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COMPARISION OF THE NEW EMULSION FORMULATION OF PROPOFOL WITH METHOHEXITONE AND THIOPENTONE FOR INDUCTION OF ANAESTHESIA IN DAY CASES
Br. J. Anaesth. (1985), 57, 725-731
COMPARISON OF THE NEW EMULSION FORMULATION OF PROPOFOL WITH METHOHEXITONE AND THIOPENTONE FOR INDUCTION OF ANAESTHESIA IN DAY CASES N. MACKENZIE AND I. S. GRANT
SUMMARY The new emulsion formulation of di-isopropyl phenol (propofol) was compared with methohexitone and thiopentone for induction of anaesthesia in day cases. Propofol produced significantly smoother induction of anaesthesia, but caused more cardiovascular and respiratory depression. Pain on injection was significantly less than with methohexitone. Post-anaesthetic recovery was superior with propofol, with virtual absence of side effects, and rapid recovery with little impairment of psychomotor function 30 min after anaesthesia.
Informed consent was obtained from each patient and the study approved by the Hospital Ethics Committee. Each patient was instructed in the use of the Leeds Psychomotor Tester. This is a compact, portable, simple apparatus capable of measuring Critical Flicker Fusion Threshold (CFFT) and Choice Reaction time (CRT) scores (Hindmarch and Parrott, 1977). For CRT measurement the subject scans an array of six small lights which are illuminated on a random basis. As soon as he PATIENTS AND METHODS detects the light he touches the appropriate button Sixty patients between the ages of 18 and 65 yr to extinguish it. The latency of this response is an undergoing minor urological surgery as day cases assessment of integrity of sensori-motor function were allocated randomly to one of three groups of and an accurate measure of psychomotor perform20 patients each. The three groups were comparable ance. The distance the subject has to move his for age, sex and weight. All were ASA Grade I or hand to touch the response button is the same for II; patients with hepatic, renal, haematological, each light, making it possible to measure motor metabolic or psychiatric disease were excluded. time separately from recognition time. The CFFT is a sensitive index of the state of CNS arousal and the ability to integrate discrete units of sensory N. MACKENZIE, M.B., CH.B., FJ.A.R.CLS.; I. S. GRANT, M.B., data. In this assessment the subject is required to CH.B., M.R.C.P., F.F.A.R.C.S.; Department of Anaesthetics, detect nicker fusion in a set of four light emitting Ninewells Teaching Hospital, Dundee.
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Propofol (di-isopropyl phenol (Diprivan)) is a comparatively new i.v. induction agent; its clinical use was first described in 1977 by Kay and Roily. Subsequent studies revealed several attractive features, particularly with regard to lack of excitatory side-effects and rapid recovery (Kay and Stephenson, 1980; Rogers et al., 1930; Rutter et al., 1980; Briggs et al., 1981; Major et al., 1981). However, these were largely outweighed by its limited solubility in water which necessitated its formulation in Cremophor EL (with the attendant risk of hypersensitivity reactions (Briggs, Clarke and Watkins, 1982)), and by the high incidence of pain on injection. An alternative formulation has been achieved with a 1 % w/v aqueous emulsion containing 10 % w/v soya bean oil, 1.2 % w/v egg phosphatide and 2.3% w/v glycerol. Initial animal studies showed anaesthetic properties similar to those of the original formulation (Glenn and Hunter, 1984). This study was designed to compare the new emulsion formulation of propofol with methohexitone and thiopentone for the induction of anaesthesia in day-case patients, with particular regard to recovery after operation.
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TABLE I.
Agc(yr) Weight (kg) Scx(M/F) Duration of anaesthetic (min)
area, where the time to opening eyes on command and repeating date of birth were recorded by an independent observer who was unaware of the induction agent used. The patient was then returned to the ward, where recovery was further assessed by measurement of CFFT and CRT scores at 30 min, 60 min, 90 min and 120 min from the end of anaesthesia. These were carried out by a second anaesthetist who was again unaware of the patient's group. Any adverse effects during this period such as headache, nausea and vomiting were noted and the i.v. injection site inspected, before the patient's discharge home, for any venous complications, such as phlebitis or thrombosis. The results were analysed statistically using t tests, Chi-squared tests and Fisher-Irwin exact probability tests, where appropriate. RESULTS
A total of 60 patients were studied, randomly allocated to three groups receiving propofol (n = 20), methohexitone (« = 20) or thiopentone (n = 20). The durations of the surgical procedures were similar in the three study groups (table I). Induction and maintenance of anaesthesia
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diodes in foveal fixation at 1 m using alternately ascending and descending frequencies. After familiarization with the apparatus, each subject had 50 practice attempts with the CRT test before base-line pre-operatdve CFFT and CRT scores were recorded. This is recommended by the designers, to preclude any possible learning effect» interfering with assessment of performance. The CRT was taken as the mean of 25 response times following five practice attempts on each occasion and the CFFT as the mean of six results, three on the ascending scale and three on the descending. On each occasion care was taken to ensure correct positioning of the apparatus and constant ambient lighting. A control group of 20 patients, matched with the. three study groups for age, sex and weight, also underwent psychomotor testing under conditions identical to those of the study group. These were patients who had not undergone surgery within 5 days of the testing and who were not receiving psycho-active drugs. No premedication was given and anaesthesia was induced by the injection of propofol 2.5 mg kg"1, 1% methohexitone l.Smgkg" 1 or 2.5 % thiopentone 5 mg kg"1, over a 20-s period, to a peripheral vein, on the dorsum of the hand. The induction time was noted (time from start of injection to cessation of counting), as were any complications during induction such as feelings on injection, movement, apnoea and other respiratory problems. The overall quality of induction was graded by the anaesthetist (the same individual in every case). Anaesthesia was maintained with 66 % nitrous oxide in oxygen supplemented with enflurane. This was administered in a standard manner, the inspired concentration being increased rapidly to 5% until surgical anaesthesia was achieved, and then reduced to 2-2.5 % thereafter. Heart rate and arterial pressure were recorded before induction and at 2-min intervals throughout the procedure; any adverse effects were noted. The anaesthetic gases were discontinued at the end of surgery and the patient transferred to a recovery
The induction time was not significantly different in the three groups at around 30 s (table II). However, there were important differences between groups with regard to complications on induction. Feelings on injection occurred in 16 patients receiving propofol, but this was described as coldness in 11 of these and as pain in only five; in these five patients the pain was either mild or moderate. With methohexitone, no patient reported coldness on injection, but 11 complained of pain and infivethis was severe. In the thiopentone group, three patients described coldness on injection, but none complained of pain. In all patients the injection was given to a small vein on the dorsum of the hand and in no patient was there
Pattern data and duration of anaesthesia {mean ± SEM) Propofol
Methohexitone
Thiopentone
Control
47.2 ±2.86 69.6 ±2.25 13/7 10.8±0.96
40.8 ±4.05 70.7 ±2.82 13/7 12.4±1.36
42.6 ±3.09 69.0±2.94 13/7 9.9±0.6O
41.2±4.78 68.6±2.16 14/6
EMULSION FORMULATION OF PROPOFOL FOR DAY CASES
727
TABLE II. Induction times (mean + SEM) and complications (No. patients). Significance values: propofol v. methohexitone—*P < 0.05, **P < 0.01, ***P < 0.001; propofol v. thiopentone—fP < 0.05,
tP < 0.02, ttP < 0.01 Methohexitone
Thiopentone
30.6 ±0.83
28.8 ±0.92
29.6 + 0.85
17 3 0**
13 7
9 11
16 4*
15 5
14.7 ±3.06
15.1 ±2.80
10.4 ±2.99
11 5 3 0
12* 9 4
8 6
6 (2 at 120 s)
0***
ot
n ot 1
7tt
TABLE III. Quality of induction and anaesthesia (No. of patients). Significance values: propofol v. methohexitone—**P < 0.01, propofol v. thiopentone—+P < 0.05
Quality of induction Good Adequate Poor Quality of anaesthesia Good Adequate Poor
Propofol
Methohexitone
Thiopentone
16 4 0
5 10 5**
10 3
5 12 3
5 13 2
8 9 3
evidence of venous problems 4 h later, before discharge home. Statistically significant differences were seen also between the groups with regard to the development of apnoea after induction, with six patients in the propofol group having apnoeic periods of greater than 60 s (two at 120 s), compared with none in the other two groups. Propofol also caused more marked decreases in systolic arterial pressure in the first 2 min after induction, with more than half the patients in this group experiencing decreases of more than 20 % compared with less than one-quarter in the other groups. The mean decrease in systolic arterial pressure in the propofol group was 30 mm Hg, compared with 18 mm Hg in the other groups. This decrease was more pronounced in those patients with higher systolic pressures initially: those with systolic arterial pressures > 130 mm Hg had a mean decrease of 41 mm Hg, compared with a 20-mm Hg decrease in those with lower initial
7t
pressures. All groups showed an increase in heart rate, 2 min after induction, of between 10 and 15 beat min"1, but there were no significant differences between the groups. Involuntarymovementoccurred in three patients receiving propofol, in nine receiving methohexitone and in one receiving thiopentone. Induction of anaesthesia was particularly smooth in the propofol group, no patients experiencing cough or hiccup, compared with four receiving methohexitone. A surprisingly high percentage of patients in whom anaesthesia was induced with thiopentone (35%) had problems with cough or hiccup at induction, and this almost certainly reflects an inadequate induction dose: 5 mg kg"1 was used for all patients, but in some this was clearly insufficient and three required additional supplements to induce anaesthesia. These findings were reflected in the subjective assessment of quality of anaesthesia (table III). Induction was good or adequate in all patients in the propofol group,
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Induction time (s) Apnoea 0-30 31-60s >60s Decrease in arterial pressure 0-20% >20% Increase in heart rate (beat min"1) Side effects Coldness Pain Involuntary movement Cough/hiccup
Propofol
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TABLE IV. Crude recovery times (mean ± SEM) and postoperative sequelae (No. of patients). Significance values: propofol v. mtthohexitone—*P < 0.05; propofol v. thiopenume— ffP < 0.01, t t t P < 0.001
Time to open eyes (min) Time to repeat date of birth (min) Sequelae Headache Nausea/vomiting Drowsiness Venous problems
Propofol
Methohexitone
Thiopentone
4.8 ±0.45
5.6±0.54
9.6±0.74ttt
5.8±0.34
7.2 ±0.58*
10.6±0.74ftt
0 0 0 0
3 3 0 0
vtt 2 vtt 0
CFFT(Hz) 30 min 60 min 90 min 120 min CRT recog. (ms) 30 min 60 min 90 min 120 min CRT motor (ms) 30 min 60 min 90 min 120 min CRT total (ms) 30 min 60 min 90 min 120 min
Propofol
Methohejritone
Thiopentone
Control
-0.5±0.33 -0.2±0.21 + 0.4 ±0.39 + 0.6±0.41
-0.9 ±0.39* -0.7 ±0.38 + 0.7 ±0.38 + 1.2±0.45*
-2.9 ±0.38*** -1.9 ±0.38*** -1.0 ±0.33** -0.6 ±0.49
0±0.27 + 0.2 ±0.33 + 0.4 ±0.30 + 0.4 ±0.35
+ 7±10 + 14±14 + 9±11 + 6±15
+ 79±23** + 13±16 -6±13 -8±13
+ 299 ±73*** + 124±33** + 62±28* + 43±20
+ 28 ±6*** + 2±9 -10±15 -12±15
+ 63 ±12*** + 20±9* + 13±12 + 2±8
+ 269±148 + 17±21 + 6±13 -14±11
+ 2±5 -2±5
+ 568±181** + 141±41** + 68±32* + 28±23
-2±7 -1±7 -5±7 -9±6
+ 31±41 + 16±14 -1±11 -6±12
+ 142 ±28*** + 32±15 + 7±13 -6±11
whereas in five from the methohexitone group and seven from the thiopentone group, induction was judged to be poor. There were no differences between the groups with regard to the quality of anaesthesia during the maintenance period. Postoperative period The frequency of complications after operation is given in table IV. None of the patients in the propofol group experienced any minor postoperative sequelae, while a significant number of those in the thiopentone group were unduly drowsy, requiring prompting in the use of the psychomotor tester, or suffered headaches in the period after operation. A few patients in the methohexitone group experienced minor problems, but this did not reach statistical significance.
0±6
-1±6 -7±6 -7±4 -2±5 0±4
The crude indices of recovery of time to open eyes and repeat date of birth after discontinuation of anaesthesia are also shown in table IV. Both were very markedly prolonged in the thiopentone group, while the time to repeat date of birth was also significantly longer with methohexitone than with propofol. The results of the psychomotor studies are tabulated in table V and displayed graphically in figures \-A. The CFFT and CRT values were all significantly impaired in the thiopentone group at 30, 60 and 90 min into the postoperative period, and some residual impairment was still present at 120 min. With methohexitone, all indices were significantly impaired at 30 min, returning to normal between 60 and 90 min. Patients receiving propofol showed no significant impairment of
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TABLE V. Psychometric data. Changes from pre-operatwe base line values (mean±SEM): *P < 0.05; **P < 0.07; ***P < 0.001
EMULSION FORMULATION OF PROPOFOL FOR DAY CASES
729
100
+2-1
o
30
PQ.001 60 Time (min)
400J
90
120
FIG. 1. Mean changes from pre-test baselines of CFFT. O = Thiopentone; x = propofol; • = methohexitone; A =£0^0)
30
I 60
I 90
I 120
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/V0.001
Time (min) •_ *• , ' ' fn^^ *£? p r e - t e s t bMetauaof motor component of CRT. O = Thiopentone; x = propofol; # = methohexitone; A = control. D
FlG
i
3
w
Me
100
4000
30
60 Time (cnin)
90
FIG. 2. Mean changes from pre-test baselines of recognition component of CRT. O = Thiopentone; x «= propofol; • = methohexitone; A =" control.
90
30
120
Time (mJn)
FIG. 4. Mean changes from pre-test baselines of CRT. O - Thiopentone; x = propofol; • => methohexitone; A •= control.
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730
psychomotor function 30 min following anaesthesia, apart from the motor component of the CRT test, which had returned to normal by 60 min. The control group showed no significant differences in either CFFT or CRT scores at any of the recording times. DISCUSSION
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This study confirms that propofol possesses many attractive features as an induction agent for day-case anaesthesia. Quality of induction was superior to that of methohexitone or thiopentone and there was little problem with excitatory side effects. Pain on injection was encountered, but in no patient was this severe. Apnoea occurred more commonly with propofol, but this was not a problem clinically as a consistent feature of the drug was the toleration of an oral airway by the patient—which made a short period of manual ventilation via a face mask simple. There was also more cardiovascular depression with propofol than with the other two drugs. While the introduction of enflurane may have contributed slightly to the cardiovascular depression, this cannot account for the greater decrease in systolic arterial pressure in the propofol group, since the respiratory depression in this group would result in less enflurane being inspired. It is likely that these findings reflect a relative overdosage for induction. Previous studies with the Cremophor formulation showed a dose-related respiratory and cardiovascular depression. Significant apnoea and hypotension occurred in the majority of patients receiving doses greater than 2 mg kg"1, but were rare in those receiving less (Briggs et al., 1981). In our study all patients received 2.5 mg kg"1 to ensure successful induction in every patient, although a smaller dose would probably be suitable for routine clinical use, and we would concur with Briggs' suggestion of 2.0 mg kg"1 as a satisfactory induction dose for the Cremophor formulation, equating this to thiopentone 4-5 mg kg"1. Quality of maintenance was similar in all groups, reflecting the standard technique used. While, in 13% of patients, this was described as poor, usually on account of airway problems, all procedures were carried out successfully. Recovery was superior in all respects in the propofol group. Minor postoperative side effects were not seen and recovery was significantly faster, both as assessed by the crude indices of eye opening and repeating
date of birth, and by the more sophisticated tests of psychomotor function. Previous studies with the original Cremophor EL formulation suggested its suitability for day-case anaesthesia. Desirable properties included rapid, smooth induction of anaesthesia, relative freedom from excitatory effects, almost total absence of emetic sequelae and rapid recovery (Kay and Stephenson, 1980; Rutter et al., 1980; Briggs et al., 1981). However, these were countered by the high incidence of pain on injection and the risk of hypersensitivity reactions to Cremophor (Briggs, Clarke and Watkins, 1982; Glen, Hunter and Thomson, 1982), hence the search for a new solubilizing agent. Recent animal work using the new emulsion formulation (Glen and Hunter, 1984) indicated that this has anaesthetic and haemodynamic effects similar to those of the Cremophor formulation. Behavioural responses also suggest that it produces less discomfort on injection. Our clinical findings would appear to bear this out. Day-case anaesthesia forms an important part of present day anaesthetic practice and it is likely that this will increase in the current financial climate. Many techniques and agents have been investigated for out-patient use, but none has received universal support (Atkinson, 1982; Loder, 1982). Most authorities would consider rapid recovery as an essential component of day-case anaesthesia, but this is often difficult to assess objectively. Suggested tests of recovery are legion, and vary from the very basic to the extremely complicated (Vickers, 1965; Doenicke, Kugler and Laub, 1967; Dixon and Thornton, 1973; Craig, Cooper and Sear, 1982). Recovery of street fitness implies a return of psychomotor function to normal. In a comprehensive review of the available tests of psychomotor function, Hindmarch (1980) concluded that critical flicker fusion threshold is the assessment of choice for investigation of change in the overall integrative activity of the central nervous system produced by psycho-active drugs, and that choice reaction time is a very sensitive measure of drug-induced changes in sensori-motor performance, particularly if it is split into its motor and recognition components. We chose these sensitive tests to assess postoperative recovery in our study, along with the gross recovery parameters of times to open eyes and repeat date of birth. Maintenance of anaesthesia was identical for all patients, consisting of 66 % nitrous oxide in
EMULSION FORMULATION OF PROPOFOL FOR DAY CASES oxygen supplemented with enflurane. It is, therefore, reasonable to attribute differences in side effects and recovery times after operation to the different induction agents used. Previous studies have shown that, for short procedures, the effects of i.v. induction agents are longer lasting than those of the volatile agent (Hannington-Kiff, 1970; Gale, 1976). In all assessments of recovery, propofol performed significantly better than the other agents.
ACKNOWLEDGEMENTS We should like to thank ICI Pharmaceuticals Division for supplies of propofol, Mr Simon Ogston, Medical Statistician, Ninewells Hospital for statistical advice and Miss Lesley Smith for secretarial assistance.
REFERENCES Atkinson, R. S. (1982). Anaesthesia for day-case surgery; in Recent Advances in Anaesthesia and Analgesia, 14th Edn, p. 81. Edinburgh: Churchill Livingstone. Briggs, L. P., Clarke, R. S. J., Dundee, J. W., Moore, J., Bahar, M., and Wright, P. J. (1981). Use of di-isopropyl phenol as main agent for short procedures. Br. J. Anaeith., 53, 1197.
Briggs, L. P., Clarke, R. S. J., and Watkins, J. (1982). An adverse reaction to the administration of disoprofol (Diprivan). Anaesthesia, 37, 1099. Craig, J., Cooper, G. M., and Sear, J. W. (1982). Recovery from day-case anaesthesia. Comparison between methohexitone, Althesin and etomidate. Br. J. Anaesth., 54, 447. Dixon, R. A., and Thornton, J. A. (1973). Tests of recovery from anaesthesia and sedation: intravenous diazepam in dentistry. Br. J. Anaesth., 45, 207. Doenicke, A., Kugler, J., and Laub, M. (1967). Evaluation of recovery and " street fitness " by EEG and psychodiagnostic tests after anaesthesia. Can. Anaesth. Soc. J., 14, 567. Gale, G. D. (1976). Recovery from methohexitone, halothane and diazepam. Br. J. Anaesth., 48, 691. Glen, J. B., and Hunter, S. C. (1984). Pharmacology of an emulsion formulation of ICI 35868. Br.J. Anaesth., 56,617. Thomson,D. S. (1982). The role of CremophorEL in anaphylactoid reactions to i.v. anaesthetics. Br. J. Anaesth., 54, 231P. Hannington-Kiff, J. G. (1970). Measurement of recovery from out-patient general anaesthesia with a simple ocular test. Br.
Med.J.,3, 132. Hindmarch, 1.(1980). Psychomotor function and psycho-active drugs. Br. J. Clin. Pharmacol., 10, 189. Parrott, A. C. (1977). Repeated dose comparisons of Nomifensine, Imipramine and placebo on subjective assessments of sleep and objective measures of psychomotor performance. Br. J. Clin. Pharmacol., 4, 167S. Kay, B., and Roily, G. (1977). ICI 35868, a new intravenous induction agent. Acta Anaesthesiol. Belg., 28, 303. Stephenson, D. K. (1980). ICI 35868 (Diprivan); a new intravenous anaesthetic. A comparison with Althesin. Anaesthesia, 35, 1182. Loder, R. E. (1982). The anaesthetist and the day-surgery unit. Anaesthesia, 37, 1037. Major, E., Verniquet, A. J. W., Waddell, T. K., Savege, T. M., Hoffler, D. E., and Aveling, W. (1981). A study of three doses of ICI 35868 for induction and maintenance of anaesthesia. Br. J. Anaesth., 53, 267. Rogers, K. M., Dewar, K. M. S., McCubbin, T. D., and Spence, A. A. (1980). Preliminary experience with ICI 35868 as an i.v. induction agent: comparison with Althesin. Br. J. Anaesth., 52, 807. Rutter, D. V., Morgan, M., Lumley, J., and Owen, R. (1980). ICI 35868 (Diprivan): a new intravenous induction agent. A comparison with methohexitone. Anaesthesia, 35, 1188. Vickers, M. D. (1965). Measurement of recovery from anaesthesia. Br. J. Anatsth., 37, 296.
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In conclusion, the new emulsion formulation, propofol, would appear to be a suitable induction agent for day-case anaesthesia. We have demonstrated its superiority to methohexitone, and the other serious contender, Althesin, has recently been withdrawn from use. Induction is rapid and smooth, pain on injection less of a problem than with the old formulation or with methohexitone; recovery is rapid and pleasant with freedom from side effects. Although cardiovascular and respiratory depression occur, they are probably dose-related and do not appear to present serious clinical problems.
731
COMPARISON OF THE NEW EMULSION FORMULATION OF PROPOFOL WITH METHOHEXITONE AND THIOPENTONE FOR INDUCTION OF ANAESTHESIA IN DAY CASES N. MACKENZIE AND I. S. GRANT
SUMMARY The new emulsion formulation of di-isopropyl phenol (propofol) was compared with methohexitone and thiopentone for induction of anaesthesia in day cases. Propofol produced significantly smoother induction of anaesthesia, but caused more cardiovascular and respiratory depression. Pain on injection was significantly less than with methohexitone. Post-anaesthetic recovery was superior with propofol, with virtual absence of side effects, and rapid recovery with little impairment of psychomotor function 30 min after anaesthesia.
Informed consent was obtained from each patient and the study approved by the Hospital Ethics Committee. Each patient was instructed in the use of the Leeds Psychomotor Tester. This is a compact, portable, simple apparatus capable of measuring Critical Flicker Fusion Threshold (CFFT) and Choice Reaction time (CRT) scores (Hindmarch and Parrott, 1977). For CRT measurement the subject scans an array of six small lights which are illuminated on a random basis. As soon as he PATIENTS AND METHODS detects the light he touches the appropriate button Sixty patients between the ages of 18 and 65 yr to extinguish it. The latency of this response is an undergoing minor urological surgery as day cases assessment of integrity of sensori-motor function were allocated randomly to one of three groups of and an accurate measure of psychomotor perform20 patients each. The three groups were comparable ance. The distance the subject has to move his for age, sex and weight. All were ASA Grade I or hand to touch the response button is the same for II; patients with hepatic, renal, haematological, each light, making it possible to measure motor metabolic or psychiatric disease were excluded. time separately from recognition time. The CFFT is a sensitive index of the state of CNS arousal and the ability to integrate discrete units of sensory N. MACKENZIE, M.B., CH.B., FJ.A.R.CLS.; I. S. GRANT, M.B., data. In this assessment the subject is required to CH.B., M.R.C.P., F.F.A.R.C.S.; Department of Anaesthetics, detect nicker fusion in a set of four light emitting Ninewells Teaching Hospital, Dundee.
Downloaded from http://bja.oxfordjournals.org/ at New York University on July 1, 2015
Propofol (di-isopropyl phenol (Diprivan)) is a comparatively new i.v. induction agent; its clinical use was first described in 1977 by Kay and Roily. Subsequent studies revealed several attractive features, particularly with regard to lack of excitatory side-effects and rapid recovery (Kay and Stephenson, 1980; Rogers et al., 1930; Rutter et al., 1980; Briggs et al., 1981; Major et al., 1981). However, these were largely outweighed by its limited solubility in water which necessitated its formulation in Cremophor EL (with the attendant risk of hypersensitivity reactions (Briggs, Clarke and Watkins, 1982)), and by the high incidence of pain on injection. An alternative formulation has been achieved with a 1 % w/v aqueous emulsion containing 10 % w/v soya bean oil, 1.2 % w/v egg phosphatide and 2.3% w/v glycerol. Initial animal studies showed anaesthetic properties similar to those of the original formulation (Glenn and Hunter, 1984). This study was designed to compare the new emulsion formulation of propofol with methohexitone and thiopentone for the induction of anaesthesia in day-case patients, with particular regard to recovery after operation.
BRITISH JOURNAL OF ANAESTHESIA
726
TABLE I.
Agc(yr) Weight (kg) Scx(M/F) Duration of anaesthetic (min)
area, where the time to opening eyes on command and repeating date of birth were recorded by an independent observer who was unaware of the induction agent used. The patient was then returned to the ward, where recovery was further assessed by measurement of CFFT and CRT scores at 30 min, 60 min, 90 min and 120 min from the end of anaesthesia. These were carried out by a second anaesthetist who was again unaware of the patient's group. Any adverse effects during this period such as headache, nausea and vomiting were noted and the i.v. injection site inspected, before the patient's discharge home, for any venous complications, such as phlebitis or thrombosis. The results were analysed statistically using t tests, Chi-squared tests and Fisher-Irwin exact probability tests, where appropriate. RESULTS
A total of 60 patients were studied, randomly allocated to three groups receiving propofol (n = 20), methohexitone (« = 20) or thiopentone (n = 20). The durations of the surgical procedures were similar in the three study groups (table I). Induction and maintenance of anaesthesia
Downloaded from http://bja.oxfordjournals.org/ at New York University on July 1, 2015
diodes in foveal fixation at 1 m using alternately ascending and descending frequencies. After familiarization with the apparatus, each subject had 50 practice attempts with the CRT test before base-line pre-operatdve CFFT and CRT scores were recorded. This is recommended by the designers, to preclude any possible learning effect» interfering with assessment of performance. The CRT was taken as the mean of 25 response times following five practice attempts on each occasion and the CFFT as the mean of six results, three on the ascending scale and three on the descending. On each occasion care was taken to ensure correct positioning of the apparatus and constant ambient lighting. A control group of 20 patients, matched with the. three study groups for age, sex and weight, also underwent psychomotor testing under conditions identical to those of the study group. These were patients who had not undergone surgery within 5 days of the testing and who were not receiving psycho-active drugs. No premedication was given and anaesthesia was induced by the injection of propofol 2.5 mg kg"1, 1% methohexitone l.Smgkg" 1 or 2.5 % thiopentone 5 mg kg"1, over a 20-s period, to a peripheral vein, on the dorsum of the hand. The induction time was noted (time from start of injection to cessation of counting), as were any complications during induction such as feelings on injection, movement, apnoea and other respiratory problems. The overall quality of induction was graded by the anaesthetist (the same individual in every case). Anaesthesia was maintained with 66 % nitrous oxide in oxygen supplemented with enflurane. This was administered in a standard manner, the inspired concentration being increased rapidly to 5% until surgical anaesthesia was achieved, and then reduced to 2-2.5 % thereafter. Heart rate and arterial pressure were recorded before induction and at 2-min intervals throughout the procedure; any adverse effects were noted. The anaesthetic gases were discontinued at the end of surgery and the patient transferred to a recovery
The induction time was not significantly different in the three groups at around 30 s (table II). However, there were important differences between groups with regard to complications on induction. Feelings on injection occurred in 16 patients receiving propofol, but this was described as coldness in 11 of these and as pain in only five; in these five patients the pain was either mild or moderate. With methohexitone, no patient reported coldness on injection, but 11 complained of pain and infivethis was severe. In the thiopentone group, three patients described coldness on injection, but none complained of pain. In all patients the injection was given to a small vein on the dorsum of the hand and in no patient was there
Pattern data and duration of anaesthesia {mean ± SEM) Propofol
Methohexitone
Thiopentone
Control
47.2 ±2.86 69.6 ±2.25 13/7 10.8±0.96
40.8 ±4.05 70.7 ±2.82 13/7 12.4±1.36
42.6 ±3.09 69.0±2.94 13/7 9.9±0.6O
41.2±4.78 68.6±2.16 14/6
EMULSION FORMULATION OF PROPOFOL FOR DAY CASES
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TABLE II. Induction times (mean + SEM) and complications (No. patients). Significance values: propofol v. methohexitone—*P < 0.05, **P < 0.01, ***P < 0.001; propofol v. thiopentone—fP < 0.05,
tP < 0.02, ttP < 0.01 Methohexitone
Thiopentone
30.6 ±0.83
28.8 ±0.92
29.6 + 0.85
17 3 0**
13 7
9 11
16 4*
15 5
14.7 ±3.06
15.1 ±2.80
10.4 ±2.99
11 5 3 0
12* 9 4
8 6
6 (2 at 120 s)
0***
ot
n ot 1
7tt
TABLE III. Quality of induction and anaesthesia (No. of patients). Significance values: propofol v. methohexitone—**P < 0.01, propofol v. thiopentone—+P < 0.05
Quality of induction Good Adequate Poor Quality of anaesthesia Good Adequate Poor
Propofol
Methohexitone
Thiopentone
16 4 0
5 10 5**
10 3
5 12 3
5 13 2
8 9 3
evidence of venous problems 4 h later, before discharge home. Statistically significant differences were seen also between the groups with regard to the development of apnoea after induction, with six patients in the propofol group having apnoeic periods of greater than 60 s (two at 120 s), compared with none in the other two groups. Propofol also caused more marked decreases in systolic arterial pressure in the first 2 min after induction, with more than half the patients in this group experiencing decreases of more than 20 % compared with less than one-quarter in the other groups. The mean decrease in systolic arterial pressure in the propofol group was 30 mm Hg, compared with 18 mm Hg in the other groups. This decrease was more pronounced in those patients with higher systolic pressures initially: those with systolic arterial pressures > 130 mm Hg had a mean decrease of 41 mm Hg, compared with a 20-mm Hg decrease in those with lower initial
7t
pressures. All groups showed an increase in heart rate, 2 min after induction, of between 10 and 15 beat min"1, but there were no significant differences between the groups. Involuntarymovementoccurred in three patients receiving propofol, in nine receiving methohexitone and in one receiving thiopentone. Induction of anaesthesia was particularly smooth in the propofol group, no patients experiencing cough or hiccup, compared with four receiving methohexitone. A surprisingly high percentage of patients in whom anaesthesia was induced with thiopentone (35%) had problems with cough or hiccup at induction, and this almost certainly reflects an inadequate induction dose: 5 mg kg"1 was used for all patients, but in some this was clearly insufficient and three required additional supplements to induce anaesthesia. These findings were reflected in the subjective assessment of quality of anaesthesia (table III). Induction was good or adequate in all patients in the propofol group,
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Induction time (s) Apnoea 0-30 31-60s >60s Decrease in arterial pressure 0-20% >20% Increase in heart rate (beat min"1) Side effects Coldness Pain Involuntary movement Cough/hiccup
Propofol
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728
TABLE IV. Crude recovery times (mean ± SEM) and postoperative sequelae (No. of patients). Significance values: propofol v. mtthohexitone—*P < 0.05; propofol v. thiopenume— ffP < 0.01, t t t P < 0.001
Time to open eyes (min) Time to repeat date of birth (min) Sequelae Headache Nausea/vomiting Drowsiness Venous problems
Propofol
Methohexitone
Thiopentone
4.8 ±0.45
5.6±0.54
9.6±0.74ttt
5.8±0.34
7.2 ±0.58*
10.6±0.74ftt
0 0 0 0
3 3 0 0
vtt 2 vtt 0
CFFT(Hz) 30 min 60 min 90 min 120 min CRT recog. (ms) 30 min 60 min 90 min 120 min CRT motor (ms) 30 min 60 min 90 min 120 min CRT total (ms) 30 min 60 min 90 min 120 min
Propofol
Methohejritone
Thiopentone
Control
-0.5±0.33 -0.2±0.21 + 0.4 ±0.39 + 0.6±0.41
-0.9 ±0.39* -0.7 ±0.38 + 0.7 ±0.38 + 1.2±0.45*
-2.9 ±0.38*** -1.9 ±0.38*** -1.0 ±0.33** -0.6 ±0.49
0±0.27 + 0.2 ±0.33 + 0.4 ±0.30 + 0.4 ±0.35
+ 7±10 + 14±14 + 9±11 + 6±15
+ 79±23** + 13±16 -6±13 -8±13
+ 299 ±73*** + 124±33** + 62±28* + 43±20
+ 28 ±6*** + 2±9 -10±15 -12±15
+ 63 ±12*** + 20±9* + 13±12 + 2±8
+ 269±148 + 17±21 + 6±13 -14±11
+ 2±5 -2±5
+ 568±181** + 141±41** + 68±32* + 28±23
-2±7 -1±7 -5±7 -9±6
+ 31±41 + 16±14 -1±11 -6±12
+ 142 ±28*** + 32±15 + 7±13 -6±11
whereas in five from the methohexitone group and seven from the thiopentone group, induction was judged to be poor. There were no differences between the groups with regard to the quality of anaesthesia during the maintenance period. Postoperative period The frequency of complications after operation is given in table IV. None of the patients in the propofol group experienced any minor postoperative sequelae, while a significant number of those in the thiopentone group were unduly drowsy, requiring prompting in the use of the psychomotor tester, or suffered headaches in the period after operation. A few patients in the methohexitone group experienced minor problems, but this did not reach statistical significance.
0±6
-1±6 -7±6 -7±4 -2±5 0±4
The crude indices of recovery of time to open eyes and repeat date of birth after discontinuation of anaesthesia are also shown in table IV. Both were very markedly prolonged in the thiopentone group, while the time to repeat date of birth was also significantly longer with methohexitone than with propofol. The results of the psychomotor studies are tabulated in table V and displayed graphically in figures \-A. The CFFT and CRT values were all significantly impaired in the thiopentone group at 30, 60 and 90 min into the postoperative period, and some residual impairment was still present at 120 min. With methohexitone, all indices were significantly impaired at 30 min, returning to normal between 60 and 90 min. Patients receiving propofol showed no significant impairment of
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TABLE V. Psychometric data. Changes from pre-operatwe base line values (mean±SEM): *P < 0.05; **P < 0.07; ***P < 0.001
EMULSION FORMULATION OF PROPOFOL FOR DAY CASES
729
100
+2-1
o
30
PQ.001 60 Time (min)
400J
90
120
FIG. 1. Mean changes from pre-test baselines of CFFT. O = Thiopentone; x = propofol; • = methohexitone; A =£0^0)
30
I 60
I 90
I 120
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/V0.001
Time (min) •_ *• , ' ' fn^^ *£? p r e - t e s t bMetauaof motor component of CRT. O = Thiopentone; x = propofol; # = methohexitone; A = control. D
FlG
i
3
w
Me
100
4000
30
60 Time (cnin)
90
FIG. 2. Mean changes from pre-test baselines of recognition component of CRT. O = Thiopentone; x «= propofol; • = methohexitone; A =" control.
90
30
120
Time (mJn)
FIG. 4. Mean changes from pre-test baselines of CRT. O - Thiopentone; x = propofol; • => methohexitone; A •= control.
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730
psychomotor function 30 min following anaesthesia, apart from the motor component of the CRT test, which had returned to normal by 60 min. The control group showed no significant differences in either CFFT or CRT scores at any of the recording times. DISCUSSION
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This study confirms that propofol possesses many attractive features as an induction agent for day-case anaesthesia. Quality of induction was superior to that of methohexitone or thiopentone and there was little problem with excitatory side effects. Pain on injection was encountered, but in no patient was this severe. Apnoea occurred more commonly with propofol, but this was not a problem clinically as a consistent feature of the drug was the toleration of an oral airway by the patient—which made a short period of manual ventilation via a face mask simple. There was also more cardiovascular depression with propofol than with the other two drugs. While the introduction of enflurane may have contributed slightly to the cardiovascular depression, this cannot account for the greater decrease in systolic arterial pressure in the propofol group, since the respiratory depression in this group would result in less enflurane being inspired. It is likely that these findings reflect a relative overdosage for induction. Previous studies with the Cremophor formulation showed a dose-related respiratory and cardiovascular depression. Significant apnoea and hypotension occurred in the majority of patients receiving doses greater than 2 mg kg"1, but were rare in those receiving less (Briggs et al., 1981). In our study all patients received 2.5 mg kg"1 to ensure successful induction in every patient, although a smaller dose would probably be suitable for routine clinical use, and we would concur with Briggs' suggestion of 2.0 mg kg"1 as a satisfactory induction dose for the Cremophor formulation, equating this to thiopentone 4-5 mg kg"1. Quality of maintenance was similar in all groups, reflecting the standard technique used. While, in 13% of patients, this was described as poor, usually on account of airway problems, all procedures were carried out successfully. Recovery was superior in all respects in the propofol group. Minor postoperative side effects were not seen and recovery was significantly faster, both as assessed by the crude indices of eye opening and repeating
date of birth, and by the more sophisticated tests of psychomotor function. Previous studies with the original Cremophor EL formulation suggested its suitability for day-case anaesthesia. Desirable properties included rapid, smooth induction of anaesthesia, relative freedom from excitatory effects, almost total absence of emetic sequelae and rapid recovery (Kay and Stephenson, 1980; Rutter et al., 1980; Briggs et al., 1981). However, these were countered by the high incidence of pain on injection and the risk of hypersensitivity reactions to Cremophor (Briggs, Clarke and Watkins, 1982; Glen, Hunter and Thomson, 1982), hence the search for a new solubilizing agent. Recent animal work using the new emulsion formulation (Glen and Hunter, 1984) indicated that this has anaesthetic and haemodynamic effects similar to those of the Cremophor formulation. Behavioural responses also suggest that it produces less discomfort on injection. Our clinical findings would appear to bear this out. Day-case anaesthesia forms an important part of present day anaesthetic practice and it is likely that this will increase in the current financial climate. Many techniques and agents have been investigated for out-patient use, but none has received universal support (Atkinson, 1982; Loder, 1982). Most authorities would consider rapid recovery as an essential component of day-case anaesthesia, but this is often difficult to assess objectively. Suggested tests of recovery are legion, and vary from the very basic to the extremely complicated (Vickers, 1965; Doenicke, Kugler and Laub, 1967; Dixon and Thornton, 1973; Craig, Cooper and Sear, 1982). Recovery of street fitness implies a return of psychomotor function to normal. In a comprehensive review of the available tests of psychomotor function, Hindmarch (1980) concluded that critical flicker fusion threshold is the assessment of choice for investigation of change in the overall integrative activity of the central nervous system produced by psycho-active drugs, and that choice reaction time is a very sensitive measure of drug-induced changes in sensori-motor performance, particularly if it is split into its motor and recognition components. We chose these sensitive tests to assess postoperative recovery in our study, along with the gross recovery parameters of times to open eyes and repeat date of birth. Maintenance of anaesthesia was identical for all patients, consisting of 66 % nitrous oxide in
EMULSION FORMULATION OF PROPOFOL FOR DAY CASES oxygen supplemented with enflurane. It is, therefore, reasonable to attribute differences in side effects and recovery times after operation to the different induction agents used. Previous studies have shown that, for short procedures, the effects of i.v. induction agents are longer lasting than those of the volatile agent (Hannington-Kiff, 1970; Gale, 1976). In all assessments of recovery, propofol performed significantly better than the other agents.
ACKNOWLEDGEMENTS We should like to thank ICI Pharmaceuticals Division for supplies of propofol, Mr Simon Ogston, Medical Statistician, Ninewells Hospital for statistical advice and Miss Lesley Smith for secretarial assistance.
REFERENCES Atkinson, R. S. (1982). Anaesthesia for day-case surgery; in Recent Advances in Anaesthesia and Analgesia, 14th Edn, p. 81. Edinburgh: Churchill Livingstone. Briggs, L. P., Clarke, R. S. J., Dundee, J. W., Moore, J., Bahar, M., and Wright, P. J. (1981). Use of di-isopropyl phenol as main agent for short procedures. Br. J. Anaeith., 53, 1197.
Briggs, L. P., Clarke, R. S. J., and Watkins, J. (1982). An adverse reaction to the administration of disoprofol (Diprivan). Anaesthesia, 37, 1099. Craig, J., Cooper, G. M., and Sear, J. W. (1982). Recovery from day-case anaesthesia. Comparison between methohexitone, Althesin and etomidate. Br. J. Anaesth., 54, 447. Dixon, R. A., and Thornton, J. A. (1973). Tests of recovery from anaesthesia and sedation: intravenous diazepam in dentistry. Br. J. Anaesth., 45, 207. Doenicke, A., Kugler, J., and Laub, M. (1967). Evaluation of recovery and " street fitness " by EEG and psychodiagnostic tests after anaesthesia. Can. Anaesth. Soc. J., 14, 567. Gale, G. D. (1976). Recovery from methohexitone, halothane and diazepam. Br. J. Anaesth., 48, 691. Glen, J. B., and Hunter, S. C. (1984). Pharmacology of an emulsion formulation of ICI 35868. Br.J. Anaesth., 56,617. Thomson,D. S. (1982). The role of CremophorEL in anaphylactoid reactions to i.v. anaesthetics. Br. J. Anaesth., 54, 231P. Hannington-Kiff, J. G. (1970). Measurement of recovery from out-patient general anaesthesia with a simple ocular test. Br.
Med.J.,3, 132. Hindmarch, 1.(1980). Psychomotor function and psycho-active drugs. Br. J. Clin. Pharmacol., 10, 189. Parrott, A. C. (1977). Repeated dose comparisons of Nomifensine, Imipramine and placebo on subjective assessments of sleep and objective measures of psychomotor performance. Br. J. Clin. Pharmacol., 4, 167S. Kay, B., and Roily, G. (1977). ICI 35868, a new intravenous induction agent. Acta Anaesthesiol. Belg., 28, 303. Stephenson, D. K. (1980). ICI 35868 (Diprivan); a new intravenous anaesthetic. A comparison with Althesin. Anaesthesia, 35, 1182. Loder, R. E. (1982). The anaesthetist and the day-surgery unit. Anaesthesia, 37, 1037. Major, E., Verniquet, A. J. W., Waddell, T. K., Savege, T. M., Hoffler, D. E., and Aveling, W. (1981). A study of three doses of ICI 35868 for induction and maintenance of anaesthesia. Br. J. Anaesth., 53, 267. Rogers, K. M., Dewar, K. M. S., McCubbin, T. D., and Spence, A. A. (1980). Preliminary experience with ICI 35868 as an i.v. induction agent: comparison with Althesin. Br. J. Anaesth., 52, 807. Rutter, D. V., Morgan, M., Lumley, J., and Owen, R. (1980). ICI 35868 (Diprivan): a new intravenous induction agent. A comparison with methohexitone. Anaesthesia, 35, 1188. Vickers, M. D. (1965). Measurement of recovery from anaesthesia. Br. J. Anatsth., 37, 296.
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In conclusion, the new emulsion formulation, propofol, would appear to be a suitable induction agent for day-case anaesthesia. We have demonstrated its superiority to methohexitone, and the other serious contender, Althesin, has recently been withdrawn from use. Induction is rapid and smooth, pain on injection less of a problem than with the old formulation or with methohexitone; recovery is rapid and pleasant with freedom from side effects. Although cardiovascular and respiratory depression occur, they are probably dose-related and do not appear to present serious clinical problems.
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