STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XX: DIAZEPAM-CONTAINING MIXTURES

Transcription

1 Brit. J. Anaesth. (97),, STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XX: DIAZEPAM-CONTAINING MIXTURES J. W. DUNDEE, W. H. K. HASLETT, S. R. KEILTY AND S. K. PANDIT BY SUMMARY Diazepam mg and pethidine mg alone were compared and in combination with or without hyoscine as pre-operative medication. Both intramuscular and intravenous routes of administration were employed. The addition of diazepam to pethidine improved its efficiency as a premedicant and decreased its side effects. In contrast the pethidine-diazepam mixture was found to be significantly more toxic than diazepam alone. The addition of hyoscine markedly improved the amnesic property and soporific effect of diazepam, but at the expense of less satisfactory methohexitone induction and a slightly delayed recovery. Of the large number of tranquillizers whose use as premedicants has been studied in recent years the two benzodiazepines, chlordiazepoxide and diazepam, are among the most promising. They cause fewer side effects than the clinically used doses of most opiates and would appear to be superior to these in their ability to allay apprehension. For routine clinical use diazepam is probably the more suitable drug because it is available commercially in a ready-made solution (Valium) as compared with chlordiazepoxide (Librium) which has to be freshly prepared before injection. Studies from this department (Haslett and Dundee, 96) showed that mg was the optimal intramuscular dose of diazepam for adults, being more satisfactory than mg. However, as it has no marked analgesic action (Haslett, 96) it would appear to be of limited value when the use of analgesic premedication is desired. This led the authors to continue the previous studies using a mixture of pethidine mg and diazepam mg. The findings are compared with those of a large series of patients premedicated with pethidine mg (Morrison et al., 969) while the numbers studied after diazepam mg were increased from to. ki view of the claims that diazepam causes an appreciable degree of amnesia (Tornetta, 96; Stevner and Endresen, 966; McQish, Andrew and Tetreault, 96), it was also thought desirable to study the value of a diazepam-hyoscine mixture. The combination of diazepam mg, pethidine mg and hyoscine. mg was included in part of the investigation. Saline was used as dummy medication. METHOD This investigation was divided into two parts, the first deals with drugs given by intramuscular injection while the second is concerned with the action of the same drugs given by the intravenous route. In both series the agents were given as routine pre-operative medication using a "blind" method where possible to healthy female patients undergoing minor gynaecological operations. Pre-operative visits were made to determine the effects of these drugs with respect to drowsiness and lack of apprehension or restlessness, and the incidence and severity of toxic reactions such as dizziness, emetic sequelae or cardiovascular effects. With the intramuscular route, the patients were seen,. 6 and 9 minutes after administration of the drug or else visited only once between the 6th and 9th minutes after injection. Details of the observations made have been described by Dundee, Moore and Nicholl (96) and reviewed in detail by Morrison, Hill and Dundee (96). J. W. DUNDEE, MJ>., PHJ>., F.F.A.R.C.S.; W. H. K. HASLETT, M.B., F.F^JLCS.I.; S. R. KEILTY, M.B., F.F.AJLC.S.; S. K. PANDIT, M.S., F.p.AJtcs., D.A.; Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland.

2 BRITISH JOURNAL OF ANAESTHESIA The effects of the drug after intravenous injection were recorded only once between the th and th minutes. The study continued with observations on the effects of these drugs on the course of anaesthesia when a standardized technique (methohexitone-nitrous oxide-oxygen) was employed and included observations on the emetic and other sequelae occurring up to 6 hours after operation. The ability of the patients to recall their journey from the ward to the operating theatre and the intravenous injection of methohexitone was ascertained by direct questioning on the evening of operation and on the following morning. Since all operations were carried out before noon, this allowed follow-up at approximately 6 and hours. This latter is a part of a more extensive study which will be reported later in detail. The significance of the difference between the various series were compared using the standard y and Student t test. The differences are considered to be significant when the likelihood of this arising by chance is less than : (P<.). RESULTS Intramuscular injection. As expected from randomly selected groups of - cases drawn from a standard patient population, there were no marked differences in the age and weight distribution of the five series and their data are not given. The incidence of desired effects of the drugs recorded 6-9 minutes after injection and diat of side effects occurring up to this time is given in table I. Pethidine-diazepam had a significantly greater soporific action than diazepam alone but did not cause more drowsiness than pethidine. Diazepam did, however, significantly increase the ability of the opiate to allay apprehension. The most notable effect of the diazepam-pethidine mixture was the very significant reduction in dizziness and sickness as compared with pethidine DROWSINESS SO IQO O APPREHENSION MEAN EFFICACY SCORE SO O_ DIZZINESS 6p EMETIC EFFECTS C J l O MEAN TOXICITY SCORE M O MINUTES -9O - [] -9 - H O MINUTES -9 B -IO O 9O Ml NUTES -7-7 MINUTES -7. I. IO FIG. Comparison of the pre-operative effects of pethidine mg and a mixture of pethidine mg and diazepam mg with respect to four aspects of drug action. Drowsiness Solid area good and fair Dizziness Solid area marked Open area slight Open area slight Apprehension Solid area moderate and marked Emetic effects Solid area vomiting Open area slight Open area nausea The overall effects of the drugs at the different time intervals are expressed as their mean eflbcacy and toxkaty scores as described by Dundee, Moore and Nicholl (96). - -

3 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XX TABLE I Percentage incidence of effects of the five premedicants studied. Figures show desired effects recorded 6-9 minutes after intramuscular injection and cumulative incidence of side effects up to that time. No. of patients Drowsiness Good Fair Slight Apprehension Absent Slight Moderate or marked Restlessness or excitement Dizziness Slight Marked Emetic Nausea Vomiting Tachycardia + beats/min. Hypotension Systolic BP fall of + mm Hg Pethidine reuuumc Hyoscine nyoscinc mg,. mg, Diazepam diazepam Pethidine diazepam mg mg mg mg Saline TABLE II Data relating to anaesthesia and the immediate postoperative period. Dosage of methohexitone (nag/kg) Average induction Average total (±SE) Percentage incidence Excitatory phenomena Respiratory upset Hypotension Systolic BP fall of + mm Hg Satisfactory induction (grades plus a) Recovery Condition minutes post-op. Awake Safe Unsafe Emetic sequelae (first 6 hours) Vomiting Nausea Diazepam mg.. ± Pethidine mg, diazepam mg.9.9 ± Pethidine mg.. ± Hyoscine. mg, diazepam mg Saline.7. ± ±

4 6 BRITISH JOURNAL OF ANAESTHESIA alone. This is further illustrated in figure, which also showed that there is some delay before the onset of the maximum sedative action (as assessed by the mean efficacy score) of the diazepampethidine mixture, compared with pethidine alone. Hyoscine increased both the soporific and anxiety-allaying action of diazepam but did so at the expense of a slightly higher incidence of dizziness. As expected, pre-operative tachycardia occurred less frequently with diazepam-hyoscine compared with any other premedicant studied. Table II lists the important data relative to the course of anaesthesia and the immediate postoperative period. The mean induction doses of methohexitone were comparable in all series. The only important finding pertaining to the total dose of barbiturate was a significant reduction (P<.) after diazepam-pethidine as compared with pethidine alone. The incidence of excitatory phenomena was significantly reduced when opiates were used, while the highest frequency followed the use of hyoscine-diazepam. The low incidence of respiratory upset following this last combination was expected, but it also occurred to a significant degree after pethidine-diazepam compared with tie placebo. Hypotension was a problem only after pethidine and its incidence was reduced by the addition of diazepam. With the exception of hyoscine-diazepam, all premedicants (including saline) were clinically acceptable with respect to their effect on methohexitone induction. When premedication was given by the intramuscular route, there was little to choose between the rapidity of recovery in the various series. However, this was slowest following pethidine alone. Postoperative nausea and/or vomiting occurred in approximately the same percentage of patients in the three non-opiate series. A more detailed comparison of that following pethidine and pethidine-diazepam is given in table HI and further demonstrates the anti-emetic effect of the tranquillizer. Intravenous injection. In view of the small number of patients in this pan of the study, the results are given in less detail (table IV). Despite this, it will be seen that the comparisons arc made on groups which are TABLE III Emetic effects of pethidine mg compared with pethidine mg + diazepam mg. Total pre- First postoperative hour First 6 postoperative hours and post- operative Mean V N V N score V N Pethidine 69. Pethidine/ diazepam Significance of difference X <. <. <. V=vomiting (including retching); N=nausea. When vomiting and nausea both occur, only vomiting is recorded. broadly comparable with regard to average age and weight. There are some quantitative differences between the effects of tie drugs as assessed - minutes after intravenous injection and the results obtained following intramuscular injection. The "placebo effect" of saline was less marked since it produced no notable drowsiness and had very little effect in allaying apprehension. The addition of pethidine to diazepam again markedly increased its soporific effect but this was not further enhanced by the addition of hyoscine. Following intravenous injection there was nothing to choose between the soporific actions of pethidine, pethidine/diazepam, pethidine/diazepam/hyoscine and hyoscine/diazepam. However, the calming effect of diazepam alone was very marked and superior to that produced by pethidine alone. This action was not enhanced by the addition of pethidine but is improved by hyoscine. The occurrence of excitement and restlessness could be correlated with the lack of soporific effects of the drugs, being most marked with saline. From the toxicity point of view it can be seen that a high incidence of dizziness occurred with all active compounds, including diazepam alone. It was most marked following pethidine but this incidence was significantly reduced by the addition of diazepam with or without hyoscine. In the pre-operative period nausea and vomiting only became a problem with pethidine alone and this was again reduced by combination with diazepam.

5 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XX 7 TABLE IV Summary of important effects recorded before, during and after anaesthesia following intravenous premedication. Pethidine mg, Pethidine Hyoscine hyoscine mg,. mg,. mg, Diazepam diazepam Pethidine diazepam diazepam Premedicant mg mg mg mg mg Saline No. of patients Average age (yr) Average weight (kg) Pre-operative effects (% incidence) Drowsiness, good and fair Apprehension absent Excitement or restlessness Dizziness Nausea or vomiting Tachycardia + beats/min Hypotension, systolic fall of + mm Hg Anaesthesia Methohexitone dosage (mg/kg) Induction (av) Total (average) % Incidence Excitatory phenomena Respiratory upset Respiratory depression Hypotension "systolic" fall of mm Hg Recovery Condition minutes after end % awake safe unsafe Emetic sequelae (first 6 post-op. hours) % nausea % vomiting ± ± ± ± ± ±. 9

6 BRITISH JOURNAL OF ANAESTHESIA In contrast, the addition of diazepam did not reduce the undesirable cardiovascular effects of the opiate. The incidence of tachycardia was highest with pethidine/diazepam/hyoscine mixture while the pethidine/diazepam and pethidine/ diazepam/hyoscine mixtures caused the highest incidence of hypotension. The overall effect of different premedicants on the total dose of methohexitone required for the standard operation is similar to that in table II. It was significantly reduced by opiate premedication and, although slightly smaller with diazepam than with saline, the differences could have arisen by chance. Each of the five premedicants studied show a significantly different effect on the course of anaesthesia as compared with saline. The opiatecontaining compounds reduced the incidence of excitatory phenomena but this was increased slightly after diazepam and significantly when diazepam/hyoscine were given. Respiratory upset (coughing, hiccough or laryngospasm) did not occur following either of the hyoscine-containing premedicants, and again its frequency was less following pethidine-diazepam as compared with pethidine alone. Respiratory depression was a major problem when combinations of pethidinediazepam were given (with or without hyoscine). Pethidine-diazepam was also followed by a high incidence of hypotension during anaesthesia. Compared with saline all premedicants delayed recovery from anaesthesia and, in contrast to the intramuscular premedication series, this was most obvious when hyoscine was used. The addition of diazepam to pethidine had a marked effect in this respect and following this combination about half the patients had no control of their reflexes minutes after the end of anaesthesia. The only notable effect on the emetic sequelae was that these were highest after pethidine and again the addition of diazepam caused some diminution in frequency, with a yet further reduction when hyoscine was added. Amnesia studies. The findings of this study are summarized in table V. This shows a marked difference in the results depending on the route of administration of the premedication. It can be seen that neither diazepam nor pethidine cause any appreciable anterograde amnesia when given by intramuscular injection, but the incidence is much increased when they are combined This synergism is also seen with intravenous injection. Incomplete data (unpublished) show about a per cent incidence of some degree of amnesia following intramuscular hyoscine, so that the combined diazepam-hyoscine mixture also demonstrates this synergism. DISCUSSION In addition to reporting the effects of diazepamcontaining mixtures, this paper demonstrates the value of the intravenous route in studying premedicants, in addition to the data obtained after the more conventional intramuscular injection. Although the number of cases was small, it demonstrated the cardiovascular toxicity of the opiate-diazepam mixtures, which was not apparent when the intramuscular route had bean used. This was noted both in the pre-operative period and during anaesthesia. Pre-operative dizziness was also more marked after intravenous than following intramuscular injection, particularly with diazepam alone. Other workers have shown the value of the intravenous route in demonstrating the toxicity of opiates (Masson, 96; Camp- TABLB V Percentage incidence of any degree of anterograde amnesia associated vnth various premedicants. Premedicants Diazepam mg Pethidine mg/diazepam mg Pethidine mg Hyoscine. mg/diazepam mg Pethidine mg/hyoscine. mg/ diazepam mg Saline Intramuscular series Intravenous series

7 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XX 9 bell. Masson and Norris, 96; Tomlin, 96), but in these instances this was an incidental finding. The intravenous route also permits the study of the effects of a combination of drugs (such as pethidine, diazepam and hyoscine) when the volume of solution would be too large for intramuscular injection. While the addition of pethidine to diazepam increased the soporific effect of the tranquillizer, this benefit was only achieved at the expense of a higher incidence of cardiovascular upset. The advantages accruing from a lower incidence of excitatory phenomena following methohexitone are not important, for under the circumstances in which one prefers this barbiturate, because of its brevity of action, opiate premedication would probably be undesirable. On the other hand, when an opiate would normally be employed for premedication, the addition of diazepam offers certain advantages in the pre-operative and postoperative periods. Its anti-emetic action is pronounced, although not as marked as that of perphenazine. or mg. It does not carry the risk of oculogyric crises which may follow the repeated use of some phenothiazines. The use of a pethidine-diazepam mixture as premedication prior to local anaesthesia would seem to be worthy of trial. However, to "settle" a restless patient having an operation under local anaesthesia, diazepam alone should be given intravenously, as the mixture causes too high an incidence of tachycardia and hypotension. The anticonvulsant action of diazepam may also be useful in these cases. The only apparent advantage following the use of diazepam-hyoscine mixtures is the degree of amnesia which it causes. This is not marked when the intramuscular route is employed and there is obviously a need for further work in this field. It would be of interest to know whether the amnesic and soporific actions of the drug are associated. The findings with the diazepam-pethidine mixture suggest that this is too simple an explanation. The marked difference between the effect of these drugs when given by intravenous and intramuscular injection also merits further study. A mixture of a smaller (-7 mg) dose of pethidine with diazepam would seem also to be worthy of investigation, as it may produce less hypotension and tachycardia than reported here. The increased incidence of excitatory phenomena following methohexitone induction (tables II and IV) can be attributed to the antanalgesic action of this combination (Dundee, 96) and is a definite disadvantage in patients scheduled for minor surgery. There would appear to be no advantages in the use of the diazepam-pethidine-hyoscine mixture, which can lead to excessive sedation. This should be remembered when it is desired to add an antisialogogue to the diazepam-pethidine combination. This does not detract from the proven value of diazepam as a non-opiate premedication. This has been confirmed in a further cases in whom results were similar to those reported previously by Haslett and Dundee (96). When the final results were incorporated into an overall evaluation of the efficacy of various opiate premedicants, Dundee, Loan and Morrison (97) found that in -mg doses it was as effective as pethidine mg and superior to pentazocine mg (Fortral), methadone mg (Physeptone), dihydrocodeine mg (DF.) and phenazocine mg (Narphen) as well as many other opiates. It certainly was less toxic than any of the opiates except phenazocine. Diazepam is well absorbed by mouth and is a useful oral pre-medicant, but it should be remembered that, under these circumstances, it may enhance the depressant effect of an opiate which may be given subsequently. ACKNOWLEDGEMENTS Thanks are due to the gynaecological and nursing staffs of Musgrave Park Hospital, Balmoral, Belfast City Hospital (Jubilee III), and the Downe Hospital (Downpatrick) for their co-operation in this study. Pethidine-diazepam mixtures were kindly supplied by Roche Products Ltd. REFERENCES Campbell, D., Masson, A. H. B., and Norris, W. (96). The clinical evaluation of narcotic and sedative drugs. II: A re-evaluation of p:thidine and pethilorfan. Brit. J. Anaesth., 7, 99. Dundee, J. W. (96). Some effects of premsdication on the induction characteristics of intravenous anaesthetics. Anaesthesia,, 99. Loan, W. B., and Morrison, J. D. (97). Studies of drugs given before anaesthesia. XIX: Opiates. Brit. J. Anaesth.,,. Moore, J., and Nicholl, R. M. (96). Studies of drugs given before anaesthesia. I: A method of pre-operative assessm:nt. Brit. J. Anaesth.,,.

8 BRITISH JOURNAL OF ANAESTHESIA Haslett, W. H. K. (96). A controlled study of diazepam and chlordiazepoxide as premedicant for a standard operation; chapter in Diazepam in Anaesthesia (eds. Knight, P. F., and Burgess, C. G.), p. 9. Bristol: Wright. Dundee, J. W. (96). Studies of drugs given before anaesthesia. XIV: Two benzodiazepine derivatives chlordiazepoxide and diazepam. Brit. J. Anaesth.,,. Masson, A. H. B. (96). Clinical assessment of analgesic drugs. () Intravenous trial. Brit. J. Anaesth., 6,. McOish, A., Andrew, D., and Tetreault, L. (96). Intravenous diazepam for psychiatric reactions following open-heart surgery. Canad. Anaesth. Soc. J.,, 6. Morrison, J. D., Hill, G. B., and Dundee. J. W. (96). Studies of drugs given before anaesthesia. XV: Evaluation of the method of study after, observations. Brit. J. Anaesth.,, 9. Loan, W. B., Dundee, J. W., McDowell, S. A., and Brown, S. S. (969). Studies of drugs given before anaesthesia. XVIII: The Synthetic opiates Brit. J. Anaesth.,, 97. Stovner, J., and Endresen, R. (966). Intravenous anaesthesia with diazepam. Proc. nd European Congress of Anaesthesiology. Ada anaesth. scand., SuppL XXTV,. Tomlin, P. J. (96). Pethidine compared with pethidine plus lavallorphan and with a placebo Brit J. Anaesth., 7,. Tometta, F. J. (96). Diazepam as pre-anesthetic medication: a double-blind study Anesth. Analg. Curr. Res.,, 9. ETUDES DE SUBSTANCES ADMINISTREES AVANT L'ANESTHESIE XX: MIXTURES CONTENANT DU DIAZEPAM SOMMAIRE On a compari entre eux mg de Diazepam et mg de Pithidine puis ces mfimes substances associees, avec ou sans hyoscine comme prenarcose. On a utilis6 tes deux voies d'administration: intramusculaire et intraveineuse. L'addition de Diazepam a la Pfthidine ameliore son efficaciti en tant que pr&netlication et artenue ses effets secondaires. Par contre ^association de Pethidine et Diazepam s'est rev&ee nettement plus toxique que le Diazepam utilise seul. L'adjonction dtiyoscine augmente tres sensiblement les proprie'tisamnesiques et l'effet soporifique du Diazepam, mais aux depends d'une induction par mithohexitone moins sarisfaisante et une recuperation plus lente. UNTERSUCHUNGEN OBER ARZNEIMITTEL BEI DER NARKOSEPRAEMEDIKATION XX: KOMBINATIONSPRAPARATE MIT DIAZEPAM ZUSAMMENFASSUNG Diazepam mg und Pethidin mg wurden einzeln, kombiniert, mit oder ohne gleichzeitige Verwendung von Hyoscine als Operationspraemedikation in ihrer Wirkung vcrglichen. Die Medikamente wurden sowohl intramuskular als intravends verabreicht. Die Zugabe von Diazepam zu Pethidin yerbesserte dessen Wirk- amkeit in der Praemedikation und verringerte die Nebsnwirkungen. Im Gegensatz dazu war die Kombination Pethidin/Diazepam eindeutig mit hoherer Toxizitat belastet als Diazepam allein. Hyoscine verbesserte deutlich die Amnesiewirkung und den Einschlafeffekt des Diazepam, allerdings auf Kosten einer unbefriedigenderen Methohexitone-Narkoseeinleitung und eincs gering verzogenen Wiedererwachens. THE UNIVERSITY OF LIVERPOOL: DEPARTMENT OF ANAESTHESIA Courses of postgraduate instruction in anaesthesia will be conducted at the University of Liverpool during the Session October 97 to September 97. Three groups of students may be accepted for these courses: (J) students from the United Kingdom or overseas who are prepared to accept designated remunerated posts in those Liverpool hospitals which permit attendance on the course; (b) those who already hold anaesthetic posts in the Liverpool area; and (c) those students who are in receipt of a Government or other grant and do not require a remunerated post The courses provide both for students who are studying the basic sciences with the Primary F.F.A.R.C.S. in view, and also for those for whom instruction and practice are necessary in the clinical subjects required for the Final F.F.A.R.C.S. (Anaesthesia, Medicine and Surgery). Fees for attendance on the course are fifteen guineas per term. Further particulars and application forms may be obtained from the Professor of Anaesthesia, Department of Anaesthesia, The University of Liverpool, P.O. Box 7, Liverpool L69 BX, and the forms should be returned, completed, not later than February th, 97.