FLUNITRAZEPAM COMPARED WITH ALTHESIN AS AN INDUCTION AGENT IN BALANCED ANAESTHESIA

Br.J. Anaesth. (1977), 49, 1041

FLUNITRAZEPAM COMPARED WITH ALTHESIN AS AN INDUCTION AGENT IN BALANCED ANAESTHESIA M. A. K. MATTILA, P. MARTIKAINEN AND K. SAILA SUMMARY

The use of benzodiazepines in anaesthesia has increased during recent years (Dundee and Haslett, 1970; Vega, 1971; Niessner, 1975; Freuchen, 0stergaard and Skafte, 1976). They are used commonly as adjuvants with other drugs such as ketamine (Mattila, 1974; Freuchen et al., 1976), Althesin, methohexitone (Mattila and Nummi, 1974), propanidid (Mattila, Rajpar and Pystynen, 1974) or as part of a neuroleptanalgesic technique (Brock-Utne et al., 1976). Fiunitrazepam (Rohypnol, Hoffmann-La Roche) is a benzodiazepine derivative with a strong hypnotic effect. It is closely related chemically to nitrazepam (Wickstrom, 1974). Stovner, Endresen and 0sterud (1973) found that flunitrazepam used i.v. as an anaesthetic induction agent was a more specific hypnotic than was diazepam. Diazepam produces a slow induction of anaesthesia with marked individual variations in response (Brown and Dundee, 1968). Fiunitrazepam has minimal effects on the circulatory and respiratory systems (Ungerer and Erasmus, 1973; Yoo, 1973). There are several reports of the use of Althesin for induction of anaesthesia (Carson, Dundee and Clarke, 1975; Dechene, 1976). Campbell and his colleagues (1971) found that it produced a rapid induction and recovery. The cardiovascular effects of Althesin are peripheral vasodilatation and a decrease in stroke volume with an increase in heart rate which maintains the cardiac output (Coleman et al., 1972). Although flunitrazepam and Althesin differ significantly in chemical structure, there are distinct MATTI

A.

K.

MATTILA, M.D.;

PEKKA MARTIKAINEN;

Kuopio University Central Hospital, Department of Anaesthesiology, SF-70210 Kuopio 21, Finland. KRISTIINA SAILA, M.SC, F. Hoffmann-La Roche & Co. AG, Department of Clinical Research, Helsinki, Finland. Correspondence to M. M.

similarities in the onset of sleep. The aim of the study was to compare flunitrazepam and Althesin as induction agents and to evaluate their contribution to balanced anaesthesia during surgery and their effects on recovery. PATIENTS AND METHODS

Ninety-seven patients (84 women, 13 men) undergoing abdominal or gynaecological operations were studied. The age of the patients varied between 13 and 78 yr (mean 42 yr) and none exhibited important medical problems. The patients were allocated randomly to two groups: 48 received flunitrazepam and 49 received Althesin. There were no statistically significant differences between the two groups with regard to sex, age, weight or duration of surgery. Premedication for all patients was scopomorphin 0.008 ml kg" 1 (hyoscine 0.6 mg, morphine chloride 20 mg per ml) i.m. 1-2 h before operation. All patients received atropine 0.01 mg kg" 1 i.v. immediately before induction. Induction of anaesthesia was with either flunitrazepam 0.05 mg kg" 1 or Althesin 70 (xlitre kg" 1 which, in accordance with the double-blind technique, were in identical, coded 5-ml syringes. The drug was injected at an even speed over 20 s in a rapidly flowing sodium chloride dextrose infusion (0.3% NaCl in 5% dextrose) into a dorsal vein of the hand. If sleep did not ensue, supplementary doses (flunitrazepam 0.01 mg kg" 1 , Althesin 20 ^litre kg"1) were given. At the time of skin incision an additional dose (flunitrazepam 0.01 mg kg" 1 , Althesin 20 (jilitre kg"1) was given to 44 patients in both groups. After loss of the eyelash reflex, suxamethonium 1 mg kg" 1 was given to facilitate endotracheal intubation. During anaesthesia, muscle relaxation was maintained with alcuronium. Following induction, pethidine 0.5 mg kg" 1 was given i.v. and, during

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The effects of fiunitrazepam and Althesin as anaesthetic induction agents were studied in a doubleblind trial in 97 patients undergoing abdominal or gynaecological surgery. There was no difference between the two preparations in respect of the quality of induction. A marked difference in the quality of maintenance of anaesthesia was seen, in favour of fiunitrazepam. Recovery was more rapid from Althesin anaesthesia. A low incidence of nausea was observed in both groups.

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Score 5—no changes in heart rate and arterial pressure Score 4—small but not clinically significant changes Score 3 and 2—moderate and significant changes respectively in heart rate and arterial pressure Score 1—extreme, potentially lethal changes. The patients' reactions to surgical stimuli were used both as a guide for supplementary medication and for evaluation purposes. All adverse reactions during induction and maintenance of anaesthesia were recorded, as was the duration of the anaesthesia. After operation the patients were observed in the recovery room for several hours: arterial pressure and heart rate were measured at about 10-min intervals and evaluated as described above. The onset of spontaneous respiration, behaviour, occurrence of nausea or vomiting, and analgesic requirements were noted. Each step in the procedure and the observations during induction and maintenance of anaesthesia were made by the same anaesthetist. The observations during the recovery phase were made by the nursing staff.

TABLE I. Induction and maintenance of anaesthesia scores in patients given flunitrazepam or Althesin. Values indicate the number of patients in each grouping Flunitrazepam Mean induction time

49.;27 ±12.46

Althesin 45.20 ±15.00

(s)±SD Induction score 5 = excellent; with ease, no excitement phase 4 = good 3 = induction with slight difficulties 2 = induction poor; excitement phase present 1 = no sleep Total Anaesthesia score 5 = excellent; no reactions to surgical stimuli 4 = good 3 = moderate; patient reacts to stimuli with movements 2 = bad; defensive reactions, e.g. movement of limbs 1 = very bad; marked defensive reactions interfering with surgical procedure Total

30

31

16 2

14 3

0

1

0 48

0 49

20

6

25 2

15 11

1

15

0

2

48

49

TABLE II. Number of patients requiring supplements . of either diazepam or thiopentone Drug Diazepam Thiopentone Total

Flunitrazepam group (n = 48) 3 3 6

Althesin group (« = 49) 12 4 16

RESULTS

Induction and maintenance of anaesthesia

The quality of induction did not differ between the two groups. The highest scores, 4 and 5 (good and excellent respectively), during maintenance of anaesthesia occurred in 45 patients in the flunitrazepam group and in 21 patients in the Althesin group (table I). Supplementary hypnotics, diazepam or thiopentone, were required by six patients in the flunitrazepam group and by 16 in the Althesin group (table II). Changes in arterial pressure and heart rate were scored four times: at induction, at the moment of incision, during maintenance of anaesthesia and

during recovery. These changes were usually small and there were no differences between the two groups (table III). The observations in the recovery room are shown in table IV. The recovery rate was rapid in 25 patients in the Althesin group and in five patients in the flunitrazepam group. Slow recovery was observed in 21 patients in the flunitrazepam group and in only four patients in the Althesin group. There were no differences between the two groups in respect of behaviour on awakening. Nausea occurred in 16 patients in the flunitrazepam group and in 11 patients in the Althesin group.

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maintenance, supplementary doses of 0.1-0.2 mg kg" 1 were given i.v. at about 30-min intervals. The patient was ventilated (12 b.p.m.) manually with 66% nitrous oxide in oxygen using a semiclosed circuit and a fresh gas flow of 3 litre min" 1 . If any signs of arousal appeared, pethidine, diazepam or thiopentone was given. The time from the start of injection of the induction agent to the loss of the eyelash reflex was recorded as the induction time. Excitement or other difficulties during induction were noted also. The arterial pressure and heart rate were measured before induction and during maintenance at about 5-min intervals. These were evaluated as follows:

FLUNITRAZEPAM COMPARED WITH ALTHESIN

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TABLE I I I . Changes in arterial pressure and heart rate during maintenance and recovery expressed as a score of 1-5. The values are number of patients in each grouping

Flunitrazepam group

Althesin group

Arterial pressure score

Arterial pressure score Total

Total Induction Incision Maintenance Recovery

5 14 8 11

15 10 17 24

21 13 19 12

6 11 4 1

1 0 0 0

48 48 48 48

2 7 10 17

19 12 19 19

Induction Incision Maintenance Recovery

3 10 5 0

1 2 0 1

49 49 49 49

Heart rate score

5

4

3

2

1

Total

5

4

3

2

1

Total

37 15 17 5

8 18 14 20

3 11 15 20

0 2 1 3

0 2 1 0

48 48 48 48

32 18 14 6

14 15 13 22

1 12 19 20

1 3 3 1

1 1 0 0

49 49 49 49

5 = no change, 4 = slight change, 3 = moderate change, 2 = significant change, 1 = extreme condition. TABLE IV. Aspects of recovery from anaesthesia in two groups of patients given either flunitrazepam or Althesin. The values are number of patients

TABLE V. Side-effects occurring in patients given flunitrazepam or Althesin. Values are number of patients in each group

Side-effects Flunitrazepam Rate of recovery rapid normal slow not known Total Behaviour calm restless excited not known Total Nausea none slight or moderate severe (vomiting) Total Pain none analgesic needed not known Total

5 20 21 2 48

36 9 1 2

Flunitrazepam

Althesin

34 4 8

41 5 1

2

0

0

1

0

1

48

49

Althesin 25 16 4 4 49

48

40 4 0 -5 49

32 11 5

38 7 4

48

49

27 21 0

25 20 2

48

49

Analgesics were given in the recovery room to 21 patients in the flunitrazepam group at an average of 150 min after awakening and to 22 patients in the

None Transient erythema Postoperative respiratory depression Laryngospasm at extubation Sweating 4tachycardia Anaphylactoid reaction Total

Althesin group at an average of 110 min after awakening. Mild, transient erythema occurred in both groups. At the onset of spontaneous respiration there was respiratory depression in eight patients of the flunitrazepam group and in one patient of the Althesin group. Laryngospasm at extubation occurred twice in the flunitrazepam group. One severe anaphylactoid reaction and one cardiovascular reaction occurred in the Althesin group (table V).

DISCUSSION

When the characteristics of induction agents are being evaluated the total course of anaesthesia and recovery

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Heart rate score

24 18 15 12

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nausea was relatively small which accords with previous studies of Althesin (Mattila, 1974). An antiemetic effect has been observed with diazepam (Dundee and Haslett, 1970; Mattila, 1974) and as the frequency of nausea was low also in our flunitrazepam group it may be that this compound has similar antiemetic properties. The occurrence of side-effects was recorded throughout the trial. Transient erythema, apparent cutaneous vasodilatation which did not cause alarm, was seen during induction in both groups. However, the anaphylactoid reaction produced in one patient by Althesin was a severe complication. This was treated successfully by i.v. fluid therapy. Similar reactions have been reported by Watt (1975) and Sutton, Garrett and McArdle (1974) with Althesin and by Dundee and others (1974) with propanidid. When Clarke and others (1975) analysed 100 reported adverse reactions with i.v. anaesthetics, they found that there were 70 reactions with Althesin, 12 with thiopentone and four with propanidid. According to the subdivision, based on symptomatology, by Clarke and others (1975) the reaction seen in our patient would belong to the "histaminoid" type. Althesin and propanidid contain the same solvent which has been implicated as the cause of these reactions (Tammisto etal.,1973). The respiratory complications in the flunitrazepam group included two patients with laryngospasm at extubation. These responded to ventilation with oxygen. In eight patients, postoperative respiratory depression was observed and assisted ventilation was required. This has been reported before with flunitrazepam and diazepam (Dundee and Haslett, 1970; Freuchen, 0stergaard and Skafte, 1976). The possibility of such complications emphasizes the importance of careful care after operation. According to the literature, flunitrazepam is a relatively slow acting induction agent (Ungerer and Erasmus, 1973) and Althesin a relatively fast acting agent (Clarke et al., 1971; Carson, Dundee and Clarke, 1975). That the induction times did not differ in this study may be explained by the rapid rate of injection and the large dose of flunitrazepam. Despite this, however, no untoward effects were seen during induction. ACKNOWLEDGEMENTS

We owe special thanks to the nursing staff of the anaesthesia department for their co-operation and understanding during the trial. We are grateful to the companies F. Hoffmann-La Roche & Co. AG, Basle, and Glaxo Ltd, Greenford, Middlesex, for supplying the drugs.

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must be considered. Signs of arousal are common during anaesthesia. The skin incision is one of the most important surgical stimuli and if the level of anaesthesia is not sufficiently deep the patient reacts with signs of arousal with an increase in heart rate and arterial pressure. During the period between induction and incision the effect of the induction agent may diminish so that anaesthesia is inadequate at the time of incision. The administration of an additional dose of the induction agent just before the incision was a satisfactory way of obviating this problem. The overall quality of anaesthesia in the flunitrazepam group was better than in the Althesin group and fewer supplementary hypnotics were needed during maintenance of anaesthesia. This indicates longer effects produced by flunitrazepam, which is reflected also in the slower recovery rate and greater incidence of respiratory depression in this group. These complications can be offset by careful observation and adequate recovery facilities. The only variable in the present study was the induction agent, and all other drugs, including premedication, were standardized. Thus the differences observed during maintenance and recovery in the two groups of patients represent effects of the induction agent. The speed of injection used in this study differed from the recommendations of the manufacturers. The average speed of 20 s was selected in order to standardize the method and to provoke any possible circulatory changes produced by rapid injection. Even so, the circulatory changes were minimal in both groups. Interpretation of cardiovascular changes during anaesthesia is always difficult (Cullen, 1974) since there may be direct pharmacological effects on the heart and peripheral vasculature, and indirect effects induced by pain. Thus, absolute changes in arterial pressure and heart rate have not been evaluated, but a relative score has been allocated to allow a comparison. The reactions to skin incision, reflected by arterial pressure and heart rate, did not differ significantly between the two groups. The circulatory effects of both flunitrazepam and Althesin have been studied frequently (Campbell et al., 1971; Savege et al., 1973; Stovner, Endresen and 0sterud, 1973) and have been shown to be stable. The most unpleasant experience for the patient in the recovery room is the sensation of nausea. The frequency of nausea and vomiting is dependent on the patients and type of surgery as well as anaesthetic techniques and drugs. In this study the frequency of

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FLUNITRAZEPAM COMPARED WITH ALTHESIN REFERENCES

Savege, T. M., Blogg, C. E., Foley, E. I., Ross, L., Lang, M., and Simpson, B. R. (1973). The cardiorespiratory effects of alfathesin and ketamine. Anaesthesia, 28, 391. Stovner, J., Endresen, R., and 0sterud, A. (1973). Intravenous anaesthesia with a new benzodiazepine Ro 5-4200. Acta Anaesthesiol. Scand., 17,163. Sutton, J. A., Garrett, R. T., and McArdle, G. K. (1974). A survey of adverse reactions to Althesin. Br.J. Anaesth., 46,798. Tammisto, T., Takki, S., Tigerstedt, I., and Kauste, A. (1973). A comparison of Althesin and thiopentone in induction of anaesthesia. Br.J. Anaesth., 45,100. Ungerer, M. J., and Erasmus, F. R. (1973). Evaluation of a new benzodiazepine, Flunitrazepam (Ro 5-4200) as an anaesthetic induction agent. 5. Afr. Med.J., 47,787. Vega, D. E. (1971). Induction del sueno anestesico con un nuevo derivado benzodiazepinico. Communication preliminar. Rev. Urug. Anest., 5,41. Watt, J. M. (1975). Anaphylactic reactions after use of CT 1341 (Althesin). Br. Med.J., 3,205. Wickstrom, E. (1974). Double-blind study on flunitrazepam (Ro 5-4200) and Mandrax. Anaesthesist, 23,90. Yoo, M. C. (1973). The effects of flunitrazepam upon respiration and circulation in man. J. Kor. Soc. Anaesth., 1,31.

COMPARAISON DU FLUNITRAZEPAM ET DE L'ALTHESINE EN TANT QU'AGENTS D'INDUCTION DANS LES ANESTHESIES EQUILIBREES RESUME

On a etudie au cours d'un essia a double inconnue effectue sur 97 malades subissant une intervention chirurgicale a l'abdomen ou une intervention gynecologique, les effets du flunitrazepam et de l'althesine utilises en tant qu'agents d'induction pour les anesthesies. On n'a constat6 aucune difference entre les deux preparations en ce qui concerne la qualite de l'induction. On a neanmoins observe une difference marquee dans le degre d'anesthesie, cette difference jouant en faveur du flunitrazepam. La reprise de conscience a et£ plus rapide avec l'althesine. Dans les deux groupes, l'incidence des nausees a ete faible.

VERGLEICH ZWISCHEN FLUNITRAZEPAM UND ALTHESIN ALS NARKOSEEINLEITUNGSMITTEL ZUSAMMENFASSUNG

Die Wirkungen von Flunitrazepam und Althesin als Narkoseeinleitungsmittel wurden in einem Doppelblindversuch bei 97 Patienten untersucht, bei denen gynakologische oder Unterleibsoperationen durchgefiihrt wurden. In der Qualitat der Narkoseeinleitung zeigten sich keine Unterschiede zwischen den beiden Praparaten, wohl aber in der Qualitat der Aufrechterhaltung der Narkose, und zwar zugunsten von Flunitrazepam. Dagegen war die Erholung aus der Althesinnarkose rascher. Bei beiden Praparaten war das Auftreten von Ubelkeit gering.

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Brock-Utne, J. G., Winning, T. J., Rubin, J., and Kingsten, H. G. G. (1976). Laryngeal incompetence during neuroleptanalgesia in combination with diazepam. Br. J. Anaesth., 48,699. Brown, S. S., and Dundee, J. W. (1968). Clinical studies of induction agents. XXV: Diazepam. Br. J. Anaesth., 40, 108. Campbell, D., Forrester, A. C , Miller, D. C , Hutton, I., Kennedy, J. A., Lawrie, T. D. V., Lorimer, A. R., and McCall, D. (1971). A preliminary clinical study of CT 1341—a steroid anaesthetic agent. Br. J. Anaesth., 43,14. Carson, I. W., Dundee, J. W., and Clarke, R. S. J. (1975). The speed of onset and potency of Althesin. Br. J. Anaesth., 47,512. Clarke, R. S. J., Dundee, J. W., Garrett, R. T., McArdle, G. K., and Sutton, J. A. (1975). Adverse reactions to intravenous anaesthetics. A survey of 100 reports. Br J. Anaesth., 47,575. Montgomery, S. J., Dundee, J. W., and Bovill, J. G. (1971). Clinical studies of induction agents. XXXIX: CT 1341, a new steroid anaesthetic. Br. J. Anaesth., 43, 947. Coleman, A. J., Downing, J. W., Leary, W. P., Moyes, D. G., and Styles, M. (1972). The immediate cardiovascular effects of Althesin (Glaxo, CT 1341), a new steroid induction agent and thiopentone in man. Anaesthesia,27,313. Cullen, J. D. (1974). Interpretation of blood-pressure measurements in anesthesia. Anesthesiology, 40,6. Dechene, J. P. (1976). Alphatesin, a new steroid anaesthetic agent. Can. Anaesth. Soc.J., 23,163. Dundee, J. W., Assem, E. S. K., Gaston, J. M., Keilty, S. R., Sutton, J. A., Clarke, R. S. J., and Grainger, D. (1974). Sensitivity to intravenous anaesthetics: a report of three cases. Br. Med.J., 1,63. Haslett, W. H. K. (1970). The benzodiazepines: a review of their actions and uses relative to anaesthetic practice. Br. J. Anaesth., 42,217. Freuchen, I., 0stergaard, J., Kuhl, J. B., and Mikkelsen, B. O. (1976). Reduction of psychomimetic side effects of Ketalar (Ketamine) by Rohypnol (Flunitrazepam). Acia Anaesthesiol. Scand., 20,97. Skafte, B. O. (1976). Flunitrazepam (Rohypnol) compared with enibomal (Narcodorm) as an anaesthetic induction agent: a controlled clinical trial. Curr. Ther. Re*., 20,36. Manila, M. A. K. (1974). Combination of ketamine and diazepam in anaesthesia for high risk geriatric patients. IV Eur. Congr. Anaesthesiol., Madrid. Abstract no. 138. Nummi, S. (1974). Diazepam as an adjunct to alfathesin, ketamine, methohexitone, and propanidid short anaesthesias. IV Eur. Congr. Anaesthesiol., Madrid. Abstract no. 94. Raj par, M., and Pystynen, P. (1974). Diazepam as an adjunct in propanidid anaesthesia for abortion. Br. J. Anaesth., 48,446. Niessner, G. (1975). Narkoseeinleitung mit Flunitrazepam in der Unfallchirurgie. Wien. Med. Wochenschr., 21, 350.

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1046 FLUNITRAZEPAM COMPARADO CON ALTESINA COMO AGENTE DE INDUCCION EN ANESTESIA EQUILIBRADA SUMARIO Los efectos de flunitrazepam y altesina como agentes de induccion fueron estudiados mediante una prueba de doble anonimato, en 97 pacientes sometidos a cirugia abdominal o

BRITISH JOURNAL OF ANAESTHESIA gineacologica. No se comprobo diferencia alguna respecto a la calidad de la induccion. Se vio una marcada diferencia en la calidad del mantenimiento de la anestesia, en favor de flunitrazepam. La recuperation de la anestesia por altesina resultaba mas rapida. En ambos grupos se noto una baja incidencia de nausea,

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