CLINICAL STUDIES OF INDUCTION AGENTS XVI: A COMPARISON OF THIOPENTONE, BUTHALITONE, HEXOBARBITONE AND THIAMYLAL AS INDUCTION AGENTS

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1 Brit. J. Anaesth. (),, CLINICAL STUDIES OF INDUCTION AGENTS XVI: A COMPARISON OF THIOPENTONE, BUTHALITONE, HEXOBARBITONE AND THIAMYLAL AS INDUCTION AGENTS BY D. W. BARRON, J. W. DUNDEE, W. R. GILMORE AND P. J. HOWARD Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland SUMMARY Results are presented of a comparative clinical trial of thiopentone, buthalitone, hexobarbitone and thiamylal, which extended over five years and was carried out by twenty-three anaesthetists. and thiamylal produced consistently good anaesthesia, but the respiratory and circulatory complications occurring with hexobarbitone and buthalitone were of sufficient frequency and severity as to make their continued use in anaesthesia difficult to justify. also caused an unacceptably high incidence of excitatory phenomena, particularly in the absence of opiate premedication. The trial was carried out in several parts, including a "double blind" study, and the results were pooled with those of three series already published from this department, to produce a total of, administrations. There was remarkable consistency in the results obtained in different parts of the investigation. Recent studies of induction agents in this department have been concerned with eugenol preparations, particularly propanidid. With the impending introduction of these compounds into clinical practice, it was considered timely to survey the action of the commercially available barbiturates. Barron and Dundee () compared the induction characteristics of nine of these compounds in electroconvulsive therapy, while Dundee () compared eight intravenous anaesthetics as main agents for a standard operation. In these two papers it was concluded that both B ( methyl, ethyl, [-methyl propyl] thiobarbiturate) and methitural ( thioethyl, [-methyl butyl], thiobarbiturate) were unsuitable for routine clinical use. On completion of these studies, it was intended to examine the remaining seven preparations using a "blind" method of administration, in which the nature of the drug being used was unknown to the anaesthetist. Unfortunately, it was not readily possible to include thialbarbitone (Kemithal) because of the smell of the solution. In addition thiobutabarbitone (Inactin) and methohexitone (Brietal) had to be excluded because of the difficulties in obtaining solutions which were equipotent with thiopentone. This paper reports the results of a group study of the remaining four drugs which was organized by, and the data analyzed by, the authors, twenty additional experienced anaesthetists providing the clinical data. Most of the participants had no previous experience of clinical investigation. Three of the drugs, thiopentone (Pentothal, Intraval), buthalitone (Transithal) and hexobarbitone (Cyclonal), are available commercially on the British market, while thiamylal (Surital) is used widely in America. For the most part these four drugs were used "blindly" and a preliminary report on this has been presented by Gilmore and Dundee (). Finally, an analysis is presented of the accumulated data obtained from more than, documented administrations of these four drugs and an attempt is made to assess their places in modern anaesthetic practice. METHOD Observations were made on fit adult subjects undergoing a variety of operations or electroconvulsive therapy. Premedication varied with the needs of the investigation. While each of the twenty-three participants employed his usual anaesthetic techniques and dosage, recorded data was limited to that obtained in patients in whom

2 CLINICAL STUDIES OF INDUCTION AGENTS XVI the induction characteristics of the barbiturates were not modified by the use of muscle relaxants or other drugs. In addition to brief clinical details of patients and dosage, the complications occurring during the induction of anaesthesia were noted on the case record described by Dundee and Moore (). These complications were grouped as excitatory phenomena (tremor, hypertonus, spontaneous involuntary muscle movement), respiratory upset (cough, hiccough, laryngospasm), marked respiratory depression (necessitating assistance to respiration) and hypotension (fall in systolic pressure in excess of mm Hg). Each induction was graded as: : uneventful; a: slight upset, not interfering with the course of anaesthesia; b: moderate upset, but not so severe as in ; : serious upset prolonging induction, or placing the patient's life in jeopardy. Where the "blind" technique was employed, all drugs were issued in ampoules the contents of which were considered to be equipotent; these contained mg of thiopentone or thiamylal and g of buthalitone or hexobarbitone. This could be made up to the equivalent of a or. per cent solution of fhiopentone and doses were recorded in ml of solution injected. The relevant data on each administration was transferred to a special book by one author (P.J.H.) who converted all induction doses to mg/kg. The whole study was spread over a period of five years. Like many other investigations, the programme was evolved rather than planned at the outset and the ultimate number of studies was governed by the earlier results. For this reason, it is simpler to present data in the order in which the various parts of the investigation were started. Some of these parts were often running concurrently and for a variety of reasons some participants were unable to continue throughout, while a few took part only in the later stages. However, before an anaesthetist embarked on the "blind" study (using the drugs without knowing the contents of the ampoule), each documented a number of thiopentone administrations in order to become acquainted with the method of recording data. In addition, each used thiamylal, buthalitone, and hexobarbitone until he became familiar with the induction characteristics of these drugs ("open" study). It was stressed that this could be more easily achieved by the use of atropine as sole premedication. Two types of blind ampoules were used. Initially, boxes of ten amber glass ampoules of each of the four drugs, labelled with a letter only, were available. As will be seen later, following the use of these, the number of drugs was reduced to three and identically shaped ampoules of thiopentone (Intraval), buthalitone (Transithal) and hexobarbitone (Cyclonal) marketed by one pharmaceutical manufacturer were used, the glass being covered completely by coloured Sellotape X in order to prevent identification of the agent by colour, especially the clear solution of hexobarbitone. In some cases nylon syringes were used, with the same object in view. These three drugs were labelled successively in groups of five and two and singly. The individually labelled ampoules were also used for electroconvulsive therapy. Generally speaking, the number of cases in each part of the investigation was fairly evenly distributed between all the participants. In the "blind" studies the anaesthetist was asked to record the induction characteristics as outlined above and to guess the identity of the drug used. With the boxes of ten ampoules, no instructions were issued about whether this guess was to be based on the contents of the whole box or on single ampoules. With the groups of five and two the guess was based on five and two administrations respectively. With the lower doses used in electroconvulsive therapy, two or three patients could often be anaesthetized from the contents of a single ampoule and the guess was naturally based on this number of cases. OPEN TRIAL The findings of all twenty-three participating anaesthetists are summarized in table I in which the results from patients who received atropine premedication are considered separately from those who were given an opiate also. All groups of patients are broadly similar in the proportions of females and the average ages and weights. Results with thiamylal and thiopentone were very similar except for a significantly higher

3 BRITISH JOURNAL OF ANAESTHESIA TABLE I Summary of the findmgs of the initial study of the induction characteristics of four intravenous anaesthetics. Atropine premedication Opiate-atropine premedication Number of cases Percentage females Average age Average weight (kg) Average dose (mg/kg) (±SET Hypotension - mm Hg + mmhg Induction Uneventful (Grade ) Troublesome (Grade ). ±.. ±.. ±.. ±.. ±.. ±.. ±.. ±. incidence of respiratory upset with the former when opiate premedication was used (-/' =.; P<.). With atropine premedication, hexobarbitone caused a significantly higher incidence of excitatory phenomena than buthalitone (/ =.; P<.), which in turn caused more than thiopentone ( y =.; P<.). These differences were less marked with opiate premedication; hexobarbitone was followed by significantly more excitatory phenomena than either thiopentone (-/=.; P<.) or buthalitone (-/ =.; P<.), but there was no significant difference between the frequency with the last two drugs. With or without opiate premedication, buthalitone was followed by a very much higher incidence of respiratory complications than any of the other drugs (P<.). With atropine premedication, thiopentone was followed by a significantly lower incidence of hypotension than either buthalitone ( /'=.; P<.) or hexobarbitone (-/ =.; P<.) but there was no difference between the incidence with the last two drugs. There was no significant difference between the hypotensive effects of any of the drugs when opiate premedication was used. BLIND TRIAL Because of the shortage of supplies, the use of thiamylal was restricted to a limited comparison with thiopentone. This part of the investigation differs from the comparison of thiopentone, buthalitone and hexobarbitone and will be discussed later. The major part of the "blind" study was carried out on subjects premedicatedwith atropine alone. The number of cases with each drug and details of the anaesthetists participating is shown in table n. There was fairly close similarity between the incidence of induction complications with each individual drug in the different parts of the study (fig. ). Except for the data obtained in electroconvulsive therapy cases (in which the dose was appreciably lower than that used in general surgical cases), all findings with each of the premedicants are pooled. Since the series with each of the three drags are strictly comparable with respect to administrators and the types of cases, and broadly comparable as to sex, age and weight of patients, the presentation of data (table HI) and analysis of findings (table TV) are in greater detail than the previous part of this investigation (table I). The differences between the drugs agree closely with those in the earlier part of the study, except for (a) a statistical, but probably not clinical, difference between the incidence of respiratory upset with hexobarbitone and thiopentone, and (b) a significantly higher incidence of hypotension with hexobarbitone than with buthalitone. With all three drugs the incidence of excitatory phenomena was Jess with opiate than with atropine premedication (P<.). Conversely, hypoten-

4 CLINICAL STUDIES OF INDUCTION AGENTS XVI ATROPINE PREMEDICATION OPIATE PREMEDICATION THJOP. BUTH. HEXO. THIOP. BUTH. HEXO. O l IO I IO I «o O O I # O O IO O O D ndd O O # IO O O D a DD. DDD z Q if> LJ O Q. I # O O IO DDDD FIG. Incidence of induction complications with three barbiturates (thiopentone, buthalitone and hexobarbitone) in different pans of the blind study. Numbers (,, and ) refer to grouping of ampoules see table II. D sion occurred more often when opiate premedication was used (P<.). Using the ridit analysis of induction grades in general surgical cases, it was found that, irrespective of the premedication, thiopentone was significantly better and hexobarbitone significantly worse than buthalitone (P<.). In the electroconvulsion therapy series, this test showed hexobarbitone to be significantly worse than either of the other two drugs. Table V summarizes the results obtained in anaesthesia for electroconvulsive therapy. As mentioned previously, the dose required is approximately two-thirds of that used for induction

5 BRITISH JOURNAL OF ANAESTHESIA TABLE II Number of cases in different parts of the "blind" study, with details of participants. Ampoules numbered in Tens Fives Twos Singles Singles for e.c.t. Total No. of cases with each drug Atropine C Participants SR Total *. Premedication No. of cases with each drug Opiate-atropine C Participants SR Total C = Consultant. SR=Senior Registrar. * Two participating senior registrars achieved consultant status during the period of the trial. TABLE III Summary of findings of "blind" studies of three intravenous anaesthetics. Percentage females Average age Average weight (kg) Average dose (mg/kg) ± SE Tremor Muscle movement Nil Cough/hiccough Laryngospasm Nil Respiratory depression Fall in systolic pressure - mm Hg + mm Hg Induction grade Uneventful () Slight upset (a) Moderate upset (b) Unsatisfactory () Atropin: premedication Opiate-atropine premedication.... Thiopantone Thioprntone.. in general surgery. The only significant finding in this study was that there was a much higher incidence of excitatory phenomena with hexobarbitone (P<.). It will be noted that the respiratory disturbance caused by buthalitone was much less in this lower dosage. It was not possible to take blood pressure readings in this part of the study. Table VI shows the percentage incidence of guesses at the identity of the "unknown drug". (In each series the few instances in which the anaesthetist was unable to hazard a guess are not included, the "corrected" percentage being calculated from the number of actual guesses.) Throughout the study, it was possible always to identify thiopentone or hexobarbitone more readily than buthalitone, particularly on single or double administrations and when small doses of

6 CLINICAL STUDIES OF INDUCTION AGENTS XVI TABLE IV Significance levels of probability (P) of difference between incidence of side effects shown in Drugs compared and buthalitcme and hexobarbitone and hexobarbitone table HI having arisen by chance. Atropine premeditation Side effects Hypotension (+) Hypotension (+) Hypotension (+) x l P <. <. <. <. <. <. <. <. <. Opiate premedication x P NS <. <. <. <. <. <. <. <. TABLE V Summary of findings in patients undergoing anaesthesia for electroconvulsive therapy. Number of cases Percentage females Average age Average weight (kg) Average dose mg/kg Induction grades a b. ±.. ±.. ±. TABLE VI Corrected percentage (see text) incidence of guesses as to identity of drugs used in blind study. Tens Fives Twos issued in Singles Singles (for e.c.l) Drug used Atropine premedication Drug guessed as Opiate premedication Drug guessed as

7 BRITISH JOURNAL OF ANAESTHESIA the drugs were used. It was also easier to identify each drug after atropine premedication than when an opiate was given. More information can be obtained from figure which shows the reasons why the various guesses were made in the "tens" and "singles" series, with atropine premedication. In the absence of complications anaesthetists usually assumed the drug to be thiopentone; when excitatory phenomena and hypotension was noted hexobarbitone was usually assumed to be the drug given, whereas respiratory upset, slight hypotension and some excitatory phenomena suggested buthalitone. It is of some interest to record (table VH) the average dose of drug (expressed as equivalent dose of thiopentone) used in the guesses referred DRUGS GUESSED AS NO GUESS THOPENTONE BUTHALITONE HEXOBARBTTONE MADE O «O O s I ro O O L O - - -tsa -E E - - O &UG T B H T B H T B H T B H FIG. Incidence of induction complications related to guess as to identity of drug given. T (thiopentone) B (buthalitone) and H (hexobarbitone) indicate actual drug used. incidence in series.

8 CLINICAL STUDIES OF INDUCTION AGENTS XVI TABLE VII Average dose of drug (expressed as equivalent doses of thiopentone) given to the groups guessed as shown above. Drug guessed as No guess possible Average dose (mg/kg).... to in figure. The largest dose was associated with the highest incidence of respiratory upset in those administrations guessed as buthalitone. Since per cent of these patients did, in fact, receive buthalitone, it would appear that respiratory complications were more frequent when large doses of the drug were given. This is in keeping with the very low incidence of respiratory upset associated with its use for electroconvulsive therapy (table V). An interesting observation was that very low doses often led to the participant being unable to guess which drug was being used. Examination of the results obtained with small doses of the drugs in electroconvulsive therapy (table V) shows that there was a lower than average incidence of respiratory upset with thiopentone and a lower incidence of excitatory phenomena with hexobarbitone. and thiamylal comparisons. Only specially prepared amber-coloured glass ampoules of. g thiamylal were available and these were issued in batches of ten for comparison with thiopentone, both being used with atropine as sole premedicant. Freshly prepared per cent solutions of thiopentone and thiamylal were used for a similar comparison using opiate premedication, supplies limiting this study to cases. The technical difficulties involved in this part of the "blind" investigation limited the number of observers to the first three authors. Table VIII analyzes the results and shows that, apart from a greater incidence of respiratory upset in the thiamylal-atropine series than in the corresponding thiopentone series (y =.; P<.), there was no significant difference between effect of the drugs. This is reflected in the distribution of the guesses at the identity of the drug used and all participants admitted that there was often no rational basis for these, the drugs being indistinguishable. OVERALL SURVEY OF EFFECTS Table IX summarizes the findings in two previous comparisons of thiopentone, buthalitone, hexobarbitone and thiamylal (Dundee,, ). It will be seen that these results are very similar to those given in tables I, HI and VIII, but with buthalitone and hexobarbitone there was a slightly lower incidence of grade cases with the standard operation. In this particular series, the grading applied to the whole anaesthetic rather than to the induction only as in the other studies and in the present investigation. Premedication drug Number of cases Patients Percentage females Average age Average weight (kg) Average dose (mg/kg) Percentage complications Hypotension ( mm Hg +) Satisfactory induction ( and a) Drug guessed as Other* TABLE Vni Analysis of thiopentone-thiamylal comparisons. Atropine. ±.. +. Opiate-atropine.±..±. * With atropine premedication this could have been hexobarbitone or buthalitone.

9 BRITISH JOURNAL OF ANAESTHESIA TABLH IX Summary of the finding of studies published by Dundee () (general surgical cases) and Dundee () (standard operation). Atropine premedicatkra Opiate premedication GENERAL SURGICAL CASES Number Average dose (mg/kg) Induction Uneventful Unsatisfactory STANDARD OPERATION Number Average dose (mg/kg) Hypotension ( + mm Anaesthesia Uneventful () Unsatisfactory ().. Hg) Clinical anaesthetists are essentially interested in the frequency and severity of complications which they are likely to encounter with intravenous agents given over a wide dose range and with a variety of premedicants. This can be assessed, with some degree of accuracy, by pooling the findings of tables I, IE, VHI, IX, and further data from the use of these drugs in electroconvulsive therapy published by Barron and Dundee in. This results in the very large numbers of cases shown in table X. These findings confirm that thiopentone and thiamylal are almost identical in their clinical actions and that either drug is to be preferred to buthalitone or hexobarbitone. Ridit analysis of the distribution of induction grades confirmed these findings. Number of cases Patients Percentage females Average age Average weight (kg) Average induction dose (mg/kg) SD Involuntary muscle movements Tremor Nil Cough/hiccough Laryngospasm Nil Marked respiratory depression Hypotension -^ mm Hg fall + mm Hg fall Completely smooth induction () Unsatisfactory induction (b+) TABLE X Summary of total data.. (.). (.). (.). (.)

10 CLINICAL STUDIES OF INDUCTION AGENTS XVI DISCUSSION The present investigation does not shed any new light on the actions of the four drugs studied. On the contrary, there is a remarkable consistency in the results when compared with the previously reported studies of these drugs. The complications with hexobarbitone and buthalitone were of sufficient severity to make these compounds easily distinguishable and in view of these conclusions it is difficult to envisage any place for their continuing use as induction agents. It may be argued that the apparent safety of hexobarbitone when injected extravenously is a point in its favour, but this applies also to methohexitone. A double "blind" comparison of the two drugs as induction agents demonstrated the superiority of methohexitone (Riding, ). There were slight, but inconsistent, differences in the incidence of respiratory upset with thiopentone and thiamylal, but since the frequency of grade l-a inductions was similar for both, these differences are probably of no clinical importance. Both drugs produced consistently good anaesthesia and are assured of retaining their present popularity. This study has suggested that the relationship between dosage and the incidence of respiratory upset and excitatory phenomena which Dundee et al. () demonstrated for methohexitone, might apply to other intravenous barbiturates. This is of major clinical importance and is being studied in further detail. ACKNOWLEDGEMENTS Generous supplies of drugs were provided by May & Baker Limited. The authors are indebted to the following anaesthetists, whose co-operation made the study possible: Drs. J. P. Alexander, A. Armstrong, M. Bookallil, S. S. Brown, H. J. Craig, W. S. Davis, J. Elliott, R. C Hamilton, J. C. Hewitt, R. King, W. R. Lamb, W. B. Loan, W. J. Love, W. N. McQeery, J. McNaul, J. Moore, R. NeUl, R. M. Nicholl, B. A. Nixon, J. E. Riding. REFERENCES Barren, D. W., and Dundee, J. W. (). Clinical studies of induction agents. : A comparison of the incidence of induction complications with nine barbiturates in electroconvulsive therapy. Brit. J. Anaesth.,,. Dundee, J. W. (). Charakteristika bei intravenoser Narkoseeinleitung. Der Anaesthesist,,. (). Clinical studies of induction agents. VII: A comparison of eight intravenous anaesthetics as main agents for a standard operation. Brit. J. Anaesth.,,. Dundee, J. W., and Moore, J. (). and methohexital: a comparison as main anaesthetic agents for a standard operation. Anaesthesia,,. Riding, J. E., Barren, D. W., and Nicholl, R. M. (). Some factors influencing the induction characteristics of methohexitone anaesthesia. Brit. J. Anaesth.,,. Gilmore, W. R., and Dundee, J. W. (). Bund studies of intravenous barbiturates: preliminary communication. Proc. st European Congress of Anaesthesiology, paper. Riding, J. E. (). Intravenous anesthesia. International Anesthesiology Clinics,,. ETUDES CLINIQUES DES INDUCTEURS DE NARCOSE XVI: COMPARAISON DU THIOPENTAL, DU BUTHALITAL, DE L'HEXOBARBITAL ET DU THIAMYLAL SOMMAIRE Les auteurs presentent les resultats d'une itude clinique comparative de ces inducteurs de narcose, etude qui s'est etendue sur cinq ans avec la collaboration de ancsthesistes. Le thiopental et le thiamylal ont toujours provoque une bonne anesthesie. Avec l'hexobarbital et le buthalital, en revanche, on a eu des complications respiratoires et circulatoires dont la frequence et la gravity font que l'emploi systematique de ces deux drogues en anesthesie est difficile a justifier. L'hexobarbital cause en outre trop souyent de l'agitation, surtout en l'absence d'une pretnedication opiacee. La presente fitude comprend plusieurs parties, dont une de tests au "double insu". Les resultats en ont M reunis avec ceux de trois autres travaux deja publics par notre dipartement, amenant ainsi a un total de. narcoses. Les divers resultats obtenus se recoupent de facon remarquable. KLINISCHE UBERPROFUNG VON MEDIKA- MENTEN FOR DIE NARKOSEEINLEITUNG XVI: EIN VERGLEICH VON THIOPENTON, BUTHALITON, HEXOBARBITON UND THIAMYLAL ALS MEDIKAMENTE FUR DIE NARKOSEEINLEITUNG ZUSAMMENFASSUNG Es werden die Ergebnisse einer funfjahrigen, von Anasthesisten durchgefuhrten klinischen Uberprufung von Thiopenton, Buthaliton, Hexobarbiton und vorgelegt Thiopenton und fuhrten stets zu einer guten Narkose, wahrend die bei Hexobarbiton und Buthaliton auftretenden respiratorischen und zirkulatorischen Komplikationen hiufig imd schwerwiegend genug waren, dafi ihre weitere Verwendung in der Anasthesie nicht zu rechtfertigen ist. Hexobarbiton verursachte aufierdem in einer unannehmbar groljen Anzahl von Fallen exzitatorische Erscheinungen, teilweise bei Abwesenheit von Opiat- Pramedikation. Die Untersuchimg wurde in verschiedenen Abschnitten durchgefuhrt, einschliefilich eines Doppelblindversuches, und die Ergebnisse wurden mit den Ergebnissen von drei bereits fruher von dieser Abteilung veroffendichten Serien zusammengefaot, sodafi sich eine Gesamtzahl von Verabfolgungen ergibt. Die Ergebnisse der verschiedenen Abschnitte der Untersuchung waren bemerkenswert konstant.