CLINICAL STUDIES OF INDUCTION AGENTS XV: A COMPARISON OF THE CUMULATIVE EFFECTS OF THIOPENTONE, METHOHEXTTONE AND PROPANIDID

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1 Brit. J. Anaesth. (1966), 38, 401 CLINICAL STUDIES OF INDUCTION AGENTS XV: A COMPARISON OF THE CUMULATIVE EFFECTS OF THIOPENTONE, METHOHEXTTONE AND PROPANIDID BY R. S. J. CLARKE AND J. W. DUNDEE Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland SUMMARY Thiopentone, methohexitone and propanidid have been given by intermittent dosage as main agent for a series of body surface operations. The requirements over the first hour show a marked falling off with the barbiturates but little decline with propanidid. This supports the experimental findings that propanidid is rapidly destroyed in the body whereas the other agents are translocated into storage depots. Among the desired properties of new intravenous anaesthetics is rapid recovery, with no "hangover", from normally used clinical doses. This is important when the drugs are to be used for very short operative procedures, particularly in outpatients. However, it means that greater and more frequent supplementary doses will be required for prolonged operations. The more cumulative the drug, the less will be the need for supplementary doses and vice versa. Soon after the introduction of thiopentone, Wyngaarden and his colleagues (1949) used the duration of action of repeated doses in animals as a means of comparing its cumulative action with that of thiamylal and this method has been used by Swanson and Chen (1953) to study a number of methylated thiobarbiturates. Such experiments could not be carried out under normal clinical conditions in man and the only alternative is to study the doses required to maintain a constant level of anaesthesia for standard operative procedure. This has been done by Ke ri Szant6 (1955, 1960) giving the intravenous anaesthetic in combination with nitrous oxide-oxygen and a muscle relaxant, but it would seem desirable to limit studies to subjects undergoing operative procedures not requiring muscular relaxation. Dundee and Riding (1955) used this as a means of comparing the cumulative effect of thiopentone and thiamylal while Dundee, Nicholl and Moore (1963) have shown that this is a satisfactory method for studying intravenous anaesthetics in man and is sufficiently sensitive to detect the effect of premedication on the dosage of methohexitone. Interest in these studies has been revived by the introduction of the eugenol intravenous anaesthetics, of which propanidid (FBA.1420; Epontol) is the most promising. Clinical trials suggest that it is shorter-acting than comparable doses of methohexitone, thiopentone or hexobarbitone (Dundee and Clarke, 1964a; Howells et al., 1964; Podlesch and Zindler, 1965). To date there have been no published studies on its use, either alone or with nitrous oxide-oxygen by intermittent injection. The present investigation compares the cumulative effects of propanidid with those of the standard intravenous drug used in this country thiopentone. The findings are also compared with those obtained by Dundee, Nicholl and Moore (1963) using methohexitone under comparable conditions. A preliminary report on these findings has been published by Dundee and Clarke (1964b). METHOD Subjects. Observations were carried out on fit adult patients of both sexes undergoing operation for varicose veins or other similar body surface procedures. Atropine 0.6 mg was given before anaesthesia. Anaesthesia. This was induced with equipotent doses of one of the three drugs under study, and main-

2 402 BRITISH JOURNAL OF ANAESTHESIA tained with intermittent doses of the same drug and 75 per cent nitrous oxide in oxygen (total gas flow of 8 l./min using a Magill semi-open circuit). The average induction doses were: thiopentone 4.1 mg/kg; methohexitone 1.7 mg/kg; propanidid 5.2 mg/kg. When oral endotracheal intubation was considered desirable this was carried out under topical lignocaine anaesthesia (direct spray or trans-tracheal) with or without paralysis obtained with suxamethonium. The response of the patient to surgical stimuli was the only indication for supplementary doses; these were kept as small as possible, so that at no time did the total dose markedly exceed the patient's requirements at that time. With increasing experience, it was often possible to predict impending movements by respiratory irregularity. The minimum duration of anaesdiesia for this study was 60 minutes and the findings are based on 162 thiopentone, 34 methohexitone and 55 propanidid cases. >- IO- "IbJ I -12 X UJ I t- UJ 2 RESULTS Figure 1 shows the average doses of the three drugs during the first hour of anaesthesia and reveals an enormous difference between propanidid and the two barbiturates. The falling off in requirements which occurs after the first fifteen minutes of anaesthesia with both thiopentone and methohexitone is much less evident with propanidid. Since the response of the nervous system to thiopentone is to some extent governed by die initial dose (Dundee, Price and Dripps, 1956) die ratio of die total to induction dose was used as a means of testing die significance of the difference between die drugs (table I). At all times noted on diis table propanidid differs significandy from either of die barbiturates at die 0.01 per cent level. At 15 and 30 minutes after induction, the ratios for diiopentone and mediohexitone differ significandy at die 5 per cent level; diereafter diey are significandy different at die 2 per cent level. There was a very wide scatter in die requirements of propanidid and diis is illustrated in figure 2 which gives die 68 per cent range (mean ± 1 standard deviation of mean) of dosage during die first hour of anaesdiesia and die total dose IO 20 TIME IN FIG. 1 io MINUTES Average dosage in mg/kg of drugs during 1 hour of a group of body surface operations. The two ordinate scales represent equipotent doses of the intravenous agents and the points refer to the average cumulative total of drugs in mg/kg during 1 hour of anaesthesia for body surface operations. TABLE I Average ratio of total to induction dose at 15-minute intervals during the first hour after anaesthesia with the three drugs studied. Minutes after induction Thiopentone (162) 1.7 ± ± ± ±0.04 Methohexitone (34) 2.1 ± ± ± ±0.12 SO Propanidid (55) 4.2 ± ± ± ±0.73 required by diose patients in whom die operation lasted for more than 1 hour. The continuing demand for supplementary doses made diis technique of anaesthesia very difficult when propanidid was used and it was

3 CLINICAL STUDIES OF INDUCTION AGENTS XV DO, 403 8O 6O o> 4O 20 3O TIME 6O IN FIG. 2 Dosage in mg/kg of propanidid during a group of body surface operations showing the mean ± 1 standard deviation (stippled area) for the first hour and the final figure for individual cases which lasted over 1 hour. 9O MINUTES I2O ISO imperative that there was no delay in filling syringes and that blocking of a needle never occurred. This applied, but to a lesser extent, with methohexitone, but here some of the difficulties were due to the involuntary spontaneous muscle movements which followed the injection of this drug. This complication rarely persisted after the first 10 minutes when the analgesic action of the nitrous oxide was manifested. Recovery paralleled the cumulative action of the drugs as being most rapid after propanidid and slowest after thiopentone. The striking difference between propanidid and the barbiturates was the completeness of the early recovery with the former. Even after doses of 5 to 7 g the patients were wide awake within 10 minutes of discontinuation of the nitrous oxide. When seen 1 hour after the end of operation, there was absolutely no doubt about which patients had been anaesthetized with propanidid. DISCUSSION This study shows that propanidid is much less cumulative than either thiopentone or methohexitone. Although methohexitone is less cumulative than thiopentone, the difference between these is not nearly as striking as that between either barbiturate and propanidid. Price (1960) has suggested that, under certain conditions the cardiovascular effects of thiopentone limit its redistribution in the body. This could occur, even in fit subjects, with the doses used in this study, and the lesser degree of hypotension found with the other two drugs may play a part in the present findings. Hypotension undoubtedly occurs after the use of large doses of propanidid, but it is more transient than that found with either of the other two drugs. Dundee (1962) has postulated that this lack of cardiovascular depression may explain the findings with another eugenol derivative, G (Estil)

4 404 BRITISH JOURNAL OF ANAESTHESIA where a linear relationship was found, over a large range, between dosage and recovery time. Keeri-Szant6 (1955, 1960) has used "drug consumption" curves to study the relative amounts of thiopentone that are redistributed in the tissues (translocated) and detoxicated (transformed in the body to an inactive form). His period of observation was much greater (4 5 hours) than in the present study and elaborate formulae (calculated with the aid of a computer) were used to express the drug requirements. This is not possible in the relatively short period of this present study, but inspection of figure 1 reveals an almost linear drug consumption curve for propanidid. It is unlikely that this could occur if redistribution were the main means of removal of the drug from the nervous tissues, since everdecreasing tissue gradients would limit this in an exponential manner. This falling off in requirements was found with both barbiturates, and with these the curves are very similar to those obtained by the Canadian worker. The present findings can be put forward as indirect evidence to suggest that metabolic transformation plays a more important part in recovery from propanidid than is the case with the two barbiturates. Brand and associates (1963) found that between 15 and 19 per cent of the body content of methohexitone was detoxicated per hour in man, the comparable figure for thiopentone being 15 per cent. These low values are in keeping with the falling off in drug requirements noted in this study. Comparable figures are not available for propanidid but it is interesting to note that, in studies on rats and rabbits using C 14, Duhm and associates (1965) found that 90 per cent of the drug (in an inactive form) was eliminated in the urine within 2 hours, with up to 6 per cent in the faeces. Putter (1965) has shown that the reaction CH 2.COO.CH 2.CH 2.CH 3 O.CH,.CO.N CH 2.COOH O.CHj is the principal route of destruction of propanidid. None of the other reactions investigated, which could split the molecule, occur rapidly enough to account for its pharmacological properties. Furthermore, Wirth and Hoffmeister (1965) found the corresponding acid to be anaesthetically inactive. Putter showed that the esterases responsible for the breakdown were present in human blood and in the liver of many animal species and, because of the brevity of the action, it appears likely that the liver is the principal site in man. Truly comparative studies of clinical recovery from propanidid and barbiturate are difficult to make. Doenicke and colleagues (1965) and Kreuscher (1965), using psychological tests, conclude that late recovery is more rapid and complete than after thiopentone. Doenicke and colleagues (1966) have shown that the e.e.g. is a better measure of wakefulness than these tests and that complete electroencephalographic recovery after an anaesthetic dose of propanidid occurs in 5-10 minutes whereas after methohexitone it takes many hours. ACKNOWLEDGEMENTS This study could not have been carried out without the co-operation of many surgical colleagues to whom the authors are grateful. Generous supplies of methohexitone were provided by Eli Lilly & Company Limited, while Dr. D. Whitfield of Farbenfabriken Bayer AG supplied propanidid. REFERENCES Brand, L., Mark, L. C, Snell, M. McM., Vrindten, P., and Dayton, P. G. (1963). Physiologic disposition of methohexital in man. Anaesthesiology, 24, 331. Doenicke, A., Giirtner, T., Kugler, J., Schellenberger, A., and Spiess, W. (1965). Experimentelle Untersuchungen iiber das Ultra-Kurznarkotikum Propanidid mit serurncholinesterasebestimmungen, EEG, psychodiagnostichen Tests und Kreislaufanalysen; in Horatz, K., Frey R., and Zindler, M., Die intravenose Kurznarkose mit dem neuen Phenoxyessigsaurederivat Propanidid (EpontoT), p.* 249. Berlin: Springer-Verlag. Kugler, J., Schellenberger, A., and Gunner, T. (1966). Recovery time after intravenous anaesthesia measured by electroencephalography. Brit. J. Anaesth. (in press). Duhm, B., Maul, W., Medenwald, H., Patzschke, K., and Wegner, L. A. (1965). Tiexperimentclle Untersuchungen mit Propanidid- U C; in Horatz, K., Frey, R., and Zindler, M., Die intravenose Kurznarkose emit dem neuen Phenoxyessigsaurederiyat Propanidid (Eponlol), p. 78. Berlin: Springer-Verlag.

5 CLINICAL STUDIES OF INDUCTION AGENTS XV 405 Dundee, J. W. (1962). Clinical studies of induction agents. Ill: The relationship between duration of anaesthesia and dosage with G Brit. J. Anaesth., 34, 790. Clarke, R. S. J. (1964a). Clinical studies of induction agents. IX: A comparative study of a new eugenol derivative, FBA.1420, with G and standard barbiturates. Brit. J. Anaesth., 36, 100. (1964b). Cumulative effects of three intravenous anaesthetics. Proc. Third World Congress of Anaesthesiology, 2, 489. Nicholl, R. M., and Moore, J. (1963). The influence of phenothiazine premedication on methohexitone dosage. Anaesthesia, 18, 41. Price, H. L., and Dripps, R. D., (1956). Acute tolerance to thioptntone in man Brit. J. Anaesth., 28, 344. Riding, J. E. (1955). A clinical trial of thiamylal as an intravenous anaesthetic in 1750 cases. Brit. J. Anaesth., 27, 381. Howells, T. H., Odcll, J. R., Hawkins, T. J., and Steanc, P. A. (1964). An introduction to FBA.1420 a new non-barbiturate intravenous anaesthetic. Brit. J. Anaesth., 36, 295. Keeri-Szint6, M. (1955). Anaesthetic dosage in thiopental-curare-nitrous oxide anaesthesia, using a thiopental-curare mixture. Canad. Anaesth. Soc. J. 2, 184. (1960). Drug consumption during thiopentonenitrous oxide-relaxant anaesthesia: the preparation and interpretation of time/dose curves. Brit. J. Anaesth., 32, 415. Kreuscher, H. (1965). Zur Strassenverkehrstuchtigkeit nach Anwendung von Propanidid; in Horatz, K., Frey, R., and Zindler, M., Die intravenose Kurznarkose mit dem neuen Phenoxyessigsdurederivat Propanidid (Epontol), p Berlin: Springer- Verlag. Podlesch, I., and Zindler, M. (1965). Klinische Erfahrungen mit Propanidid; in Horatz, K., Frey, R., and Zindler, M., Die intravenose Kurznarkose mit dem neuen Phenoxyessigsdurederivat Propanidid (Epontol), p Berlin: Springer-Verlag. Price, H. L., (1960). A dynamic concept of the distribution of thiopental by the human body. Anaesthesiology, 21, 40. Putter, J. (1965). Uber den fermentativen Abbau des Propanidid; in Horatz, K., Frey, R., and Zindler, M., Die intravenose Kurznarkose mit dem neuen Phenoxyessigsdurederivat Propanidid (Epontol), p. 61. Berlin: Springer-Verlag. Swanson, E. E., and Chen, K. K. (1953). Ultra-short acting thiobarbirurate acids. Proc. Soc. exp. Biol. (N.Y.), 82, 212. Wirth, W., and Hoffmeister, F. (1965). Pharrnakologische Untersuchungen mit Propanidid (3- Methoxy (N, N - diathylcarbamoylmethoxy)- pheylessigsaure-n-propylester); in Horatz, K. Frey, R., and Zindler, M., Die inlravenose Kurznarkose mil dem neuen Phenoxyessigsdurederivat Propanidid (Epontol); p. 17, Berlin: Springer- Verlag. Wyngaarden, J. B., Woods, L. A., Ridley, R. and Seevers, M. H. (1949). Anesthetic properties of sodium 5-allyl-5-(l methyl-butyl)-2 thiobarbiturate (surital) and certain other thiobarbiturates in dogs. J. Pharmacol, exp. Ther., 95, 322. ETUDES CLINIQUES DES AGENTS D'INDUCTION XV: COMPARAISON DES EFFETS CUMULATIFS DE LA THIOPENTONE, DE LA METHOHEXITONE ET DU PROPANIDIDE SOMMAIRE La thiopentone, la m thohexitone et le propanidide ont cti donnes d'une facon intermittente comme agent principal dans une serie d'operations superficielles. Les besoins dans la premiere heure montrent une nette diminution avec les barbituriques mais peu avec le propanidide. Ceci confirme les resultats expirimentaux selon lesquels le propanidide est rapidement ddtruit dans l'organisme alors que les autres agents sont transportes dans des dipdts de reserve. KLINISCHE PROFUNG VON MEDIKAMENTEN FUR DIE NARKOSEEINLEITUNG XV: EIN VERGLEICH DER KUMULATIONS- WIRKUNG VON THIOPENTONE, METHOHEXITONE UND PROPANIDID ZUSAMMENFASSUNG Bei einer Serie von dermatologischen Operationen wurde als Hauptnarkosemittel Thiopentone, Methohexitone oder Propanidid in unterteilten Dosen gegeben. Der Narkosemittelbedarf wahrend der ersten Stunde zeigt einen steilen Abfall bei den Barbituraten und einen geringen Abfall beim Propanidid. Dies unterbaut die experimentellen Befunde, dafl das Propanidid im Korper rasch abgebaut wird, wahrend die anderen Substanzen in die Speicherraume iibergefuhrt werden.