 ~628 295 at 40 ~ C 921 1145 670 Gasdenslty (Air = 1) 2 6 2 4 2 5 4 4 Lower flammablhty hmlt I,~ o_~ 2 0% 1 9% ~ 2% *4 0% A~r 1 9~ 1 7% 4 2~ ,75% 02-25% NzO 4 0% I Mmlmflm spark lgmtlon energy, mtlhjoules for 30-/o of vapour m dry 02 0 39 high -- 4% 0 05 0 13 -- 6% 0.01 0 02 0 80 8% 0 01 0 01 0 08 Solublhty m water ml/100 ml 8 0 0 7 0 8 0 4 Od/H20 ratxo at 37 5 ~ C 3 2 41 45 91 Blood concentratmn for surgical anaesthesia (mgm %) 50-150 30--40 ,ca 25 17-38 *dry gas rmxture

*Fluoromar@ was supphed by the Ohm Chemxeal and Surgmal Eqmpment Company, a davlslon of Atr Reduction, Inc. **Presented at the Annual Meetang, Canachan Anaesthelasts" Soctety, Mont Trem'blant, Quebec, June 1956. * ** Montreal, Quebec 5

Can. Anaes. Soc.'J., vol. 4, no 1, Jan, 1957 6 CANADIAN ANAESTHETISTS' SOCIETY JOUBNAL In 1958, Lu eta/. (8) reported a study of fluorinated hydrocarbons and ethers; they concluded that the partially fluorinated ethyl vinyl ether may be useful as an anaesthetic. Later, on April 10, 1958, following extensive investigations in animals, Krantz (4) submitted Dr. M. Sadove to an open-drop administration of Fluoromar| The results were gratifying and encouraging for further studies. In Canada, this new ether was employed for the Jlrst time (by the author) on February 8, 1954. The subsequent adminisb'ation..; constituted a study of the agent primarily in paediatric anaesthesia. Uowever, a number of adults also received this ether. Of the 178 cases in which Fluoromar was given, 158 were for dental procedures. The observations were based on the value of this fluorinated ether as an analgesic and a supplement to mitrous oxide and oxygen anaesthesia compared to other volatile agents-in particular, trichloroethylene. Properties (Table I) The formula of Trifluoroethyl vinyl ether is simillar to that of ethyl vinyl ether but three hydrogen molecules are replaced by three fluorine molecules (CFsCH2-O-CH2---CH2) (4). It is an unsaturated fluorinated ether. The compound has a specific gravity of 1.18 at 25~ and is volatile, eolourless, with a markedly less pungent odour than that of ethyl vinyl ether. This latter property alone was most acceptable to both young and old alike. Because its boiling r RESPIRATORY ARREST min~ cc/Ko INDUCTION

15- o ///////o,j //////,

,/ / / / / //////, o.//// // // /L. ,), i

05" OE

OOHGI:~

| 0'2 04 0~6 '0'8 I'0 1~2 14 A ETHYL ETHER R GYGLOPROPYL METHYL ETHER H METHYL ALLYL ETHER G 6YGLOPROPYL ETHYL ETHER cc/Kg INDUCTION F n. PROPYL METHYL ETHER D GYCLOPROPYL V|NYL ETHER 3" ISOPROPYL METHYL ETHER E DIVI~It'L ETHER K PflOPENYL ETHYL ETHER F ISOPROPENYL VINYL ETHER L TRIFLuOROETHYL G ETHYl. VINYL ETHER VINYL ETHER FxctraE 1 Safety margin for ethers (K_rantz et al ) SLATER: TB1FLUOROETHYL VINYL ETI-IE2P, 7 point is 42.7~ compared to 28.4 of divinyl ether and 87~ of trichloroethylene, it can be used in open drop techniques for children. Kzantz has demonstrated that the margin of safety is somewhat comparable to that of diethyl ether (Fig. 1). Fluoromar is quite stable in closed absorption systems. (6, 7) but is sensitive to light. Therefore, 0.1 per cent phenyl-alpha-naphthylamine is added as an inhibitor, retarding decomposition to the toxic trifluoroethanol and acetedde- hyde (6). Management The majonty of patients selected for this study were children requiring exodontia or operative dentistry (8, 9). Some procedures, were short extractions, while others were d~cult and long. The average dent'd filling operation took one and one-quarter horns (Table II). The remaining twenty eases were not

TABLE II DURATION OF ANAESTHESIA Ttme No. of patients Less than 5 minutes 8 5-15 mmutes 69 15-30 minutes 45 30-60 mmutes 26 1-1 hours 14 l{-l{ hours 6 l~-lz1 3 hours 7 1~--2 hours 3 dental but did offer an opportunity for observing other clinical phenomena. :In other instances student volunteers were subjects Sor analgesia tests, with various types of "inhalers." The ages of the patients ranged from 6 weeks to 60 years "(Table III).

TABLE III AGE DISTRIBUTION

Age No. of patients 6 weeks- 1 year 6 l- 5 years 4{1 5-10 years 66 11)-15 years 2"3 1,5-20 years 5 20-25 years 12 25-35 years 5 35-45 years 9 45--55 years 6 55-60 years :3

Because of the desirability ,of having rapid recoveries With early (ff not im- mediate) ambulation, premedication was kept to a minimum. The usual pre- medicant was a barbiturate, seconat or nembutal, admln,_'stered to the patient 1-1~ hours before operation. Occasionally, additional codeine with acetylsali- cylie acid was given to .adults to potentiate the barbiturate. Patients who were 8 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL hospitalized were given a combination of barbiturate, morphine, and scopolamine or 3arbiturate with nisentil or demerol. Very few were in this last category. Approxmaately 85 per cent of the cases rec61ved barbll:urate alone. This offered an excellent opportunity of noting the presence or absence of excessive secretions or cardiac irregularities. Many indwiduals, especially children, object to an i~nducHon with any agent having a strange odour. Therefore they were first rendered unconscious with lugh flow nitrous oxide and air. The face mask or nasal inhaler was usually off the face at this point. As soon as hyperventilation was noted (and before evidence of cyanosis), 20 per cent oxygen was added along with Fluoromar. Fluoromar was usually administered from the Heldbrmk Trimar vaporizer, and the initial setting was at :~9 or ~10 for 2 to 8 minut,~s; then, as the breathing became quiet, t_a~s settang was immediately changed to r or r Below this, the concentration of Fluoromar was insufficient to maintain an even plane of anaesthesia. The technique just described was adequate for all dental extractions. Operative dentistry for fillings was managed in muda the same manner except that following the mtrous oxlde-oxygen-Fluoromar sequence, a minimal dose of succinylehohne was gwen intravenously. A nasotracheal tube was then inserted by direct vision or blindly, and anaesthesia maintained by the high flow technique of 80:20 nitrous oxide, oxygen and Fluc,romar. Spontaneous breathing returned witlun a matter of 2 or 3 minutes; during this time artificial resptrahon is instituted Penod~c inflation of the chest assured better alveolar gas exchange. The anaesthetic equipment employed was of the s~andard unmodified types Vmethene, ether, and trichloroethylene vaporizers had individual differences, but, with expenence, the appropriate settings were achieved without dlflaculty.

Observations Trifluoroethyl vinyl ether was found to be a most interesting and unusual ether. Generally speakmg, the agent appeared to fulfil the role of a potent safe supplement to mtrous oxide-oxygen anaesthesia. There were several striking chnlcal observations noted in this study: 1. Fluoromar did not have the irritating effects on both respiratory and sahvary systems as compared to trichloroethylene, diethyl ether and divinyl ether. 2. The agent was most acceptable to the patients and operatin~ personnel. Children reacted favourably to the pleasant odour and did not exhi 9it evidence of lingering objectionable odours after operation, as they do with diethyl ether. This fact alone seemed to reduce the incidence of nausea, vomiting, coughing and increased salivation. 3. The onset of analgesia and anaesthesia with nitrous oxide--oxygen-Fluoromar sequence was smooth and without evidence of breath-holding, laryngospasm or excitement. 4. Although the agent seems to be very potent, it has a margin of safety greater than that of divinyl ether, cyclopropane, and chloroform and ethyl chloride. It is somewhat comparable to diethyl ether. SLATE~, TmFLUOROETttYL VINYL ETHER 9 5. The transition frol~ hght to deeper planes and back to hghter levels of anaesthesia was accomplished smoothly and without untoward effeets on the subject. The resprratory pattern resembled that of eyelopropane but the eye signs paralleled those of ethyl vinyl ether. It was obvious that the patients were never in deep surgical anae~;thesia and yet their breathing was quiet and un- laboured. In the beginning, this confused the anaesthetist; what appearer to be deep anaesthesia, as judged by the respirations, would often be light, aid the patient would move his head, legs, or arms. This rarely delayed the operation, for a shght increase in Fluoromar concentration eliminated these movements. 6. Better management was attained when the Fluoromar concentration in the inhaled mixture was lmtially high, and then tapered off to a minimal level. When vaporization was gradually increased, there was more evidence of excitement, retching, and sahvation. 7. In the concentrations of Flue1 omar employed for dental surgery, there were no untoward cardiovascular comphcatmns. As xn the case of o,ther commonly used anaesthetics, overdosage for a long, period produced brac~ycardia in two eases. This was obviated by "flusltnng" tlKe patients with oxygen and reducing the quantity of inhaled agent. There was no evidence ot: hypotension in this series. 8 The administrataon of opiates before operation and the use of thiopental for Induction, diminished s~gnfflcantly the quantity of Fluoromar required for smooth maintenance of anaesthesia. 9 Where no relaxant was given prior to mtubahon, it was necessary to maintain Fluoromar at a high concentration for an average 'of five minutes. The tame allowed for introducing the laryngoscope and endotracheal babe was indeed limited, b~t of no great concern. 10. In the group of subjects observed, there was no ewdenee of convulsions, "running" movements, or other central nervous system dist-urbanees. 11. In all instances, the recoveries were amazir~gly rapid. Even more remark- able was the qmck mental orientation with absence of throbbing headaches and eplgastrie pains commonly seen with trichloroethylene and nitrous oxide. 12. The type of anaesthetic machine employed was unimportant. However, vaporizers with short bottles and some form of wick were preferred. Heat of vaponzahon presented no problem because of the low concentrations of the agent used. 18. Fluoromar can be administered by any of the inhalers such as the Cyprane, Duke, Trihte, and the Goldman vinethene inhaler. The Emotrfl type of apparatus is better suited for this purpose since it maintains a more eonsiste~at concentra- t-ion over a longer period o~ tame as observed clinically. "]~erefore" there would seem to be a possibility for its use in dental afialgesia. 'l~he main difficulty is that Fluoromar does not remain in the blood stream for long (5) and the analgesic effects disappear rapidly. Trichloroethylene is much better from this standpoint. 14. Lastly, although the jaws did not relax completely, mouth props were inserted without too much clifl~culty. 15. Complications are listed in Table IV. 10 CANADIAN ANAESTHETISTS' SOCIETY JOI.Iti~AL TABLE IV C OMPLICAT,I ONS No of cases 1. Breath-holdmg--rmld 3 --severe 0 2 Prolonged induction 1 3 Laryngospasm--mfid 1 ----severe 0 4 Vomltmg~durmg mductm, n 1 ~durmg maintenance 9 ~durmg recovery 4 5. Retchmg~durmg anaesthesm 2 ~durmg recovery 1 6. Stridor during operation 2 7. Increased secretions 4 8 Excesswe sweating 1 9 Bradycardia 2 10 Inadequate anaesthesm 4

SUI~/ff.ABu 1. The pharmacologic properties of trifluoroethyl vinyl ether (Fluoromar~) are outlined. 2. Favourable climcal observations of Flu oromar in dentistry indicate ~ts use as an adjuvant to nitrous oxide--oxygen analgesia and anaesthesia. 8. Statistical data are presented.

l~s~ Depuis les travaux de Krantz, publi6s en 1947, on connalt les propri6t6s analg6siques de l'6ther-vinylique (Vinamar~) qui en font un agent surtout utile en anesthfisie p6diatrktue et ehez le patient ambtdant. Plus tam, en 1958, Lu et ses collaborateurs, puis Krantz, font paraltre une etude sur l'6ther 6thyl-vinylique ituor6 (Fluoromar| L'auteur du pr6sent travail est le premier ~t l'employer au Canada, le 8 f6vrier 1954. I1 en 6tudie la valeur et comme analg6sique et comme compMment de l'anesth6sie protoxyde d azote-oxygene. I1 le compare d'autres agents volatils, en partietflier, le trmhlorc.thyleae. Propridtds Le Fluoromar~ est un 6ther fluor6 non satuv6, volatile, incolore, avee une odeur moins p6n6trante que celle de l'6ther 6thyl-vinylique; son point d'6buUi- tion ~ 42.7~ permet de l'employer en goUtte ~ goutte chez les enfants. I1 est stable en circuit ferm6, mais se d6compose au contact de la lumi~re en acetal- d6hyde et en trifluor6thanol, produit tr~s toxique. Emploi Les observations de l'auteur portent sur 178 cas dent 158 de chirurgm dentaire. La majorit6 des patients sont des enfants; toutefois, l'~ge de ceux ~ qui fl fut adm~nistr~ varie de 6 semaines ~ 60 ans. Dans 85 pour cent des eas, on empl0ie settlement un barbiturique comme pr6m6dication, 1--1~ hrs avant l'op6ration; quelquefois on lui associe de la cod6ine, de I'A.A.S., de la morphine-scopolamine, SLA.TE~: TRIFLUOROETHYL VINYL ETHER 11 du nisental ou encore du dSm~rol. ]_,'induction se fair au protoxyde d'azote ~t l'air libre; d~s le d~but de rhyperventilation, on ajoute de l'oxyg~ne ~t une concentration de 20 pour ten! en m~me tern ~s que le Fluoromar~. On administre cet agent au moyen d'un vaporisat.~ur Held ~rink Trimar@ que l'en fixe ~t :~9--10 pendant les 2--8 premieres minutes, pour les extractions denta~'s. On diminue ensuite ~ r comme dose d'entretien. Pour les obturatio'ns dentaires, une intubation nasotrach~ale est pratiqu~e. L'induction se fa~t ~elle que d~erite plus haut; au moment de l'intubation, quelques mgms de succbaylcholine sent administr~s par vole intraveineuse. L'anesth~sie se maintient e~asuite en semi- ferm~ avec du protoxyde d'~zote et oxyg~ne 4:1 et le Fluorom~tr~. Conclusions Le Fluoromar| s'est avSr~ un complSment puissant, et stir ~t la lois, de l'anesth~sie au protoxyde d'azot~oxyg&ne. Comme caractSristiques propres, soulignons les suivantes: 1. Lo Fluoromar| est d6pourvu d'effets irritants sur les voles ~respiratoires et salivaires. 2. Son odeur se tel&re assez facilement aussi bien par les patients clue par le personnel qui l'administre; absence d'odeurs d~sa~r~ables et persistantes dans la pSriode post-op~ratoire, comme avec l'~ther dl~t_aylique. Ce fait seul semble ~tre responsable de la diminution dans l'incidence des naus~es, vomisements, de la toux et de l'augmentation de la salivation. ~. L'~tablissement de l'analg~sie et de l'anesth~sie se fait sans incidents, v.g., Laryngospasme ou agitation, 4. Sa marge de s$curit~ se compare ~ celle de l'$ther diSthylique; elle dSpasse celle de l"~ther dwinylique, du eyclopropane, du chloroforme et du chlorure d'~thyle. 5. Le passage de plans lSgers ~ des plans plus profonds et inversement se fait sans me,dents meme^ s~ l anesthes~e~ . est mamtenueo sup~rfictelle,. la resptration. o des patients est calme et se s s~ms diflqcult6s. 6. On obtient un meilleur contr61e de l'anesthSsie en employant des concentrations plus ~lev~es de Fluoromar| au d~but pour diminuer ensuite graduelle- ment. 7. L'aute~r n'a pas nots de complications cardio-vasculaires; le surdosage peut entralner de la bradycardie qui disparalt en oxyg~nant abondamment le patient. 8. L'emploi d'opiac~s en pr~m~dication et de pentothal pour l'induction contribuent ~ diminuer la quantit~ de Fluoromar~ requise pour une anesth~sie adgquate. 9. Si on ne donne pas de curare avant l'intubation, il faut xrtaintenir les concentrations ~lev~es de Fluoromar| pendant environ 5 minutes. 10. Pas de convulsions ni autres sig~aes d'atteinte du syst~me nerveux central front ~t~ notSs. 11. Le r~vefl est tr~s rapide; le patient peut reprendre aussit6t son aetivit$ mentale sans accuser de ces violentes c~phal~es ou douleurs ~ 3igastriques qui se produisent s[ souvent avec le trichlor~,.thyl~ne et protoxyde c'~zote. CANADIAN ANAESTHETISTS' SOCIETY JOITIRNAL 12. On pr6f6re des vaporisateurs ~ petites bouteilles. 18. On peut administrer le Fluoromar~ au moyen dd n'importe lequel des irdaalateurs suivants: Cyprane, Duke, Trilite ou le M.I.E. Le type Emotril semble le mieux adapt6, car il peut maintenir une concentration plus unfforme pendant une plus longue p6node de temps. La phts graade diflleult6 vient de ce clue le Fluoromar| s'6hmine rapidement et que l'analg6sie est de tr6s courte dur6e. 14. L'introduction d'un ouvre-bouche peut se faire assez facilement

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