Abstract
The purpose of this study was to evaluate the intranasal use of 1.5 μg/kg atomized dexmedetomidine for sedation in patients undergoing mandibular third molar removal. Eighteen patients underwent third molar removal in two surgical sessions. Patients were randomly assigned to receive intranasal water (placebo group) or 1.5 μg/kg atomized dexmedetomidine (group D) at the first session. The alternate regimen was used during the second session. Local anaesthesia was injected 30 min after placebo/sedative administration. Pain from local anaesthesia infiltration was rated on a scale from zero (no pain) to 10 (worst pain imaginable). Sedation status was measured every 10 min by a blinded observer with a modified Observer’s Assessment of Alertness/Sedation (OAA/S) scale and the bispectral index (BIS). Adverse reactions and analgesic consumption were recorded. Sedation values in group D were significantly different from placebo at 20–30 min, peaked at 40–50 min, and returned to placebo levels at 70–80 min after intranasal drug administration. Group D displayed decreased heart rate and systolic blood pressure, but the decreases did not exceed 20% of the baseline values. Intranasal administration of 1.5 μg/kg atomized dexmedetomidine is effective, convenient, and safe as a sedative for patients undergoing third molar extraction.
The appropriate method and medication chosen for sedation depend on the clinical situation. Intravenous therapy is the gold standard for sedation, allowing rapid onset with a titratable effect. However, although ideal for any major procedure, an intravenous (i.v.) sedative can be resource-consuming for minor to moderate procedures. Moreover, establishing an i.v. access is painful and frightening for many patients. According to numerous studies, the use of intranasal medications for sedation during dental procedures is easy, effective, and associated with few safety issues.
The nasal atomization device delivers intranasal medication in a fine mist, which ensures that the exact dose and volume are delivered, enhances absorption, and improves bioavailability (through the nose–brain pathway) for fast and effective drug delivery.
Dexmedetomidine is a potent and highly selective specific alpha-2 adrenoreceptor agonist that has both sedative and analgesic effects. The primary site of action of dexmedetomidine is the locus coeruleus and not the cerebral cortex; therefore, its induced sedation is characterized by an easy and quick arousal, resembling natural sleep. In addition, the analgesic properties of dexmedetomidine could potentially alleviate pain after tooth extraction. Yuen et al. found the intranasal administration of dexmedetomidine to be effective, well tolerated, and convenient in healthy volunteers. Clinical studies of intranasal dexmedetomidine administration to produce sedation and possible analgesia are ongoing.
The aim of this study was to evaluate the use of intranasal atomized dexmedetomidine (1.5 μg/kg) for the sedation of patients referred from an orthodontic department for the removal of bilaterally impacted mandibular third molars.
Methods
Study design
To reduce the risk of pharmacogenetic variability, a crossover design was chosen for this prospective, double-blind, randomized clinical study. Each subject participated in two surgical sessions, with extraction of a single third molar during each session. Each patient was randomly assigned (by computer-generated number) to receive either intranasal water (placebo group) or intranasal 1.5 μg/kg atomized dexmedetomidine (group D) at the first session. The alternate regimen was used during the second session.
The dose of 1.5 μg/kg dexmedetomidine was chosen on the basis of clinical trial results, which showed that the intranasal administration of 1.5 μg/kg dexmedetomidine in healthy volunteers resulted in an effective and safe sedation level in approximately 92% of subjects. Atomization was used to prevent the relatively long onset encountered with intranasal drug administration.
Patients
Participants included in the study were referred from an orthodontic department to a department of oral and maxillofacial surgery for bilateral third molar removal. Inclusion criteria were an American Society of Anesthesiologists (ASA) physical status of I and an age of 20–28 years. Exclusion criteria included a body mass index (BMI) >27 kg/m 2 and pregnancy. The patients with a BMI of more than 27 kg/m 2 were excluded because at values over 25 kg/m 2 the patient is considered overweight and may need special consideration during treatment; this could have affected the results of the study. All married women were required to undergo a urine pregnancy test to ensure that they were not pregnant. Before the procedure, patients were administered Corah’s Dental Anxiety Scale, Revised (DAS-R) in its Arabic language translation, which assesses anxiety up to a moderate to high level (score from 9 to 14). Radiologic results were examined to confirm that all extractions for all patients (in both procedures) were of similar difficulty.
Experimental procedures
Standard preoperative instructions were given. Patients were instructed to take nothing by mouth after midnight and were scheduled for morning appointments. All the surgeries were performed in a fully equipped oral maxillofacial department sedation clinic. Items required for resuscitation, such as oxygen ventilation (bag-mask) and intubation materials, resuscitation drugs, and equipment, including a defibrillator, were readily available at the clinic. All surgeries were conducted by one maxillofacial consultant.
An independent investigator (the attending anaesthesiologist) prepared and administered the drug or placebo (water) in a 2.5-ml syringe. A parenteral preparation of 100 μg/ml dexmedetomidine (Hospira ® ) was used without dilution at a dose of 1.5 μg/kg, and 0.9% saline was added to make a final volume of 1.5 ml. The volume of placebo was equivalent to 1.5 ml. The syringe containing the drug/placebo was attached via a lure lock connector to a nasal mucosal atomization device (MAD ® , Wolfe Troy Medical Inc., Utah, USA). Care was taken to eliminate ‘dead space’ within the delivery system ( Fig. 1 ).
At approximately 30 min before the planned procedure, the drug or placebo was sprayed into both nostrils of the subject, preferably while the subject was seated in a semi-reclining position in the dental chair. After administration, the subject was allowed to attain a more comfortable position. The patient, operating surgeon, and observer were blinded to the drug administered in each session.
At 30 min after drug administration, local anaesthesia (LA) was administered, in accordance with a standard protocol, with two 1.8-ml carpules of 2% lidocaine with 1:80,000 epinephrine. The reaction of the patient to the injection was observed, and pain was rated with a numerical rating scale (NRS) ranging from zero (no pain) to 10 (worst pain imaginable). After the efficacy of LA was confirmed, the surgery commenced.
Sedation status was assessed by a blinded observer with a modified Observer’s Assessment of Alertness/Sedation (OAA/S) scale ( Table 1 ) and bispectral index (BIS) every 10 min throughout the study. Patients were monitored via noninvasive blood pressure cuff, 3-lead electrocardiogram (ECG), BIS, and pulse oximeter throughout the entire study period (from administration of the drug to 30 min into the recovery period). The initial heart rate (HR), oxygen saturation (SpO 2 ), respiratory rate (RR), and systolic blood pressure (sBP) were measured before intranasal administration of medication (as baseline). The HR and SpO 2 were continuously measured, whereas sBP and RR were recorded every 10 min, throughout the study period. After the surgery, physiological parameters were recorded at 10-min intervals while the patient was recumbent in a recovery bed. Adverse effects, including hypotension (sBP <70 mmHg), bradycardia (HR <60 beats/min), oxygen desaturation (SpO 2 <92%), respiratory depression, nausea/vomiting, dry mouth, and shivering, were recorded.
| 6 | Appears alert and awake, responds readily to name spoken in normal tone |
| 5 | Appears asleep but responds readily to name spoken in normal tone |
| 4 | Lethargic response to name spoken in normal tone |
| 3 | Responds only after name is called loudly or repeatedly |
| 2 | Responds only after mild prodding or shaking |
| 1 | Does not respond to mild prodding or shaking |
| 0 | Does not respond to noxious stimulus |
Postoperative pain medication was prescribed as ibuprofen tablets (400 mg) taken as needed every 6 h. Patients were discharged with a responsible escort, in accordance with the standard department discharge criteria. Patients were asked to report information about the occurrence of adverse reactions and analgesic consumption (i.e. number of ibuprofen tablets consumed in the first two postoperative days and the time of their first intake).
Patients returned to the oral and maxillofacial surgery sedation clinic for the second surgical procedure at least 10 days after the first surgery. Third molar extraction was performed under the same setup as described above, except with the alternate sedation (placebo/dexmedetomidine) regimen. Any patient who experienced severe anxiety at any stage of treatment was excluded from the study and received treatment as appropriate at the discretion of the attending consultant.
Statistical analysis
Statistical analyses were performed with SPSS version 16.0 (SPSS, Chicago, IL, USA). Numerical data were analyzed by an unpaired Student’s t -test to detect differences between the groups. Differences with a P -value of <0.05 were considered statistically significant.
Results
A total of 18 patients were included in this study. The average time between the two sessions was 17.5 ± 5.5 days. The two groups showed similar surgical durations (i.e. time from LA injection to the end of the surgery). Patients tolerated intranasal administration of dexmedetomidine or water well, with no complaints of local irritation ( Table 2 ). None of the subjects were anxious at baseline. No patient experienced severe anxiety at any stage of treatment.
| Number of patients | 18 |
| Age (years) | 25 ± 3.9 |
| Sex (M/F) | 10/8 |
| Body mass index (kg/m 2 ) | 25.1 ± 1.87 |
| Time between two surgical sessions (days) | 17.5 ± 5.5 |
| Acceptance of nasal administration | |
| Placebo | 18 |
| Dexmedetomidine | 18 |
| Duration of surgery (min) | |
| Placebo session | 30 ± 7 |
| Dexmedetomidine session | 28 ± 9 |
Figs 2 and 3 show the time courses for the BIS results and the modified OAA/S scores. Significant sedation was achieved in group D. The sedation values in group D became significantly different from placebo at 20 min (OAA/S) or 30 min (BIS), reached a maximum level at 40 min (mean OAA/S 3.6 ± 0.78) or 50 min (mean BIS 75% ± 5.17%), and returned to placebo levels at 70 min (BIS) or 80 min (OAA/S) after intranasal drug administration. At the time of LA injection, group D displayed significant sedation (BIS 79% ± 4.2%, OAA/S 3.7 ± 0.9).
