CLINICAL STUDIES OF INDUCTION AGENTS VIH: A COMPARISON OF THE EFFECTS OF ATROPINE AND HYOSCINE ON THE COURSE AND SEQUELAE OF TfflOPENTONE ANAESTHESIA

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1 Brit. J. Anaesth. (),, CLINICAL STUDIES OF INDUCTION AGENTS VIH: A COMPARISON OF THE EFFECTS OF ATROPINE AND HYOSCINE ON THE COURSE AND SEQUELAE OF TfflOPENTONE ANAESTHESIA BY JOHN W. DUNDEE, C. A. G. ARMSTRONG AND J. P. ALEXANDER Department of Anaesthetics, The Queen's University of Belfast; Musgrave Park Hospital, Balmoral; Mid-Ulster Hospital, Magherafelt; and South Tyrone Hospital, Dungannon, Northern Ireland SUMMARY A standard operative procedure and anaesthetic technique were employed to compare the effects of. mg atropine and. mg hyoscine, given as part or all of premedication, on the course of thiopentone anaesthesia. The incidence and severity of muscle movement following induction was increased by the use of hyoscine, but not to the same extent as previously found with methohexitone. This effect was not seen when the antdsialogogues were combined with pethidine mg or papaveretum mg. Both these opiates increased the incidence of vomiting and nausea; hyoscine appeared to be a better anti-emetic than atropine. Hyoscine delayed recovery from anaesthesia, but there was no evidence to show that it "potentiated" thiopentone. Despite the introduction of new anticholinergic drugs, atropine and hyoscine (Scopolamine) are still the most widely used antisialogogues, and one or other forms part of most premedicant mixtures. Their pharmacology has recently been reviewed by Eger (). Clinically used doses of both drugs cause an increase in sensitivity to somatic pain (Dundee, Nicholl and Moore, ). However, while the antanalgesic action of. mg of hyoscine persists for at least hour after intramuscular or subcutaneous injection, this effect of a comparable (. mg) dose of atropine has worn off after about minutes (Moore and Dundee, ). Thus hyoscine can be considered an antanalgesic premedication, whereas there is neither analgesia or antanalgesia with atropine. In addition to being a better sedative, the commonly used. mg dose of hyoscine is more potent in suppressing salivary and mucus secretions during anaesthesia than. mg of atropine (Wyant and Dobkin, ). Hyoscine also causes a lesser degree of tachycardia than does atropine, and Lambrechts and Parkhouse () found that it increased the duration of postoperative amnesia. Against these advantages it is known that hyoscine has less effect on vagal activity than atropine, and its use can be followed by postoperative excitement in elderly patients. When investigating the actions of methohexitone in man Dundee and Moore (a) found that hyoscine premedication resulted in a significantly greater incidence of excitatory phenomena than atropine. This was attributed to the antanalgesic effect of the hyoscine and its importance has since been verified in a much larger series of cases (Dundee et al., ). The concept that premedication can affect the induction characteristics of a barbiturate was first conclusively demonstrated by Dundee and Riding in. With thiopentone and Inactin, it was found that induction was appreciably smoother when atropine-opiate (morphine or pethidine) was employed as compared with the case when atropine alone was used. This has since been shown to apply to other barbiturates (Dundee, ; Dundee, Barren and King, ), and nonbarbiturates (Riding et al., ). The present study was designed primarily to see if hyoscine ptemedication would affect thiopentone anaesthesia in a manner similar to methohexitone. During the investigation it became obvious that the anti-emetic effects of

2 BRITISH JOURNAL OF ANAESTHESIA atropine and hyoscine could also be compared at the same time. This was of great clinical importance in view of Riding's () demonstration of the value of atropine in reducing emetic sequelae which followed morphia premedication, and the work of Isaacs () who found, in human volunteers, diat apomorphine-induced vomiting was prevented more effectively by hyoscine than atropine. Hyoscine is known to be useful in reducing the incidence of travel sickness (Chinn et al., ), while Greene et al. () claim that it has a "superior specific prophylactic effect on postanaesthetic emesis". METHOD OF STUDY Healthy female patients scheduled for uterine curettage, with or without dilatation of the cervix, formed the subjects for this study. The choice of patients and nature of operations follows the recommendations of Dundee, Nicholl and Moore (). Premedication, which was given about hour before induction, consisted of an intramuscular injection of one of the following: Atropine. mg Hyoscme Hyoscine. mg Pethidine mg: atropine. mg Pethidine mg: hyoscine. mg Papaveretum mg: atropine. mg Papaveretum mg: hyoscine. mg Pethidine and papaveretum were chosen as opiates against which to test the anti-emetic action of atropine and hyoscine because they are commercially available as mixtures with hyoscine. The study was carried out simultaneously in diree hospitals and the total percentage of patients receiving each premedication is approximately the same for each. Anaesthesia was induced with diiopentone mg/kg, and maintained with per cent nitrous oxide in oxygen, further supplementary doses of barbiturate being given as required. Observations during and after anaesthesia were made as described by Dundee, Moore and Nicholl () for methohexitone. Patients were visited by one of the authors about hour after anaesthesia and again hours after operation, and the occurrence of nausea or vomiting at these times was noted. Recording and analysis of emetic sequelae were according to the scheme described by Dundee, Nicholl and Moore (). PATIENTS Table I shows that each group was broadly comparable as regards the average ages and weights of the patients. There was no significant differences between the duration of anaesthesia with the different forms of premedication. Course of anaesthesia. The relevant data is given in table H. There was a significant increase (P<.) in the incidence of excitatory phenomena following hyoscine alone as compared with other forms of premedication, but no differences between any of the other series. There were no marked differences in the frequency of respiratory upset or marked respiratory depression between atropine and hyoscine irrespective of sedation. Substitution of hyoscine for atropine did not increase the frequency or duration of arterial hypotension to a significant degree; however, the Premedication TABLE I Details of patients and duration of Atropine. mg Hyoscine. mg Pethidine mg; atropine. mg Pethidine mg; hyoscine. mg Papaveretum mg; atropine. mg Papaveretum mg; hyoscine. mg No. of patients operation. Age Average of Weight (kg) series Duration of anaesthesia (min) 8. ±.. ±.8. ±.. ±. 8. ±.. ±.

3 CLINICAL STUDIES OF INDUCTION AGENTS VHI TABLE II Percentage incidence of complications during anaesthesia, grades of anaesthesia and condition of patient minutes after the end of operation. Opiate used Nil Pethidine Papaveretum Antisialogogue Atropine Hyoscine Atropine Hyoscine Atropine Hyoscine Excitatory phenomena Tremor Involuntary muscle movement Nil Respiratory upset Cough/hiccough Laryngospasm Nil Marked respiratory depression Fall in systolic blood pressure (M mm Hg + mm Hg Duration of hypotension* min - min + min Grade of anaesthesia a b Condition at end of operation Awake Safe Unsafe Percentage of patients with fall in systolic pressure in excess of mm Hg addition of papaveretum had a marked effect. The incidence of falls in systolic pressure exceeding mm Hg was significantly greater (x*=.; P<.) after papaveretum with atropine than after atropine alone, and after papaveretum with hyoscine than following hyoscine alone (x =.; P<.). Hypotension was more prolonged after papaveretum with hyoscine than after any other premedication studied. In order to facilitate comparison between the hypotensive effects of the different series, a factor was calculated from the severity and duration of blood pressure fall, as previously described (Dundee, ). The factors for different forms of premedication are as follows: Atropine. Hyoscine. Pethidine with atropine. Pethidine with hyoscine. Papaveretum with atropine. Papaveretum with hyoscine. These figures confirm the relatively greater depressant effect of both papaveretum and hyoscine, particularly when given together. Judged by the incidence of grades of anaesthesia, the overall course was worse after hyoscine than after atropine premedication (P<. by both x a and ridit analysis). There was no difference between the two pethidine series, and the papaveretum with atropine and papaveretum with hyoscine series did not differ significantly, despite the lower incidence of grade anaesthesia after the latter premedication. Dosage. The average initial and total doses of thiopentone in each series are shown in table HI. There are no gross differences between any of the groups and, while the ratio of total to induction dose is invariably higher after hyoscine than atropine, the differences never become statistically significant. There is no definite evidence to suggest that

4 BRITISH JOURNAL OF ANAESTHESIA TABLE III Average induction and total doses of thiopentone in the various series. Average induction dose (mg/kg) Atropine. ±. Hyoscine. ±. Pethidine with atropine. ±. Pethidine with hyoscine. ±. Papaveretum with atropine. ±. Papaveretum with hyoscine. ±. Average total dose (mg/kg). ±.. ±.. ±..±. ±..±. Total dose Induction dose hyoscine reduces the requirements of thiopentone for the standard operation, although some reduction occurred when hyoscine was combined with papaveretum. In view of the similarity in total dosage for the several series, there is no doubt that the use of hyoscine delays recovery from anaesthesia (table II). There is a consistently significant reduction (P<.) in the number of patients classed as "awake", minutes after the end of the operation with this drug as compared with atropine, whether an opiate was or was not employed. Emetic sequelae. There was a reduction in the incidence of vomiting during the first hour after anaesthesia, with hyoscine as compared with atropine (table TV). This was, however, only significant (P<.) when an opiate was used The incidence of nausea was not markedly affected by hyoscine, but total emetic symptoms were consistently reduced to a significant degree during the first hour after anaesthesia. The differences between the atropine and hyoscine series were varied between the first and sixth hour after operation and followed no definite pattern. There was, however, a significantly lower incidence of total emetic symptoms following papaveretum with hyoscine than after papaveretum with atropine (x = 8.8; P<.) during this period. It was only with these two forms of premedication that a significant difference in the frequency of vomiting was found over the total first hours after operation (,\ =.8; P<.). Table IV shows also the average postoperative emetic score associated with each of the six forms of premedication. While no statistical significance can be attached to differences in the mean scores, they suggest that hyoscine is a better antiemetic than atropine. The frequency of distribution of the score has been analyzed using the TABLE IV Percentage incidence of emetic sequelae during the first hour, - hours and first hours after operation, with the average emetic scores for each group. Atropine Hyoscine Pethidine with atropine Hethidine with hyoscine Papaveretum with atropine Papaveretum with hyoscine V - hr N 8 Time after end of operation V - hr N V First hours N Nil 8 8 Average emetic score V=vomiting; N=nausea: when vomiting and nausea both occurred, this was recorded as vomiting

5 CLINICAL STUDIES OF INDUCTION AGENTS Vm ridit analysis method (Belville, Bross and Howland, ; Dundee, Nicholl and Moore, ), the result being shown in figure. There is no significant difference between the overall effect of hyoscine and atropine, but both pethidine and papaveretum increased the frequency and severity of symptoms. Papaveretum was worse in this respect than pethidine. As already mentioned, it was only with papaveretum that hyoscine exerted a significant prolonged anti-emetic effect, compared with atropine. DISCUSSION Although this investigation has shown that hyoscine increases the incidence of excitatory phenomena following induction with thiopentone, the effect is not as marked as that following the combination of hyoscine with methohexitone (Dundee and Moore, a). A comparison of the percentage of cases in which the upset was of sufficient severity as to interfere with the course of anaesthesia (grades b and ) shows the following: Methohexitone Thiopentone Atropine Hyoscine 8 Pethidine with atropine Pethidine with hyoscine Nevertheless it is probably inadvisable to recommend hyoscine as sole premedicant when a barbiturate is to be employed without supplementary anaesthesia. ATROPINE A HYOSCINE H PETHIDINE (A) (A) PETHIDINE (A) PETHIDINE (H) (A) (A) (H) AVERAGE RIDIT PREMEDICATION FIG. Incidence and severity of postoperative sequelae with different premedications compared using the method of ridit analysis. ^B Control series (identified distribution). Vertical lines indicate mean ridit. ^^^ Series compared with the control. Blocks indicate per cent limits.

6 BRITISH JOURNAL OF ANAESTHESIA This study demonstrates that thiopentone is less affected by antanalgesic premedication than methohexitone, presumably due to the methyl side chain in the latter drug. This is shown by the inability of hyoscine to increase the incidence of excitatory phenomena when combined with potent analgesics such as pethidine or papaveretum. Another finding which may be attributed to the more prolonged antanalgesic action of hyoscine, as compared with morphine, is the larger total dose of barbiturate required during anaesthesia. This has been shown to apply to methohexitone when hyoscine (Dundee and Moore, a) or antanalgesic phenothiazines (Dundee and Moore, b) are given as premedication. Orkin, Bergman and Nathanson () found that hyoscine reduced the dose of thiopentone required to produce sleep, but this must be distinguished from the dose necessary to maintain surgical anaesthesia in the presence of strong stimulation. It seems reasonable to expect that any drug which increases sensitivity to somatic pain will necessitate a larger dose of cerebral depressant to achieve the same degree of anaesthesia. It was unexpected to find that papaveretum was followed by a higher incidence of hypotension during operation than non-opiate premedication or pethidine. This aspect of the action of this very popular premedication warrants further study. This paper once again emphasizes the importance of opiate premedication as a factor in postoperative vomiting and nausea. It also shows that hyoscine is a more potent anti-emetic than atropine. However, hyoscine seems to be very short acting, causing a more consistent reduction in incidence during the first hour after anaesthesia than during the next hours. This was particularly noted when pethidine was used in premedication. It is unlikely that this is due to the shorter action of the pethidine, as compared with papaveretum, because the incidence of total emetic symptoms with both opiates combined with hyoscine is about the same. However, the delay in recovery of consciousness in all series receiving hyoscine, as compared with the comparable group who were given atropine, may play a part in the lower incidence of vomiting with the former drug. The enthusiasm of the report of the anti-emetic action of hyoscine by Green and his colleagues () may be due to the fact that these observers recorded symptoms only in the first hour after operation. Their series was very well controlled, being limited to one operation and one anaesthetic (cyclopropane and oxygen), but unfortunately they did not study the combination of hyoscine and an opiate. In a much smaller but equally well controlled series of patients, anaesthetized with methohexitone and nitrous oxide with oxygen, Dundee and Moore (a) found a significant reduction in emetic symptoms during the first hour after operation with pethidine with hyoscine premedication, as compared with pethidine with atropine, but this reduction was more than counteracted by the higher incidence during the - hour period. On the other hand, Riding () who likewise limited his observations to patients having one operation with the same anaesthetic technique (thiopentone alone), found a marked reduction in symptoms during the first hours after operation with morphine mg and hyoscine. mg (. per cent) as compared with morphine alone (. per cent) or morphine with atropine. mg (. per cent) or. mg (. per cent). It is obvious from these contradictory views that the anti-emetic action of hyoscine deserves further detailed study, since other investigations of its action (Collins, ; Blatchford, ) are insufficiently controlled to be of value. REFERENCES Belville, J. W., Bross, I. D. J., and Howland, W. C. (). A method for the clinical evaluation of anti-emetic agents. Attesthesiology,,. Blatchford, E. (). Studies of anti^metic drugs: a comparative study of cyclizine (Marzine), pipamazine (Mornidine), trimethobenzamide (Tigan) and hyoscine. Canad. Anaesth. Soc. J., 8,. Chinn, H. T., Handford, S. W., Cone, T. E. jr., and Smith, P. K. (). Effectiveness of various drugs for prophylaxis of sea sickness. Amer. J. Med.,,. Collins, C. U. (). Scopolamin and morphin as a preliminary to general anesthesia: a report based on an experience of eleven hundred cases. /. Amer. med. Ass.,,. Dundee, J. W. (). Charakteristika bei intravenoser Narkoseeinleitung. Der Anaesthesist,,. (). Clinical studies of induction agents. VII: A comparison of eight intravenous agents as main anaesthetics for a standard operation. Brit. J. Anaesth.,, 8. Barron, D. W., and King, R. (). The effect of methylation on ethyl-methyl-propyl thiobarbiturate. Brit. J. Anaesth.,,.

7 CLINICAL STUDIES OF INDUCTION AGENTS Vm Dundee, J. W., and Moore, J. (a). The effect of scopolamine on methohexital anaesthesia. Anaesthesia,,. (b). The effects of premedication with phenothiazine derivatives on the course of methohexitone anaesthesia. Brit. J. Anacsth.,, 8. NichoU, R. M. (). Studies of drugs given before anaesthesia. II: A method for assessing their influence on the course of anaesthesia. Brit. J. Anaesth.,,. Nicholl, R. M., and Moore, J. (). Alterations in response to somatic pain associated with anaesthesia. VIII: The effects of atropine and hyoscine. Brit. J. Anaesth.,,. (). Studies of drugs given before anaesthesia. Ill: A method for studying their effect on postoperative vomiting and nausea Brit J. Anaesth.,,. Riding, J. E. (). A comparison of Inactin and thiopentone as intravenous anaesthetics. Brit. J. Anaesth.,,. Barron, D. W., and Nicholl, R. M. (). Some factors influencing the induction characteristics of methohexitone anaesthesia. Brit. J. Anaesth.,,. Eger, E.. (). Atropine, scopolamine and related compounds. Anesthesiology,,. Greene, B. A., Berkowitz, S., Goffen, B. S., Anthony, B. G, and Kratz, J. (). Demonstration of superior "specific" prophylactic effect of Scopolamine on postanesthetic emesis. N.Y. med. J.,,. Isaacs, B. (). The influence of hyoscine and atropine on apomorphine induced vomiting in man. Clin. Sci.,,. Lambrechts, W., and Parkhouse, J. (). Postoperative amnesia. Brit. J. Anaesth.,,. Moore, J., and Dundee, J. W. (). Alterations in response to somatic pain associated with anaesthesia. XII: Further studies with atropine Brit J. Anaesth.,,. Orkin, L. R.. Bergman, P. S., and Nathanson, M. (). Effect of atropine, scopolamine and meperidine on man. Anesthesiology,,. Riding, J. E. (). Postoperative vomiting. Proc rov Soc. Med.,.. Dundee, J. W., Rajagopalan, M. S., Hamilton, R. C, and Baskett, P. J. F. (). Clinical studies of induction agents. VI: Miscellaneous observations with G... Brit. J. Anaesth., Wyant, G. M., and Dobkin, A. B. (). Antisialogogue drugs in man: comparison of atropine, scopolamine (-hyoscine) and -hyoscyamine (Bellafoline). Anaesthesia,, ETUDES CLINIQUES DE MEDICAMENTS ANESTHESIANTS VIII: COMPARAISON DES EFFETS DE L'ATRO- PINE ET D'HYOSCINE SUR LE COURS ET SUR LES SUITES DE L'ANESTHfiSIE PAR THIO- PENTONE SOMMAIRE Un procede d'operation-standard et de technique d'anesthdsie fut employ^ pour comparer les effete de. mg d'atropine et de. mg d'hyoscine consideres comme faisant partie de toute pre'-anesthesie pendant le cours des traitements au thiopentone. Le nombre de cas et le caractere marque de mouvements musculaires apres pre-m&iication tait aggrave' par l'emploi d'hyoscine, mais il n'atteignit pas le meme caractere de gravity que celui observe' apres emploi de me'thohexitone, prealablement essayed Cet effet ne fut pas constate lorsque les anti-sialagogues etaient associes avec mg de p^thidine ou avec mg de papaveretum. Ces deux derniers derives d'opium augmenterent la frequence des vomissements et des nausees. l'hyoscine semblant etre un meilleur anti-em tique que l'atropine. Elle retarda le r^tablissement apres anesth^sie, mais rien ne montra qu'elle renforce l'effet de thiopentone. KLINISCHE UNTERSUCHUNGEN VON SUBSTANZEN ZUR NARKOSEEINLEITUNG VIII: EIN VERGLEICH DER WIRKUNG VON ATROPIN UND SKOPOLAMIN AUF DEN VERLAUF UND DIE NACHWIRKUNGEN DER THIOPENTON-ANAESTHESIE ZUSAMMENFASSUNO FUr den Vergleich der Wirkung von. mg Atropin und mg Skopolamin als Teil oder ausschliessliche Pra-Medikation auf den Verlauf der Thiopenton- Anaesthesie wurde ein Standard-Operationsverfahren und -narkosetechnik angewandt Durch die Verwendung von Skopolamin wurde die HMuftgkeit und die Stance der Muskelaktionen im Verlauf der Einleitung gesteigert, aber nicht im selben Ausmafi, wie es kurzlich bei Methohexiton festgestellt wurde. Diese Wirkung wurde bei Kombination des Sekretions-hemmenden Mittels mit mg Pethidine oder mg Papaverin nicht gesehen. Beide Opiate verursachten ein vermehrtes Auftreten von Brechreiz und Erbrechen, Skopolamin schien ein besseres Antiemetikum zu sein als Atropin. Skopolamin verzogerte das Erwachen von der Anaesthesie, aber es fand sich kein Hinweis, dao es Thiopentin "potentiert".