Efficacy of oral midazolam prior to intravenous sedation for the removal of third molars
Neil H. Luyk, Brian D. Whitley Dept. of Oral Medicine and Oral Surgery, School of Dentistry, Dunedin, New Zealand
N. H. Luyk, B. D Whitley." Efficacy of oral midazolam prior to intravenous sedation for the removal of third molars. Int. J. Oral Maxillofac. Surg. 1991; 20: 264-267. Abstract. The combination of oral and intravenous sedation has not been well investigated and this study examined the combination's effect on amnesia, anxiety, cardiovascular stability and recovery in a double blind, cross-over, placebo controlled trial. Patients were given 7.5 mg oral m i d a z o l a m or placebo 1 h prior to intravenous m i d a z o l a m and surgery. This investigation demonstrated significant anxiolysis, amnesia and patient preference for oral midazolam compared to placebo. There was no significant effect on cardiovascular stability, the intravenous dose of m i d a z o l a m used or post-operative recovery. L o w dose oral midazolam prior to intravenous sedation may be beneficial in very anxious patients, particularly if surgery is delayed.
Patients experience anxiety prior to dental and oral surgical procedures 16, 17 to the extent that they avoid necessary dental visits 17' 29. Both intravenous and oral sedation have been used in the management of anxious patients. Intravenous sedation has several advantages in that it has a rapid onset, can be titrated to individual response, and can be useffin combination with other sedatives. Agents taken orally are easy to administer, lower in overhead costs, t h e i r drug reactions are generally less severe, they require only minimal training to administer u' 24, and they can be taken at home. The combination of oral and intravenous sedation has not been documented adequately, particularly when the oral sedation is taken immediately prior to the intravenous sedation. This combination may help to reduce both pre-operative anxiety and the dose of intravenous sedative necessary to achieve satisfactory sedation. M i d a z o l a m is a 1,4-benzodiazepine derivative with a unique chemical structure. M i d a z o l a m has a fast absorption rate when taken orally and is rapidly excreted, with an elimination half-life of only 2 h 15. Peak plasma levels of the drug have been reported to occur between 0.5 h and 1 h following oral administration 9. Midazolam's advantages
include good cardiovascular stability, transient and mild respiratory depression, 10w frequency of venous irritation, production of anterograde amnesia and short duration of action in compariso n with other benzodiazepines 15. There is limited information on the amnesic, sedative, anxiolytic or recovery effects of a combination of oral premedicatiofl, using midazolam, given prior to intravenous sedation. The pur r pose of this study was to examine these parameters in a double blind, cross-over manner.
Material and methods Thirty-three fit and healthy adults (ASA I and II) with similarly impacted lower 3rd molars, requiring surgical removal under local analgesia and intravenous (iv) sedation, were invited to participate in this study. The Area Health Board Ethics Committee's approval was obtained and patients gave their informed; written consent. Patients who had taken any form of sedative or hypnotic medication within the previous month were excluded. They were advised that they would be administered a placebo and an active drug at different times. Patients reported 1 h prior to their operation time. On arrival at the clinic, they were escorted to a quiet room where they completed an anxiety visual analogue scale (VAS)2°, a Trieger coordination
Key words: sedation; midazolam; ambulatory, surgery. Accepted for publication 27 April 1991
test (TCT) 25and digit symbol substitution test (DSST) 22 and their blood pressure (BP) and pulse rate (PR) were measured with a Copal UA519 digital sphygmomanometer (Copal, Tokyo, Japan). Midazolam 7.5 mg or an identical appearing placebo tablet was then administered orally on a double blind basis, the drug allocation for the first side being determined randomly. Half an hour after medication, patients completed further VAS, TCT and DSST tests and their BP and PR were recorded. At 1 h after medication, these were repeated. Patients were shown 2 visual stimuli held for 5 s approximately 1 m in front of them. Coloured pictures of common objects (e.g. a cat) on a white background were used and patients asked to recognise them 2. They were told that they would be asked to recall the pictures at their next review appointment. The patients were then escorted to the dental surgery and seated in a slightly recumbent position in the dental chair. Patients were monitored with a pulse oximeter during the procedure. An iv catheter was placed in an antecubital fossa vein and intravenous midazolam, in a concentration of 1 mg/ml in normal saline, was titrated at a rate of 1 mg/ml until the patient was clinically sedated (i.e. exhibited slurred speech, a relaxed appearance~ ptosis and/or stated they felt relaxed). The amount of midazolam used to achieve sedation was noted. Three minutes after sedation with iv midazolam, patients were seated upright, completed VAS, TCT, DSST tests, had their BP and PR measured and were shown 2 different picture stimuli. Local analgesia was adminis-
Efficacy o f oral midazolam Table 1. Mean visual analogue scale scores (-+ SD)
Drug Placebo Midazolam
Presedation
30 rain postsedation
1h postsedation
post-IV
30 min post-IV
35.2_+ 16.2 31.0_+17.5 30.0_+17.0 21.9_+15.5 23.l _+20.0 36.2_+17.9 27.3_+14.9 22.6_+15.6" 18.5_+12.2 25.5_+19.0
* Significantly different from placebo p < 0.05.
tered using 2% lignocaine with 1:80,000 adrenaline on all occasions: 4 ml for the removal of upper and lower 3rd molars on one side and 2 ml for the removal of a lower only. Equal volumes were used for each side, The surgical procedure was then undertaken, the side to be completed first was also randomly allocated. At least half an hour followingthe iv midazolam, patients again completed VAS, TCT, DSST tests and had their BP and PR recorded. If surgery was not completed after half an hour, the measurements were delayed until completion. At 1 h following the administration of iv midazolam a further TCT and DSST were administered. The patient was then assessed for discharge into the care of a responsible adult and both were given the normal post-operative instructions. At the 1 week post-operative check, patients were asked to recall the 4 pictures. At least 2 weeks later tile second side was completed by the same surgeon using the same protocol. On this occasion, however, the second oral drug, either midazolam 7.5 mg or placebo, was administered. At followup, a week later, patients were asked, in addition to recalling the different pictures, for their preference between the 2 oral medications. Analysis of data
Data for the placebo and oral midazolam sides were analysed using the paired Student's t test, Variance over time for the VAS, TCT and DSST for each drug were evaluated using a one-way, repeated measures ANOVA and the Student-Newman-Keul's test. Patients recall of the pictures shown and their preference between the 2 drugs was assessed using a chi-square test. The level of significance for this study was set at the 5% level. Results
Two patients had been unable to return for the second surgery, thus 31 patients completed the investigation (17 men and 14 women); median age 21 years (range 18-32 years) and median weight 68 kg (range 48-90 kg). There were no significant differences between mean operation times: 31.1 min with oral midazolam and 33.1 min with placebo. Also there was no significant difference between sides in the doses of i.v. midazolam: placebo side received a mean of
0.06 mg/kg (_+0.02 SD) and the oral midazolam side a mean of 0.05 mg/kg (-!-_0.01 SD). Subjective assessment of anxiety by the patient using the VAS is documented in Table 1. The only significant difference between the 2 drugs can be seen at 1 h following ingestion, when the oral midazolam side demonstrated a significant reduction in mean anxiety levels compared with the placebo side. An analysis of variance over time for the placebo side shows that the pre-sedation VAS was only significantly different (p < 0.05) from the post-iv and post-surgical levels and hence the oral placebo did not give rise to a significant reduction in pre-operative anxiety. However, the iv midazolam did give rise to significant reduction in preoperative anxiety and there was a decline in anxiety at the end of treatment. An analysis of variance over time for the midazolam side demonstrated that the pre-sedation VAS was significantly different from all the other VAS scores and hence oral midazolam led to a reduction in anxiety levels measured subjectively by the patient half an hour and 1 h after taking the medication. Also following iv midazolam, there was a further significant reduction in anxiety levels. There were no significant differences in systolic or diastolic blood pressures and pulse rates between the 2 oral medications. As differences in these variables over time were not controlled for either administration of adrenaline or changes in postural position, they can not be meaningfully reported. Overall, changes over time with these variables were small and not clinically significant. The pulse oximeter readings did not fall below a level of 94% oxygen saturation for either of the study medications.
265
The following results were observed with the TCT (Table 2). There were significant differences between the midazolam and placebo sides at 0.5 h and 1 h following ingestion of the tablets, the midazolam side scoring higher (representing less co-ordination). When analysing the data over time, there was a significant increase in the TCT score following iv midazolam for both sides compared with the other values. Although both the 0.5 and 1 h scores following iv midazolam were apparently higher than the pre-iv scores, these scores were not significantly different. The DSST showed similar results to the TCT (Table 3). There was a significant reduction in DSST score between the midazolam and the placebo side at 1 h post-sedation (p
Neil H. Luyk, Brian D. Whitley Dept. of Oral Medicine and Oral Surgery, School of Dentistry, Dunedin, New Zealand
N. H. Luyk, B. D Whitley." Efficacy of oral midazolam prior to intravenous sedation for the removal of third molars. Int. J. Oral Maxillofac. Surg. 1991; 20: 264-267. Abstract. The combination of oral and intravenous sedation has not been well investigated and this study examined the combination's effect on amnesia, anxiety, cardiovascular stability and recovery in a double blind, cross-over, placebo controlled trial. Patients were given 7.5 mg oral m i d a z o l a m or placebo 1 h prior to intravenous m i d a z o l a m and surgery. This investigation demonstrated significant anxiolysis, amnesia and patient preference for oral midazolam compared to placebo. There was no significant effect on cardiovascular stability, the intravenous dose of m i d a z o l a m used or post-operative recovery. L o w dose oral midazolam prior to intravenous sedation may be beneficial in very anxious patients, particularly if surgery is delayed.
Patients experience anxiety prior to dental and oral surgical procedures 16, 17 to the extent that they avoid necessary dental visits 17' 29. Both intravenous and oral sedation have been used in the management of anxious patients. Intravenous sedation has several advantages in that it has a rapid onset, can be titrated to individual response, and can be useffin combination with other sedatives. Agents taken orally are easy to administer, lower in overhead costs, t h e i r drug reactions are generally less severe, they require only minimal training to administer u' 24, and they can be taken at home. The combination of oral and intravenous sedation has not been documented adequately, particularly when the oral sedation is taken immediately prior to the intravenous sedation. This combination may help to reduce both pre-operative anxiety and the dose of intravenous sedative necessary to achieve satisfactory sedation. M i d a z o l a m is a 1,4-benzodiazepine derivative with a unique chemical structure. M i d a z o l a m has a fast absorption rate when taken orally and is rapidly excreted, with an elimination half-life of only 2 h 15. Peak plasma levels of the drug have been reported to occur between 0.5 h and 1 h following oral administration 9. Midazolam's advantages
include good cardiovascular stability, transient and mild respiratory depression, 10w frequency of venous irritation, production of anterograde amnesia and short duration of action in compariso n with other benzodiazepines 15. There is limited information on the amnesic, sedative, anxiolytic or recovery effects of a combination of oral premedicatiofl, using midazolam, given prior to intravenous sedation. The pur r pose of this study was to examine these parameters in a double blind, cross-over manner.
Material and methods Thirty-three fit and healthy adults (ASA I and II) with similarly impacted lower 3rd molars, requiring surgical removal under local analgesia and intravenous (iv) sedation, were invited to participate in this study. The Area Health Board Ethics Committee's approval was obtained and patients gave their informed; written consent. Patients who had taken any form of sedative or hypnotic medication within the previous month were excluded. They were advised that they would be administered a placebo and an active drug at different times. Patients reported 1 h prior to their operation time. On arrival at the clinic, they were escorted to a quiet room where they completed an anxiety visual analogue scale (VAS)2°, a Trieger coordination
Key words: sedation; midazolam; ambulatory, surgery. Accepted for publication 27 April 1991
test (TCT) 25and digit symbol substitution test (DSST) 22 and their blood pressure (BP) and pulse rate (PR) were measured with a Copal UA519 digital sphygmomanometer (Copal, Tokyo, Japan). Midazolam 7.5 mg or an identical appearing placebo tablet was then administered orally on a double blind basis, the drug allocation for the first side being determined randomly. Half an hour after medication, patients completed further VAS, TCT and DSST tests and their BP and PR were recorded. At 1 h after medication, these were repeated. Patients were shown 2 visual stimuli held for 5 s approximately 1 m in front of them. Coloured pictures of common objects (e.g. a cat) on a white background were used and patients asked to recognise them 2. They were told that they would be asked to recall the pictures at their next review appointment. The patients were then escorted to the dental surgery and seated in a slightly recumbent position in the dental chair. Patients were monitored with a pulse oximeter during the procedure. An iv catheter was placed in an antecubital fossa vein and intravenous midazolam, in a concentration of 1 mg/ml in normal saline, was titrated at a rate of 1 mg/ml until the patient was clinically sedated (i.e. exhibited slurred speech, a relaxed appearance~ ptosis and/or stated they felt relaxed). The amount of midazolam used to achieve sedation was noted. Three minutes after sedation with iv midazolam, patients were seated upright, completed VAS, TCT, DSST tests, had their BP and PR measured and were shown 2 different picture stimuli. Local analgesia was adminis-
Efficacy o f oral midazolam Table 1. Mean visual analogue scale scores (-+ SD)
Drug Placebo Midazolam
Presedation
30 rain postsedation
1h postsedation
post-IV
30 min post-IV
35.2_+ 16.2 31.0_+17.5 30.0_+17.0 21.9_+15.5 23.l _+20.0 36.2_+17.9 27.3_+14.9 22.6_+15.6" 18.5_+12.2 25.5_+19.0
* Significantly different from placebo p < 0.05.
tered using 2% lignocaine with 1:80,000 adrenaline on all occasions: 4 ml for the removal of upper and lower 3rd molars on one side and 2 ml for the removal of a lower only. Equal volumes were used for each side, The surgical procedure was then undertaken, the side to be completed first was also randomly allocated. At least half an hour followingthe iv midazolam, patients again completed VAS, TCT, DSST tests and had their BP and PR recorded. If surgery was not completed after half an hour, the measurements were delayed until completion. At 1 h following the administration of iv midazolam a further TCT and DSST were administered. The patient was then assessed for discharge into the care of a responsible adult and both were given the normal post-operative instructions. At the 1 week post-operative check, patients were asked to recall the 4 pictures. At least 2 weeks later tile second side was completed by the same surgeon using the same protocol. On this occasion, however, the second oral drug, either midazolam 7.5 mg or placebo, was administered. At followup, a week later, patients were asked, in addition to recalling the different pictures, for their preference between the 2 oral medications. Analysis of data
Data for the placebo and oral midazolam sides were analysed using the paired Student's t test, Variance over time for the VAS, TCT and DSST for each drug were evaluated using a one-way, repeated measures ANOVA and the Student-Newman-Keul's test. Patients recall of the pictures shown and their preference between the 2 drugs was assessed using a chi-square test. The level of significance for this study was set at the 5% level. Results
Two patients had been unable to return for the second surgery, thus 31 patients completed the investigation (17 men and 14 women); median age 21 years (range 18-32 years) and median weight 68 kg (range 48-90 kg). There were no significant differences between mean operation times: 31.1 min with oral midazolam and 33.1 min with placebo. Also there was no significant difference between sides in the doses of i.v. midazolam: placebo side received a mean of
0.06 mg/kg (_+0.02 SD) and the oral midazolam side a mean of 0.05 mg/kg (-!-_0.01 SD). Subjective assessment of anxiety by the patient using the VAS is documented in Table 1. The only significant difference between the 2 drugs can be seen at 1 h following ingestion, when the oral midazolam side demonstrated a significant reduction in mean anxiety levels compared with the placebo side. An analysis of variance over time for the placebo side shows that the pre-sedation VAS was only significantly different (p < 0.05) from the post-iv and post-surgical levels and hence the oral placebo did not give rise to a significant reduction in pre-operative anxiety. However, the iv midazolam did give rise to significant reduction in preoperative anxiety and there was a decline in anxiety at the end of treatment. An analysis of variance over time for the midazolam side demonstrated that the pre-sedation VAS was significantly different from all the other VAS scores and hence oral midazolam led to a reduction in anxiety levels measured subjectively by the patient half an hour and 1 h after taking the medication. Also following iv midazolam, there was a further significant reduction in anxiety levels. There were no significant differences in systolic or diastolic blood pressures and pulse rates between the 2 oral medications. As differences in these variables over time were not controlled for either administration of adrenaline or changes in postural position, they can not be meaningfully reported. Overall, changes over time with these variables were small and not clinically significant. The pulse oximeter readings did not fall below a level of 94% oxygen saturation for either of the study medications.
265
The following results were observed with the TCT (Table 2). There were significant differences between the midazolam and placebo sides at 0.5 h and 1 h following ingestion of the tablets, the midazolam side scoring higher (representing less co-ordination). When analysing the data over time, there was a significant increase in the TCT score following iv midazolam for both sides compared with the other values. Although both the 0.5 and 1 h scores following iv midazolam were apparently higher than the pre-iv scores, these scores were not significantly different. The DSST showed similar results to the TCT (Table 3). There was a significant reduction in DSST score between the midazolam and the placebo side at 1 h post-sedation (p
