CLINICAL STUDIES OF INDUCTION AGENTS XII: THE INFLUENCE OF SOME PREMEDICANTS ON THE COURSE AND SEQUELAE OF FROPANIDID ANAESTHESIA

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1 Brit. J. Anaesth. (196), 37, 1 CLINICAL STUDIES OF INDUCTION AGENTS XII: THE INFLUENCE OF SOME PREMEDICANTS ON THE COURSE AND SEQUELAE OF FROPANIDID ANAESTHESIA BY RICHARD S. J. CLARKE AND JOHN W. DUNDEE Department of Anaesthetics, The Queen's University of Belfast, Musgrave Park Hospital, Balmoral, Northern Irel SUMMARY Studies were carried out using propanidid-nitrous oxide-oxygen as anaesthesia for minor gynaecological operations with varying premedicants. Commonly used antiemetics hyoscine, cyclizine promethazine increased the incidence severity of excitatory phenomena to an intolerable degree. This was accompanied by a great increase in propanidid dosage as compared with a control series premedicated with alone. Despite this large dosage hypotension was infrequent return of consciousness prompt. Morphine pethidine potentiated propanidid by decreasing the total requirements of anaesthetic, but their use was followed by a great increase in vomiting nausea. Although the other premedicants reduced the emetic sequelae, their use before propanidid is not recommended. In the early clinical trials of propanidid both Dundee Clarke (196) Goldman Kennedy (196) observed a high incidence of nausea vomiting. This usually occurred immediately at the termination of the anaesthetic may have been partly due to the rapid return of consciousness. Since emetic sequelae are troublesome complications of an otherwise promising new intravenous agent, it seemed necessary to determine whether the pre-operative use of well-known anti-emetics would influence the course of anaesthesia. This is particularly important since hyoscine, cyclizine promethazine all markedly increase the incidence of excitatory phenomena with methohexitone (Dundee Moore, 1961a, b; Nicholl, Moore Dundee, 196) hyoscine promethazine have a similar but less marked effect on thiopentone (Dundee, Armstrong Alexer, 196; Dundee, Nicholl Moore, 196). This paper reports a study designed to determine the effect of the premedicant use of these anti-emetics on propanidid anaesthesia, using the data obtained with alone as a control. The study also includes the two commonly used opiate premedicants morphine pethidine. METHOD The patients were fit women scheduled for minor gynaecological operations. In order to validate comparison of emetic sequelae, half the patients in each group underwent cervical dilatation uterine curettage, while the other half had procedures not involving cervical dilatation, largely curettage of incomplete abortions (Dundee, Nicholl Moore, 196). Premedicants were as follows:.6 mg; hyoscine. mg; pethidine 1 mg with.6 mg; morphine 1 mg with.6 mg; cyclizine mg with.6 mg; promethazine mg with.6 mg; promethazine mg with hyoscine. mg. Injections were given intramuscularly 6-9 minutes before anaesthesia. Anaesthesia was induced with propanidid mg/kg maintained with 7 per cent nitrous oxide in oxygen, intermittent doses of propanidid being given as required. No other drugs were given except when it was necessary to give suxamethonium to control violent movements. Details of the observations made during after anaesthesia, the method of grading, of assessing emetic sequelae have been fully described by

2 BRITISH JOURNAL OF ANAESTHESIA Dundee, Moore Nicholl (196) Dundee, Nicholl Moore (196). Table I gives the number of cases in each series shows that each is broadly comparable as regards age weight. The reasons for the small number of observations with some of the premedicants will be apparent when the results are presented. TABLE I Details of patients studied Pethidine Morphine Cyclizine hyoscine Number Average Average of age weight patients (yr) (kg) RESULTS Table II shows the percentage incidence of complications occurring during anaesthesia. There was a slight but insignificant reduction in excitatory phenomena with pethidine- or mor- TABLE II Observations on course of propanidid, nitrous oxide oxygen anaesthesia with various premedicant dru^s Premedication Pethidine Morphine Cyclizine phine- as compared with alone. Premedication with hyoscine, cyclizine-, promethazine- or promethazine-hyoscine was followed by a very great increase in the incidence severity of tremors spontaneous involuntary muscle movement as compared with the other premedicants. Laryngospasm was notable by its absence with any form of premedication cough or hiccough was an infrequent complication except after cyclizine. There was no instance of respiratory depression of such severity as to necessitate assistance. Because of the small number of cases in some of the series, too much attention cannot be paid to the variation in frequency of hypotension with different premedicants. In spite of the much larger total doses of propanidid required after the anti-emetic premedicants (table IH) the frequency duration of hypotension was not greater than after alone. The overall course of anaesthesia (as shown by the distribution of grades) was best after opiate or alone as premedication. -hyoscine was the worst premedicant in this respect, but with hyoscine alone, promethazine- cyclizine- the inci- hyoscine PERCENTAGE COMPLICATIONS Excitatory phenomena Tremor Involuntary movement Nil Respiratory upset Cough hiccough Laryngospasm Nil oog Fall in systolic B.P. of 1 mm+ 1 Under min* 7 + min* ooo 1 1 OVERALL COURSE OF ANAESTHESU % Uneventful (Grade 1) 7 % Slight upset (Grade a) 19 % Moderate upset (Grade b) % Marked upset (Grade 3) OOOO Calculated as percentage or total patients showing hypotension.

3 CLINICAL STUDIES OF INDUCTION AGENTS XE 3 TABLE III Data on dosage of propanidid rapidity of recovery with different premedicants. Average duration of anaesthesia (min) Average dose propanidid (mg/kg) Initial Total Ratio of total to induction dose % need of supplementary doses Condition of patient two minutes after end of operation % Awake % Safe % Unsafe Pethidine Morphine Cyclizine hyoscine TABLE IV Percentage incidence of emetic sequelae following propanidid anaesthesia with different premedications. Premedications Pethidine Morphine Cyclizine hyoscine First V hour N V = vomiting (including retching). 1-6 hours V 16 8 N 1 16 V N First 6 hours Nil N = nausea. score Average score sick patients only dence of grades b 3 was still too high to recommend the use of these drugs before propanidid. Table HI gives the data on the duration of anaesthesia, dosage of propanidid rapidity of recovery. The longer duration of anaesthesia with cyclizine-, promethazine- promethazine-hyoscine premedications was undoubtedly due to the difficulties in producing satisfactory operating conditions in these cases. This increase in duration alone is not, however, sufficient to account for the greater total dose of propanidid used, the higher incidence of need for supplementary doses after these forms of preanaesthetic medication, to a lesser extent after hyoscine. All four combinations increased the requirements of propanidid, as compared with the patients who were premedicated with only. (The average total dosage after promethazine-hyoscine would probably have been greater than that required with promethazine had it not been necessary to give mg of suxamethonium to two patients to gain control of the anaesthesia.) The lowest total requirements

4 BRITISH JOURNAL OF ANAESTHESIA of propanidid followed morphine- premedication, while part of this may be attributed to the shorter duration of anaesthesia, there is some evidence to suggest that both opiate preparations potentiate propanidid. Data on the condition of the patients minutes after the end of anaesthesia must be interpreted in relation to both the duration of anaesthesia the total dose of propanidid used. As was to be expected, fewer patients were recorded as being "awake" when the larger doses referred to above were given but the number classed as "unsafe" was very low, except after promethazine-. The effect of hyoscine in delaying return of consciousness was not nearly as marked as that found after thiopentone (Dundee, Armstrong Alexer, 196) or methohexitone (Clarke, Dundee Moore, 196; Dundee, Moore Clarke, 196). The number of observations is too small to assess the relative anti-emetic effect of the various premedicants, but hyoscine, cyclizine-, promethazine- promethazine-hyoscine were all followed by fewer emetic symptoms during the first hour after anaesthesia than alone. It was surprising to find that hyoscine caused a significantly higher incidence of "late" nausea than, while the other anti-emetics completely abolished emetic symptoms during the 1-6 hour period after operation. Judged by the average emetic score, any of the four premedicants discussed above resulted in a significant reduction in the overall incidence, rather than in the severity of nausea vomiting. Morphine with pethidine with significantly increased the incidence severity of both the early late emetic sequelae, in the dosage used, morphine was much worse than pethidine in this respect. None of the premedicants studied had any influence on the occurrence of postoperative hypotension, which was only seen on two occasions in the whole series of 1 cases. Although complete return of mental faculties appeared to be slightly delayed after promethazine hyoscine, as compared with other premedicants, patients were alert more quickly after propanidid than after diiopentone or methohexitone. DISCUSSION Propanidid has been shown to behave similarly to methohexitone thiopentone with respect to the effect of premedication on the course of anaesthesia. Drugs which decrease sensitivity to somatic pain decrease the incidence of excitatory phenomena, while antanalgesic premedication increases the frequency severity of this complication (fig. 1). There is a less well defined relationship between the analgesic or antanalgesic action of the premedication the total dose of propanidid required for a stard operation. z + O- o- - O O O O 6 8O CO % EXCITATORY PHENOMENA K> O 3O O RATIO. OF TOTAL TO INDUCTION DOSE FIG. 1 Relationship between the analgesia index of the premedication incidence of excitatory phenomena found with propanidid, the ratio of total to induction dose of this anaesthetic required for a stard operative procedure. Figures for analgesia indices of the various premedicants were obtained in the papers by Dundee, Nicholl Moore (1961), Nicholl, Moore Dundee (196) Dundee, Love Moore (1963). While the effect of morphine pethidine would appear to be a true potentiation of propanidid anaesthesia, the action of the antanalgesic drugs is more difficult to explain. There would appear to be three facets of this action. There is, firstly, an increase in tremor spontaneous involuntary muscle movements (including hypertonus) before surgical stimulation. Secondly, patients react more vigorously to surgical stimuli require much larger doses of anaesthetic to maintain good operating conditions. Thirdly, increased requirements of propanidid were very noticeable, even when patients were not moving in response to stimulation, this could be demonstrated by the rapid return of the corneal or swallowing reflexes. On occasions, patients even

5 CLINICAL STUDIES OF INDUCTION AGENTS XII opened their eyes very soon after what was considered to be a large total dose of propanidid, although they did not react unduly to the surgical stimuli. The first two effects may be related, in that the initial "spontaneous" muscle activity could have been induced by minor stimuli such as the application of adhesive tape to the arm, inflation of the blood pressure cuff, removal of the theatre gown or movement of the patient into the lithotomy position. Some of the most uncontrollable excitatory manifestations occurred in patients who were subsequently found to have a full bladder, which could have acted as a stimulus. For want of a better description the effect of these premedicants could be referred to as "anti-hypnotic" or "anti-anaesthetic", but the mechanism by which this effect is produced is not clear. This study once again shows the importance of analgesia as a necessary part of surgical anaesthesia. If patients are rendered more sensitive to somatic pain as the result of giving an antanalgesic premedication then the whole balance of anaesthesia will be upset. They will require larger doses of anaesthetic to maintain sleep, in the lighter planes of anaesthesia they will react in an exaggerated manner to surgical stimulation. This is a special problem with propanidid because of the rapidity with which its effect wears off. Further studies are necessary to show whether it still applies when propanidid is used only as an induction agent, until such information is available, it is recommended that the drug should only be used after premedication with or opiate. The effect of the different premedicants in increasing or decreasing postoperative vomiting was in accordance with expectation requires little comment. The high incidence of delayed nausea after hyoscine was also found by Dundee, Armstrong Alexer (196) with thiopentone. It may be related to the high incidence of pre-operative dizziness which Clarke, Dundee Moore (196) found after this drug. Not only will the effect of other anti-emetics, particularly those with a less marked antanalgesic action, need to be studied, but attention should be given to the possible anti-emetic effect of halothane (Novoa, 196). Rajagopalan Dundee (1963) found that it reduced the incidence of emetic sequelae after G.9., while Haumann Foster (1963) have shown that a short exposure to halothane reduces by per cent the incidence of vomiting following trichloroethylene. ACKNOWLEDGMENTS Thanks are due to our gynaecological colleagues at Musgrave Park Hospital, for their co-operation in this study, to Dr. Donald Whitfield, of Farbenfabriken Bayer AG, who provided generous supplies of propanidid (FBA.1) showed a continuing interest in this work. REFERENCES Clarke, R. S. J., Dundee, J. W., Moore, J. (196). Studies of drugs given before anaesthesia. IV: hyoscine. Brit. J. Anaesth., 36, 68. Dundee, J. W., Armstrong, C. A. G., Alexer, J. P. (196). Clinical studies of induction agents. VIII: A comparison of the effects of hyoscine on the course sequelae of thiopentone anaesthesia. Brit. J. Anaesth., 36, 39. Clarke, R. S. J. (196). Clinical studies of induction agents. IX: A comparative study of a new eugenol derivative, FBA.1, with G.9. stard barbiturates. Brit. J. Anaesth., 36, 1. Love, W. J., Moore, J. (1963). Alterations in response to somatic pain associated with anaesthesia. XV: Further studies with phenothiazine derivatives similar drugs. Brit. J. Anaesih., 3, 97. Moore, J. (1961a). The effect of scopolamine on methohexital anaesthesia. Anaesthesia, (1961b). The effects of premedication with phenothiazine derivatives on the course of methohexitone anaesthesia. Brit. J. Anaesth., 33, 38. Clarke, R. S. J. (196). Studies of drugs given before anaesthesia. V: Pethidine 1 mg alone with or hyoscine. Brit. J. Anaesth.. 36, 73. Nicholl, R. M. (196). Studies of drugs given before anaesthesia. II: A method for assessing their influence on the course of anaesthesia. Brit. J. Anaesth., 3, 3. Nicholl, R. M., Moore, J. (1961). Alterations in response to somatic pain associated with anaesthesia. VIII: The effects of hyoscine. Brit. J. Anaesth., 33, 6. (196). Studies of drugs given before anaesthesia. Ill: A method for the studying of their effects on postoperative vomiting nausea. Brit. J. Anaesth., 3, 7. (196). Clinical studies of induction agents. X: The effect of phenothiazine premedication on thiopentone anaesthesia. Brit. J. Anaesth., 36, 16. Goldman, V., Kennedy, P. (196). A non-barbiturate intravenous anaesthetic: report of a pilot trial. Anaesthesia, 19,. Haumann, J. Le R., Foster, P. A. (1963). The antiemetic effect of halothane. Brit. J. Anaesth., 3, 11.

6 6 BRITISH JOURNAL OF ANAESTHESIA Nicholl, R. M., Moore, J., Dundee, J. W. (196). Alterations in response to somatic pain associated with anaesthesia. XI: Two non-phenothiazine anti-emetics: cyclizine trimethobenzarrude. Brit. J. Anaeslh., 3, 87. Novoa, R. R. (196). The anti-emetic action of Fluothane: a comparative study in obstetrical anaesthesia. Canad. Anaeslh. Soc. /., 7, 19. Rajagopalan, M. S., Dundee, J. W. (1963). Clinical studies of induction agents. V: The use of G.9. as an induction agent for a stard operation. Brit. J. Anaesth., 3, 19. ETUDE CLINIQUE DES AGENTS D'INDUCTION XII: L'INFLUENCE DE QUELQUES PREMEDICATIONS SUR DEVOLUTION ET LES SEQUELLES DE L'ANESTHESIE AU PROPANIDIDE SOMMAIRE On a realist des Crudes ou, pour l'anesthesie dans des operations gynicologiques mineures, on a utilisi le melange propanidide-oxyde nitreux-oxygene avec une premidication variable. Les anti-eme'tiques employes ordinairement, l'hyoscine, la cyclizine et la prom thazine, ont augments l'incidence et la gravity des phinomenes d'excitation a un degri intolerable. Ceci accompagnait une forte augmentation de la dose de propanidide en comparaison avec une s6rie temoin premediquee par l' seule. Malgr cette forte posologie, l'hypotension a et rare, et le retour i la conscience rapide. La morphine et la pithidine ont potentialise' le propanidide en faisant diminuer le besoin total d'anesthesique, mais leur utilisation itait suivie d'une forte augmentation des vomissements et nausees. Bien que les autres premedications aient reduit les sequelles emitiques, il n'est pas recommi de les utiliser avant le propanidide. KLINISCHE UNTERSUCHUNG VON MEDIKAMENTEN ZUR NARKOSEEINLEITUNG XII: DER EINFLUSS EINIGER MEDIKAMENTE FOR DIE PRAMEDIKATION AUF DEN VERLAUF UND DIE NACHWIRKUNGEN DER PROPANIDID-NARKOSE ZUSAMMENFASSUNG Es wurden verschiedene Medikamente fur die Pramedikation bei Propanidid-Lachgas-Sauerstoff-Narkosen fur kleinere gynakologische Eingriffe untersucht. Bei den allgemein iiblichen Antiemetika, Skopolamin, Zyklizin und Promethazin waren die Haufigkeit und die Schwere der exzitatorischen Phanomene bis zu einem unertraglichen AusmaO gesteigert. Damit verbunden war em erheblicher Anstieg der Propanidid- Dosierung im Vergleich zu den Kontrollen, bei denen nur Atropin als Pramedikation gegeben wurden. Trotz der hohen Dosis kam es nur selten zur Hypotension und das Wiedererlangen des BewuOtseins war prompt. Morphin und Pethidin potentierten die Propanidid-Wirkung durch Verminderung des Gesamtbedtrfes des Anasthetikums, aber ihre Verwendung bedingten eine erhebliche Zunahme an Erbrechen und Brechreiz. Obwohl ere Medikamente fur die Pramedikation das Erbrechen und den Brechreiz verminderten, wird deren Anwendung vor Propanidid nicht empfohlen.