Anesth Analg 1999;89:893
© 1999 International Anesthesia Research Society
AMBULATORY ANESTHESIA
Comparison of the Sedation and Recovery Profiles of Ro 48-6791, a New Benzodiazepine, and Midazolam in Combination with Meperidine for Outpatient Endoscopic Procedures
Jun Tang, MD*,
Baoguo Wang, MD*,
Paul F. White, PhD, MD, FANZCA*,
Michele Gold, PhD , and
Julian Gold, MD
*Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Texas; and
Department of Anesthesiology, Cedars-Sinai Medical Center, Los Angeles, California
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Abstract
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In this randomized, double-blinded study, we compared the onset and recovery characteristics of an investigational benzodiazepine, Ro 48-6791 (when administered alone or combined with meperidine), a midazolam-meperidine combination for sedation during gastrointestinal (GI) endoscopic procedures. Ninety consenting outpatients scheduled for upper or lower GI procedures were randomly assigned as follows: Group I received midazolam 1 mg IV and meperidine 50 mg; Group II received Ro 48-6791 0.5 mg IV and meperidine 50 mg; or Group III received Ro 48-6791 1.0 mg IV alone. If the level of sedation did not achieve an Observer’s Assessment of Alertness/Sedation (OAA/S) score of 4 (where 5 = awake/alert to 1 = asleep) in  2 min, a second bolus dose, equal to half of the original dose of midazolam or Ro 48-6791, was administered. The onset time was defined as the time to achieve an OAA/S score of 4. During the procedure, a bolus dose equal to half of the total induction dose was given to maintain an OAA/S score of 4. The induction and maintenance dosages, as well as recovery times to an OAA/S score of 5, were recorded. A heel-toe line walk (HTLW) test used to determine the time to "fitness for discharge." Although the onset times were similar in all three groups, the induction dosages were significantly reduced in Group II compared with Groups I and III. There were significantly more patients requiring supplemental sedative boluses and "rescue" analgesia with Ro 48-6791 than with midazolam. The Ro 48-6791 groups also experienced more dizziness after the procedures. Ro 48-6791 was associated with a higher incidence of inadequate sedation (18% vs 3%) without the opioid. The time for the HTLW test to return to baseline values after the procedure was similar among the three groups. However, the Ro 48-6791 groups had significantly reduced times to return to an OAA/S score of 5 and to achieve the baseline HTLW value after the last dose of the benzodiazepine. In conclusion, compared with midazolam, Ro 48-6791 is more potent and may be associated with a more rapid early recovery after endoscopic GI procedures. However, sedation with Ro 48-6791 required more supplemental bolus doses and "rescue" analgesic medication and was associated with a higher incidence of dizziness.
Implications: The investigational water-soluble benzodiazepine, Ro 48-6791, is a more potent sedative than midazolam, which appears to have a slightly shorter duration of action. Unfortunately, use of Ro 48-6791 increased the requirement for supplemental doses of the sedative medication and the need for "rescue" analgesics during the procedure and was associated with more dizziness after the procedure.
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Introduction
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Benzodiazepines are the most commonly used drugs for producing sedation during diagnostic and therapeutic gastrointestinal (GI) endoscopy (1). The prototypic benzodiazepine, diazepam, has some disadvantages for outpatient procedures, including a long elimination half-life, active metabolites, and local venous complications (e.g., pain on injection and thrombophlebitis) (2,3). Midazolam, a water-soluble benzodiazepine, is more potent than diazepam (4) and is allegedly associated with a faster onset and recovery from the sedative effect, a more profound amnesic action, and a reduced incidence of injection pain and thrombophlebitis (5–7). However, other investigators have reported that recovery times from diazepam- and midazolam-induced sedation were similar (4,8,9). Furthermore, White et al. (9) noted that the slope of the dose-response curve for sedation was much steeper with midazolam compared with diazepam, which suggests that midazolam may possess a smaller margin of safety and greater need for careful titration to achieve the desired clinical end-point without untoward side effects.
Ro 48-6791, 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5, 6-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepin-6-one, is a new water-soluble benzodiazepine that has agonistic activity at central benzodiazepine receptors and has been reported to be more potent than midazolam in volunteers (10,11). These preliminary studies have also suggested that Ro 48-6791 possesses a more favorable pharmacokinetic profile than midazolam. In this randomized, double-blinded study, the onset of action and clinical recovery profile of Ro 48-6791 was compared with midazolam in outpatients undergoing GI endoscopic procedures with or without opioid analgesic premedication.
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Methods
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After obtaining institutional review board approval and written, informed consent, 90 ASA physical status I or II outpatients scheduled to undergo elective gastroscopic or colonoscopic procedures were randomly assigned to one of three sedative treatment groups according to a computer-generated random numbers table: Group I, meperidine-midazolam; Group II, meperidine-Ro 48-6791; and Group III, saline-Ro 48-6791. The exclusion criteria included patients who had documented allergic reactions to a benzodiazepine, were more than 20% above their ideal body weight, had acute narrow angle glaucoma, clinically significant cardiovascular or pulmonary disease, renal or hepatic failure, psychiatric disease, alcohol or drug abuse, had taken any benzodiazepine within 48 h before the study, were pregnant or breast feeding, or were unable to perform psychometric testing. Patients were asked to provide a detailed medical history, as well as demographic information (including age, weight, height, and history of alcohol or drug consumption).
In this study, the visual analog scale (VAS) for sedation (with 0 = none to 100 = extremely sleepy) and the Observer’s Assessment of Alertness/Sedation (OAA/S) scale [with a composite score of 1 = unresponsive to 5 = awake and alert (12) (Appendix 1)] were used for assessing the patient’s level of sedation. A 5-m heel-toe line walk (HTLW) test was used for evaluating the patient’s psychomotor function (13) and to determine the time to being judged "fit for discharge" after the procedure.
In the preoperative holding area, the baseline sedation VAS and the OAA/S composite scores, as well as the time to successfully complete the HTLW test, were determined. On arrival in the GI procedure room, standard monitoring devices, consisting of a noninvasive blood pressure cuff, pulse oximeter probe, and electrocardiogram, were placed. The systolic, diastolic, and mean arterial pressures, as well as heart rate, respiratory rate, and SpO2 values were recorded. Meperidine 50 mg IV (Groups I and II) or saline 1 ml (Group III) was injected 3–5 min before the induction of sedation with either midazolam 1 mg IV (Group I), Ro 48-6791 0.5 mg IV (Group II), or 1.0 mg IV (Group III). The initial (induction) dose of the sedative study medication was administered from a numbered (unlabeled) 5-mL syringe over 30 s. The time to successful onset of sedation was defined as the interval from the administration of the first dose of the benzodiazepine to the time the patient’s OAA/S score decreased to 4. If an OAA/S score of 4 was not achieved within 2 min, a supplemental dose (equal to 50% of the initial induction dose) was administered over 30 s every minute until an OAA/S score of 4 was achieved. During the procedure, all patients were maintained at an OAA/S score of 3 or 4. If the patient’s OAA/S score returned to 5 during the procedure, half of the total induction dose was administered over 30 s. If the OAA/S score remained unchanged after 120 s, an additional incremental dose (equal to 25% of the total induction dose) was administered over 30 s every minute until an OAA/S score of 4 was achieved. Abdominal distress (e.g., severe cramping) during the procedure was treated with "rescue" bolus doses of meperidine 25 mg IV. Vital signs and OAA/S scores were recorded at 1-min intervals during the induction period and at 5-min intervals for the remainder of the procedure. Lactated Ringer’s solution 500–1000 mL IV was infused during the procedure.
One of the blinded investigators assessed the level of sedation and determined the need to administer supplemental doses of the study medication during the procedure. The onset of sedation (i.e., the time from the initial dose of the study drug to achieving an OAA/S score of 4), the procedure time (i.e., the time from insertion to removal of the endoscope), and the total dosage (and the number of boluses) of sedative medication and meperidine during the procedure were recorded. During the study period, "oversedation" (defined as an OAA/S score <3), as well as other side effects (e.g., hiccuping, coughing, abdominal cramping, nausea, dizziness), was recorded. If the duration of apnea exceeded 10 s or if the SpO2 value decreased to <90%, supplemental oxygen was administered.
During the recovery period, the OAA/S composite score was determined at 5-min intervals until the score returned to the baseline value. The times to recovery from the sedative effect of the study drug (i.e., return to an OAA/S composite score of 5), to ambulating alone (i.e., standing, taking one to two steps, pivoting, and sitting in a chair without experiencing dizziness), and the time to be considered "fit for discharge" (i.e., return to baseline HTLW test scores) were also recorded. The sedation VAS was repeated when the patient’s OAA/S composite score returned to 5. Amnesia was assessed using picture recall before administration of any sedative medication, when an OAA/S score of 4 was first achieved, and during and at the end of the procedure. At the time of discharge, the patients were asked to identify the pictures they had been shown earlier. After the procedure, the gastroenterologist assessed the quality of the endoscopic conditions as adequate or inadequate. Similarly, the blinded observer evaluated the quality of the recovery as either adequate or inadequate.
A one-way analysis of variance was used to compare the continuous variables among the three sedative treatment groups. If a significant difference was found, the Newman-Keuls multiple-comparison test was performed to determine intergroup differences. Categorical variables were analyzed using the  2 test or Fisher’s exact test, as appropriate. All tests were two-sided and a P value < 0.05 was considered statistically significant. Data are presented as mean values ± SD, n, or percentages.
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Results
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The three sedative treatment groups were comparable with respect to age, weight, height, ASA physical status, as well as type and duration of the GI procedures (Table 1). The desired level of sedation (OAA/S score of 4) was achieved in all of the patients before the start of the procedure. Although the onset times were similar (Table 2), the induction dosage of Ro 48-6791 was significantly smaller than the dosage of midazolam in patients receiving meperidine for premedication (1.0 ± 0.5 vs 2.0 ± 1.0). Premedication with meperidine decreased the initial Ro 48-6791 dosage requirement by 50%. During the procedure, use of Ro 48-6791 was associated with an increased requirement for supplemental boluses of the sedative medication, and also required more boluses of the "rescue" analgesic. One or more episodes of transient oxygen desaturation occurred in 25% of the patients receiving Ro 48-6791 compared with a 37% incidence in the midazolam group (not significant). The incidence of oversedation (OAA/S <3) during the procedure was very small and did not differ between the two benzodiazepine groups. When Ro 48-6791 was administered alone, a significantly larger percentage of patients were judged by the gastroenterologist to be inadequately sedated (Table 2).
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Table 2. The Onset of Action, Dosages of the Study Medication for Induction and Maintenance of Sedation, As Well As the Quality of Sedation and Side Effects During the Procedure Among the Three Sedative Groups
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Recovery times to an OAA/S score of 5 after Ro 48-6791 were consistently shorter compared with midazolam (Table 3). Although the times to return to baseline performance on the psychomotor (HTLW) test after the procedure were not significantly different between the Ro 48-6791 and midazolam groups, use of Ro 48-6791 was associated with significantly decreased times to ambulation and to the return of the HTLW test to baseline values after the last dose of the study drug. Picture recall at the end of the procedure was nonsignificantly reduced in Group III compared with the midazolam group (Table 3). However, the incidence of postprocedural side effects (e.g., dizziness) was higher in the Ro 48-6791 groups. The overall quality of recovery was judged to be adequate in more than 90% of patients in all three groups.
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Table 3. Recovery Variables After the Procedure (or the Last Bolus Dose of the Study Drug) and the Quality of the Recovery in the Three Sedative Groups
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Discussion
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This preliminary study with the investigational water-soluble benzodiazepine, Ro 48-6791, in outpatients suggests that it could be a safe and effective alternative to midazolam for sedation during GI endoscopic procedures. Benzodiazepines are widely used for sedation during GI procedures because they have not only sedative but also amnesic and anxiolytic properties (14), which reduce the anxiety associated with repeat endoscopies (15). Although its anxiolytic activity was not evaluated, Ro 48-6791 appears to possess similar amnestic properties to midazolam.
Midazolam has become the most commonly used parenteral benzodiazepine for sedation because of its ease of titration, low incidence of pain on injection and tissue irritation, and highly acceptable recovery profile. Many investigators have reported that midazolam produces more profound amnesia than diazepam when used for GI endoscopic procedures (4,5,7,8,13,16,17); however, others have found no difference between the two drugs (18,19). Although the elimination half-life of midazolam is significantly shorter than that of diazepam (20), recovery profiles after sedation with the two benzodiazepines are similar (4,7–9,17,21). Because large doses of midazolam can result in prolonged postoperative sedation (22), the search continues for a parenteral benzodiazepine with a shorter duration of action and less interpatient variability (23).
Ro 48-6791 possesses full agonistic activity at benzodiazepine receptors in the central nervous system (Hoffmann-La Roche Ltd, data on file, 1994). In a volunteer study (10), Ro 48-6791 was shown to be well tolerated and to produce dose-dependent central nervous system depression. A pharmacokinetic analysis of Ro 48-6791 revealed a higher plasma clearance rate than midazolam, contributing to a shorter elimination half-life (11). When Ro 48-6791 and midazolam were administered to produce similar sedative effects, the onset times and durations of action were similar (10). In the present study, both Ro 48-6791 and midazolam produced similar onset times, but the induction dose of Ro 48-6791 was 50% less than midazolam, which suggests that the new benzodiazepine is approximately twice as potent as midazolam. During the procedures, significantly more supplemental doses of the sedative and analgesic drugs were administered to the patients in the Ro 48-6791 groups, which suggests that the investigational benzodiazepine possesses a shorter duration of clinical effect. Consistent with our findings, Hering et al. (11) reported that Ro 48-6791 was 2.5 times more potent than midazolam with a shorter duration of action in human volunteers. Although the recovery from the psychomotor impairment after the end of the procedure did not significantly differ between midazolam and Ro 48-6791, the times to ambulating and to recovery from psychomotor impairment (HTLW) after the last dose of the benzodiazepine were decreased by 35% and 22%, respectively, compared with midazolam.
Analogous to the findings of Boldy et al. (24) with diazepam, the use of Ro 48-6791 after premedication with meperidine produced better conditions for endoscopic procedures than Ro 48-6791 alone. In our study, meperidine decreased the initial sedative dosage of Ro 48-6791 by 50% compared with when the new benzodiazepine was administered alone. Although decreases in SpO2, and even transient apneic episodes, have been reported during GI endoscopy procedures (25,26), none of our patients experienced apnea, and the incidences of transient oxygen desaturation did not differ among the three study groups.
Whereas a variety of psychomotor tests have been used to detect residual effects of benzodiazepines (13,27), the ability of patients to stand steadily and walk along a straight line has been suggested as a sensitive test for quantifying the residual effects of midazolam (13). Although early recovery from the residual sedative effects of Ro 48-6791 appeared to be more rapid than with midazolam, later recovery endpoints (e.g., the time to be considered "fit for discharge") after the end of the procedure were similar for the two benzodiazepines. These results also confirm the recent findings in patients receiving this investigational benzodiazepine during ambulatory surgery performed under local or regional anesthesia (28). Given the limitations in the study design, the comparative sedative and recovery profiles of Ro 48-6791 and midazolam could only be evaluated in combination with meperidine. However, the information regarding the use of Ro 48-6791 (Group III) alone suggests that the adjunctive use of an opioid analgesic significantly improved the endoscopic conditions.
In conclusion, the investigational benzodiazepine Ro 48-6791 appears to be a safe and effective alternative to midazolam for sedation during GI endoscopic procedures. Compared with midazolam, Ro 48-6791 is more potent, has a shorter duration of action, and possesses a more rapid early recovery from its residual sedative effect. Although patients who received Ro 48-6791 required more "rescue" medications during the endoscopic procedure, recovery times to achieve an OAA/S score of 5 and baseline HTLW values were significantly decreased after the last dose of Ro 48-6791 compared with midazolam. However, times to "fitness for discharge" after the procedure were similar with both benzodiazepines.
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Acknowledgments
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Supported, in part, by a research grant from Hoffmann-La Roche, Inc, Nutley, NJ, and the Ambulatory Anesthesia Research Foundation in Dallas (PFW, President).
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Footnotes
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Address correspondence and reprint requests to Dr. Paul F. White, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, F2.208, Dallas, TX 75235-9068. Address e-mail to paul.white@email.swmed.edu.
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Accepted for publication June 28, 1999.
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Abstract
Introduction
