British Journal of Anaesthesia 1990; 64: 675-681
PSYCHOMOTOR RECOVERY AFTER THREE METHODS OF SEDATION DURING SPINAL ANAESTHESIA I. G. KESTIN, P. B. HARVEY AND C. NIXON
In a double-blinded study, we have investigated psychomotor recovery after three sedation schemes during spinal anaesthesia for transurethral resection of prostate. Thirty-nine patients were allocated randomly to receive i.v. midazolam only, i.v. midazolam with antagonism by f/umazenil or an infusion of propofol. The psychomotor tests were of long and short term memory, critical flicker fusion threshold, attention and concentration, cognition, mental arithmetic, and sedation and anxiety levels, and were performed before operation and at 30 min, 60 min, 2 h and 24 h after operation. Free recall of a picture learning task was the most sensitive test, showing a significant impairment in all groups, persisting for more than 2 h. Propofol was associated with the most rapid recovery and least impairment compared with preoperative baseline. Performance improved in all the tests after antagonism with f/umazenil, but was still significantly impaired compared with baseline in tests of picture recall and letter deletion. Significant decreases in performance in all tests were detected 1 h after flumazenil. No increase in anxiety was recorded after flumazenil. We conclude that infusion of propofol is the technique with the most rapid recovery, while only brief and incomplete antagonism of the effects of midazolam may be expected with flumazenil. KEY WORDS Recovery: psychomotor propofol. flumazenil.
function.
Sedation: midazolam.
mental confusion is one of the signs of TURP syndrome, and this sign is masked by general anaesthesia. The advantages of regional anaesthesia may be lost if the patient remains heavily sedated at the end of a procedure, and it has been suggested also that heavy sedation may have been associated with cardiac arrest during spinal anaesthesia [3]. It is possible that propofol or midazolam with flumazenil might provide perioperative sedation, but with rapid postoperative psychomotor recovery. We have therefore compared psychomotor recovery after three sedation schemes: midazolam alone, midazolam with flumazenil at the end of surgery, and an infusion of propofol. PATIENTS AND METHODS
After District Ethics Committee approval and informed patient consent, we studied 39 patients undergoing TURP under spinal anaesthesia using a randomized, double-blind method. Patient exclusions included those with CNS disorders or concurrent benzodiazepine therapy. The psychomotor tests were administered to the patients in the same order by the same investigator on the day before surgery and at 30 min, 60 min, 2 h and 24 h after operation. Memory. One minute to memorize a card showing pictures of nine familiar objects. Critical flicker fusion threshold (CFFT). This was measured three times with ascending frequency and three times in descending frequency and the mean of the six readings taken as the CFFT. I. G. KESTTN*,
Some of the advantages of regional anaesthesia in the elderly include diminution in postoperative confusion- and mental deterioration [1,2]. An additional advantage of regional anaesthesia for transurethral resection of prostate (TURP) is that
F.F./LR.C.S. ;
P.B.HARVEY,
F.F.A.R.C.S.;
C.
NIXON, F.F.A.R.C.S.; Department of Anaesthesia, Plymouth General Hospital, Plymouth PL4 8QQ. Accepted for Publication: June 16, 1989. •Present address, for correspondence: Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary, Bristol BS2 8HW.
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
SUMMARY
676
Serial 7s. Reverse counting aloud from 100 to 44 in steps of 7. The time taken and number of errors were scored. Letter deletion. One minute to delete as many of the letters p and b as possible. Correct deletions and the errors (incorrect deletions or omissions) were scored. Forward and backward digit span.
midazolam 1 mg were given i.v. until the patient reached sedation level 3, and further midazolam was given i.v. to maintain this level of sedation during surgery. The anaesthetist was unaware of the group to which the patient belonged. In group P, propofol was given using a loading dose and three-stage infusion scheme. The suggested dose in the study programme was: loading dose of 0.5 mg kg"1 over 20 s, followed immediately by an infusion of 5 mg kg"1 h"1 for 10 min, 4 mg kg"1 h"1 for 10 min and 3 mg kg"1 h"1 thereafter. The anaesthetist was free to choose a multiple of this whole scheme on clinical grounds, and could vary the maintenance infusion rate to maintain the patient at sedation level 3. In all three groups, 0.5% bupivacaine in 8% glucose was used for the spinal block and the patient breathed 40 % oxygen during surgery. The following sedation scale was used: 1 = fully alert and orientated; 2 = drowsy; 3 = eyes closed, rousable to command; 4 = eyes closed, reusable with mild physical stimuli, for example earlobe tug; 5 = asleep, unrousable with mild physical stimuli. The sedation level was recorded every 5 min during surgery. In the Recovery Unit, the first psychomotor tests were administered 30 min after the end of surgery. At 50 min after surgery, 5 ml of either flumazenil 500 ug (group MF) or saline (groups MS and P) was given in a double-blinded method: 2 ml initially, followed at 1-min intervals by 1-ml increments. The psychomotor tests were repeated at 60 min, 2 h and 24 h after surgery. Data analysis
The continuously variable data were analysed for normality by the Schapiro-Wilk test. Skewed data were transformed logarithmically and tested for normality. These data subsets were analysed by ANOVA for repeated measures, with pairwise comparisons made using the Fisher protected least significant difference method. Ordinal data were analysed by the Kruskal-Wallis test, with pairwise comparisons made using the method suggested by Conover [4]. The overall statistical significance level was 5 %.
Anaesthetic management
No premedication was used and the patients were allocated randomly to one of three groups: group MS—i.v. midazolam only; group MF—i.v. midazolam followed by antagonism with flumazenil; group P—i.v. propofol. In groups MS and MF, increments of
RESULTS
There were 13 patients in each group, and no significant differences between the groups (table I). In the propofol group, the mean initial loading dose was 0.54 mg kg"1 (range 0.5-0.7 mg kg"1),
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
Reverse counting. The number of errors and time taken to write all the numbers from 1000 down to 976. Backward spelling of a common five-letter word. Patients then performed a simple unscored task so that the interval between Memory and Picture recall was always 15 min. Picture recall. The patient was asked to recall the objects memorized in the first test (1 min allowed), and the number recalled was taken as the free recall score. Verbal clues were given for the remaining objects, and any additional objects remembered were noted as the verbal cued recall score. Then the patient was given another picture card showing 20 objects, including the nine original objects, and asked to point out those that had appeared on the original card. The total number recognized was taken as the visual recognition score (the patient was told that incorrect identifications were subtracted from the score, to discourage guessing). There were five different cards used for the picture recall test, together with a corresponding pair for the visual recognition test. No object on any of the cards appeared in more than one test sequence. Before the patient performed the postoperative test, two 10-cm visual analogue scales (VAS) were used to measure the patient's own subjective assessment of sedation and anxiety. One end of the sedation scale was randomly labelled "asleep", and the other "mentally fully alert", and the distance from the alert end was measured as the sedation score. One end of the anxiety scale was labelled "worst anxiety possible", the other "completely calm" and the central 1-cm area was shaded and labelled "usual"; the distance from the calm end was taken as the anxiety score.
BRITISH JOURNAL OF ANAESTHESIA
677
PSYCHOMOTOR RECOVERY TABLE I. Patient and anaesthetic data (mean (SD))
Group MS (n = 13) M F ( n = 13) P (n = 13)
Age (yr)
Weight (kg)
Duration of sedation (min)
Midazolam dose (mg kg"1)
68(7) 73(5) 71(7)
72 (10) 77(7) 71 (10)
46(12) 45(11) 40(12)
0.08 (0.02) 0.07 (0.03)
o 45 P 40 35 30 25 20
Before op.
30 min
24 h
60 min 2h Time after op.
FIG. 1. Serial 7s test (mean, SEM) in the midazolam-saline (MS) (A)> midazolam-flumazenil (MF) ( • ) and propofol (P) (x) groups. P < 0.05 compared with: * group P; $ group MS; f preoperative baseline.
35 34' 33 ^ 32
t31 &30 t*
29 28 27
t* Before op.
30 min
60 min Time after op.
2h
24h
FIG. 2. Critical flicker fusion threshold (CFFT) (mean, SEM) in the midazolam-saline (MS) (A), midazolam-flumazeni] (MF) ( • ) and propofol (P) (x) groups. P < 0.05 compared with: * group P; $ group MS; t preoperative baseline.
followed by the two short-duration infusions with the appropriate doses. All patients achieved sedation level 2 or 3 within 5 min, and the mean rate of the maintenance infusion of propofol
was 3.7 mg kg"1 h"1 (95 % confidence limits 3.1-3.9 mg kg"1 h"1). Three patients received additional i.v. boluses of propofol 20-40 mg to achieve a brief increase in sedation level. There
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
65 60 55
BRITISH JOURNAL OF ANAESTHESIA
678 120 115 110 105 3100
§ 95 i= 90 85 80 75 70
30min
60min Time after op.
2h
24 h
FIG. 3. Reverse counting test (mean, SEM) in the midazolam-saline (MS) (A), midazoUm-flumazeni] (MF) ( • ) and propofol (P) (x) groups. P < 0.05 compared with: *group P; \ preoperative baseline.
TABLE II. Postoperative anxiety scores (mean (SD)) Postoperative anxiety scores (cm) Group
30min
60 min
2h
24 h
MS MF P
6.1(1.2) 5.8(1.2) 6.5(1.1)
6.2 (0.7) 6.3(1.1) 5.9(1.0)
5.7 (0.8) 5.9 (0.9) 5.6 (0.7)
5.2 (0.5) 5.5(0.5) 5.1 (0.4)
TABLE IV. Free recall: number of objects recalled (median (range)). P < 0.05 compared with: * group P; %group MS; t preoperative baseline Postoperative score Group MS
baseline
P
Postoperative sedation score (cm) Group MS MF P
30 min
60 min
7.3* (6.5-8.0) 7.5* (6.7-8.2)
6.4* (5.7-7.0) 4.0$t (3.5-4.4)
2h
24 h
3.8
0.9
(2.6-4.6)
(0.5-1.2)
3.9
0.7
(3.2-4.5)
(0.5-1.1)
5.1
3.7
2.6
0.7
(4.1-5.9)
(2.5-4.6)
(1.9-3.1)
(0.3-1.1)
were no significant differences between groups in duration or depth of sedation. Four patients received i.m. pethidine for postoperative analgesia within the first 24 h, and were excluded from the 24-h psychomotor testing. There were no significant differences between the three groups in baseline preoperative performance in any of the tests. The results of the psychomotor tests are shown
It* (0-4)
6
(3-9) TABLE III. Postoperative sedation scores (mean (95% confidence limits)). P < 0.05 compared with: * group P; $ group MS; -\30-min score
It* (0-4)
6
(4-8) MF
30 min 60 min
0+*
(0-3)
5
(4-9)
3t
(1-7)
3tS
(0-5)
4t
(1-5)
2h
2f* (1-4) 2f* (1-3)
4t
(2-5)
24 h
4t (3-6)
5+
(3-6) 5
(4-7)
in figures 1-3 and tables II-V. There were no significant changes between any of the groups or from baseline performance within each group in the following tests: verbal cued recall, visual recognition recall, forward digit span or error rate in serial 7s and reverse counting. 30 min after anaesthesia
There were no significant differences between groups MS and MF and both groups were significantly different from group P and their own baseline performance in the following tests: free recall, CFFT, serial 7s, letter deletion, reverse counting, and backward spelling. There was a significant difference from baseline performance in groups MS and MF in reverse digit span. The VAS score for sedation—arousal in these groups was significantly different from group P, in which free recall, CFFT and serial 7s tests were significantly different from their own baseline.
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
Before op.
PSYCHOMOTOR RECOVERY
679
TABLE V. Letter deletion test: number of letters deleted (median (range)). | P < 0-OS compared with preoperative baseline
Postoperative scores Group MS
baseline
30min
60min
26
12f (7-24) 16.5f (4-31)
15t
19+
(4-28)
(9-42)
(17-39) MF P
24
(13-38) 21.5 (11-35)
15t
(8-34)
2h
18
(8-30)
24 h 26.5 (7-38) 31.5 (17-45)
19
17
19
24
(7-33)
(9-31)
(8-39)
(17-^3) Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
was profound memory deficit for free recall at the picture learning task, while performance of the After administration of flumazenil, performance was improved significantly in group MF visual recognition test was unimpaired. This compared with group MS in tests of free recall, difference between performance in tests of free CFFT, serial 7s, backward spelling, backward recall compared with visual recognition recall has digit span and the sedation score, but was been shown to be associated with low levels of significantly below baseline in free recall and sedation with benzodiazepines [5]. In that study [5], free recall was impaired initially, with relative letter deletion (tables IV, V). preservation of recognition recall, and as the dose There were no significant differences between of benzodiazepine was increased, recognition groups MF and P, or between group P and their recall was affected progressively. baseline performance except for free recall. Both our study and that of Sage, Close and Boas Flumazenil was associated with a decrease in [5] would suggest, therefore, that, the memory sedation, but no increase in anxiety (tables II, deficit with low doses of benzodiazepines involves III). access to memory trace, rather than formation (as memory is available for recognition but not for 2 h after anaesthesia There were no significant differences between free recall). Other workers have suggested othergroups MS and MF, and both groups were wise : that benzodiazepines affect principally consignificantly inferior to group P and their own solidation and storage memory processes, rather than access [6, 7]. Using an auditory learning task, baseline performance in the following tests: free Clarke and colleagues [7] found that both free recall, CFFT and serial 7s. recall and verbal recognition were affected by benzodiazepines, and concluded that the memory 24 h after anaesthesia deficit was in the consolidation process. However, There were no differences between the three as shown by Sage's group, this pattern is characgroups or from their own baseline performance in teristic of larger doses of benzodiazepines. Clarke any of the tests except for free recall, where and colleagues found also that visual recognition groups MS and MF were below baseline per- was not affected by benzodiazepines, which would formance. support the hypothesis that the memory deficit involves access, rather than formation (at least for visual material). DISCUSSION Forward digit span was found to be unaffected The psychomotor tests used in this study tested the patients for memory, both "long term" by sedation with midazolam, whereas there was (picture recall) and "short term" (digit span), significant impairment at 30 min in the test of attention and concentration (serial 7s, reverse backward digit span in the midazolam groups. counting and spelling), central integration Other studies have shown that short term memory (CFFT), cognition (mental arithmetic, backward is not affected by benzodiazepines [6]. Backward digit span and backward spelling), and subjective digit span, therefore, must involve additional cognitive mechanisms sensitive to midazolam, in assessment of sedation and anxiety. addition to short term memory, which is not The obvious effect of sedation with midazolam 60 min after anaesthesia
680
Even though the doses of midazolam used in this study were relatively low (mean 0.075 mg kg"1), diminished cognition, memory attention and concentration and central integration persisted for more than 2 h in the midazolam group. Sedation with an infusion of propofol was found to be associated with the most rapid psychomotor recovery. The propofol scheme used in this study was derived from the study by Roberts and colleagues [16], who reported a regimen designed to achieve and maintain a blood concentration of 3 ug ml"1 within 2 min. This concentration is sufficient for surgical anaesthesia; as the pharmacokinetics of propofol are linear [17], multiples of this regimen should alter blood concentration accordingly. The concentration that produces sedation rather than anaesthesia is not known, so it was chosen initially in this study to use 50 % of the dose regimen used by Roberts [16], giving an estimated blood concentration of
1.5 ug ml"1. The advantage of using this loading dose and three-stage infusion technique is that all the patients were sedated within 5 min. Another study of an infusion of propofol for sedation used a two-stage infusion technique without a loading dose, and the patients required 26 min to achieve the maintenance sedation level [18]. We conclude that an infusion of propofol is the technique with the most rapid recovery after sedation during spinal anaesthesia. The cognitive and amnesic effects of low dose midazolam sedation may persist for more than 2 h after operation, and flumazenil may antagonize only briefly and incompletely these effects of midazolam. REFERENCES 1. Chung F, Meier R, Lautenschlager E, Cannichael FJ, Chung A. General or spinal anesthesia: which is better in the elderly? Anesthtsiology 1987; 67: 422-427. 2. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiologica Scandinavica 1980; 24: 279-287. 3. Caplan RA, Ward RJ, Posner K, Cheney FW. Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of predisposing factors. Antsthtsiobgy 1988; 68: 5-11. 4. Conover WJ. Practical Nonparametric Statistics. New York: John Wiley and Sons, 1980; 230-231. 5. Sage DJ, Close A, Boas RA. Reversal of midazolam sedation with Ancxate. British Journal of Anaesthesia 1987; 59: 459-464. 6. O'Boyle C, Lambe R, Darragh A, Taffe W, Brick I, Kenny M. Ro 15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability. British Journal of Anaesthesia 1983; 55: 349-355. 7. Clarke RPF, Eccersley PS, Frisby JP, Thornton JA. The amnesic effects of diazepam (Valium). British Journal of Anaesthesia 1970; 42: 690-697. 8. Adam N. Disruption of memory functions associated with general anesthetics. In: Kilstrom JF, Evans FJ, eds. Functional Disorders of Memory. Hillsdale, New Jersey: Lawrence Erlbaum Association, 1979; 227. 9. Darragh A, Lambe R, Scully M, Brick I, O'Boyle C, Wilson Downie W. Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15-1788. Lancet 1981; 2: 8-10. 10. Lauven PM, Schwilden H, Stoeckel H, Greenblatt DJ. The effects of a benzodiazepine antagonist Ro 15-1788 in the presence of stable concentrations of midazolam. Anesthesiology 1985; 63: 61-64. 11. Kirkegaard L, Knudsen L, Jensen S, Kruse A. Benzodiazepine antagonist Ro 15-1788. Antagonism of diazepam sedation in outpatients undergoing gastroscopy. Anaesthesia 1986; 41: 1184-1188. 12. Louis M, Forster A, Suter PM, Gemperle M. Clinical and hemodynamic effects of a specific benzodiazepine antagonist (Ro 15-1788) after open heart surgery. Anesthesiology 1984; 61: A61. 13. Ricou R, Forster A, Bruckner A, Chastonay P, Gemperle M. Clinical evaluation of a specific benzodiazepine
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
affected by midazolam. This has been found also by Adam [8]. Backward spelling probably tests the same mechanisms as backward digit span, and both tests in this study showed a similar pattern of results. Flumazenil was found to antagonize only partially most of the psychomotor effects of midazolam. Performance after flumazenil had been given did not consistently achieve preoperative levels. Some studies in volunteers have shown full antagonism of the cognitive and amnesic effects of midazolam with large doses of flumazenil—either 200 mg orally [6,9] or 10 mg i.v. [10]. All clinical studies have documented excellent antagonism of sedation after larger doses of benzodiazepines than used in this study [5, 11]. Flumazenil was associated with greater alertness, but no increase in anxiety; some studies have reported increases in anxiety after large doses of flumazenil [12, 13]. The duration of the flumazenil antagonism was brief: 1 h after flumazenil, patients were indistinguishable from the group who received midazolam alone, and were below baseline performance in several tests. Resedation has been reported also in other studies [5, 6, 14, 15]. The implications of these results are that only brief and incomplete antagonism of the amnesic and cognitive effects of midazolam may be expected from i.v. flumazenil. Oral flumazenil has been shown to have a longer duration of action, but there was still evidence of resedation at 6 h [6]. This is likely to limit its routine use in clinical anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
PSYCHOMOTOR RECOVERY antagonist (Ro 15-1788). Studies in elderly patients after regional anaesthesia under benzodiazepine sedation. British Journal of Anaesthesia 1986; 58: 1005-1011. 14. Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15-1788). Clinical Pharmacokinetics 1988; 14: 1-12. 15. Duvaldestein P, Lebrault C, Guirimand F, Raimbault E. Efficacy of flumazenil reversal after midazolam induced anesthesia. Anesthesiology 1988; 63: A560. 16. Roberts FL, Dixon J, Lewis GTR, Tackley RM, PrysRoberts C. Induction and maintenance of propofol
681 anaesthesia. A manual infusion scheme. Anaesthesia 1988; 43 (Suppl.): 14-17. 17. Spelina KR, Coates DP, Monk CR, Prys-Roberts C, Norley I, Turtle MJ. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. I: Patients premedicated with morphine sulphate. British Journal of Anaesthesia 1986; 58: 1080-1084. 18. Wilson E, Mackenzie N, Grant IS. A comparison of propofol and midazolam by infusion to provide sedation in patients who receive spinal anaesthesia. Anaesthesia 1988; 43 (Suppl.): 91-94.
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
PSYCHOMOTOR RECOVERY AFTER THREE METHODS OF SEDATION DURING SPINAL ANAESTHESIA I. G. KESTIN, P. B. HARVEY AND C. NIXON
In a double-blinded study, we have investigated psychomotor recovery after three sedation schemes during spinal anaesthesia for transurethral resection of prostate. Thirty-nine patients were allocated randomly to receive i.v. midazolam only, i.v. midazolam with antagonism by f/umazenil or an infusion of propofol. The psychomotor tests were of long and short term memory, critical flicker fusion threshold, attention and concentration, cognition, mental arithmetic, and sedation and anxiety levels, and were performed before operation and at 30 min, 60 min, 2 h and 24 h after operation. Free recall of a picture learning task was the most sensitive test, showing a significant impairment in all groups, persisting for more than 2 h. Propofol was associated with the most rapid recovery and least impairment compared with preoperative baseline. Performance improved in all the tests after antagonism with f/umazenil, but was still significantly impaired compared with baseline in tests of picture recall and letter deletion. Significant decreases in performance in all tests were detected 1 h after flumazenil. No increase in anxiety was recorded after flumazenil. We conclude that infusion of propofol is the technique with the most rapid recovery, while only brief and incomplete antagonism of the effects of midazolam may be expected with flumazenil. KEY WORDS Recovery: psychomotor propofol. flumazenil.
function.
Sedation: midazolam.
mental confusion is one of the signs of TURP syndrome, and this sign is masked by general anaesthesia. The advantages of regional anaesthesia may be lost if the patient remains heavily sedated at the end of a procedure, and it has been suggested also that heavy sedation may have been associated with cardiac arrest during spinal anaesthesia [3]. It is possible that propofol or midazolam with flumazenil might provide perioperative sedation, but with rapid postoperative psychomotor recovery. We have therefore compared psychomotor recovery after three sedation schemes: midazolam alone, midazolam with flumazenil at the end of surgery, and an infusion of propofol. PATIENTS AND METHODS
After District Ethics Committee approval and informed patient consent, we studied 39 patients undergoing TURP under spinal anaesthesia using a randomized, double-blind method. Patient exclusions included those with CNS disorders or concurrent benzodiazepine therapy. The psychomotor tests were administered to the patients in the same order by the same investigator on the day before surgery and at 30 min, 60 min, 2 h and 24 h after operation. Memory. One minute to memorize a card showing pictures of nine familiar objects. Critical flicker fusion threshold (CFFT). This was measured three times with ascending frequency and three times in descending frequency and the mean of the six readings taken as the CFFT. I. G. KESTTN*,
Some of the advantages of regional anaesthesia in the elderly include diminution in postoperative confusion- and mental deterioration [1,2]. An additional advantage of regional anaesthesia for transurethral resection of prostate (TURP) is that
F.F./LR.C.S. ;
P.B.HARVEY,
F.F.A.R.C.S.;
C.
NIXON, F.F.A.R.C.S.; Department of Anaesthesia, Plymouth General Hospital, Plymouth PL4 8QQ. Accepted for Publication: June 16, 1989. •Present address, for correspondence: Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary, Bristol BS2 8HW.
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
SUMMARY
676
Serial 7s. Reverse counting aloud from 100 to 44 in steps of 7. The time taken and number of errors were scored. Letter deletion. One minute to delete as many of the letters p and b as possible. Correct deletions and the errors (incorrect deletions or omissions) were scored. Forward and backward digit span.
midazolam 1 mg were given i.v. until the patient reached sedation level 3, and further midazolam was given i.v. to maintain this level of sedation during surgery. The anaesthetist was unaware of the group to which the patient belonged. In group P, propofol was given using a loading dose and three-stage infusion scheme. The suggested dose in the study programme was: loading dose of 0.5 mg kg"1 over 20 s, followed immediately by an infusion of 5 mg kg"1 h"1 for 10 min, 4 mg kg"1 h"1 for 10 min and 3 mg kg"1 h"1 thereafter. The anaesthetist was free to choose a multiple of this whole scheme on clinical grounds, and could vary the maintenance infusion rate to maintain the patient at sedation level 3. In all three groups, 0.5% bupivacaine in 8% glucose was used for the spinal block and the patient breathed 40 % oxygen during surgery. The following sedation scale was used: 1 = fully alert and orientated; 2 = drowsy; 3 = eyes closed, rousable to command; 4 = eyes closed, reusable with mild physical stimuli, for example earlobe tug; 5 = asleep, unrousable with mild physical stimuli. The sedation level was recorded every 5 min during surgery. In the Recovery Unit, the first psychomotor tests were administered 30 min after the end of surgery. At 50 min after surgery, 5 ml of either flumazenil 500 ug (group MF) or saline (groups MS and P) was given in a double-blinded method: 2 ml initially, followed at 1-min intervals by 1-ml increments. The psychomotor tests were repeated at 60 min, 2 h and 24 h after surgery. Data analysis
The continuously variable data were analysed for normality by the Schapiro-Wilk test. Skewed data were transformed logarithmically and tested for normality. These data subsets were analysed by ANOVA for repeated measures, with pairwise comparisons made using the Fisher protected least significant difference method. Ordinal data were analysed by the Kruskal-Wallis test, with pairwise comparisons made using the method suggested by Conover [4]. The overall statistical significance level was 5 %.
Anaesthetic management
No premedication was used and the patients were allocated randomly to one of three groups: group MS—i.v. midazolam only; group MF—i.v. midazolam followed by antagonism with flumazenil; group P—i.v. propofol. In groups MS and MF, increments of
RESULTS
There were 13 patients in each group, and no significant differences between the groups (table I). In the propofol group, the mean initial loading dose was 0.54 mg kg"1 (range 0.5-0.7 mg kg"1),
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
Reverse counting. The number of errors and time taken to write all the numbers from 1000 down to 976. Backward spelling of a common five-letter word. Patients then performed a simple unscored task so that the interval between Memory and Picture recall was always 15 min. Picture recall. The patient was asked to recall the objects memorized in the first test (1 min allowed), and the number recalled was taken as the free recall score. Verbal clues were given for the remaining objects, and any additional objects remembered were noted as the verbal cued recall score. Then the patient was given another picture card showing 20 objects, including the nine original objects, and asked to point out those that had appeared on the original card. The total number recognized was taken as the visual recognition score (the patient was told that incorrect identifications were subtracted from the score, to discourage guessing). There were five different cards used for the picture recall test, together with a corresponding pair for the visual recognition test. No object on any of the cards appeared in more than one test sequence. Before the patient performed the postoperative test, two 10-cm visual analogue scales (VAS) were used to measure the patient's own subjective assessment of sedation and anxiety. One end of the sedation scale was randomly labelled "asleep", and the other "mentally fully alert", and the distance from the alert end was measured as the sedation score. One end of the anxiety scale was labelled "worst anxiety possible", the other "completely calm" and the central 1-cm area was shaded and labelled "usual"; the distance from the calm end was taken as the anxiety score.
BRITISH JOURNAL OF ANAESTHESIA
677
PSYCHOMOTOR RECOVERY TABLE I. Patient and anaesthetic data (mean (SD))
Group MS (n = 13) M F ( n = 13) P (n = 13)
Age (yr)
Weight (kg)
Duration of sedation (min)
Midazolam dose (mg kg"1)
68(7) 73(5) 71(7)
72 (10) 77(7) 71 (10)
46(12) 45(11) 40(12)
0.08 (0.02) 0.07 (0.03)
o 45 P 40 35 30 25 20
Before op.
30 min
24 h
60 min 2h Time after op.
FIG. 1. Serial 7s test (mean, SEM) in the midazolam-saline (MS) (A)> midazolam-flumazenil (MF) ( • ) and propofol (P) (x) groups. P < 0.05 compared with: * group P; $ group MS; f preoperative baseline.
35 34' 33 ^ 32
t31 &30 t*
29 28 27
t* Before op.
30 min
60 min Time after op.
2h
24h
FIG. 2. Critical flicker fusion threshold (CFFT) (mean, SEM) in the midazolam-saline (MS) (A), midazolam-flumazeni] (MF) ( • ) and propofol (P) (x) groups. P < 0.05 compared with: * group P; $ group MS; t preoperative baseline.
followed by the two short-duration infusions with the appropriate doses. All patients achieved sedation level 2 or 3 within 5 min, and the mean rate of the maintenance infusion of propofol
was 3.7 mg kg"1 h"1 (95 % confidence limits 3.1-3.9 mg kg"1 h"1). Three patients received additional i.v. boluses of propofol 20-40 mg to achieve a brief increase in sedation level. There
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
65 60 55
BRITISH JOURNAL OF ANAESTHESIA
678 120 115 110 105 3100
§ 95 i= 90 85 80 75 70
30min
60min Time after op.
2h
24 h
FIG. 3. Reverse counting test (mean, SEM) in the midazolam-saline (MS) (A), midazoUm-flumazeni] (MF) ( • ) and propofol (P) (x) groups. P < 0.05 compared with: *group P; \ preoperative baseline.
TABLE II. Postoperative anxiety scores (mean (SD)) Postoperative anxiety scores (cm) Group
30min
60 min
2h
24 h
MS MF P
6.1(1.2) 5.8(1.2) 6.5(1.1)
6.2 (0.7) 6.3(1.1) 5.9(1.0)
5.7 (0.8) 5.9 (0.9) 5.6 (0.7)
5.2 (0.5) 5.5(0.5) 5.1 (0.4)
TABLE IV. Free recall: number of objects recalled (median (range)). P < 0.05 compared with: * group P; %group MS; t preoperative baseline Postoperative score Group MS
baseline
P
Postoperative sedation score (cm) Group MS MF P
30 min
60 min
7.3* (6.5-8.0) 7.5* (6.7-8.2)
6.4* (5.7-7.0) 4.0$t (3.5-4.4)
2h
24 h
3.8
0.9
(2.6-4.6)
(0.5-1.2)
3.9
0.7
(3.2-4.5)
(0.5-1.1)
5.1
3.7
2.6
0.7
(4.1-5.9)
(2.5-4.6)
(1.9-3.1)
(0.3-1.1)
were no significant differences between groups in duration or depth of sedation. Four patients received i.m. pethidine for postoperative analgesia within the first 24 h, and were excluded from the 24-h psychomotor testing. There were no significant differences between the three groups in baseline preoperative performance in any of the tests. The results of the psychomotor tests are shown
It* (0-4)
6
(3-9) TABLE III. Postoperative sedation scores (mean (95% confidence limits)). P < 0.05 compared with: * group P; $ group MS; -\30-min score
It* (0-4)
6
(4-8) MF
30 min 60 min
0+*
(0-3)
5
(4-9)
3t
(1-7)
3tS
(0-5)
4t
(1-5)
2h
2f* (1-4) 2f* (1-3)
4t
(2-5)
24 h
4t (3-6)
5+
(3-6) 5
(4-7)
in figures 1-3 and tables II-V. There were no significant changes between any of the groups or from baseline performance within each group in the following tests: verbal cued recall, visual recognition recall, forward digit span or error rate in serial 7s and reverse counting. 30 min after anaesthesia
There were no significant differences between groups MS and MF and both groups were significantly different from group P and their own baseline performance in the following tests: free recall, CFFT, serial 7s, letter deletion, reverse counting, and backward spelling. There was a significant difference from baseline performance in groups MS and MF in reverse digit span. The VAS score for sedation—arousal in these groups was significantly different from group P, in which free recall, CFFT and serial 7s tests were significantly different from their own baseline.
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
Before op.
PSYCHOMOTOR RECOVERY
679
TABLE V. Letter deletion test: number of letters deleted (median (range)). | P < 0-OS compared with preoperative baseline
Postoperative scores Group MS
baseline
30min
60min
26
12f (7-24) 16.5f (4-31)
15t
19+
(4-28)
(9-42)
(17-39) MF P
24
(13-38) 21.5 (11-35)
15t
(8-34)
2h
18
(8-30)
24 h 26.5 (7-38) 31.5 (17-45)
19
17
19
24
(7-33)
(9-31)
(8-39)
(17-^3) Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
was profound memory deficit for free recall at the picture learning task, while performance of the After administration of flumazenil, performance was improved significantly in group MF visual recognition test was unimpaired. This compared with group MS in tests of free recall, difference between performance in tests of free CFFT, serial 7s, backward spelling, backward recall compared with visual recognition recall has digit span and the sedation score, but was been shown to be associated with low levels of significantly below baseline in free recall and sedation with benzodiazepines [5]. In that study [5], free recall was impaired initially, with relative letter deletion (tables IV, V). preservation of recognition recall, and as the dose There were no significant differences between of benzodiazepine was increased, recognition groups MF and P, or between group P and their recall was affected progressively. baseline performance except for free recall. Both our study and that of Sage, Close and Boas Flumazenil was associated with a decrease in [5] would suggest, therefore, that, the memory sedation, but no increase in anxiety (tables II, deficit with low doses of benzodiazepines involves III). access to memory trace, rather than formation (as memory is available for recognition but not for 2 h after anaesthesia There were no significant differences between free recall). Other workers have suggested othergroups MS and MF, and both groups were wise : that benzodiazepines affect principally consignificantly inferior to group P and their own solidation and storage memory processes, rather than access [6, 7]. Using an auditory learning task, baseline performance in the following tests: free Clarke and colleagues [7] found that both free recall, CFFT and serial 7s. recall and verbal recognition were affected by benzodiazepines, and concluded that the memory 24 h after anaesthesia deficit was in the consolidation process. However, There were no differences between the three as shown by Sage's group, this pattern is characgroups or from their own baseline performance in teristic of larger doses of benzodiazepines. Clarke any of the tests except for free recall, where and colleagues found also that visual recognition groups MS and MF were below baseline per- was not affected by benzodiazepines, which would formance. support the hypothesis that the memory deficit involves access, rather than formation (at least for visual material). DISCUSSION Forward digit span was found to be unaffected The psychomotor tests used in this study tested the patients for memory, both "long term" by sedation with midazolam, whereas there was (picture recall) and "short term" (digit span), significant impairment at 30 min in the test of attention and concentration (serial 7s, reverse backward digit span in the midazolam groups. counting and spelling), central integration Other studies have shown that short term memory (CFFT), cognition (mental arithmetic, backward is not affected by benzodiazepines [6]. Backward digit span and backward spelling), and subjective digit span, therefore, must involve additional cognitive mechanisms sensitive to midazolam, in assessment of sedation and anxiety. addition to short term memory, which is not The obvious effect of sedation with midazolam 60 min after anaesthesia
680
Even though the doses of midazolam used in this study were relatively low (mean 0.075 mg kg"1), diminished cognition, memory attention and concentration and central integration persisted for more than 2 h in the midazolam group. Sedation with an infusion of propofol was found to be associated with the most rapid psychomotor recovery. The propofol scheme used in this study was derived from the study by Roberts and colleagues [16], who reported a regimen designed to achieve and maintain a blood concentration of 3 ug ml"1 within 2 min. This concentration is sufficient for surgical anaesthesia; as the pharmacokinetics of propofol are linear [17], multiples of this regimen should alter blood concentration accordingly. The concentration that produces sedation rather than anaesthesia is not known, so it was chosen initially in this study to use 50 % of the dose regimen used by Roberts [16], giving an estimated blood concentration of
1.5 ug ml"1. The advantage of using this loading dose and three-stage infusion technique is that all the patients were sedated within 5 min. Another study of an infusion of propofol for sedation used a two-stage infusion technique without a loading dose, and the patients required 26 min to achieve the maintenance sedation level [18]. We conclude that an infusion of propofol is the technique with the most rapid recovery after sedation during spinal anaesthesia. The cognitive and amnesic effects of low dose midazolam sedation may persist for more than 2 h after operation, and flumazenil may antagonize only briefly and incompletely these effects of midazolam. REFERENCES 1. Chung F, Meier R, Lautenschlager E, Cannichael FJ, Chung A. General or spinal anesthesia: which is better in the elderly? Anesthtsiology 1987; 67: 422-427. 2. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiologica Scandinavica 1980; 24: 279-287. 3. Caplan RA, Ward RJ, Posner K, Cheney FW. Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of predisposing factors. Antsthtsiobgy 1988; 68: 5-11. 4. Conover WJ. Practical Nonparametric Statistics. New York: John Wiley and Sons, 1980; 230-231. 5. Sage DJ, Close A, Boas RA. Reversal of midazolam sedation with Ancxate. British Journal of Anaesthesia 1987; 59: 459-464. 6. O'Boyle C, Lambe R, Darragh A, Taffe W, Brick I, Kenny M. Ro 15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability. British Journal of Anaesthesia 1983; 55: 349-355. 7. Clarke RPF, Eccersley PS, Frisby JP, Thornton JA. The amnesic effects of diazepam (Valium). British Journal of Anaesthesia 1970; 42: 690-697. 8. Adam N. Disruption of memory functions associated with general anesthetics. In: Kilstrom JF, Evans FJ, eds. Functional Disorders of Memory. Hillsdale, New Jersey: Lawrence Erlbaum Association, 1979; 227. 9. Darragh A, Lambe R, Scully M, Brick I, O'Boyle C, Wilson Downie W. Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15-1788. Lancet 1981; 2: 8-10. 10. Lauven PM, Schwilden H, Stoeckel H, Greenblatt DJ. The effects of a benzodiazepine antagonist Ro 15-1788 in the presence of stable concentrations of midazolam. Anesthesiology 1985; 63: 61-64. 11. Kirkegaard L, Knudsen L, Jensen S, Kruse A. Benzodiazepine antagonist Ro 15-1788. Antagonism of diazepam sedation in outpatients undergoing gastroscopy. Anaesthesia 1986; 41: 1184-1188. 12. Louis M, Forster A, Suter PM, Gemperle M. Clinical and hemodynamic effects of a specific benzodiazepine antagonist (Ro 15-1788) after open heart surgery. Anesthesiology 1984; 61: A61. 13. Ricou R, Forster A, Bruckner A, Chastonay P, Gemperle M. Clinical evaluation of a specific benzodiazepine
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
affected by midazolam. This has been found also by Adam [8]. Backward spelling probably tests the same mechanisms as backward digit span, and both tests in this study showed a similar pattern of results. Flumazenil was found to antagonize only partially most of the psychomotor effects of midazolam. Performance after flumazenil had been given did not consistently achieve preoperative levels. Some studies in volunteers have shown full antagonism of the cognitive and amnesic effects of midazolam with large doses of flumazenil—either 200 mg orally [6,9] or 10 mg i.v. [10]. All clinical studies have documented excellent antagonism of sedation after larger doses of benzodiazepines than used in this study [5, 11]. Flumazenil was associated with greater alertness, but no increase in anxiety; some studies have reported increases in anxiety after large doses of flumazenil [12, 13]. The duration of the flumazenil antagonism was brief: 1 h after flumazenil, patients were indistinguishable from the group who received midazolam alone, and were below baseline performance in several tests. Resedation has been reported also in other studies [5, 6, 14, 15]. The implications of these results are that only brief and incomplete antagonism of the amnesic and cognitive effects of midazolam may be expected from i.v. flumazenil. Oral flumazenil has been shown to have a longer duration of action, but there was still evidence of resedation at 6 h [6]. This is likely to limit its routine use in clinical anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
PSYCHOMOTOR RECOVERY antagonist (Ro 15-1788). Studies in elderly patients after regional anaesthesia under benzodiazepine sedation. British Journal of Anaesthesia 1986; 58: 1005-1011. 14. Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15-1788). Clinical Pharmacokinetics 1988; 14: 1-12. 15. Duvaldestein P, Lebrault C, Guirimand F, Raimbault E. Efficacy of flumazenil reversal after midazolam induced anesthesia. Anesthesiology 1988; 63: A560. 16. Roberts FL, Dixon J, Lewis GTR, Tackley RM, PrysRoberts C. Induction and maintenance of propofol
681 anaesthesia. A manual infusion scheme. Anaesthesia 1988; 43 (Suppl.): 14-17. 17. Spelina KR, Coates DP, Monk CR, Prys-Roberts C, Norley I, Turtle MJ. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. I: Patients premedicated with morphine sulphate. British Journal of Anaesthesia 1986; 58: 1080-1084. 18. Wilson E, Mackenzie N, Grant IS. A comparison of propofol and midazolam by infusion to provide sedation in patients who receive spinal anaesthesia. Anaesthesia 1988; 43 (Suppl.): 91-94.
Downloaded from http://bja.oxfordjournals.org/ at University of Arizona on December 18, 2014
