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Oral Clonidine Pre-treatment and Diazepam/Meperidine Sedation
1 Section of Primary Care, Correspondence: * corresponding author, hall.611{at}osu.edu
Clonidine has recently been used as a pre-operative medication and sedative/anxiolytic drug. Its extended duration of action makes it suitable for longer procedures. In this randomized, crossover, placebo-controlled clinical trial, we characterized the effects of oral clonidine pre-treatment on intravenous diazepam/meperidine sedation using the bi-spectral index (BIS) in 13 participants. Clonidine significantly increased the numbers of BIS-depressed readings and percent memory loss during sedation, while reducing total diazepam and post-operative analgesic dosages by 44% and 55%, respectively. Systolic, diastolic, and mean arterial blood pressures, as well as pulse rates, were reduced. Respiratory rate, oxygen saturation, end-tidal CO2, and recovery from sedation were unchanged. Participants, surgeons, and sedationists preferred clonidine over the placebo. Clonidine pre-treatment increased and prolonged sedation and amnesia and stabilized vital signs while significantly decreasing diazepam and post-operative analgesic usage. These results suggest that pre-operative clonidine administration could be a useful supplement to intravenous sedation for dental procedures of long duration.
Key Words: clonidine • BIS • diazepam • meperidine • IV sedation
Clonidine is an alpha-2 agonist that was introduced 38 years ago as a treatment for hypertension (Barnett and Cantor, 1968). It has also been used to prevent and/or treat many conditions, including syncope (Hilz et al., 2002) and chronic pain (Puke and Wiesenfeld-Hallin, 1993). Recently, clonidine has been utilized as a pre-operative medication to provide anxiolysis (Beer et al., 2001), sedation (Karhuvaara et al., 1991; Ramesh et al., 1997; Khan et al., 1999), analgesia (Siiba et al., 1999), hemodynamic stability (Laisalmi et al., 2001), saliva control (Arya et al., 1997), and anti-emetic effects (Frank et al., 1999). It also possesses sedative (Flacke et al., 1987; Murai et al., 1995), anesthetic (Flacke et al., 1987), and analgesic (Flacke et al., 1987; Samso et al., 1996) sparing properties that reduce the dosages of other medications. Clonidine exhibits anxiolytic effects independent of sedation (Handley and Mithani, 1984) and also reduces the peri-operative plasma levels of catecholamines (Flacke et al., 1987; Galeotti et al., 2004) and prolactin (Samso et al., 1996). Previous studies have demonstrated that pre-treatment with clonidine not only potentiates benzodiazepine (Salonen et al., 1992), narcotic, and other drug effects, but also prolongs and stabilizes their activities (Laisalmi et al., 2001). Oral clonidine pre-treatment prior to surgical extraction of third molars decreases intravenous (IV) midazolam dosage by 45% (Murai et al., 1995). None of these studies utilized objective measures of sedation. The Bispectral Index (BIS), which provides a sensitive and objective measure of sedation, has not been previously used for assessing the effects of oral clonidine pre-treatment on long-term diazepam/meperidine IV sedation. In this clinical trial, we characterized and quantified the effects of oral clonidine pre-treatment on diazepam/meperidine IV sedation during periodontal surgical procedures of long duration. We hypothesized that pre-treatment with clonidine would significantly increase the numbers of BIS-depressed readings, prolong sedation and amnesia, and reduce diazepam and post-operative analgesic usage.
Participants The study protocol and informed consent form were approved by The Ohio State University Institutional Review Board. All participants provided written informed consent. Inclusion criteria were: (1) adults with American Society of Anesthesiologists ASA1 or ASA2 health status, (2) severe chronic periodontal disease and/or the need for dental implant(s), and (3) treatment plan including at least 2 periodontal surgical procedures requiring IV sedation of at least 2 hrs’ duration. Exclusion criteria were: (1) neurological or psychiatric disease; (2) sleep disorders; (3) severe asthma; (4) uncontrolled hypertension; (5) insulin-dependent diabetes; (6) relative or absolute contraindication to local anesthesia, diazepam, meperidine, or clonidine, including pregnancy; and (7) a history of substance abuse. The number of participants required for this study was determined by power analysis of data from a previous BIS study (Hall et al., 2002) indicating that a ‘least significant number’ greater than 13 should provide statistically and critically significant data (  = 0.05, β  0.20 or less). Sixteen (16) participants were enrolled.
Experimental Design
Study Procedures One hour after oral pre-medication, all baseline measurements were repeated, and another object photograph was shown. A 20-gauge IV Jelco catheter (Ethicon Inc., Arlington, TX, USA) was then placed in each person’s arm or hand. IV lines were maintained with 5% dextrose and normal saline at a rate of 100 mL/hr. Talking and background noise were minimized, because persons sedated with clonidine are easy to arouse (Hall et al., 2001). Participants breathed 4 L/min of 100% O2 via nasal cannula during venipuncture, sedation, and recovery. Participants were given IV meperidine (Demerol®), at a dose of 0.35 mg/kg of body weight. After 10 min, each participant received IV diazepam (Valium®), 2.5 mg/min titrated to reach an OAA/S value between 3 and 4. Lidocaine (Xylocaine®), 2% with 1:100,000 epinephrine, was then administered. Subsequent diazepam doses (2.5 mg/min) were titrated as needed to maintain an OAA/S level of 3–4. At the end of each of 4 30-minute periods per session, participants were shown additional object photographs. At the end of each two-hour session, all original baseline measurements were repeated. Recall and recognition were tested after final recovery via a post-session follow-up questionnaire. The sedationist and surgeon also completed post-session questionnaires. All participants were given analgesic prescriptions (acetaminophen/hydrocodone 500/5 mg; 1–2 tablets q 4–6 hrs) to be taken as needed for pain. Participants were asked to record the number of prescription pain pills taken on the days following surgery. Participants also completed a post-study questionnaire following their second session.
Statistical Analysis
Study Population and Sedation Parameters Three of the 16 participants did not complete the study, because they missed their second session. Participants completing the study (10/31/2003-12/08/2004) included nine females (42 ± 15 yrs, 64 ± 16 kg) and four males (52 ± 3 yrs, 93 ± 16 kg). No study participants experienced or reported untoward reactions or complications from pre-operative clonidine/placebo administration or intravenous sedation. No participants required emergency treatments. The "clonidine codes" were not revealed until the study was completed.
Clonidine pre-treatment significantly increased the numbers of statistically depressed BIS readings (#BIS) compared with placebo sessions (Table 1
Vital Signs Clonidine pre-treatment significantly decreased pulse rate, systolic, diastolic, and mean arterial pressures compared with pre-treatment baseline values (Table 2  ). Vital sign reductions were statistically significant (p < 0.05) at each of 24 readings during 2 hrs of IV sedation. Respiratory rates, pulse oximetry saturations, and end-tidal CO2 readings exhibited no significant differences among experimental clonidine, placebo, and pre-treatment baseline values. All measured vital signs did show smaller standard deviations following clonidine pre-treatment compared with placebo. These reductions in participant vital sign standard deviations were statistically significant (|t| < 0.05) for diastolic blood pressure, mean arterial blood pressure, pulse, and respirations.
Intra-operative Diazepam & Post-operative Analgesic Dosages, Survey Responses Clonidine significantly reduced total two-hour diazepam dosage by 44% (|z| < 0.005, Table 3 ). Compared with placebo pre-treatment, the average size of the increments (3.3 mg vs. 2.6 mg) was also significantly reduced by clonidine pre-treatment (|z| < 0.005). The average number of diazepam increments (6.2 vs. 4.2) was also reduced by oral clonidine pre-treatment (|z|< 0.005, Table 3). Participants self-administered 55% fewer pain pills (6.0 vs. 2.7) on the day of their surgeries following procedures completed with clonidine pre-treatment vs. control sessions (|z|< 0.0002, Table 4).
Participant, surgeon, and sedationist survey responses generally indicated a preference for sedation with oral clonidine pre-treatment (Table 4  ). Sedationists’ post-session and participants’ post-study evaluations of quality of sedation favored clonidine pre-treatment by statistically significant margins compared with placebo (p < 0.05). Sedationists and surgeons also indicated that clonidine pre-treatment produced a more even sedation (p < 0.05). A significant majority of participants (p < 0.05) also believed that sessions with clonidine pre-treatment caused more amnesia.
All measures of recovery with clonidine pre-treatment—including sedationist, surgeon, and participant surveys, BIS and OAA/S results—demonstrated no significant differences compared with placebo values. All event memory differences between sessions with and without clonidine pre-treatment were not statistically significant (Table 4
Current dental treatment includes more complex procedures that require longer (two- to three-hour) appointments to complete. These procedures, including periodontal surgery and implant placement, are often performed under local anesthesia supplemented by IV conscious sedation. Sedation provides greater patient comfort, better patient cooperation, and improved operator control. The most commonly used sedative drug regimens include benzodiazepines, narcotics, and other relatively short-acting drugs. This short duration necessitates frequent and multiple re-dosage, which contributes to uneven sedation (Longnecker, 1987). The present randomized, cross-over, placebo-controlled clinical trial investigated the effects of oral clonidine pre-treatment on diazepam/meperidine IV sedation during periodontal surgical procedures of long duration. The results indicate that oral clonidine pre-treatment has a significant effect on sedation parameters (both objective and subjective), on vital signs, and on IV sedative and post-operative analgesic drug usage. Clonidine pre-treatment significantly increased the number of depressed BIS readings (#BIS) and final % Memory Loss compared with both baseline and placebo values. Clonidine did not increase the magnitude of BIS, OAA/S, and EMG depression of each individual datapoint compared with depressed datapoints without clonidine pre-treatment. BIS Area Under the Curve, OAA/S Area Under the Curve, #OAA/S, EMG Area Under the Curve, and #EMG values during 2 hrs of sedation with and without clonidine pre-treatment were not significantly different. Amnesia induced by BIS-sensitive agents was initially apparent in individuals with BIS readings under 90 (Hall et al., 2002). Profound amnesia was associated with BIS readings under 80 (Glass et al., 1997). BIS can differentiate sedative vs. vital sign stabilizing effects of clonidine. Increased periods of BIS depression with clonidine pre-treatment indicate potentiation of sedative effects in addition to the observed stabilizing effects on blood pressure and heart rate. The results of this study and previous investigations (Hall et al., 2002; Matsuzaki and Tanaka, 2004) support the use of BIS to monitor conscious sedation. BIS depression during conscious sedation may not be as uniform as it is during general anesthesia, depending on the sedation agents used, the dosage administered, and the individuals selected. In contrast to general anesthesia, attempting to titrate IV conscious sedation to a pre-determined BIS value (endpoint) and to maintain that BIS reading throughout sedation can result in over-dosage. However, BIS can act as an effective dependable alarm, warning of over-sedation. For conscious sedation monitoring, BIS alarms can be set at 70–75. Recovery assessments (patient, sedationist, and surgeon survey responses) and parameters (BIS, OAA/S) showed no significant differences between clonidine and placebo groups. All vital signs exhibited less variation and smaller standard deviations with clonidine pre-treatment. When used as a low-dose oral pre-medication, clonidine rarely caused clinically significant bradycardia and/or hypotension requiring treatment (Mikawa et al., 1993). The decreases in heart rate and blood pressure with oral clonidine pre-treatment had no harmful consequences during this study. These findings are confirmed and reinforced by a large body of literature (Jarvis et al., 1992; Mikawa et al., 1993; Arya et al., 1997; Ramesh et al., 1997; Beer et al., 2001; Laisalmi et al., 2001; Nishina et al., 2002). Clonidine pre-treatment does not cause respiratory depression (Jarvis et al., 1992; Prause et al., 2000). Clonidine may have altered the pharmacokinetics of diazepam, since the average times between consecutive doses were increased by clonidine pre-treatment. Oral clonidine is a relatively inexpensive drug ($0.10–$0.15 per 0.1 mg). The retail cost of IV meperidine and diazepam or midazolam averages $5.00 to $10.00 per person. The 44% overall reduction in total benzodiazepine usage and relatively reduced fixed IV narcotic dosage with clonidine could contribute to a meaningful reduction in adverse sedation events and a decrease in the cost of sedation (Valles et al., 1998). The 55% decrease in patient-administered analgesics could also improve post-operative care. The results of this study indicate that oral clonidine pre-treatment is a useful and valuable supplement to intravenous sedation for dental procedures of long duration.
This study was supported by Aspect Medical Systems, Inc. and the Ohio State University College of Dentistry Sections of Periodontology and Primary Care. Aspect Medical Systems, Inc. provided BIS monitoring equipment and related supplies. This work was based on a thesis submitted to The Ohio State University Graduate School in partial fulfillment of the requirements for the Master of Science degree. A preliminary report was presented as an abstract (#910) at the IADR/AADR/CADR 83rd General Session (March 9-12, 2005) in Baltimore, MD, USA. Received for publication June 20, 2005. Revision received May 1, 2006. Accepted for publication June 5, 2006.
Journal of Dental Research, Vol. 85, No. 9,
854-858 (2006)
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ABSTRACT
INTRODUCTION
0.01 considered significant. BIS Area Under the Curve, OAA/S Area Under the Curve, and EMG Area Under the Curve values represent areas under the curves for two-hour sedation sessions. Average % Memory Loss (Recall + Recognition) values were determined for all two-hour sedation sessions. A 20% Memory Loss result indicated that a person failed to recall and/or recognize 20% of the object pictures correctly. Parametric vital sign data were evaluated by Dunnett’s Method with Bonferroni Adjustments, and p < 0.05 was considered as significant. Vital sign standard deviations, numbers of significantly depressed BIS readings (#BIS), numbers of significantly depressed OAA/S readings (#OAA/S), numbers of significantly depressed EMG readings (#EMG), BIS Area Under the Curve, OAA/S Area Under the Curve, and EMG Area Under the Curve values were analyzed by paired two-tailed t tests with |t| < 0.05 considered as significant. Numbers of pain pills and two-hour diazepam dosages were compared by Wilcoxon Signed-rank tests, with |z| < 0.05 considered as significant. Percent Memory Loss amnesia data and survey responses were evaluated by chi-square likelihood ratios, with p