Postoperative Vomiting: a Review and Present Status of Treatment

POSTOPERATIVE VOMITING: A REVIEW ~ND ~?RESENT STATUS OF TREATMENT*

L. E. SI2vlONSEN, M.D., C.NI., and S. L. VANDEWAjTER,M.D., r.R.c.r. (c.) t

POSTOPERATIVE VO~vlITING remains one of the most I frequent complications en- countered by the anaesthetist. Although considered no|more than a nuisance complication, it can, in certain cases, contribute to more ~lSan just discomfort for the patient; it can threaten his very life either immediately through aspiration, or later by serious loss bf fluids and electrolytes. It cap also add considerable strain on some operation wounds. After Wang and Boxison 1 further delineated the vomit ng centre in 1952, most of the succeeding research and investigation into the ~ontrol of vomiting has centred about those drugs that have a depressant actio 1 on the chemoreceptor trigger zone (C.T.Z.). Out of these investigations have c ~me much valuable and interesting data which the anaesthetist may use as additio ns to his ever-expanding resources to provide safety and comfort to the surgical patient.

THE VOMXTn~OCENTaE Neurophysiologists have long accepted the existence of a vomiting centre. Located in the medulla in the solitary tract and the dgrsal part of the lateral reticular formation, it lies in close relationship to ma:ay other centres whose functions are associated with the vomiting act such ts salivation, spasmodic respiratory movements, and forced inspiration. ~ Lying lorsolateral to the vagal nuclei and close to the vomiting centre in the area pos :rema of thefloor of the fourth ventricle is an accessory vomiting centre which Ihas been designated as the C.T.Z. The C.T.Z. is a receptor centre, the functio~ of which is to act as a funnel for many afferents arriving centrally from lower levels and to channel these stimuli to the emetic centre which co-ordinates aUthe nervous and chemical stimuli that converge on it. The C.T.Z. is not a relay for all afferents, however, since those stimuli which originate in the autonomic nerve endings of the gut, ~ kidneys, uterus, or the heart4 travel via the vagus nerve or sympathetic nervous isystem, or both, reaching the vomiting centre directly without traversing the C.T.~. Other stimuli affecting the vomiting centre directly are those arising from (a) hypoxia of.-the centre, as for example from increased cerebrospinal fluid pressure, or (b) psychic stimuli from the cerebral cortex. The pathways and ori g in of stimuli causin g vomitin ~ ma y be summarized as in Table I. It seems reasonable, therefore, that pharmacological efforts to con- trot nausea and vomiting might well be directed at interrupting one of these reflex arcs. *Presented at the Annual Meeting of the Canadian Anaesthetists' Society, Montebello, P.Q., May 8--11, 1961. Wrom the Department of Anaesthesia, Queen's University, Kingston, Ontario. 51 Can. Anaes. Soc. J., vol. 9, no. 1, January, 1962 52 CANADIAN ANAESTHETISTS"SOCIETY JOUBNAL TAI}LE ][ CAUSES OF VOMITING i 1. Indirectly via C.T.Z. (a) Blood-borne chemical stimuli (b) Vestibular stimuli ( motion sickgess ) (c) Certain metabolic and endocrin 9 stimuli producing vomiting of pregnancy 2. Directly via vomiting centre (a) Stimuli arising from the wall of the g~t or heart (b) Hypoxia of the centre-increased inttacranial pressure, anaemia, anoxaemia as in high altitudes (c) Psychic stimuli-pain, smell, taste, sight

INCIDENCE AND FACTORS RELA?FED TO POSTOPERATIVE VOMITING Severa~ extensive series of investigations into the incidence~f postoperative nausea and vomiting have been reported. The wide range of ~sults reflect the magnitude of the variations of techniqge, agents used, ability of the anaesthetist, and dependability of the observer. Waters ~ in 1936, in a series of 10,000 cases, reported an over-all incidence of 40.6 per cent. In 1955, Dent 6 found a_~nincidence of 27.2 per cent land Burt'es and Peckett 7 an incidence of 32 per cent. iThese investigations include all types of surgery and anaesthetic techniques. ~control series by Gordon et al. s in 1954 reported an over-all incidence of 41 per cent. Knapp and Beecher ~ in 1956, using a standard sequence of nitrous oxidel oxygen, and ether for various types of operations, found an incidence as high as 82 per cent whereas Dobkin's 1~ over-alt incidence, excluding those with gastri6 suction, was only 15.5 per cent. Factors relating to postoperative ndusea and vomiting are many and varied. In an excellent review by Belleville, 11 the most consistent factor noted was the sex difference; women vomited much more ,commonly than men with no decrease in the female incidence until the eighth decade of life. Men, on the other hand, had a decreasing incidence with age./Boni~bal~ felt that the age group 40 to 60 had the highest incidence. When morphine is used as a premedicant, there is a higher incidence noted than with meperidine. TM The incidenVe of nausea and :~hme~nL dPlPoT::t t:mbo:g~gh::thm ~ e ~h: st~i o~h: t :~la~: n :~:~~ eolxi~ and thiopentone. Because of,the decr/ased probability of forcing irritating gases into the stomach, those patients who l are intubated vomit less,' than those who receive their anaesthetic by mask. 6,11,1a Hypotension during surgery increases the incidence, possibly owing to anoxaemla of the vomiting eentretll The incidence is also directly proportional to th6 length of anaesthesiaT.~,~2,~*; but Belleville, ~ on the other hand, felt that the ~eidenee decreased in proportion to the length of postoperative sleeping time. Robbie in found that operationsf lasting less than half an hour or longer than one hour were followed by a lower incidence than operations lasting between one-half and one hour. The same author felt that with breast operations there was a higher; ineJ[denee than with operations at ~other sites. Dent, 6 however, found that more persons having head ~nd neck surgery vomited than those having intra-abdominal or extra-abdominal operations. IThis ,SI~IONSEN & VANDEWATER: POSTOPERATIVE VQMITING 53 / can be expected since the solitary tract that receive~aff~rents from the facial, od~176 eal,g and vagu s nerves is also the site of the vomitin, g centre. Burtles and Peckett 7 have shown that the Trendelenbttrg ,~r reyersed Trendelenburg positions were associated with a higher incidence 'lprol~ably because a large proportion of operations! in these positions are carried Out in the female, for example, gTnaecological abdominal surgery, varicose veir~ surgery, thyroideeto- mies and mastectomies." The ]owest vomiting inciderme ~as associated with the lithotomyposition.

CAUSES OF POSTOPERATIVE VO~'I~TING0i I

/ 1. Circulating anaesthbtic a~ents or break-down product~., 2. Hypoxia-o~f the vo~niting centre from any catrse such as hypotension or increased intracranial pressure. 3. Psychogenic or cortical, including odours, sights, taste I. 4. Gastric irritants, e.g., anaesthetic vapors. f .5. Distention or traction of viscera from surgical ma!nipulation. 6. Movements of the patient's head (motion sickness ). 7. Emergency patient with a full stomach. 8. Stimulation of vagus, glassopharyngeal, or facial neryes from surgery in the vicinity of {hese nerves. 9. Idiopathic or undetermined factors: (a) position dlaring surgery, (b) site of surgery, e.g., breast, pelvis, (c) sex and age.

Tim ROLE Or THE ANTI-EMETICS In a review of the existing literature of the past decade or so, it appears that most of the investigation into postoperative nausea and vomiting centres about the anti-emetic properties of the antihistamines, phenothiazine derivatives, and other unrelated compounds such as trimethoxybenzamide. / However, a very old drug with anti-emetic properties ig one which tends to be lost in the myriad of new compounds: scopolamine.

H C---- C------CHe CHi20H /l 1 I I/----~ 0 I N-CHa CH.O.CO.C, k k \I t I ----; H C C---- CH., Scopolamine

The antinauseant property of scopolamine has beet~ appreciated for many years although the site of action has not been clarified. Its ability to block impulses from the cortex to the medulla 16 helps support Goodman and Gillman's !7 opinion that scopolamine's site of action in motion sickness protection is likely cortical or directly on the utricular maculae. It may also be assumed that part of its anti-emetic efficacy may lie in its ability to block vagal impulses to the vomiting centre from the bowel and heart. Because~0 f the number of other antinauseants in common use, and also because of ~e undesirable side effects 54 CANADIAN ANAESTHEtiSTS' SOCIETY JOUtlNAL of the drug such as drowsiness, tachyCardla, , and vasual disturb. 9n ees m lar er doses, it perhaps is not the drug of c~aOiee m the prevention or treatment!of nausea and vomiting. When antihistamines were discpverr (by accident)to havre antinause~t properties, numerous investigationsl Wer~ carried out on a varie~ of these drugs: Those found to be most useful Wer~' dimenl~ydrmate" (Dramamine)," ' " i8,i9,~i if!: diphenhydramine (Benadryl),Z".2a ~nd ~yclizine lactate (Marzine ,.12,!8,~4,~5O@er antihistaminics such as propherlpyri'i~tamine i(or Trimeton)i chlorcycli~ (Perazil), and meclizine (Bonami~e) are also listed 6 as g~wng s~gnifieant pr0,1 tection against motion sickness as ~omFared With a placebo but~ not of sufflci'nt imp~ta~ace to elaborate upon in a reviev of this nature.

} ,,I ! 0 0 N , , CHo. CH~ () I 1 N CH_~ CH,., / ~ I t H C~ N N ,/ "N, /" ~ Cyclizine lalctatef CH3 CH3 Clt3 CH3 Diphenhydramine (

CH 3--( //\I o ? CH~ Dime~hydrillate

Although dimenhydrina~,.differs from diphenhydramine by the additioo 0f 8-chlorotheophylline, the radi'cal contributes, nothing to the antitemetie a.ctio~I ~0f the drug and the two drugs are considered equal in effect. 2~ Followmg i~e classical work of Gay and Carlin6r2.s ~nto theprevention and treatment of s~- sickness, dimenhydrinate was investigated by several groups and found to b~a effective anti,emetic, with results t compared with chlorpromaziOe, ranging from satisfactory ~9 to good. TM As Kulasavag~and McCawley 3o point6d out, howevr dimenhydrinate fails to protect agains~stimuI# arising in the stpmach, ~us ~ugi gesting that its site of action is elsewhere thafl on,the~'vomiting leentre or o~:~e afferents, travellin g centrally from ithe gut. The only significant ide~i effect~_nbtd ~rom the use of dimenhydrinate were pain at the site of injection TM and oc~sl0n: ally prolonged drowsiness, ls'19

A P iperazine derivative, cyclizinei lactate (Marzine), was:als6, investigate ~by Moore, who found that cycl,zme redaced nausea and vomlting~o approx~matdy one-half that found iasin~ a plaeeb@ Similar reductions in ~e incidence Wde SIMONSEN & VANDEWATER: POSTOPERATIVE VOMITING 55 L found by others. 1 .21 Ho~eever, in a series of 852 cas~s u~ing meelizixae (Bona- mine), cyclizine (Ms_rzine), and saline placebos, Tillman3~ found i that there was no apparent advantage in!the use of either drug. This ~erh~ps supports Goodman and Gillman's 32 contention that most of these antihistamines have been statistical successes and the relief gained may be "more obviou~ to ~he statistician than to the patient." Although the antihelmintic phenothiozine has no an~histaminic or C.N.S. depressant action, derivatives of the nucleus possess these as well as many other properties. .j\/s\~ l il tl /

\ H Phenothiazine

Chlorpromazine hydrochloride (Largactil, Thorazine),|although not the first phenothiazine derivative discovered, enjoyed the position of being the most thoroughly investigated. Its anti-emetic properties were found to be of the highest order both in apomorphine-induced vomiting in dogs 33 and in humans following surgeryY 4 Its site of action, and indeed the site of action of all t3heno- thiazines in inhibiting vomiting, is at the C.T.Z. Chlol promazine lacks antihistaminic activity, does not appear to control motion ickness, and does not prevent vomiting produced by cardiac glycosides. 85 ~IL / s\iG

I CH._,CH.~CH eN (CH~) _~. HC1 Chlorpromazine H C1

Promethazine hydrochloride (Phenergan) was the firs! phenothiazine derivative to be discovered and, unlike chlorpromazine, it has strong antihistaminic properties. Its postoperative anti-emetic activity was compared with that of chlorpromazine by Burtles and Peckett 7 and it was found to be equally as potent and without the disturbing side effects of chlorpromazin~, such as hypotension with tachycardia, z6 vasodilatation, and pain at the site of ir@ction. ~r /s\/%

1 CH.~CH--N--(CH3) 2"HCI I CH3 Promethazine HC1

Another phenothiazine compound, prochlorperazine ih_ydrochloride (Stemetil, Compazine) was found to be equally effective as prombthazine 14 but seemed to 56 CANADIAN ANAESTHETISTS" SOCIETY JOUBNAL allow for a shorter postoperative reeove~/ time. Bovdas.. compared, the drug wi~: chlorpromazine: both protected against apomorphme, hydergme, and swing b~t failed to protect against copper sulphate cedilanid.

! H /,~L,,.,cl

CH~CH,,CH N--CH3" (C4H404) ~

1 P r ochlprper zme" indicate

Wang a9 demonstrated that a fourth d~rivative of phenothiazine, perphenazine (Tril~ was from 16.6 to 47.8 times haore potent than chlorp~mazine in pre, venting apomorphine-induced vomiting the higher figure bein~freached when stronger stimuli were applied. This findi lg that the drug gains in relative efficacy as the stimulus is increased was confirmed clinically by Phillips et al. 4~ In contrast to chlorpromazine's total ineffectiven,.~ss in combatting emesis induced by lanatoside C, 85 perphenazine was iq~t( effective. It has two troublesomeI side effects: prolonged drowsiness occurring~in 38 to 52.6 per cent of Phillips' series4~ and a Parkinsonian-type reactiona~ which usually clears in 24 hours. Dob~ a~ found that perphenazine not only redt}ces postoperative vomiting tO one-thUd compared with controls, but also that th~ drug is helpful in relieving hiccoughs I //\/s.~..,~. %/%x/\/%c1 ICH'CH"CH"~N O N--CH.,CH oOH ) - _ _ I erphenazine

A flourinated phenothiazine derivative, triflupromazine hydrochlorlde'" (Ves- prin) has been shown to have anti-emeti, properties. A significant decrease in pDst~ operative emesis has been "found by several authors, 41,42A3 whenl'it is used boN intravenously and intramuscXu!arly: Hy ,ote,nsion was the only tndesirable sld~ effect occurring in 8.3 per cent of Davies series 41 to 62 per dmt of SheinFer's series43; this could be relieved simply I by elevating the foot oi the bed orj~ some cases using vasopressors. Dav:ies41 suggests that the hypotc~nsion produ~ ~ by trittupromazine may be partly icardiogenic in nature, being better relieved by desoxyephedrine than by metho~qamine. ~/N/s x./%~

E CH~CH~CH~N(CH~) ~- HC1 Triflupromazine HCI SIMONSEN & VANDEWATER: POSTOPERATIVE IVOMITING 57 Pipamazine (Mornidine) will also produce hypoS:ensign' but onlyI i~ doses in excess of that necessary tO produce statistically significaflt results as a postoperative anti-emetic. 4.

I /_\ //9 CH~CH:CH~N \.__~--C~NH, Pipamazine

TltlMETHOXYBENZAMII)E (TITANI A substituted benzamide, trimethoxybenzamide hych'ochloride (Tigan), was developed as a specific anti-emetic having a direct effept on the C.T.Z. Because it is neither an antihistamine nor a phenothiazine, it was hoped, that the tmdesirable side effects of these two drugs, such as dro~vsiness and hypotension, might be avoided. An investigation by Schalleck 4~ using dogs found that the drug had about one-tenth the potency of chlorprom~zine in preventing apomorphine-induced vomiting and had no depressant effect on the reticular- activating system. While chlorpromazine causes a ~rolonged fall in blood pressure, which is attributed to an action on the vasoc,.onstrictor centres, in the brainstem, trimethoxybenzamide had much less effect. This fact along with the absence of behavior changes and slowing of EEl?, patterns suggests that this drug has a more specific action on the centres of zontrolling emesis. In an investigation conducted at the Kingston Gel leral Hospital using 200 rag. of trimethoxybenzamide hydrochloride intramuscularly following all types of surgery but with certain exclusions (emergency surgery, operations requiring massive transfusions, patients having severe hypotension or bronchospasm, and children under sixteen years) sufllcient evidence was~lnot obtained to confirm that this drug was an effective postoperative anti-emetic agent. Using a dguble blind technique, the active agent or a placebo was iniected immediately upon the arrival of the patient in the recovery room and the results noted quarter- hourly over a two- to four-hour period. Those who recover promptly after rela- tively short and minor procedures and are free of hypotension, nausea, vomiting, pain, etc., are discharged quickly while those who l~ave had more extensivej procedures and are slower to recover are kept for longer periods, occasionally overnight. The action of the drug is felt to have disappeared by the end of four hours, and further records of nausea and vomiting or the absence thereof areJ not considered beyond this point. In a total of 500lpostoperative patients, ~oup receiving the placebo gave an incidence of 16.60 per cent whereas similar series using 200 rag. of trimethoxybenzamide had an incidence of 12.45 per cent, a reduction of only 4.15 per cent, which is not statistically significanl~ according to the chi-square test. This finding agrees with Blatchford, 44 who suggested that because of the lack of side effects it might be employed in large~ doses. The series is being continued, therefore, using 400 mg. of the drug, and a report of the next 500 cases will be presented at a later date. 58 CANADIAN ANAESTHETISTS' SOCIETY JOLrRNAL Sheiner 46 found that the intravenous u~e of 200 rag. of iTigan Was useful i~. treating laryngospasm or coughingocqurriI~g during or after anaesthesia.

}~tEOPERATIVE ~UsE (~F ANTI-EMETICS The routine preoperative use of anJ anti-emeticL is not~ felt justified and the reasons for this opinion are well stated in an editorial by Keats. 47 He feels that 80-90 per cent of patients given a pre-operative antiemetic will have! been treated unnecessarily because vomiting will no t occOr in approximately 70 per!cent of these patients and ano~er 10-20 per cent will vomit even though 149 Thus, in order to gain a 10 to 20 per cent decrease ml i the mcldenceIo * of nausea and " vo~xting,i ,' 80-90 per c~nt-~o~f the patients are treated unnecessarily-and exposed t~; the discomfort and unwanted side actmns" of these drugs.i IFurthermore, were the~a~'~ specific" drug without side. aetmns,. its. routine. use would | not be justified. . from t]~e pointi of wew. of expense if nothing else, if so little beneficial effect can be anticipated in so few patients. Lorhan, ~5 on the other hand, felt that ~he preoperative administration of an anti-emetic would be valuable priorio cOtaract surgery under local anaesthesi because of the possibility of rupture of the wound, iris prolapse, a~d occasionai loss of ocular content if' vomiting or retching occurred. This routine use could perhaps also be extended to complicated ophthalmic surgery under any form of anaesthesia as well as to immobilization of fractures of the facial ibones, plastic~ facial and oral surgery, and other similar/forms of surgery where disasters migh! occur ff postoperative vomiting ensued.

SUNIlk~AI~YAND ICONCLUSIONS A brief summary of the anatomy ant physiology of the vomiting centre ii presented along with a review of the ncidence and factors related to p9s!, operative vomiting. The roles of scopola mine, antihistamines, and many of th~ phenothiazine derivatives now in popula use as presented by several mvestlgg, tors are reviewed. It appears that as the potency and efficacy ~ef a particular postoperative anti-emetic ~"increases, th~ toxicitv and unwantec side effec~ [ also increase, an example being perphfenazine.'Under the con( [itions of our investigation, trimethoxybenzamide doejs not appear to reduce postoperatiye nausea and vormtmg to a stat!stically slgmficant [ , degree although a further tn~lif. using a double dose may alter this opinion. The routine preoperative administr~. fion of anti-emetics is not justifiedlexeept in certain cases, such as in cataract and facial surgery where post-opera~tive vomiting might prove disas!r0us. The trimethoxybenzamide hydrochloride (HCI) was supplied arid its trial supported, by the Hoffman-LaRoehe Company, Montreal I

B~suMf~ Nous avons resume'" bri~vement l'anatomie et la physiologic du c~,ntre du volms~' sement, puis nous avons 6tudi6 la fr6qUence~~ des vomissements post-op~ratoiris et aussi les facteurs qui Ies mfluencen~. ' Nous avons~ etudle' "" le role/de^ la scopola, SIMONSEN 8t VANDEWATER: POSTOPERATIVE yOMITING 59 mine, des antihistaminiques et de plusieurs d6riv6s ~te la ph6notiazinetl~_ ,en usage cottrant actuellement et domme le font plusieurs cherchet~rs. I1 semble qu ~t mesure qu'augmentent le pouvoir et l'efiqcacit6 d'un ant i~n6ti~ue post-op6ratoire par- tieulier, augmentent 6galement la toxicit6 et les effets secondaires ind6sirables; exernple: ]a perph~nazine. Dans nos conditions d'exl~rience, la trim6thoxy- benzamide ne semble pas diminuer les naus~eS et les vomissements post- operatolres de fa~on apprecmble statlstiquement, blen I qu un nouvel essai, en employan,:t! une double: dose, pourralt modifier. notr~ opimon. L , administration de routine, a la suite des opera~ons, de medications anti~metiques n est pas ]ush- fiable, except6 dans les cas de cataracte ou de chirBrgie de la face oCT les vomissements post-op~ratoires pourraient entrainer an d~sastre,

REFERENCES 1. W~a~rc, S. C., & BoPasoN, H. L A New Concept of Organization of the Central Emetic Mechanism: Recent Studies on the Sites of Action of Apomorphine, Copper Sulfate and Cardiac Glycosides. Gastroenterology 22:1 (1952). 2. W~c, S.C. Localization of the Salivator/Centre in the Medulla of the Cat. J. Neuro- physiol. 6:195 (1943). 3. BEST, C. H. & TAVLOa, N. B. Physiological Basis for Medical Practice, 7th ed. Balti- more, M.D.: Williams & Wilkins Co. ( 1961 ). P. 701 4. I-IATCnFm, R. A., & Wv.iss, S. Studies on Vomiting. J, Pharmaeo!l. & Exper. Therap. 22: 139 ( 1923 ). 5. WATERS, R. M. Present Status of Cyclopropane. Brit. Me~t. J. 2:i013 (1936). 6. D~T, S, J.; RAM~DaA, V.i & STEPHEN, C. R. i Postoperative Vomiting: Incidence, Analysis and Therapeutic Measures in 3000 patients. Anr 16:464 (1955). 7. BUaTLES, R., & PECKETT, B. W. Postoperative Vomiting~ Some Factors affecting its Incidence. Brit. J. Anaesth. 29:114 (1957). 8. Gore)ON, R. A.; VANDEWATER, S. L.; SLEATH, G. E.; & CAPL~, D. A Study of the Value of Dimenhydrinate and Promethazine Hydrochlo~ide in the Control of Post- anaesthetic Vomiting. Canad. Anaesth. Soc. J. 1 : 95 (1954). 9. KN,~PP, M. R., & BF.ECnY_~, H. K. Post-anaesthetic NauSea, Vomiting and Retching. Evaluation of the Antiemetic Drugs Dimenhydrinate~i (Dramamine), Chlorproma- zine, and Pentobarbital Sodium. J.A.M.A. 160:376 (1956). 10. DoBma~r, A. B. Perphenazine in Clinical Anaesthesia. Canad. Anaesth. Soc. J. 6:375 (1959). 11. B~LLVaLLE,J. W.; BROSS, I. D. J., & HOWLAND, W. S. Postoperative Nausea and Vomit- ing. IV. Factors Related to Postoperative Nausea and ~omiting. Anesthesiology 21: 186 ( 1960 ). 12. BONICA, J. j.; CREEPS, W.; MONK, B.; & BENNETT, B. Postoperative Nausea and Vomit- ing. Western J. Surg. 67:332 (1959). 13. MARCVS, P. S:, & SHEEnA~r, J. S. Treatment of Postoperative Vomiting. Anesthesiology 16:423 (1955) 14. HOWAT, D. D.C. Anti-emetic Drugs in Anaesthesia. Anaesthesia 15:289 (1960). I5. ROBBrE, D. S. Post-anaesthetic Vomiting and Anti-emeti~ Drugs. Anaesthesia 14:349 (1959). I I6. TESOmErU~, H. S. Uses and Abuses of Scopo|amine--A Clarification. Anesth. & hnalg t $8:103 (1959). 17. COODMArr L. S & GrLMAN, A. The Pharmacological Basis of Therapeutics. 2nd ed~ , New York: MacMillan Company (1955). 18. MOORE, D. C.; ANDERSON, L. G.; WrmELER, G.; & SCrtEmT, J. The Use of Parenteral Diaanamine to Control Postoperative Vormting: A ~ReportI of 1].92 Cases. Anesthesiology 13:354 (1952) 19. HUM_E, R. B., & WINNER, W. K. The Use of Dramamine in Control of Postoperativ~ Nausea and Vomiting. Anesthesiology 13:302 (1952). i -90. CA~tPBELL, E.H. The Effectiveness of Dramamine in l~e~eving the Vestibular Reactions Following the Labyrinthine. Fenestrationo Operation.. LaUrngoscopei 59: 1261 (1949).' I 60 CA~NADIAN A NAESTHE'/IISTS'~ ~SOCIETY JOURNAL 21. WO::dE~ it g. . . 6 5 ntlon of Post perative Nausea 22. LOFSTr~U~, J. E., & NVm~nFa~CF_~, C t E. Irradiation Sickness; Histamifie Effect Treaied with Benedryl; A Preliminary Report. Am. J. Roentgenol. & Radi~um Therapy 56: 211 (1946). 23. BIGNALL, J. a., & CROFTON, J. AntihiStaminic Drugs in-Treatmen[ of Nausea a,d Vomiting due to Streptomycin. Bri t. Me d. J. 1 : 13 (1949). 24. MoonE, D. C.; BamENBAUCH, L. D.;IPrcc~o~I , ~. F.; ADAMS, P. A.; & Lm-OSTRUM, C. iA: Control of PoStoperative Vomiting with Marezine: A Double Blind Study. Anesthesio~ logy 17:690 (1956). 25. Lonn_~N, P. H. Cyclizine Lactate (M~rezine) fo~" Postoperatix~e Control of Nausea and Vomiting after Cataract Surgery: Arlaesth. & Analg. 37:247 (1958~. 26. RoBsoN, J. M., & IO~FZ~E, C. A. R~cent Adwmces in Pharmacology. ~nd ed. London: J. A. Churchill Ltd. (1956). P. 163. 27. WHITE, J. M.; 'FREEDI~fAN, D.; McCawLr~Y, E. L.; & GRAY, W. D. Effect Of Cer[ain Dialkyl-substituted Amin0alkyl-bdaring/Compounds on Apomorphine-induced Emesis! . Federation Proc. 9:325 (1950). 28. G~. N, & CxaLmF_a~, P. E. The prevention and Treatment of~ Motion Sickness, Bull. Johns Hopkins Hospital 84:470 (1949). 29. CAPLIN, D., & SMrrH, C. A Comparisodof the Anti-emetic Effects d~ Dimenhydrinate, Promethazine Hydrochloride, arid Chlorpromazine Following Anaesthesia. Ca~ Anaesth. Soc. J. 2:191 (1955). 30. KULASAVACE,R. j., & McCAwr~Y, E.L. Correspondence. J.A.M.A. 145:429 (19fl'13. 31. TmLMAN, W. W.; WISE, G. F.; & Cn~,wr'om~, O. B. Evaluation iof Marezihe~-a~ Bonamine in Lowering the Incidence of Postoperative Vomiting. Anesthesiology 17: 11~ (1956). 32. GOODMAN, L. S., & GmMaN, A. The Pharmacological Basis of Therapeutics. 2nd ed., 1st printing. New York: MacMillan Co. 1(1955). P. 664. 33. BovD, E. M.; BOYD, C. E.; & CASS~LT., W.A. The Anti-emetic ActiOn of Chlorproma' zine Hydrochloride. Canad. M.A.J: 70:276 (1954). ] 34. VANDEWA'r~xa, S. L., & GORDON, R.A. I~argactil in Anaesthesia. Canad. Anaesth. Soc. J. 35. GLx~O,2:23 (1955). V. V-, & W~c, S. C. Dual Mec hanism of An"ti-e me t'cI Ac tl"on of 10-(,r-Di, methylaminopropyl)-2-Chlorophenothiazine hydrochloride (Chlorprornazine) in Dogs, J. Pharmacol. & Exper. Therap. 114:358 (1955). 36. DoB~, A. B.; K.mDtrFr, C. J.; & wy.~w, G. M. Indications for Chlorpromazine (Largactil, Thorazine) in Clinical Anaesthesia. Anaesth. & Analg. 36:38 (1957 i. 37. DFa~Ps, R. D.; VAt,DAM, L. D.; Preach, IE. D..; OEC~, S. R.; & LUR~, A. A. The Use of Chlorpromazine in Anaesthesia and ~urgery. Ann. Surg. 142:774 (1955). 38. Bo~D, E.M. Antemetic Action of Proclorperazine. Canad. M.A.J. 76:286 (1957). 39. W,~rc, S. C. Perphenaz/ne, a Potent arid Effective Antiemetie. J. Pharmacol. & E~er.

Therap. 12~: 306 (1958). ' . I 40. PHILLIPS, O. C.; NELSON, A. T.; LYons, Vr B.; GRAFF, T. D.; H.~ms,.L.C.; & Faazma, T. M. The Effect of Tri~afon on Postanesthetic Nausea, Retching and Vomiting. Anaesth. & An~4lg. 39:38 (1.~60). :: 41. A~, F. J. JR. Treatment\0f Ambulatory and Hospitalized Psychiatric Patients witl~ Trilafon. Diseases of the Nervous System 18:394 ( 1957 ). 42. McI~rr~m~, J. w. R. Ataractics and the/Recovery Room with Reference to Trifluproma, zine, I. Canad. Anaesth. Soc. J. 7i 176 J(1960). 43. Sn-~rNr_~a, B. A Preliminary Repo~ on Postot~rative Use of Fesprin by Drip Methodi Anaesth. & Analg. 39: 435 (19..610). , 44. Br.ATCmeOaD, E. Studies of Anti,me.fie Drugs: A Comparative S~udy of Cyclizine (Marzme), P~pamazme (Morm~me),.,1 I Trhnethobenzamide (Tigan), and Hyoseme:I* ? Canad. Anaesth_ Soc. J. 8:159 (1961).I 45. SCH~L~CK, W.; H~SE, G. A.; I~iaa-~, E. F.; & BACDO~r, R. E. Anti~emeiSc Activity of 4-(2-Dimethylaminoethoxy)-N-(3,4,5-Trimethoxybenzoyl) Benzylamlne Hydroehloridel J. Pharmol. & Exper. Therap. 126:270 I(1959). 46. SHE~a, B. Use of Trimethobenzamide i(Tigan) in Anaesthesia. Canad- M.A.J. S& !377 (1960). 47. K~ATS, A.S. Editorial. Anesthesiology 2!: 213 (1960).