CLINICAL STUDIES OF INDUCTION AGENTS XXXVI: KETAMINE

Brit. J. Anaesth. (1970), 42, 875

CLINICAL STUDIES OF INDUCTION AGENTS XXXVI: KETAMINE BY

J. W. D. KNOX, J. G. BovaL, R. S. J. CLARKE AND J. W. DUNDEE SUMMARY

Ketamine (Ketalar: Cl-581) is a recently introduced anaesthetic agent which can be given by the intravenous or intramuscular routes. It is 2-(o-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride (fig. 1), being chemically related to phencyclidine (Sernyl: Cl-395) and cyclohexamine (Cl-400) but bearing no similarity to either the barbiturates or eugenols. It is available as a clear aqueous solution containing 10 mg or 50 mg ketamine base per ml for intravenous or intramuscular injection respectively. Solutions are slightly acid, with pH in the 3.5-5.5 range. The pharmacology of ketamine was reported by Chen (1965) and by McCarthy and associates (1965) who described it as being a compound with cataleptic, analgesic and anaesthetic action but without hypnotic properties. Chen (1969) later defined catalepsy as a "characteristic akinetic state with a loss of orthostatic reflexes but without impairment of consciousness in which the extremities appear to be paralyzed by motor and sensory failure". The early clinical pharmacological studies of Domino, Chodoff and Corssen (1965) from Ann Arbor, Michigan, led to the drug being used in anaesthesia. The manufacturers class it as a "rapid-acting non-barbiturate general anaesthetic" but Corssen and Domino (1966) describe its effect as "dissociative anaesthesia", characterized by complete analgesia combined with only superficial sleep (Corssen, 1968).

This term has also been used by European workers (Langrehr, 1969). Many of the reported studies with ketamine, amounting to over 12,000 administrations, were carried out in children. Although the drug has been used in adults, many of the trials have been uncontrolled, employing a variety of premedicants (or omitting mention of premedication in the reports), using different induction doses by both intravenous and intramuscular routes and embracing a wide variety of surgical procedures. This has naturally given variable results. Although ketamine has only become available in this country since late 1969, it must be pointed out that the first studies with it began in 1957 and it was first used in man as long ago as 1964. In keeping with a well-established pattern of clinical trials from this department, it was felt necessary to use ketamine as main agent in our initial cases. This was done without depressant premedication and this paper reports the findings in 125 cases. Where applicable the findings are related to dosage and compared with our own published data on barbiturates. Preliminary reports on this have appeared elsewhere (Clarke, Knox and Dundee, 1970; Dundee et al., 1970). J. W. D. KNOX, M.R, F.F.A.RX.S.; J. G. Bovnx, M.B., F.F.A.R-CS.; R. S. J. CLARKE, MJ>., PH.D., F.F.A.R.CS.; J. W. DUNDEE, MJ)., PH.D., F.F^JLCS.; Department of

Anaesthetics, The Queen's University of Belfast, Northern Ireland.

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The intravenous anaesthetic ketamine has been given to patients undergoing minor gynaecological surgery after atropine prcmedication in initial doses ranging from 1.0 to 3.0 mg/kg. The chief induction complications were hypertension and hypertonus, the incidence of which was only broadly related to dosage. Recovery of consciousness was rapid, though marred by a high incidence of delirium at all dose levels. This delirium was sometimes sufficiently severe and prolonged as to necessitate tranquillization with diazepam. Hallucinations at this stage were so unpleasant that patient acceptance was much lower than with the barbiturates.

BRITISH JOURNAL OF ANAESTHESIA

876

HCL

PHENCYCLIDINE

(Cl 395)

RESULTS

Table I shows that the groups of patients were broadly comparable with respect to age, weight and the duration of anaesthesia. CH2

CH2

y.

CH X

CH2

NH.CH3 . HCL

C

KETAMINE

(Cl 581)

1 Formulae of phencydidinc and ketamine. FIG.

METHOD

Studies were carried out on fit patients scheduled for minor gynaecological surgery. Atropine 0.6 mg by intramuscular injection was the sole premedication. In five groups, each of 25 patients, anaesthesia was induced with 1.0, 1.5, 2.0, 2.5 and 3.0 mg/kg respectively of ketamine injected over 4560 seconds. Anaesthesia was continued with nitrous oxide-oxygen with further small doses of ketamine as required. Subsequent observations were similar to those described in studies of other intravenous induction agents (Dundee, Moore and Nicholl, 1962; Clarke and Dundee, 1965).

Anaesthesia. Induction was rapid and quiet but often accompanied by some degree of hypertonus. The limb stiffness was sometimes such that the patient could not be put into the lithotomy position. On two occasions the hypertonus was marked and involved the jaw muscles to such an extent that the airway became obstructed and cyanosis occurred. With the exception of two patients at the lower dose levels (table II), the doses employed caused loss of consciousness. The number of patients requiring further ketamine prior to the start of surgery was high (56 per cent) with induction doses up to 2 mg/kg, but 2 mg/kg and over appeared to be adequate. Apart from the cardiovascular effects, none of the other induction complications were a source of trouble, although 18 per cent of patients developed a rash following injection. We did not find weals following the rash and it had generally subsided within 10 minutes. There was no evidence of histamine release at the injection site. In the majority of patients the blood pressure

TABLE I

Data of patients induced toith varying doses of ketamine. Induction dose of ketamine (mg/kg) Average age (yr) Average weight (kg) Mean duration of anaesthesia (min)

1.0

1.5

2.0

2.5

3.0

27.8 59.6

31.4 58.1

33.0 63.4

35.2 59.6

31.1 58.2

8.7 ±0.7

10.8 ±1.10

13.2-hl.25

11.4 + 1.40

9.6 + 1.09

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Disturbances at the end of operation were graded as "slight" or "severe" and their duration as "transient" (up to 10 minutes) or "prolonged" (over 10 minutes). In order to assess the significance of the effects of ketamine from the patients' point of view, their opinions of the procedure was sought on the day after operation. Each patient was asked whether, in the event of her needing another operation, she would be happy to have the same anaesthetic. A comparable group of 200 patients induced with methohexitone were similarly questioned to provide control data.

877

CLINICAL STUDIES OF INDUCTION AGENTS—XXXVI TABLE II

Details of dosage and complications

of anaesthesia, excluding those affecting the cardiovascular system. Induction dose of ketamine (mg/kg) 1.0

1.5

1 11 15

1 12 13

1.53 ±0.14

2.0

2.5

3.0

0 2 10

2.12±0.14

0 4 14 2.46 ±0.13

2.86 ±0.10

0 0 0 3.0

0

1

0

0

1

4 1 0 4

3 1 0 4

2 1 0 4

11

6 1 0 6

rose steadily over the 3-5 minutes following induction, die individual and mean maximum rises in systolic being shown in figure 2 which also shows die peak systolic pressures recorded during anaesdiesia. The mean systolic rise (table HI) shows a slight, but not significant, relation-

0 0 5

ship to die induction dose. Diastolic blood pressure paralleled tie systolic and not infrequently reached 110-130 mm Hg. The hypertension was on occasions sustained for up to half an hour, but die systolic pressure usually had returned to widiin 20 rnm Hg of die resting level

•

i i sol

<

\

\

TIME

S

IN

35

MMUTES

A— £

IOCH

3 «o

&

J

3 Typical blood pressure and heart rate changes during and after ketamine anaesthesia. K = 1 1 0 mg ketamine given Lv. A = Awake. B = Slightly restless. C = Crying. D5 = Diazepam 5 mg given i.v. E = Quiet and drowsy. FIG.

FIG. 2 Rise in systolic pressure and peak systolic pressure at different levels of dosage in mg/kg. Closed circles represent individual readings and the horizontal line; the mean.

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Number requiring additional dose: to induce sleep for start of surgery at any time Total dose (mg/kg) Number needing halothane to control hyper Lonus Induction complications: Excitatory phenomena Respiratory upset Respiratory depression Erythematous rash

878

BRITISH JOURNAL OF ANAESTHESIA TABLE III

Cardiovascular effects recorded during induction and maintenance of anaesthesia. Induction dose of ketamine (mg/kg) 1.5

2.0

Z5

3.0

26 ±3.3

24 ±2.8

32 ±4.4

29±2.9

34±3.2

8 3 14 25 ±5.3

7 3 15 20 ±3.7

5 6 14 28 ±7.2

11 4 10 13 ±2.7

7 6 12 18 ±4.6

16 2 7 8 ±2.5

15 5 5 7 ±1.9

12 4 9 18 ±7.2

16 4 5 7 ±2.4

12 5 8 13 ±3.5

0 16 9 + 15

0 20 5 + 10

1 17 7 + 13

0 15 10 + 15

0 19 6 + 15

18 2 5 6

19 1 5 10

16 2 7 16

17 2 6 8

18 2 5 7

within 10 minutes. A typical blood pressure chart is shown in figure 3. Pulse rate changes were not marked and usually of short duration. Taking all these effects into consideration, anaesthesia was graded in a manner similar to that used in previous studies of intravenous anaesthetics and the findings are shown in table IV. Since hypertension had often subsided prior to the start of surgery a similar grading scheme was applied to the maintenance of anaesthesia. There is an obvious tendency towards more complications with the higher doses. The pooled data show that ketamine leaves a lot to be desired as an induction agent for minor surgery in unpremedicated adults, the overall percentage incidences of assessments being: Induction Maintenance Smooth Slight upset Moderate to severe complication Very troublesome or potentially dangerous

25 59

45 28

18

18

10

9

Recovery. The majority of patients opened their eyes on command 2 minutes after discontinuing nitrous oxide (table V) and it was uncommon for a patient not to have regained jaw tone and full control of reflexes by this rime, In many instances there was difficulty in assessing the exact moment of return of consciousness, since patients would gaze vacantly into space and appear to be out of touch with their surroundings. Although the average time to "recovery" following induction doses of 3.0 mg/kg was greater than with 1.0 mg/kg the difference was not significant, presumably due to the small numbers of patients in each series. Table VI lists the troublesome postoperative sequelae recorded during the first 6 hours after surgery. Emergence delirium or excitement were common and these increased somewhat in severity with dosage but the pattern of changes was not clear cut. A small (2.5-5.0 mg) dose of diazepam intravenously rapidly controlled these symptoms, but larger doses re-induced anaesthesia and caused respiratory depression. Three patients complained of severe pain soon after recovery

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Mean rise in systolic pressure Duration of any rise (min) -5 6-10 11 + Average Time taken to return to control + 20 (min) -5 6-10 11 + Average Pube rate changes (beats/min) -20 + 20 + 21-40 Mean —5 6-10 11 + Time taken to return to control+10 (min) Average

1.0

879

CLINICAL STUDIES OF INDUCTION AGENTS—XXXVI TABLE IV

Overall assessment of induction and course of anaesthesia. Induction dose of ketamine (mg/kg) 1.5

2.0

8 13

7 9

7

9

18

6

3 10

4

6

5

1

7

0

3

4

0

5

16 5 3

14 4 3

10 6 9

14 10 1

3 10 6

1

4

0

0

6

2.5

3.0

TABLE V

Data on recovery. Induction dose of ketamine (mg/kg)

Condition 2 minutes after end of surgery Awake Safe Unsafe Range of recovery times (min) -5 5-20 21 + Mean time to return of consciousness (min)

1.0

1.5

2.0

2.5

3.0

17 7 1

19 4 2

15 10 0

10 14 1

9 14

22 2 1

20 3 2

20 2

20 3 2

20 4 1

5 ±1.6

7 ±2.7

3

5 ±1.5

7 ±1.8

2

10 ±4.9

TABLE VI

Troublesome postoperative

sequelae.

Induction dose of ketamine (mg/kg)

Emergence delirium or excitement Mild transient prolonged Severe transient prolonged Required medication Dreams Pleasant Unpleasant Dizziness First 6 hours Visual disturbances Nystagmus Inability to focus Size disturbances Diplopia

Colours

1.0

1.5

2.0

2.5

3.0

1 3

4 2

1

3 2

0 3

2 1

2

0 4

0 2

1 7

1

1

1

2

6

5 8

3 10

6 7

4 7

2 14

14

5

10

9

13

1 3 3 0 1

0 2 1 0 1

2 2 1 2 2

0 1 2 1 4

2 2 2 2

5

1

5

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Induction Uneventful Slight upset Moderate to severe complication Very troublesome or dangerous Course of anaesthesia: Smooth Slight trouble Moderately troublesome Very troublesome or dangerous

1.0

BRITISH JOURNAL OF ANAESTHESIA

880 TABLE VII

Emetic sequelae, and comparison with data from a similar operation with methohexitone-nitrous oxide-oxygen anaesthesia {300 cases: atropine premedication; Dundee, 1963). Barbiturate AU doses (methohexitone) (%) (%)

Induction dose of ketamine (mg/kg) 1.0

1.5

2.0

2.5

3.0

2 3

3 5

3 1

2 3

2 2

12 11

9 9

5 2

4 4

5 3

6 3

8 3

22 12

6 8

18 5 2

14 4 7

16 6 3

13 6 6

12 8 5

59 23 18

73 12 15

TABLE VIII

Percentage incidence of patient acceptance. Preference

1.0

1.5

2.0

2.5

3.0

Total ketamine

Methohexitone control

Yes Don't know No

15 1 9

6 6 13

6 5 14

6 6 13

3 4 18

29% 18% 53%

83% 9% 8%

TABLE IX Incidence of complications and recovery times in relation to induction dose of ketamine.

Induction dose (mg/kg) 2 and under Number of subjects Mean age (yr) Mean weight (kg) Mean duration of anaesthesia (min) % need of supplementing doses % Induction complications Excitatory phenomena Respiratory upset Erythematous rash Cardiovascular effects Mean rise in systolic pressure (mm Hg) % 21-10 % 41 + Mean duration of rise (min) % 6-10 % 11 + Mean time taken to return to control + 20 mm Hg (min) Mean pulse change (beats/min) Mean duration (to control + 10 beats/min) (min) Two minutes after end of surgery % awake % safe Mean recovery time (min) % —5 min

% 21+ min

over 2 50 33 59

75 31 60 10.8 ±0.67

10.5 ±0.82

56

20

12 4 16

34 2 22

27.6 ±1.1 31

31.4±2.2 50

18 24.2 ±3.23

15.1 ±1.5

16 57

20 44

18

+ 1Z8

9.6 + 15.0

10.8

7.4

11.1

68 28

36 56

5.8 + 1.1

6.3 ±1.1

82 8

80 6

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First hour Nausea Vomiting 1-6 hours Nausea Vomiting First 6 postoperative hours Nil Nausea Vomiting

CLINICAL STUDIES OF INDUCTION AGENTS—XXXVI

Patient acceptance. Not every patient could give a definite answer as to whether she would like ketamine again (table Vlil). However, it is obvious that this was not a popular agent from the patient's viewpoint and did not compare favourably with methohexitone in this respect. Dose effects. Since the findings with ketamine are not doserelated, as with barbiturates and propanidid, the data were further analyzed to see what relationship did exist (table DC). Induction doses of over 2 mg/kg caused a mean rise in systolic pressure of 31.4 ±2.2 mm Hg, which is not significantly higher than the 27.6 ±1.1 recorded with doses of 2 mg/kg and under. The time taken for the pressure to return to within 20 mm Hg of the control was similar for the two dose groups, as were the pulse rate changes. Although mean recovery time was similar with induction doses up to and including 2 mg/kg (5.8 ±1.1 minutes) as with doses of over 2 mg/kg (6.3 ± 1.1 minutes) the incidence of awake patients 2 minutes after surgery with the lower induction dose of ketamine (68 per cent) was significantly higher (P<0.0005) than with the higher dose (36 per cent). Table X shows a definite relationship between undesirable sequelae and total dose of ketamine given and this also applies very markedly to patient preference for the drug. DISCUSSION

Two aspects of this study require comment—the unexpectedly high incidence of side effects during and following anaesthesia and the absence of an

TABLE X

Percentage incidence of disturbing sequelae and of patient's acceptance of this form of anaesthesia (as judged by their willingness to have it again) related to the total dose of ketamine given. Total dose (mg/kg) Emergence delirium Mild Severe Dreams Pleasant Unpleasant Patient acceptance Yes Don't know No

-2

2-3

3+

13 19

27 12

9 27

19 23

13 33

18 38

48 13 39

27 19

18 20 62

54

obvious dose-response effect. In contrast with methohexitone, cough and hiccup are not features of anaesthesia with ketamine. However, in keeping with the findings of Corssen and Domino (1966), hypertonus was a common finding. This is the probable reason for the claims that the airway is well maintained with ketamine, but, as mentioned previously, jaw tone can be excessive at times. Only on two occasions did we find muscle rigidity interfering with the surgical procedure, as reported by Brown, Cole and Murray (1970) in children. Spontaneous involuntary muscle movement was less frequent than after normal doses of methohexitone but nevertheless occurred in 12 per cent of patients with doses up to and including 2 mg/kg and in 34 per cent of those receiving more than 2 mg/kg. This high incidence does not appear to have been recorded by other workers, who may have thought that these were too trivial to mention. Although the occurrence of an erythematous rash is mentioned in the literature, the incidence (18 per cent) which we have found is higher than that recorded elsewhere. Almost every clinical paper mentions hypertension occurring after ketamine, but not all workers regard this as troublesome. As can be seen from figure 2, the peak systolic pressure was in excess of 200 mm Hg in an appreciable number of patients and this action could be looked upon as alarming (Corssen and Domino, 1966). In table XI and figure 4 the rises in systolic and mean arterial blood pressures are shown in relation to the resting pressure and the findings fail to confirm those of Gjessing (1968) that the in-

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and this appeared to "trigger off" emergence delirium. All three had bimanual replacement of a retroverted uterus, a procedure which would normally be followed by pain. Table VII lists the emetic sequelae with different induction doses and compares the findings with those reported with methohexitone by Dundee (1963). Except with the smallest induction dose, ketamine was followed by more vomiting and/or nausea than methohexitone. The difference was particularly marked 1-6 hours after anaesthesia where the incidence with any dose of ketamine was significantly higher (P<0.05) than with methohexitone.

881

882

BRITISH JOURNAL OF ANAESTHESIA clear, but the pressure rise is prevented by epidural anaesthesia (Traber and Wilson, 1969). It is important to note that excessive rises in pressure rapidly respond to halothane. Although recovery from ketamine was fairly rapid (table V) there was a period of variable 8OT

SYSTOLIC

60-•

40- • UI

cc in ui

IE

—5fe 8O

BLOOD 9O

RESTING 60

PRESSURE

o ? 5O+ 4O+ 2O*T|

O J-

FIG. 4 Peak blood-pressure changes in relation to initial reading.

TABLE XI

Relationship between rise in blood pressure and resting level. Initial dose of ketamine (mg/kg) Patients with control systolic pressure <120 mm Hg Average (mm Hg) Increase in pressure (mm Hg) Increase in pressure (percentage) Patients with control systolic pressure >120 mm Hg Average (mm Hg) Increase in pressure (mm Hg) Increase in pressure (percentage) Patients with control mean pressure <93 mm Hg Average (mm Hg) Increase in pressure (mm Hg) Increase in pressure (percentage) Patients with control mean pressure >93 mm Hg Average (mm Hg) Increase in pressure (mm Hg) Increase in pressure (percentage)

MEAN

0.5-2.0

>2.0

115 29.9 + 2.9 26.0

115 33.7 ±3.3 29.3

134 34.5+3.9 25.7

132 34.0 ±5.1 25.8

21.4±2.3 24.9

86 25.3 ±1.6 29.4

102 25.6 ±2.5 25.1

101 25.5 ±4.2 25.2

86

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crease is less where the initial pressure is high. A factor in this difference may be the absence of hypotensive patients in our series. There was no significant relationship between pressure rise and dose of ketamine given (tables HI and XI; figs. 2 and 4). We had no complaints of excessive bleeding accompanying the blood pressure rise but other workers have commented on this with different types of surgery (Wilson, Traber and McCoy, 1968). Since the rate of injection was fairly constant in this study one cannot comment on the view of Corssen and Domino (1966) that the greatest increases in arterial pressure occur when the speed of injection is fast. However, these latter workers found a significant increase in pressure even when ketamine was given as an infusion over a 5-minute period. From studies in dogs, Dowdy and Kaya (1968) proposed that one cause of hypertension is depression of the frequency response of the baroreceptors. They also comment that the depression phase of the arterial pressure—which we have not seen—is due at least in part to the negative inotropic effect on the myocardium. Studies in humans by Virtue and associates (1967) and by Kreuscher and Gauch (1967) indicate that hypertension could be due to an increased cardiac output, but ketamine appears to be a direct myocardial depressant in high doses (Traber, Wilson and Priano, 1968). The role of the sympathetic nervous system in these changes is not

CLINICAL STUDIES OF INDUCTION AGENTS—XXXVI

From the many published reports, we were not surprised to encounter emergence delirium and hallucinations. In data supplied by the manufacturers, based on over 12,000 unselected administrations, Albin and Dresner (1969) reported psychic abnormalities and hallucinations in under 2 per cent of patients, dreams in about 7 per cent and what we would class as "emergence delirium" (confusion, with and without vocalization, excitement or irrational behaviour) in 2.8 per cent of subjects. All are agreed that these complications are rarely seen in children, but in making allowance for the fact that the patients in our series were all adults, the incidence and severity of these complications were greater than expected. A number of workers have noted that psychological disturbances were more distressing to the patients if they were aroused early in the recovery phase (Pannacciulli, Sordi and Trazzi, 1966; Corssen et al., 1969b) although this experience is not universal (Pavy, 1966). In the present series patients were quickly moved off the operating table into a bed and left for a time in a fairly busy recovery bay. Occasionally crying and delirium occurred when patients were still in the operating theatre (and being disturbed) but in an appreciable number this was first seen when they

were undisturbed either in the recovery area or when returned to the ward. Thus no clear pattern of events was observed in this present study. The sex of the patients, and the nature and duration of the operations may all be interrelated factors in the high incidence of postoperative delirium, particularly since Lear and associates (1959) have listed these factors as contributing to the delirium after cydohexamine (Cl-400). In a very small study Soetens (1969) found delirium and undesirable mental effects occurring only in women. The incidence is less with more prolonged operations (Dundee et al., 1970) presumably because the period of maximal undesirable cerebral effect of ketamine occurs when the patients are still unconscious. The absence of depressant premedication has also led to the high incidence of delirium hallucinations (Matorras and Felipe, 1970). Our subsequent studies (Dundee et al., 1970) have shown that although opiates such as pethidine and papaveretum and other hypnotics, e.g. pentobarbitone, reduced the incidence of delirium to some extent, they did not abolish it altogether. We have no data on the influence of age on recovery upset, since all our patients were in the reproductive years of life, but everyone appears to agree that unpleasant sequelae do not occur in children. Neither can we confirm the finding that the addition of halothane reduces unpleasant sequelae (Stocker, 1969), but this seems worthy of investigation. Considering that ketamine is classed as an analgesic, it was surprising to find patients complaining of severe pain soon after operation. The period of analgesic produced by ketamine is brief (Nolte et al., 1969) and it would appear to be more effective in somatic than in visceral pain. Corssen and Domino (1966) have, in fact, used the term "somatoanalgesia" to describe this action of ketamine. Many writers refer to salivation occurring after ketamine (Stanley et al., 1968; Brown, Cole and Murray, 1970; Corssen, Miyasaka and Domino, 1968). In our study this was prevented by preoperative atropine but subsequently we have given ketamine to more than 300 adults without antisialogogue premedication and not encountered any trouble. Ketamine shows a very different response to

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duration between the time when the patients could open their eyes and respond to command and when they are fully awake. This occurs, even in the absence of delirium and for this reason we would be hesitant to recommend its use for outpatient anaesthesia in adults. The time of establishing verbal contact with patients was shorter in the present series than in that reported by King and Stephen (1967), but similar to that of Wilson, Fotias and Dillon (1969). Recorded incidences of postoperative emetic effects with ketamine ranged from nil (Chodoff and Stella, 1966; King and Stephen, 1967; Matorras and Felipe, 1970) to figures lower than those found in the present study (Corssen et al., 1969a; Telivuo and Vaisanen, 1970). Our high incidence may be due to the sex of the patients and the nature of the operation, and for this reason comparable data obtained after the use of methohexitone are given in table VII. The figures certainly appear to incriminate ketamine specifically, particularly in the late postoperative period.

883

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BRITISH JOURNAL OF ANAESTHESIA

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Clarke, R. S. J., Knox, J. W. D., and Dundee, J. W. (1970). The effect of dosage and premedkation on the action of ketamine. Brit. J. Anaesth, 42, 799. Corssen, G. (1968). Allgemeine klinische erfahrungen mit ketamine bei mehr als 1500 fallen. Der Anaesthetist, 18, 25. Domino, E. F. (1966). Dissociative anesthesia: further pharmacologic studies and first clinical experience with phtncyclidine derivative Cl-581. Anesth. Analg. Curr. Res., 45, 29. Groves, E. H., Gomez, S., and Allen, R. J. (1969a). Ketamine: its place in anesthesia for neurosurgical diagnostic procedures. Anesth. Analg. Curr. Res., 48, 181. Hayward, J. R., Gunter, J. W., and Groves, E. H. (1969b). A new parenteral anesthesia for oral surgery. J. oral Surg., 27, 627. Miyasaka, M., and Domino, E. F. (1968). Changing concepts in pain control during surgery. Dissociative anesthesia with Cl-581: a progress report. Anesth. Analg. Curr. Res., 47, 746. Domino, E. F., Chodoff, P., and Corssen, G. (1965). Pharmacologic effects of Cl-581, a new dissociative anesthetic, in man. Clin. Pharmacol. Ther., 6, 279. Dowdy, E. G., and Kaya, K. (1968). Studies of the mechanism of cardiovascular responses to Cl-581. Anesthesiology, 29, 931. ACKNOWLEDGEMENTS Dunde:, J. W. (1963). Clinical studies of induction Our continuing thanks are due to the gynaecological agents. VII: A comparison of eight intravenous staff of Musgrave Park Hospital, Balmoral, for their anaesthetics as main agents for a standard operaco-operation in this study. We are also grateful to tion. Brit. J. Anaesth., 35, 784. Dr John Gorringe and Dr Lorna Lees, of Parke, Davis Bovill, J., Knox, J. W. D., Clarke, R. S. J., & Co., for their interest in this work and for providing Black, G. W., Love, S. H. S., Moore, J., generous supplies of Ketalar. Elliott, J., Pandit, S. K., and Coppel, D. L. (1970). Ketamine: a preliminary report on its use as an REFERENCES induction agent. Lancet, 1, 1370. Albin, M. S., and Dresner, A. J. (1969). Emergence Moore, J., and Nicholl, R. M. (1962). Studies of reactions associated with the administration of drugs given b:fore anaesthesia. II: A method for ketamine hydrochloride (Ketalar—Parke-Davis). assessing their influence on the course of anaesRead before the International Symposium on thesia. Brit. J. Anaesth., 34, 523. 5 L'anesthesie vigile et subvigile , Ostend, Belgium, Gjessing, J. (1968). Ketamine (Cl-581) in clinical April 17-20. anaesthesia. Acta anaesth. scand., 12, 15. Barren, D. W., and Dundee, J. W. (1967). Clinical studies of induction agents. XVII: Relation be- King, C H., and Stephen, C R. (1967). A new intravenous or intramuscular anesthetic. Anesthesiology, tween dosage and side effects of intravenous bar28, 258. biturates. Brit. J. Anaesth., 39, 24. Brown, T. C K., Cole, W. H. J., and Murray, G. H. Kreuscher, H., and Gauch, H. (1967). Die wirkung des phencyclidinderivates Ketamine (Cl-581) auf das (1970). Ketamine: a new anaesthetic agent. Aust. kardiovasculare system des menschen. Der AnaesN.Z. J. Surg., 39, 305. thesist, 16, 229. Chen, G. (1965). Evaluation of phencyclidine-type cataleptic activity. Arch. int. Pharmacodyn., 157, Langrehr, D. (1969). Dissoziative anesthesie durch 193. ketamine. Actuelle Chirurgie, 4, 71. (1969). Pharmacology of ketamine. Der Anaes- Lear, E., Suntay, R., Pallin, I. M., and Chiron, A. E. thesist, 18, 24. (1959). Cyclohexamine (Cl-400): a new intraChodoff P., and Stella, J. G. (1966). Use of Cl-581 a venous agent. Anesthesiology, 20, 330. phencyclidine derivative for obstetric anesthesia. Matorras, A. A., and Felipe, M. A. L. (1V70). Selection Anesth. Analg. Curr. Res., 45, 527. of indications on the use of Cl-581 and observaClarke, R. S. J. and Dundee, J. W. (1965). Clinical tions on 198 cases; in Progress in Anaesthesiology, studies of induction agents. XII: The influence of p. 1000. Amsterdam: Excerpta Medica Foundation. some pretnedicants on the course and sequelae of propanidid anaesthesia. Brit. J. Anaesth., 37, 51. McCarthy, D. A., Chen, G., Kaump, D. H., and Ensor, C (1965). General anesthetic and other pharmaco(1970). Toxic effects of intravenous anacslogical properties of 2-(0-chlorophenyl)-2-methylthitics: a comparison of propanidid with thiopentone; in Progress in Anaesthesiology, p. 1189. amino cydohexanone HC1 (Cl-581). J. New Drugs, Amsterdam: Excepta Medica Foundation. 5,21.

increasing dosage from that found with barbiturates (Barren and Dundee, 1967) and propanidid (Clarke and Dundee, 1970). Side effects increase with dosage of these latter drugs, but over the dose range studied this was not observed with ketamine. The nature of the present investigation does not allow the duration of action to be related to dosage, but this has been shown clearly in the studies carried out in volunteers by Domino, Chodoff and Corssen (1965). Reference has been made to the fact that ketamine may not be suitable for out-patient anaesthesia in adults. In the light of present findings it is hard to agree that it should be recommended for short procedures (Corssen et al., 1969b) particularly in the absence of depressant premedication. This latter continued with a volatile inhalational adjuvant may reduce the possibility of undesirable cardiovascular effects or unpleasant sequelae.

CLINICAL STUDIES OF INDUCTION AGENTS—XXXVI Nolte, H., Teuteberg, H., Dudeck, J., Munchhoff, W., and Rumpf, K. (1969). Vergleichende untersuchungen uber die analgesic nach anaesthesien mit ketamine, thiopental und propanidid. Der Anaesthesist, 18, 24. Pannacciulli, E., Sordi, L., and Trazzi, R. (1966). The hallucinogen Cl-581 and its use in anaesthesiology.

Giom. ital. Mai. Torino, 20, 61. Pavy, J. K. (1966). Further studies with Cl-581. Paper presented at the Scientific Meeting of the Australian Society of Anaesthetists, Sydney, November 4-10. Soetens, A. (1969). Klinische erhahrungen mit ketamine als intensives narkosemittel fur kurze eingriffe. Der Anaesthetist, 18, 26. Stanley, V., Hunt, J., Willis, K. W., and Stephen, C. R. (1968). Cardiovascular and respiratory function with Cl-581. Anesth. Analg. Curr. Res., 47, 760. Stocker, L. (1969). Klinische erfahrungen mit ketamine bei eingriffen im zahn-mund-und kieferbereich. Der Anaesthesist, 18. 26. Telivuo, L. J., and Vaisanen, R. (1970). Clinical experience with a phencyclidine derivative Cl-581; in Progress in Anaesthesiology, p. 1192. Amsterdam: Excerpta Medica Foundation. Traber, D. L., and Wilson, R. D. (1969). Involvement of the sympathetic nervous system in the pressor response to ketamine. Anesth. Analg. Curr. Res., 48, 248. Priano, L. L. (1968). Differentiation of the cardiovascular effects of Cl-581. Anesth. Analg. Curr. Res., 47, 769. Virtue, R. W., Alanis, J. M., Man, M., Lafargue, R. T., Vogel, J. H. K., and Metcalf, D. R. (1967). An anesthetic agent: 2-orthochlorophenyl, 2-methylamino cydohexanone HQ (Cl-581). Anesthesiology, 28, 823. Wilson, G. H., Fotias, N. A., and Dillon, J. B. (1969). Ketamine: a new anesthetic for use in pediatric neuroroentgenologic procedures. Amer. J. RoentgenoL, 106, 434. Wilson, R. D., Traber, D. L., and McCoy, N. R. (1968). Cardiornilmonary effects of Cl-581—the new dissociative anesthetic. Sth. med. J. (Bgham Ala.), 61, 692.

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ETUDES CLINIQUES D'AGENTS D ' l N D U C TION XXXVI:

KETAMINE

SOMMAIRE

L'anesthesique intraveineux Ketamine a iti administre' & des patients subissant une intervention chirurgicale gynecologique mineure, apres premedication a ratropine, a une posologie initiale de 1,0 a 3,0 mg/kg. Les complications majeures de l'induction furent lTiypertension et 1'hypertonie, dont la frequence ne fut que relativement proportionelle a la dose. Le regain de conscience fut rapide, mais complique par une forte incidence de delire a chacune des posologies. Ce delire fut parfois suffisamment severe et prolong^, pour necessiter la tranquilisation au diazepam. Les hallucinations furent a ce stade si deplaisantes que 1'acceptation par le patient fut beaucoup moins bonne que celle des barbituriques.

KLINISCHE U N T E R S U C H U N G E N ZUR NARKOSEEINLEITUNG XXXVI: KETAMIN ZUSAMMENFASSUNG

Nach Praemedikation mit Atropin wurde das intravenose Anaesthetikum Ketamin in einer Dosierung von 1,0 bis 3,0 mg/kg bei solchen Patienten benutzt, bei denen kleine gynakologische Operationen durchgefuhrt wurden. Die HauptkompUkationen wahrend der Einleitungsphase waren Hypertension und Hypertonie, im groOen und ganzen war die Haufigkeit von der Dosis abhangig. Wiederaufwachen stellte sich schnell ein, war jedoch durch eine Vielzahl vonn BewufltseinsstSrungen bei alien Dosen getriibL Das Delirium war manchmal so schwer und solange andauernd, dafi eine Beruhigung mit Diazepam notwendig wurde. In diesem Zustand kam es zu so unangenehmen Halluzinationen, daO die Vertraglichkeit schlechter war als die von Barbituraten.

FIFTH WORLD CONGRESS OF ANAESTHESIOLOGISTS Please note change of dates: The Congress will take place in Kyoto, Japan, on SEPTEMBER 19-23, 1972. The Belgian Professional Association of Specialists in Anaesthesia and Reanimation is to organize a three-weeks group tour from Brussels to the Far East, open to all anaesthetists of Western Europe and their families. The journey can thus be accomplished on the most advantageous terms. Booking is done on guaranteed periodical payments in advance. For further particulars apply to Dr. Et. Troch, Marcel de Backerstraat 2, Ekeren 2 (Antwerp), Belgium.