Clonidine as a drug for intravenous conscious sedation

 Clonidine, an α₂-adrenoceptor agonist, was introduced to clinical practice in the 1960s because of its antihypertensive effect. It has several beneficial actions during the perioperative period, particularly for medically compromised patients. The objective of this study was to evaluate the effects of clonidine as a drug for intravenous conscious sedation. We assessed the effects of intravenous clonidine on the hemodynamic and sympathoadrenergic responses to nociceptive stimuli and we evaluated its sedative and analgesic effects. Twenty-five volunteers aged between 23 and 25 years were included in this study. They received clonidine intravenously at 2 μg/kg. Constant-current, square-wave stimuli were delivered as nociceptive stimuli to the median nerve of the arm. We measured blood pressure, heart rate, cardiac output, and plasma concentrations of noradrenaline, adrenaline, and cortisol. The sedative and analgesic effects were measured by visual analogue scales. Changes in heart rate and blood pressure were not significantly different between the clonidine and control groups. Cardiac output tended to decrease after clonidine administration. Clonidine exerted its greatest sedative effect 30 min after injection. Noradrenaline concentration reached its nadir 15 min after clonidine administration. The time course of adrenaline concentrations was similar to that of noradrenaline. The plasma concentration of cortisol decreased in both groups. The most common adverse effect was dry mouth. In conclusion, intravenous clonidine, at a dose of 2 μg/kg, did not induce significant bradycardia, hypotension, or severe side effects in the healthy volunteer. It attenuated the adrenergic response to electrical stimulation. The results suggested that clonidine is a useful drug for intravenous sedation. Received: October 17, 2000 / Accepted: May 21, 2002     

Comparison of sedation,amnesia, and patient comfort produced by intravenous and rectal diazepam

In a cross-over study, intravenous diazepam was compared with rectal diazepam for sedation in outpatient oral surgery. Fifty-four operations were performed on 27 patients. Recovery from sedation, experience during the postoperative course, amnesia, estimation of the sedative effect, and patient preference of method of sedation were studied. The recovery times of the sedation methods did not differ. Sedative effects after the first operation were estimated as good by 87% of patients given intravenous sedation and by 75% of those given rectal sedation. However, there was a significant relationship between the subjective experience of stronger sedative effect and preference of sedation method that favored the intravenous technique. The degree of amnesia was significantly higher during intravenous sedation, but a high degree of amnesia was not related to patients' preference for a sedation method. Neither sedation method produced any local side effects.     

Intravenous or rectal diazepam for outpatient sedation in minor oral surgery

In a randomized cross-over study on sedation in outpatient oral surgery, intravenous and rectal administration of diazepam were compared. The mean dose for intravenous diazepam was 0.22 mg X kg-1 (range 0.15-0.38) and for rectal diazepam 0.58 mg X kg-1 (range 0.50-0.71). The determining factors for the patients' preference for sedation method, apprehension, effect produced by the sedative, recovery from sedation and the postoperative course were studied. The patients preferred the session in which they experienced stronger effect, regardless of the route of administration. Patient preference for sedation method did not differ when optimal dose regimens were used, and a preset dose of 10 mg rectal diazepam did not produce the desired effect. Apprehension was significantly higher prior to and during the first operation than the second operation, and all patients recovered from sedation within 2 1/2 hours after the administration.     

Double-blind comparison of nalbuphine and meperidine in combination with diazepam for intravenous conscious sedation in oral surgery outpatients

Nalbuphine and meperidine were compared as analgesic components of intravenous conscious sedation in a double-blind, prospective trial of 47 patients undergoing elective oral surgery. Subjects were evaluated for pain intensity, pain relief, anxiety, sedation, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery 83% of patients who had received nalbuphine and 86% of patients treated with meperidine indicated complete pain relief. One observed adverse reaction was attributed to meperidine and another to the sedative component diazepam. No statistically significant differences were observed between nalbuphine and meperidine treatments.     

Rectal sedation with diazepam or midazolam during extractions of traumatized primary incisors: a prospective, randomized, double-blind trial in Swedish children aged 1.5-3.5 years.

The aim of this study was to compare rectal sedation with diazepam and rectal sedation with midazolam with regard to sedative effect, treatment acceptance, and amnesia. Ninety children, 1.5-3.5 years of age, consecutively referred for extractions of traumatized primary incisors were randomly sedated with diazepam (0.7 mg/kg body weight) or midazolam (0.3 mg/kg body weight). The study design was randomized and double-blind. The level of sedation (state of mind) was assessed prior to and 10 and 60 min after administration of the drug by use of a behavioral scale (Wilton). The children's acceptance of procedures was assessed using another behavioral scale (Holst) during administration of the sedative, application of topical anesthesia, injection of a local anesthesia, and extraction. Amnesia was evaluated by the parents on the following day, with the child being asked standardized questions. Parental ratings of the child's and their own distress during and after treatment were made on a visual analog scale (VAS). No differences were found between the sedatives concerning level of sedation during treatment, acceptance of procedures, or amnesia. At discharge, 60 min after administration of the sedative, the children receiving diazepam were significantly more agitated (P=0.006). Parental rating on a VAS of the child's discomfort after treatment was significantly higher in the diazepam group (P=0.006). There was a tendency for children with poor acceptance of the rectal administration to display a more negative acceptance of the dental treatment. In conclusion, the present results, in combination with known pharmacological advantages, indicate that midazolam is preferable in outpatients when sedation is needed and amnesia is desirable.     

A study of the effectiveness of oral midazolam as a dental pre-operative sedative and hypnotic

Orally administered Midazolam at dosages of 0.5, 0.6, and 0.75 mg/kg was used with 34 healthy, uncooperative pediatric dental patients. Effective pre-operative sedation occurred within approximately 15 minutes with a 30- to 40-mlnute duration of action. Blood pressure and respiration remained stable throughout. The numbers and types of procedures performed were dependent on the degree of sedation, the behavior of the patient, the experience of the operator, and the operator's ability to administer the medication. The ideal dosage appears to be 0.6 mg/kg, with an average change of 1.43 Frankel Units in behavior modification. A dosage of 0.5 mg/kg appears to yield erratic results, while a dosage of 0.75 mg/kg offers little advantage with greater potential for adverse reactions. The oral administration of Midazolam for pediatric patients with extreme behavioral problems, such as Attention Deficit Hyperactive Disorder, was of little advantage and may produce an idiosyncratic reaction. Midazolam's quick onset and short duration of action, coupled with its ideal properties of sedation, relaxation, and amnesia, offer a viable alternative for treating the anxious, uncooperative pediatric dental patient .     

Assessment of stress during periodontal surgery with intravenous sedation and with local anesthesia only

Ten patients with moderate to advanced periodontal disease were subjected to two similar periodontal surgical procedures. Each patient received either intravenous conscious sedation with local anesthesia or local anesthesia only. The stress-reducing effects of a conscious sedation regimen consisting of pentobarbital, meperidine, and diazepam were evaluated in these patients. Stress was evaluated by monitoring changes in serum cortisol, human growth hormone, and vital signs. Blood samples were obtained at 15- to 30-minute intervals throughout each procedure and were evaluated for serum cortisol and growth hormone. The conscious sedation group had significantly lower serum cortisol levels and lower systolic blood pressure, indicating that the patients having periodontal surgery with conscious sedation experienced reduced stress. Physiologic stability was maintained for each patient, indicating that this conscious sedation regimen can be used to reduce measurable parameters of stress that patients develop during periodontal surgery.     

Benzodiazepine reversal with flumazenil--a review of the literature.

Benzodiazepines such as Valium (diazepam) or Versed (midazolam), as used in dental procedures for intravenous sedation, have been a boon to the profession. Yet in the event of sedation problems, no agent exists that consistently reverses all clinical effects of these drugs. This problem does not exist with narcotics, frequently employed in tandem with benzodiazepines, since an effective reversal agent, Narcan (naloxone hydrochloride), exists. It would be advantageous to effectively reverse benzodiazepines in cases of acute emergency with respiratory depression or paradoxical reactions, and to allow quick, full recovery after short dental procedures. None of the drugs currently available for benzodiazepine reversal, such as physostigmine, give consistent clinical results. The purpose of this paper is to discuss Flumazenil, a new specific benzodiazepine receptor antagonist, and its possible use for dental sedation procedures.     

Rectal sedation with diazepam or midazolam during extractions of traumatized primary incisors: a prospective,randomized, double-blind trial in Swedish children aged 1.5-3.5 years

The aim of this study was to compare rectal sedation with diazepam and rectal sedation with midazolam with regard to sedative effect, treatment acceptance, and amnesia. Ninety children, 1.5-3.5 years of age, consecutively referred for extractions of traumatized primary incisors were randomly sedated with diazepam (0.7 mg/kg body weight) or midazolam (0.3 mg/kg body weight). The study design was randomized and double-blind. The level of sedation (state of mind) was assessed prior to and 10 and 60 min after administration of the drug by use of a behavioral scale (Wilton). The children's acceptance of procedures was assessed using another behavioral scale (Holst) during administration of the sedative, application of topical anesthesia, injection of a local anesthesia, and extraction. Amnesia was evaluated by the parents on the following day, with the child being asked standardized questions. Parental ratings of the child's and their own distress during and after treatment were made on a visual analog scale (VAS). No differences were found between the sedatives concerning level of sedation during treatment, acceptance of procedures, or amnesia. At discharge, 60 min after administration of the sedative, the children receiving diazepam were significantly more agitated (P = 0.006). Parental rating on a VAS of the child's discomfort after treatment was significantly higher in the diazepam group (P = 0.006). There was a tendency for children with poor acceptance of the rectal administration to display a more negative acceptance of the dental treatment. In conclusion, the present results, in combination with known pharmacological advantages, indicate that midazolam is preferable in outpatients when sedation is needed and amnesia is desirable.     

The effect of chronic clonidine administration on salivary glands and caries in the rat

Clonidine is a widely prescribed, centrally acting antihypertensive with proposed pharmacologic mechanisms of stimulation of central postsynaptic alpha(2)-adrenergic receptors and agonist activity at presynaptic alpha(2)-adrenergic receptors, interfering with peripheral regulation of norepinephrine and acetylcholine release. Both of these mechanisms are capable of adversely influencing salivary output and composition, potentially leaving an individual with increased caries risk. The purpose of the present study was to determine the effect of chronic administration of clonidine on saliva, salivary glands, and caries in rats. Sprague-Dawley rat pups were infected with Streptococcus sobrinus, given Diet 2000 and 10% sucrose water ad libitum, and either desalivated, or treated with clonidine HCl (125 or 250 microg/kg administered daily for 28 days by means of osmotic minipumps), or assigned as controls. There were no statistical differences in stimulated parotid or submandibular gland salivary output or sublingual gland weights among the groups. The weight of the submandibular glands as a percent of total body weight was significantly decreased in animals that received clonidine when compared with controls. Sulcal caries scores in both clonidine groups and smooth surface caries scores in the high clonidine group were increased when compared with control animals. Positive control animals (desalivated) had significantly higher caries scores than all other groups. These data show that chronic administration of clonidine significantly decreases submandibular gland weight and increases susceptibility to dental caries.     

Prolonged recovery after intravenous diazepam

Prolonged recovery from intravenous diazepam after the day of administration has been examined in 2,468 consecutive patients who underwent oral surgery and general dentistry. Patients ranged in age from 2 to 94 years and received a mean diazepam dose of 19 mg, either by itself or with small amounts of methohexital sodium. Recovery was assessed by use of a questionnaire, and the answers were related to sexual gender, age, weight, dosage, procedure, duration, level of apprehension, and results of the sedation.     

Acceptance and side effects of nitrous oxide oxygen sedation for oral surgical procedures.

Two hundred and forty-one treatment sessions with nitrous oxide oxygen sedation were performed in 194 patients undergoing ambulatory oral surgery procedures. Removal of mesiodentes and tooth transplants were the most frequent procedures in age groups under 13 years, while removal of impacted teeth was predominant in older age groups. Local anesthesia was used in addition to inhalation sedation in 238 sessions. Median gas volume rate was 10 l/min, median concentration 50% and median duration of procedures 31 min. In 10 sessions (4.1%) sedation was not accepted, while in 25 (10.4%) sessions the procedure could be completed with some difficulty. No potentially dangerous complications were noted. Side effects occurred in 18 sessions in 16 patients. All side effects were minor and easily handled. Logistic regression analysis revealed that failure, defined as poor acceptance and/or presence of side effects, was associated with ASA class 2 and general apprehension, especially based on previous negative experience with medical or dental treatment. Nitrous oxide oxygen sedation is a reliable, efficient and safe adjunct to local anesthesia in both healthy children and adults undergoing ambulatory oral surgery procedures.     

Effect of clonidine on the efficacy of lignocaine local anesthesia in dentistry: A systematic review and meta‐analysis of randomized,controlled trials

Alternatives to adrenaline with lignocaine local anesthesia, such as clonidine, have been trialed in various randomized, controlled trials. Therefore, the aim of the present systematic review was to compile the available evidence on using clonidine with lignocaine for dental anesthesia. Electronic databases were searched for eligible studies. A data‐extraction form was created, extracted data were analyzed using non‐Cochrane mode in RevMan 5.3 software. Heterogeneity between the studies were assessed using the forest plot, I² statistics (where >50% was considered to have moderate‐to‐severe heterogeneity), and χ²‐test. Random‐effects models were used because of moderate heterogeneity. Five studies were included for the final review. While clonidine was found to significantly shorten the onset of local anesthesia when measured subjectively, no significant difference was observed objectively. No significant difference was observed in the duration and postoperative analgesia. Stable hemodynamic parameters within the safe range were observed postoperatively when clonidine was used. Clonidine could be considered as an alternative to adrenaline in cases of contraindications to adrenaline, such as like cardiac abnormalities, hypertension, and diabetes.     

A comparative study of intravenous diazepam and midazolam for oral surgery

Intravenous diazepam was compared with intravenous midazolam for conscious sedation in a single-blind study of 50 Hong Kong Chinese patients acting as their own controls. Verrill's sign was used as the end-point of sedation, and bilateral, similarly impacted lower third molars served as the surgical model. The drugs produced comparable levels of sedation, stable vital signs, and good operating conditions in all patients. Midazolam had numerous advantages over diazepam: more rapid onset of sedation, less pain during injection, profound anterograde amnesia, and fewer postoperative complications. The incidence of thrombophlebitis was low with both drugs and appears to be so in Chinese in general. A significant majority of the patients preferred sedation to other techniques and midazolam to diazepam.     

An evaluation of the amnesic effects of diazepam sedation

Twenty subjects, 13 female and 7 male, aged 16 to 37 years, were studied to determine the effects on memory of intravenous sedation with diazepam (Valium). Three tests were performed: 1) the Weschler Logical Memory Scale; 2) memory of three geometric shapes; and 3) memory of three objects presented in a drawing. Logical memory items were presented before and after sedation; other tests were presented after sedation. Anterograde amnesia was produced by diazepam sedation. No retrograde amnesia was observed. A significant drug effect was found between the pre-drug and post-drug retention intervals (T+ = 2; P less than 0.005). Post-drug recognition scores were found to be approximately 42% of pre-drug recognition scores. The anterograde amnesia produced with diazepam was probably due to decreased arousal of the subject, and decreased attention to rehearsal of short-term memory stimuli, resulting in a lack of storage of the stimuli.     

Effects of intravenous midazolam and diazepam on patient response, percentage of oxygen saturation, and hemodynamic factors during periodontal surgery

BACKGROUND: The purpose of this double-masked study was to evaluate effects of intravenous sedation (IVS) using midazolam or diazepam during periodontal procedures on patient recall, psychomotor response, oxygen saturation, and hemodynamic factors. METHODS: Seventeen patients received either two or three scheduled periodontal surgeries under IVS with midazolam, diazepam, or placebo control. Patients were monitored throughout the procedure for hemodynamic variables, percent oxygen saturation, level of recall of common objects presented at baseline, and psychomotor function via the perceptual speed test (PST). RESULTS: Fifteen patients completed the study with average titrated dosages of 3.3 and 12.1 mg for midazolam and diazepam, respectively. Within the limitations of the study, there were few differences observed between the drugs with regard to hemodynamic variables, oxygen saturation, and overall percentage of objects recalled by patients sedated with either drug. However, midazolam was found to cause a greater incidence of amnesia lasting up to 30 minutes when compared to placebo. Patients on diazepam required an average of 15 minutes longer to recover accuracy as measured by the PST. CONCLUSIONS: The results suggest that diazepam and midazolam each may have advantages for IVS. In procedures lasting over 45 minutes, diazepam appears to be more clinically advantageous including a wider margin of safety during titration and gradual recovery. Midazolam may be used for shorter procedures for faster onset of action, predictable amnesic effects, and relatively rapid recovery.     

Accumulated oropharyngeal water increases coughing during dental treatment with intravenous sedation

Summary  In dental procedures performed under intravenous sedation in patients with intellectual disabilities, procedures are sometimes interrupted by the cough reflex, which may be triggered by intraoral use of water and/or increased secretion stimulating the pharyngeal/laryngeal mucosa, or by those irritating the tracheal mucosa directly through anesthetics-induced impairment of the laryngeal closure reflex. We investigated relationships between frequency of coughing episodes and intraoral use of water, water remaining in the oropharyngeal space, and mean infusion rate of propofol during dental treatments performed under intravenous sedation with midazolam and propofol. Twenty-one intellectually disabled patients were enrolled. After induction, a 14 Fr. suction catheter was inserted nasally, which was fixed where oropharyngeal suction could be done most effectively. Patients were divided into three groups according to the amount of intraoral use of water, amount of oropharyngeal suction and mean infusion rate of propofol. The amount of oropharyngeal suction significantly correlated with intraoral use of water. Frequency of coughing episodes significantly correlated with amount of oropharyngeal suction per minute. However, coughing episodes correlated neither with intraoral use of water nor with infusion rate of propofol. These findings suggested that accumulation of water in the oropharynx increased vulnerability to the cough reflex in dental treatments performed under intravenous sedation.     

Comparison of clonidine and epinephrine in lidocaine anaesthesia for lower third molar surgery

The admixture of clonidine or epinephrine to lidocaine for inferior alveolar nerve block was studied with regard to onset, duration, intensity of anaesthesia, postoperative analgesia, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), ST segment depression > or =1 mm and cardiac arrhythmias. Forty healthy patients (ASA I) received 2 ml 2% lidocaine with clonidine (15 microg/ml; n = 20) or epinephrine (12.5 microg/ml; n = 20) in a double-blind fashion for lower third molar surgery. Duration and intensity were not different between groups, while onset was significantly different by subjective evaluation. The need for postoperative pain medication was significantly lower in the clonidine group. There was a significant decrease in SBP and MAP in both groups 35 min after administration of anaesthesia compared with basal values, while DBP was significantly lower only in the clonidine group. There was no significant difference in SBP, DBP and MAP between groups. HR was significantly increased in the epinephrine group 5 min after administration of anaesthesia and during surgery compared with the clonidine group and with basal values. The presented data suggest that clonidine could be a useful and safe alternative to epinephrine for intraoral block anaesthesia.     

The effectiveness of flurazepam as night sedation prior to the removal of third molars

Anxiety prior to dental treatment is a well-recognized problem. Although oral sedation has been recommended the night before appointments to reduce this anxiety, there are no well-controlled studies to support this claim. The present double-blind cross-over study investigated the effect of 30 mg of flurazepam taken the night before the removal of impacted third molars. Preoperative anxiety, visuomotor performance and sleep patterns were investigated in 20 adult patients with similarly impacted third molars. While preoperative flurazepam led to a statistically significant improvement in sleep patterns, there was no reduction in pre-operative anxiety on the morning of surgery. In addition, the flurazepam-treated group demonstrated significantly impaired visuo-motor performance 60 min after intravenous sedation compared to this group where intravenous sedation was used only preceded by placebo. Patients had a significant preference for flurazepam over placebo as a night-time sedative.     

Diazepam (valium) in premedication. Experimental findings

The anxiolytic and analgesic effects of 10 mg of orally administered diazepam (Valium) were assessed on 10 volunteers. The electrodermal activity was recorded during two experimental sessions while cutaneous electrical stimulations were administered to the subjects. On one hand, the anxiolytic activity of diazepam could be observed by a decrease of both autonomic nervous system and anticipatory activities. On the other hand, an increase of the pain threshold could be shown under diazepam by lower responses to the stimulations. These results confirm that diazepam can be useful in anxious patients undergoing dental procedures.