COMPARISON OF DIAZEPAM WITH MIDAZOLAM AS I.V. SEDATION FOR OUTPATIENT GASTROSCOPY

Br. J. Anaesth. (989), 63, 7-73 COMPARISON OF DIAZEPAM WITH MIDAZOLAM AS I.V. SEDATION FOR OUTPATIENT GASTROSCOPY L. D. SANDERS, J. DAVIES-EVANS, M. ROSEN AND J. O. ROBINSON Day-case sedation should be efficient, reliable, short-acting, free from short and long-term after effects and provide anxiolysis. Some clinicia coider that amnesia for the procedure is desirable [-2]. Diazepam produces these effects but may cause delayed recovery attributed to a long terminal elimination half-life of 2-37 h, and active metabolites [3-4]. Enterohepatic recirculation also occurs, producing peaks in plasma concentratio and subjective feelings of sedation at 6-8 h and 2 h after injection [5-6]. Diazepam also has a high incidence of pain on injection and thrombophlebitis [7]. In comparison, midazolam has the advantage of a faster oet of action [7] and a short half-life of 60-90 min [8]. It is reputed to be an effective amnesic [9] and anxiolytic [0] agent, and an efficient sedative, with a rapid recovery rate []. Patients undergoing gastroscopy are discharged approximately 2 h after the procedure; it is essential to give advice on activities such as driving or operating machinery. However, it is necessary to eure that there is no significant residual amnesia at this stage, or these itructio may be forgotten. Most studies comparing diazepam with midazolam for gastroscopy have examined short-term recovery and largely ignored the post-discharge period [0-3]. This study has examined psychomotor and cognitive recovery from sedation for 30 h after administration with comparable doses of two benzodiazepines [7]: diazepam and midazolam. LALAGE D. SANDERS, PH.D.; MICHAEL ROSEN, M.B., CH.B., F.F.A.R.C.S. ; Department of Anaesthetics, University of Wales, College of Medicine, Heath Park, Cardiff CF4 4XW. JILL DAVIES-EVANS, B.A.(HONS), Department of Psychology, North Wales Hospital, Denbigh. JAMES O. ROBINSON, PH.D., F.B.P.S., Department of Psychology, University College, Cardiff. Accepted for Publication: June 4, 989. Correspondence to M.R. SUMMARY We studied patients in a double-blind investigation to compare psychomotor and cognitive recovery for 30 h after sedation for day-case gastroscopy with i.v. diazepam 0.5 mg kg' or midazolam 0.07 mg kg-. Significantly more patients reported side effects at 7, 0 and 30 h postgastroscopy after diazepam than after midazolam (? < 0.05). Compared with baseline, the midazolam group was significantly impaired in critical flicker fusion threshold, reaction time, dexterity and visualization tasks up to 4 h after administration (? < 0.05). There was a significant association between midazolam and amnesia for the procedure (? < 0.00). PATIENTS AND METHODS The study was approved by the Hospital Ethics Committee. After giving informed coent, patients of ASA classes I and II, aged 2-75 yr and scheduled for day-case gastroscopy were allocated randomly to receive either diazepam or midazolam for sedation. Exclusio comprised patients receiving cimetidine, which is believed to affect the metabolism of benzodiazepines [4], those taking sedatives as hypnotics or tranquilizers, and those who drank more than 5 units of alcohol daily. Procedure Both the patient and the psychologist who assessed recovery were blind to the identity of the sedative. On arrival in hospital, each patient was itructed in and allowed to become familiar with the psychometric tests, after which baseline measurements were made. Patients were premedicated with atropine 0.6 mg and given two 60- mg amethocaine lozenges. In the endoscopy theatre, either midazolam 0.07 mg kg" i.v. or diazepam 0.5 mg kg" i.v. was administered. The

SEDATION FOR OUTPATIENT GASTROSCOPY 727 administration of an incremental dose was determined by the clinical judgement of the endoscopist. Patient co-operation during the gastroscopy was recorded on a 00-mm visual analogue scale (VAS) labelled "endoscopy impossible" and "full co-operation", and incidents of nausea, vomiting, gagging, coughing or laryngeal spasm were noted. Psychomotor performance was assessed at.5 h after administration in the day unit and again at 4, 8, 20 and 30 h in the patient's home. Psychometric tests Of the six formal tests in the battery, the first three assessed psychomotor functio and the last three purely cognitive functio. Choice Reaction Time (CRT). This was measured with the Leeds Psychomotor Tester, which records both the total time from presentation of stimulus to completion of respoe and the time from presentation to initiation of respoe. Movement time was calculated by subtracting initiation time from total time. Dexterity. A loop was guided along a twisted length of wire; when the loop touched the wire a buzzing sound was emitted. For each hand, the time taken to complete the task was recorded, as was the number of touches. Although this task incorporates a visual component, it is primarily assessing manual dexterity. Deletion of P. Every P was deleted from a page of randomly typed upper case letters. Two scores were obtained: the number of lines completed and the numbers of errors made. This requires motor skills, but is largely a measure of cognitive function, involving both perception and concentration [5]. Digit span. Strings of numbers increasing in length from three were recited to the patient, who had to repeat the string correctly, but in reverse order. This was continued until two coecutive errors were made; this provided an indication of short-term auditory memory capacity [6]. stimuli [7]. This task is purely visual, and does not involve a motor component. Critical Flicker Fusion (CFF) Threshold. Using the Leeds Psychomotor Tester, the frequencies (Hz) at which both a nickering light appeared fused and the commencement of flicker could be detected in a fused light were measured three times. This provides a measure of cortical arousal. Recall of the procedure was tested by questioning the patient on peri-operative events. Subject effects At 3-h intervals for 30 h after drug admitration, patients were presented with a check-list of the following subjective after-effects: sleepiness, clumsiness, double vision, nausea, weakness, confusion, slurred speech and needing help with mobility. The psychometric data were analysed using a paired t test and a Wilcoxon test to seek evidence of impairment. Mann-Whitney or an analysis of co-variance (ANOVA), with the baseline measure taken as the co-variate to control for individual differences in initial performance, or where appropriate a chi-square test, was used to assess differential drug effects. RESULTS Data were collected for patients. Five patients receiving midazolam and 0 receiving diazepam were female. There was no significant difference in age or in weight between the groups (table I). The total mean doses of drugs required to achieve satisfactory sedation were midazolam 0.093 mg kg" (a mean increase of 0.023 mg kg" (33%) over the proposed rate) and diazepam 0.57 mg kg" (mean increase of 0.007 mg kg" (5 %)). The endoscopist's rating of patient co-operation during gastroscopy appeared to be higher for the diazepam group, but this difference was not significant (P < 0.05). The incidence of TABLE I. Details of patients (mean (SD)) Visualization. On a sheet of paper were printed eight sets of 0 interwoven curved lines; each line was traced from its source to its end-point. A time limit of 3 min was set, with the number of lines traced correctly and incorrectly recorded to give an indication of ability to discriminate visual Age (yr) Weight (kg) Dose (mg) (mg kg" ) Midazolam 56.0(7.) 65. (3.3) 6.2 (2.6) 0.093 (0.29) Diazepam 5.0(3.4) 64.5(2.) 0. (2.) 0.57(0.23)

728 BRITISH JOURNAL OF ANAESTHESIA TABLE II. Quality of sedation VAS patient co-operation, operator assessed (mean (SD)) No. patients with Coughing Laryngeal spasm Gagging Nausea Vomiting Problem-free gastroscopy n Midazolam Diazepam P Midazolam Diazepam 77.9(29.6) 90.0(.) TABLE III. Number of patients with side effects 4 25 89 7 5 <0.05 Time after drug (h) 0 5 2 <0.05 3 2 33 20 45 24 5 27 25 2 0 32 7 30 05 < 0.05 problems during gastroscopy did not differ between the two groups (table II). Psychometric results One patient who received diazepam was unrousable for the psychometric assessment at 4 h. Psychomotor results. Although there was no evidence of significant impairment in total CRT, the midazolam group was significantly slower in the movement component at.5 and 4 h (P < 0.05) compared with baseline performance (fig. ). However, analysis of variance to assess the differential effect of the drugs failed to reach significance (P < 0.05), which casts some doubt on the significance of the pair-wise t tests. At.5 h, both groups took longer to complete the dexterity task and made more errors than at baseline; however, the only significant difference was in the time taken by the midazolam group (P < 0.05). The two scores in the P-deletion task deteriorated at.5 h for both groups, but this was not significant (P > 0.05). For both drug groups in the initiation time in the CRT, and for the diazepam group in the number completed in the P-deletion task, there was a significant improvement in performance with time. Cognitive function tests. There was no impairment from the digit span test for each group. The visualization task (fig. 2) showed that performance deteriorated at.5 h for both groups; this was significant only for the number traced correctly by the midazolam group (P < 0.05). CFF data showed a significant (P < 0.05) lowering of the threshold in the midazolam group, indicating impairment, at.5 h; nevertheless, analysis of variance revealed no significant difference of effect between the two drugs (P > 0.05)..2-.0-0.8- o E 0.6 o 0.4 O I I 0.2 0 6 2 8 Time after drug (h) FIG.. Mean (SEM) CRT score. = Midazolam; x = diazepam. time. 24 30 = Total CRT, = initiation

SEDATION FOR OUTPATIENT GASTROSCOPY 729 30-i 25-20- 5-0- 5-2 8 24 30 Time after drug (h) FIG. 2. Mean (SEM) visualization task, number correct. # = Midazolam; x = diazepam. The scores from the visualization task exhibited significant improvement in both drug groups after.5 h. Recall of perioperative events showed a significant differential drug effect (P < 0.00). By the following day all but one of the midazolam group had no recall of the procedure after the injection, whereas all but one of the diazepam group could recall the procedure after administration of the drug. Two of the midazolam and one of the diazepam group said they could recall the procedure on their return from day theatre, but later had no memory of this, or of the procedure. Subject effects. There was no significant difference between the two groups in the mean number of side-effects at any of the test points. However, the frequency with which patients exhibited one or more side effects was different between the two groups (table III). Significantly more of the diazepam group reported at least one side-effect at 7, 0 and 30 h after administration of the drug. Because 3 h post-gastroscopy coincided with the middle of the night for more than 50 % of the sample, the rate of completion at this point was low (eight in the midazolam and four in the diazepam group). DISCUSSION The total dose of midazolam administered varied more from the anticipated range than did the total dose of diazepam, although the initial doses were within the range of commonly established equipotency. This reflects not only the endoscopists' lack of experience with midazolam, but also the less predictable respoe produced. This suggests that administration of midazolam requires skill and experience in determining a satisfactory dose. Our data suggest that both drugs are equally suitable for sedation for gastroscopy. It was not possible for the endoscopist to be blinded to this study, and there were some informal comments which indicated some reservatio on using a drug other than diazepam, which was the standard sedative in use in the Day Unit. However, there was no evidence that the quality of sedation differed significantly between these two benzodiazepines. Whilst midazolam produced slower immediate recovery than diazepam, it also produced fewer long-term effects and more complete recovery. The results of psychometric testing were disappointing. These measures did not detect impairment, even when it was evident to the patient and to the psychologist at the time of assessment. There are three possible explanatio for this. First, it may be that the tests were not assessing functio most likely to be affected by benzodiazepines, although deletion of P, CRT, CFF and digit span have effectively demotrated impairment in studies involving these benzodiazepines [8-20]. Our dexterity task also may

730 BRITISH JOURNAL OF ANAESTHESIA have lacked the seitivity of the peg-board task used in other studies. Second, performance tended to improve with practice. Whilst the patients had a limited opportunity to become familiar with the tests before baseline measurements, full practice sessio were not possible because they would have disrupted the work of the Day Unit. Third, the purpose of the study was to assess recovery for up to 30 h, and this precluded uniformity of environmental conditio in which the tests were administered. The first two assessments were made in the Day Unit, and the remaining four were conducted in the patient's home. In this setting the patient was likely to be more relaxed and assured, and there were changes in the lighting and in the positio of patient and machinery. It is apparent from these results that the degree of amnesia caused by the two benzodiazepines differed significantly; there was coiderable anterograde amnesia following midazolam. It may be that a sedative which produces a high incidence of amnesia is desirable for procedures such as gastroscopy, which may be unpleasant. Two of the patients who received diazepam spontaneously volunteered the information that they would not wish to undergo gastroscopy again. However, the assumption that amnesic qualities are desirable in sedatives raises an important ethical issue. It is evident that the administration of a drug which is known to delete subsequent events from the patient's memory has the potential to affect the manner in which the patient is treated. When signing coent procedures, patients should be informed of the likelihood of drug-induced amnesia. Diazepam was more likely to produce sideeffects. This was significant only in the evening of the day of gastroscopy, and on the following day. 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