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Intranasal atomized dexmedetomidine for sedation during third molar extraction
Int. J. Oral Maxillofac. Surg. 2013; 42: 857–862 http://dx.doi.org/10.1016/j.ijom.2013.02.003, available online at http://www.sciencedirect.com
Clinical Paper Oral Surgery
Intranasal atomized dexmedetomidine for sedation during third molar extraction
N. Nooh1, S. A. Sheta1,2, W. A. Abdullah1,3, A. A. Abdelhalim2 1
Department of Oral and Maxillofacial Surgery, King Saudi University, Riyadh, Saudi Arabia; 2Anesthesia Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 3Oral Surgery Department, Mansoura University, Mansoura, Egypt
N. Nooh, S. A. Sheta, W. A. Abdullah, A. A. Abdelhalim: Intranasal atomized dexmedetomidine for sedation during third molar extraction. Int. J. Oral Maxillofac. Surg. 2013; 42: 857–862. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. The purpose of this study was to evaluate the intranasal use of 1.5 mg/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 mg/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 mg/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.1 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.2 According to numerous studies, the use of intranasal medications 0901-5027/070857 + 06 $36.00/0
for sedation during dental procedures is easy, effective, and associated with few safety issues.3–6 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.7 Dexmedetomidine is a potent and highly selective specific alpha-2 adrenor-
Key words: atomized; intranasal; dexmedetomidine; dental sedation; third molar extraction. Accepted for publication 8 February 2013 Available online 14 March 2013
eceptor 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.8 In addition, the analgesic properties of dexmedetomidine could potentially alleviate pain after tooth extraction.9,10 Yuen et al. found the intranasal administration of dexmedetomidine to be effective, well tolerated,
# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
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and convenient in healthy volunteers.11 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 mg/kg) for the sedation of patients referred from an orthodontic department for the removal of bilaterally impacted mandibular third molars. Methods
Fig. 1. Mucosal atomization device (MAD) nasal spray.
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 mg/kg atomized dexmedetomidine (group D) at the first session. The alternate regimen was used during the second session. The dose of 1.5 mg/kg dexmedetomidine was chosen on the basis of clinical trial results, which showed that the intranasal administration of 1.5 mg/kg dexmedetomidine in healthy volunteers resulted in an effective and safe sedation level in approximately 92% of subjects.11 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 I12 and an age of 20–28 years. Exclusion criteria included a body mass index (BMI) >27 kg/m2 and pregnancy. The patients with a BMI of more than 27 kg/m2 were excluded because at values over 25 kg/m2 the patient is considered overweight13 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).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 (bagmask) 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 mg/ml dexmedetomidine (Hospira1) was used without dilution at a dose of 1.5 mg/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 (MAD1, 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).15 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)13 scale (Table 1) and bispectral index (BIS)16 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 (SpO2), respiratory rate (RR), and systolic blood pressure (sBP) were measured before intranasal administration of medication (as baseline). The HR and SpO2 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 (SpO2 <92%), respiratory depression, nausea/vomiting, dry mouth, and shivering, were recorded. Table 1. Modified Observer’s Assessment of Alertness/Sedation scale. 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
Intranasal atomized dexmedetomidine for sedation
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20 Session P Session D
0 BL 10 min 20 min 30 min LA 40 min 50 min 60 min 70 min 80 min 90 min
*Significant differences (P<0.05) Fig. 2. Bispectral index (BIS) results in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
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. 18 25 3.9 10/8 25.1 1.87 17.5 5.5
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). Both sBP and HR were significantly decreased in group D compared to placebo at 30 and 60 min after intranasal drug administration (before LA). These
8
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6 modified OAA/S (0 - 6)
Statistical analysis
Table 2. Patient characteristics. Number of patients Age (years) Sex (M/F) Body mass index (kg/m2) Time between two surgical sessions (days) Acceptance of nasal administration Placebo Dexmedetomidine Duration of surgery (min) Placebo session Dexmedetomidine session
120
BIS (0-100%)
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.
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5 4 3 2 1
Session P Session D
18 18 30 7 28 9
M, male; F, female. Data are expressed as the mean SD, or number of patients.
0 BL
10 min 20 min 30 min
LA
40 min 50 min 60 min 70 min 80 min 90 min
*Significant differences (P<0.05) Fig. 3. Results of the modified Observer’s Assessment of Alertness/Sedation (OAA/S) scale in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
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sBP (mmHg)
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Session P Session D
0 BL
10 min 20 min 30 min
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Fig. 4. Systolic blood pressure (sBP) in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
100 90
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HR (beat/ min)
70 60 50 40 30 20 Session P
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0 BL 10 min 20 min 30 min LA 40 min 50 min 60 min 70 min 80 min 90 min
Fig. 5. Heart rate (HR) in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
Table 3. Pain score and analgesic consumption results. NRS pain score during LA infiltration Median time to first oral analgesic use (min) Number of analgesic tablets (day 1 and day 2 PO)
Placebo
Dexmedetomidine
P-value
3.9 1.6 167 71
3.7 1.5 191 91
0.60 0.40
6.5 2.1
5.6 1.4
0.13
NRS, numerical rating scale; LA, local anaesthesia; PO, postoperative. Data are expressed as the mean SD.
parameters had normalized to the placebo levels by 70 min (Figs 4 and 5). The decrease in HR and sBP never exceeded 20% of the baseline value. No significant differences were observed between the groups in terms of the pain score during LA injection, median time to first oral analgesic use, and number of analgesic tablets used by patients on the first and second postoperative days (Table 3). Two cases of dry mouth were reported in the placebo group versus six cases in the study group. Group D experienced minor adverse effects, including mild shivering (n = 1) and dizziness (n = 2), while these two complications did not appear in the placebo group. Conduction abnormalities, bradycardia, and significant hypotension were not observed. There were no cases of oxygen desaturation or respiratory depression. Discussion
This study evaluated the intranasal administration of atomized dexmedetomidine to sedate adult patients undergoing mandibular third molar removal. The objective and subjective results showed that 1.5 mg/kg dexmedetomidine produced effective sedation with minimal side effects. Previous studies utilizing intranasal sedatives have primarily involved paediatric populations or noncompliant mentally disabled adults.3,4 The present study is unique in that healthy adult patients comprised the study population. The use of the atomized form of intranasal dexmedetomidine, which may improve bioavailability issues,10 is another novel feature of this study. Dexmedetomidine can be administered i.v. to achieve an exponential dose-dependent level of sedation. However, because this route of administration is invasive, researchers have examined other delivery methods. Extravascular routes provide milder forms of sedation. Oral administration of dexmedetomidine results in poor bioavailability (16%), probably due to extensive first bypass. Similar results have been obtained for buccally administered dexmedetomidine, due to the inevitable swallowing of the drug.17,18 The results from intramuscular administration are erratic, with different studies showing variable sedative effects.19–21 Among all the extravascular routes of administration of dexmedetomidine, the intranasal route appears to have the most similar pharmacodynamics and sedative effects to the i.v. administered drug; however, the time to the maximal sedative effect and duration of the effect can vary.22
Intranasal atomized dexmedetomidine for sedation Studies in healthy volunteers have shown that dexmedetomidine sedation can be reliably monitored with BIS.23 Another study advised the combined use of BIS and the OAA/S scale, to obtain complementary data on the response of the patient to sedation.24 Therefore we utilized both tools to assess sedation. In our study, LA injection was performed at 30 min after intranasal administration of dexmedetomidine. Modified OAA/S and BIS revealed that significant sedation compared to placebo commenced at 30 min after dexmedetomidine administration, and the highest level of sedation was achieved at 40–50 min (modified OAA/S 3.6, BIS 75%). Although this study was not designed to measure the exact onset and peak effect of using 1.5 mg/kg atomized intranasal dexmedetomidine to produce sedation, our findings can be compared to those of previous studies. Using 1 and 1.5 mg/kg intranasal dexmedetomidine, a previous study reported onset times of 45–60 min, with a peak sedative effect after approximately 90– 105 min.11 Our use of atomized dexmedetomidine is the key reason for the discrepancy of our results from these previous findings. Higher drug serum levels are achieved when a drug is given in its atomized form, due to a more extensive distribution of the medication across the nasal mucosa and increased bioavailability of the drug.7 In addition, because atomized medication is delivered as a mist, it is less likely to be blown back out of the nose. In another study, 0.5 and 1 mg/kg intranasal dexmedetomidine were utilized as premedication in healthy children aged 2– 12 years.25 Especially with the 1 mg/kg dose, effective sedation was achieved within a specified premedication period of 45–60 min, as evidenced by ease of parental separation. The premedication period, which reflected the expected onset, was relatively longer than the onset in our study. This discrepancy may be related to differences in the clinical situation, age group, drug doses, and delivery method of the medications. However, the authors in this previous trial were forced to transfer some children to the operating room slightly earlier, to avoid interfering with the normal operating room schedule, and still had satisfactory sedation. The same authors also conducted a prospective, double-blind, randomized controlled trial of 1 mg/kg intranasal dexmedetomidine compared to placebo as premedication for children in the same age group.24 They reported a median time of sedation onset
of 25 min (95% CI: 25–30 min). They concluded that there is some flexibility in the premedication period with 1 mg/ kg intranasal dexmedetomidine, provided that the drug is given at least 30 min in advance. We observed that the sedation status of the patients returned to baseline by 70– 80 min after atomized intranasal dexmedetomidine was administered, and all the patients were easily roused at the end of the study period. However, recovery from sedation was detected 10 min earlier with BIS than with modified OAA/S. Similarly, using BIS and the OAA/S scale with propofol and fentanyl sedation in outpatient gynaecological surgeries, researchers reported earlier detection of sedation with BIS than with the OAA/S scale.26 Regardless, a sedative duration of 70–80 min was sufficiently long to perform third molar extraction, and the short recovery period was convenient for outpatient dental sedation purposes. The analgesic effect of dexmedetomidine is controversial. Some studies have suggested that the drug has analgesic properties and that it exerts its analgesic effect at the spinal cord and supra-spinal levels.8–10 However, other reports have not found such analgesic activity.11,22 In a previous randomized, double-blind study, when used as an i.v. sedative during third molar surgery under LA, dexmedetomidine did not offer additional analgesic benefit compared to midazolam.27,28 Our results were inconclusive in terms of the possible analgesic effects of intranasal dexmedetomidine. The response to pain at the time of LA infiltration, as evidenced by NRS pain scores, was not improved with dexmedetomidine. The site of action of dexmedetomidine is in the locus coeruleus of the central nervous system, where it induces a state similar to natural sleep.8 Therefore, it is not surprising that external stimulation should facilitate arousal. Hence, the patients responded to LA infiltration similarly in both the placebo and dexmedetomidine sessions. Furthermore, the time to intake of the first oral analgesic tablet was not significantly postponed and the daily oral analgesic consumption was similar after intranasal dexmedetomidine compared to placebo. More studies are underway to clarify the analgesic properties of dexmedetomidine, with particular focus on the effectiveness of its peripheral analgesic effect. Haemodynamic effects were observed with the use of 1.5 mg/kg intranasal dexmedetomidine; however, they were clinically insignificant. The reduction in HR
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and sBP never exceeded 20% of the baseline values, and both parameters returned to near-normal values by about 60 min after dexmedetomidine administration. Similarly, previous studies observed clinically insignificant haemodynamic effects requiring no intervention after intranasal dexmedetomidine administration to healthy volunteers and children.11,25 In conclusion, intranasal administration of 1.5 mg/kg atomized dexmedetomidine was clinically effective, convenient, and safe for the sedation of patients undergoing third molar extraction. Funding
None. Competing interests
None declared. Ethical approval
The local ethics committee approved the study; all patients gave written informed consent for participation. Approved by the College of Dentistry Research Centre, King Saud University, Saudi Arabia as non-funded research (No. NF 2339). References 1. Leitch J, Lennox C, Robb N. Recent advances in conscious sedation. Dent Update 2005;32:2–3. 2. Abdullah WA, Sheta SA, Nooh NS. Inhaled methoxyflurane (Penthrox) sedation for third molar extraction: a comparison to nitrous oxide sedation. Aust Dent J 2011;56: 296–301. 3. Fuks AB, Kaufman E, Ram D, Hovav S, Shapira J. Assessment of two doses of intranasal midazolam for sedation of young pediatric dental patients. Pediatr Dent 1994;16:301–5. 4. Fukuta O, Braham RL, Yanase H, Kurosu K. The sedative effect of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 2. Optimal concentration of intranasal midazolam. J Clin Pediatr Dent 1994;18:259–65. 5. Gilchrist F, Cairns AM, Leitch JA. The use of intranasal midazolam in the treatment of paediatric dental patients. Anaesthesia 2007;62:1262–5. 6. Hartgraves PM, Primosch RE. An evaluation of oral and nasal midazolam for pediatric dental sedation. ASDC J Dent Child 1994; 61:175–81. 7. Merkus P, Ebbens FA, Muller B, Fokkens WJ. The ‘best method’ of topical nasal drug delivery: comparison of seven techniques. Rhinology 2006;44:102–7.
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8. MacDonald E, Scheinin M. Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system. J Physiol Pharmacol 1995;46:241–58. 9. Gurbet A, Basagan-Mogol E, Turker G, Ugun F, Kaya FN, Ozcan B. Intraoperative infusion of dexmedetomidine reduces perioperative analgesic requirements. Can J Anaesth 2006;53:646–52. 10. Unlugenc H, Gunduz M, Guler T, Yagmur O, Isik G. The effect of preanesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anaesthesiol 2005;22:386–91. 11. Yuen VM, Irwin MG, Hui TW, Yuen MK, Lee LH. A double-blind, crossover assessment of the sedative and analgesic effects of intranasal dexmedetomidine. Anesth Analg 2007;105:374–80. 12. Owens WD, Felts JA, Spitznagel EL. ASA physical status classification: a study of consistency of ratings. Anaesthetic 1978;49: 239–43. 13. World Health Organization. BMI classification. http://www.who.int/bmi/index.isp?introPage=intro3.html [accessibility verified]. 14. Clarke JH, Rustvold S. Norman Corah’s dental questionnaire and dental concerns assessment. Revised 1998. Oregon Health Sciences University School of Dentistry; 1993. http://www.ncchc.org/pubs/CC/dental_anxiety_tools.pdf [accessibility verified 30.05.06]. 15. Ware LJ, Epps CD, Herr KA, Packard A. Evaluation of the revised faces pain scale, verbal descriptor scale, numeric rating scale, and Iowa pain thermometer in older minority adults. Pain Manage Nurs 2006; 7:117–25.
16. Sadhasivam S, Ganesh A, Robison A, Kaye R, Watch MF. Validation of the bispectral index monitor for measuring the depth of sedation in children. Anesth Analg 2006; 102:383–8. 17. Cohen LB, Delegge MH, Aisenberg J, Brill JV, Inadomi JM, Kochman ML, Piorkowski Jr JD. AGA institute review of endoscopic sedation. Gastroenterology 2007;133:675–701. 18. Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. Anesthesiology 1992;77:1125–33. 19. Anttila M, Penttila J, Helminen A, Vuorilehto L, Scheinin H. Bioavailability of dexmedetomidine after extravascular doses in healthy subjects. Br J Clin Pharmacol 2003;56:691–3. 20. Scheinin H, Karhuvaara S, Olkkola KT, Kallio A, Anttila M, Vuorilehto L, Scheinin M. Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine. Clin Pharmacol Ther 1992;52:537–46. 21. Scheinin H, Jaakola ML, Sjo¨vall S, AliMelkkila¨ T, Kaukinen S, Turunen J, Kanto J. Intramuscular dexmedetomidine as premedication for general anesthesia. A comparative multicenter study. Anesthesiology 1993;78:1065–75. 22. Virkkila M, Ali-Melkkila T, Kanto J, Turunen J, Scheinin H. Dexmedetomidine as intramuscular premedication for day-case cataract surgery. A comparative study of dexmedetomidine, midazolam and placebo. Anaesthesia 1994;49:853–8. 23. Yuen VM. Dexmedetomidine: perioperative applications in children. Paediatr Anaesth 2010;20:256–64. 24. Haenggi M, Ypparila H, Hauser K, Caviezel C, Korhonen I, Takala J, Jakob SM. The
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effects of dexmedetomidine/remifentanil and midazolam/remifentanil on auditoryevoked potentials and electroencephalogram at light-to-moderate sedation levels in healthy subjects. Anesth Analg 2006;103:1163–9. Kang JG, Lee SM, Lim SW, Chung IS, Hahm TS, Kim JK, et al. Correlation of AEP, BIS and OAA/S scores under stepwise sedation using propofol TCI in orthopedic patients undergoing total knee replacement arthroplasty under spinal anesthesia. Korean J Anesthesiol 2004;46:284–92. Yuen VM, Hui TW, Irwin MG, Yuen MK. A comparison of intranasal dexmedetomidine and oral midazolam for premedication in pediatric anesthesia: a double-blinded randomized controlled trial. Anesth Analg 2008;106:1715–21. Yolluatakan T, Bombaci E, C ¸ olakoglu S, C ¸ evik B, Berkel Yildirim G. Assessment of sedation: the comparison of BIS with OAA/S and modified Wilson scales: A164. Eur J Anaesthesiol 2004;21:41. Cheung CW, Ying CL, Chiu WK, Wong GT, Ng KF, Irwin MG. A comparison of dexmedetomidine and midazolam for sedation in third molar surgery. Anaesthesia 2007;62: 1132–8.
Address: Nasser Nooh Department of Oral and Maxillofacial Surgery Dental College King Saud University Riyadh Saudi Arabia Tel: +966 556048558 E-mail: [email protected]
Clinical Paper Oral Surgery
Intranasal atomized dexmedetomidine for sedation during third molar extraction
N. Nooh1, S. A. Sheta1,2, W. A. Abdullah1,3, A. A. Abdelhalim2 1
Department of Oral and Maxillofacial Surgery, King Saudi University, Riyadh, Saudi Arabia; 2Anesthesia Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 3Oral Surgery Department, Mansoura University, Mansoura, Egypt
N. Nooh, S. A. Sheta, W. A. Abdullah, A. A. Abdelhalim: Intranasal atomized dexmedetomidine for sedation during third molar extraction. Int. J. Oral Maxillofac. Surg. 2013; 42: 857–862. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. The purpose of this study was to evaluate the intranasal use of 1.5 mg/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 mg/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 mg/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.1 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.2 According to numerous studies, the use of intranasal medications 0901-5027/070857 + 06 $36.00/0
for sedation during dental procedures is easy, effective, and associated with few safety issues.3–6 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.7 Dexmedetomidine is a potent and highly selective specific alpha-2 adrenor-
Key words: atomized; intranasal; dexmedetomidine; dental sedation; third molar extraction. Accepted for publication 8 February 2013 Available online 14 March 2013
eceptor 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.8 In addition, the analgesic properties of dexmedetomidine could potentially alleviate pain after tooth extraction.9,10 Yuen et al. found the intranasal administration of dexmedetomidine to be effective, well tolerated,
# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
858
Nooh et al.
and convenient in healthy volunteers.11 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 mg/kg) for the sedation of patients referred from an orthodontic department for the removal of bilaterally impacted mandibular third molars. Methods
Fig. 1. Mucosal atomization device (MAD) nasal spray.
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 mg/kg atomized dexmedetomidine (group D) at the first session. The alternate regimen was used during the second session. The dose of 1.5 mg/kg dexmedetomidine was chosen on the basis of clinical trial results, which showed that the intranasal administration of 1.5 mg/kg dexmedetomidine in healthy volunteers resulted in an effective and safe sedation level in approximately 92% of subjects.11 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 I12 and an age of 20–28 years. Exclusion criteria included a body mass index (BMI) >27 kg/m2 and pregnancy. The patients with a BMI of more than 27 kg/m2 were excluded because at values over 25 kg/m2 the patient is considered overweight13 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).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 (bagmask) 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 mg/ml dexmedetomidine (Hospira1) was used without dilution at a dose of 1.5 mg/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 (MAD1, 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).15 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)13 scale (Table 1) and bispectral index (BIS)16 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 (SpO2), respiratory rate (RR), and systolic blood pressure (sBP) were measured before intranasal administration of medication (as baseline). The HR and SpO2 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 (SpO2 <92%), respiratory depression, nausea/vomiting, dry mouth, and shivering, were recorded. Table 1. Modified Observer’s Assessment of Alertness/Sedation scale. 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
Intranasal atomized dexmedetomidine for sedation
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20 Session P Session D
0 BL 10 min 20 min 30 min LA 40 min 50 min 60 min 70 min 80 min 90 min
*Significant differences (P<0.05) Fig. 2. Bispectral index (BIS) results in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
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. 18 25 3.9 10/8 25.1 1.87 17.5 5.5
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). Both sBP and HR were significantly decreased in group D compared to placebo at 30 and 60 min after intranasal drug administration (before LA). These
8
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6 modified OAA/S (0 - 6)
Statistical analysis
Table 2. Patient characteristics. Number of patients Age (years) Sex (M/F) Body mass index (kg/m2) Time between two surgical sessions (days) Acceptance of nasal administration Placebo Dexmedetomidine Duration of surgery (min) Placebo session Dexmedetomidine session
120
BIS (0-100%)
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.
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5 4 3 2 1
Session P Session D
18 18 30 7 28 9
M, male; F, female. Data are expressed as the mean SD, or number of patients.
0 BL
10 min 20 min 30 min
LA
40 min 50 min 60 min 70 min 80 min 90 min
*Significant differences (P<0.05) Fig. 3. Results of the modified Observer’s Assessment of Alertness/Sedation (OAA/S) scale in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
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Nooh et al. 140
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sBP (mmHg)
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80
60
40
20
Session P Session D
0 BL
10 min 20 min 30 min
LA
40 min 50 min 60 min 70 min 80 min 90 min
Fig. 4. Systolic blood pressure (sBP) in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
100 90
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HR (beat/ min)
70 60 50 40 30 20 Session P
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Session D
0 BL 10 min 20 min 30 min LA 40 min 50 min 60 min 70 min 80 min 90 min
Fig. 5. Heart rate (HR) in the placebo and dexmedetomidine (1.5 mg/kg) groups (BL, baseline; LA, local anaesthesia). Data are shown as mean SD; *P < 0.05.
Table 3. Pain score and analgesic consumption results. NRS pain score during LA infiltration Median time to first oral analgesic use (min) Number of analgesic tablets (day 1 and day 2 PO)
Placebo
Dexmedetomidine
P-value
3.9 1.6 167 71
3.7 1.5 191 91
0.60 0.40
6.5 2.1
5.6 1.4
0.13
NRS, numerical rating scale; LA, local anaesthesia; PO, postoperative. Data are expressed as the mean SD.
parameters had normalized to the placebo levels by 70 min (Figs 4 and 5). The decrease in HR and sBP never exceeded 20% of the baseline value. No significant differences were observed between the groups in terms of the pain score during LA injection, median time to first oral analgesic use, and number of analgesic tablets used by patients on the first and second postoperative days (Table 3). Two cases of dry mouth were reported in the placebo group versus six cases in the study group. Group D experienced minor adverse effects, including mild shivering (n = 1) and dizziness (n = 2), while these two complications did not appear in the placebo group. Conduction abnormalities, bradycardia, and significant hypotension were not observed. There were no cases of oxygen desaturation or respiratory depression. Discussion
This study evaluated the intranasal administration of atomized dexmedetomidine to sedate adult patients undergoing mandibular third molar removal. The objective and subjective results showed that 1.5 mg/kg dexmedetomidine produced effective sedation with minimal side effects. Previous studies utilizing intranasal sedatives have primarily involved paediatric populations or noncompliant mentally disabled adults.3,4 The present study is unique in that healthy adult patients comprised the study population. The use of the atomized form of intranasal dexmedetomidine, which may improve bioavailability issues,10 is another novel feature of this study. Dexmedetomidine can be administered i.v. to achieve an exponential dose-dependent level of sedation. However, because this route of administration is invasive, researchers have examined other delivery methods. Extravascular routes provide milder forms of sedation. Oral administration of dexmedetomidine results in poor bioavailability (16%), probably due to extensive first bypass. Similar results have been obtained for buccally administered dexmedetomidine, due to the inevitable swallowing of the drug.17,18 The results from intramuscular administration are erratic, with different studies showing variable sedative effects.19–21 Among all the extravascular routes of administration of dexmedetomidine, the intranasal route appears to have the most similar pharmacodynamics and sedative effects to the i.v. administered drug; however, the time to the maximal sedative effect and duration of the effect can vary.22
Intranasal atomized dexmedetomidine for sedation Studies in healthy volunteers have shown that dexmedetomidine sedation can be reliably monitored with BIS.23 Another study advised the combined use of BIS and the OAA/S scale, to obtain complementary data on the response of the patient to sedation.24 Therefore we utilized both tools to assess sedation. In our study, LA injection was performed at 30 min after intranasal administration of dexmedetomidine. Modified OAA/S and BIS revealed that significant sedation compared to placebo commenced at 30 min after dexmedetomidine administration, and the highest level of sedation was achieved at 40–50 min (modified OAA/S 3.6, BIS 75%). Although this study was not designed to measure the exact onset and peak effect of using 1.5 mg/kg atomized intranasal dexmedetomidine to produce sedation, our findings can be compared to those of previous studies. Using 1 and 1.5 mg/kg intranasal dexmedetomidine, a previous study reported onset times of 45–60 min, with a peak sedative effect after approximately 90– 105 min.11 Our use of atomized dexmedetomidine is the key reason for the discrepancy of our results from these previous findings. Higher drug serum levels are achieved when a drug is given in its atomized form, due to a more extensive distribution of the medication across the nasal mucosa and increased bioavailability of the drug.7 In addition, because atomized medication is delivered as a mist, it is less likely to be blown back out of the nose. In another study, 0.5 and 1 mg/kg intranasal dexmedetomidine were utilized as premedication in healthy children aged 2– 12 years.25 Especially with the 1 mg/kg dose, effective sedation was achieved within a specified premedication period of 45–60 min, as evidenced by ease of parental separation. The premedication period, which reflected the expected onset, was relatively longer than the onset in our study. This discrepancy may be related to differences in the clinical situation, age group, drug doses, and delivery method of the medications. However, the authors in this previous trial were forced to transfer some children to the operating room slightly earlier, to avoid interfering with the normal operating room schedule, and still had satisfactory sedation. The same authors also conducted a prospective, double-blind, randomized controlled trial of 1 mg/kg intranasal dexmedetomidine compared to placebo as premedication for children in the same age group.24 They reported a median time of sedation onset
of 25 min (95% CI: 25–30 min). They concluded that there is some flexibility in the premedication period with 1 mg/ kg intranasal dexmedetomidine, provided that the drug is given at least 30 min in advance. We observed that the sedation status of the patients returned to baseline by 70– 80 min after atomized intranasal dexmedetomidine was administered, and all the patients were easily roused at the end of the study period. However, recovery from sedation was detected 10 min earlier with BIS than with modified OAA/S. Similarly, using BIS and the OAA/S scale with propofol and fentanyl sedation in outpatient gynaecological surgeries, researchers reported earlier detection of sedation with BIS than with the OAA/S scale.26 Regardless, a sedative duration of 70–80 min was sufficiently long to perform third molar extraction, and the short recovery period was convenient for outpatient dental sedation purposes. The analgesic effect of dexmedetomidine is controversial. Some studies have suggested that the drug has analgesic properties and that it exerts its analgesic effect at the spinal cord and supra-spinal levels.8–10 However, other reports have not found such analgesic activity.11,22 In a previous randomized, double-blind study, when used as an i.v. sedative during third molar surgery under LA, dexmedetomidine did not offer additional analgesic benefit compared to midazolam.27,28 Our results were inconclusive in terms of the possible analgesic effects of intranasal dexmedetomidine. The response to pain at the time of LA infiltration, as evidenced by NRS pain scores, was not improved with dexmedetomidine. The site of action of dexmedetomidine is in the locus coeruleus of the central nervous system, where it induces a state similar to natural sleep.8 Therefore, it is not surprising that external stimulation should facilitate arousal. Hence, the patients responded to LA infiltration similarly in both the placebo and dexmedetomidine sessions. Furthermore, the time to intake of the first oral analgesic tablet was not significantly postponed and the daily oral analgesic consumption was similar after intranasal dexmedetomidine compared to placebo. More studies are underway to clarify the analgesic properties of dexmedetomidine, with particular focus on the effectiveness of its peripheral analgesic effect. Haemodynamic effects were observed with the use of 1.5 mg/kg intranasal dexmedetomidine; however, they were clinically insignificant. The reduction in HR
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and sBP never exceeded 20% of the baseline values, and both parameters returned to near-normal values by about 60 min after dexmedetomidine administration. Similarly, previous studies observed clinically insignificant haemodynamic effects requiring no intervention after intranasal dexmedetomidine administration to healthy volunteers and children.11,25 In conclusion, intranasal administration of 1.5 mg/kg atomized dexmedetomidine was clinically effective, convenient, and safe for the sedation of patients undergoing third molar extraction. Funding
None. Competing interests
None declared. Ethical approval
The local ethics committee approved the study; all patients gave written informed consent for participation. Approved by the College of Dentistry Research Centre, King Saud University, Saudi Arabia as non-funded research (No. NF 2339). References 1. Leitch J, Lennox C, Robb N. Recent advances in conscious sedation. Dent Update 2005;32:2–3. 2. Abdullah WA, Sheta SA, Nooh NS. Inhaled methoxyflurane (Penthrox) sedation for third molar extraction: a comparison to nitrous oxide sedation. Aust Dent J 2011;56: 296–301. 3. Fuks AB, Kaufman E, Ram D, Hovav S, Shapira J. Assessment of two doses of intranasal midazolam for sedation of young pediatric dental patients. Pediatr Dent 1994;16:301–5. 4. Fukuta O, Braham RL, Yanase H, Kurosu K. The sedative effect of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 2. Optimal concentration of intranasal midazolam. J Clin Pediatr Dent 1994;18:259–65. 5. Gilchrist F, Cairns AM, Leitch JA. The use of intranasal midazolam in the treatment of paediatric dental patients. Anaesthesia 2007;62:1262–5. 6. Hartgraves PM, Primosch RE. An evaluation of oral and nasal midazolam for pediatric dental sedation. ASDC J Dent Child 1994; 61:175–81. 7. Merkus P, Ebbens FA, Muller B, Fokkens WJ. The ‘best method’ of topical nasal drug delivery: comparison of seven techniques. Rhinology 2006;44:102–7.
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8. MacDonald E, Scheinin M. Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system. J Physiol Pharmacol 1995;46:241–58. 9. Gurbet A, Basagan-Mogol E, Turker G, Ugun F, Kaya FN, Ozcan B. Intraoperative infusion of dexmedetomidine reduces perioperative analgesic requirements. Can J Anaesth 2006;53:646–52. 10. Unlugenc H, Gunduz M, Guler T, Yagmur O, Isik G. The effect of preanesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anaesthesiol 2005;22:386–91. 11. Yuen VM, Irwin MG, Hui TW, Yuen MK, Lee LH. A double-blind, crossover assessment of the sedative and analgesic effects of intranasal dexmedetomidine. Anesth Analg 2007;105:374–80. 12. Owens WD, Felts JA, Spitznagel EL. ASA physical status classification: a study of consistency of ratings. Anaesthetic 1978;49: 239–43. 13. World Health Organization. BMI classification. http://www.who.int/bmi/index.isp?introPage=intro3.html [accessibility verified]. 14. Clarke JH, Rustvold S. Norman Corah’s dental questionnaire and dental concerns assessment. Revised 1998. Oregon Health Sciences University School of Dentistry; 1993. http://www.ncchc.org/pubs/CC/dental_anxiety_tools.pdf [accessibility verified 30.05.06]. 15. Ware LJ, Epps CD, Herr KA, Packard A. Evaluation of the revised faces pain scale, verbal descriptor scale, numeric rating scale, and Iowa pain thermometer in older minority adults. Pain Manage Nurs 2006; 7:117–25.
16. Sadhasivam S, Ganesh A, Robison A, Kaye R, Watch MF. Validation of the bispectral index monitor for measuring the depth of sedation in children. Anesth Analg 2006; 102:383–8. 17. Cohen LB, Delegge MH, Aisenberg J, Brill JV, Inadomi JM, Kochman ML, Piorkowski Jr JD. AGA institute review of endoscopic sedation. Gastroenterology 2007;133:675–701. 18. Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. Anesthesiology 1992;77:1125–33. 19. Anttila M, Penttila J, Helminen A, Vuorilehto L, Scheinin H. Bioavailability of dexmedetomidine after extravascular doses in healthy subjects. Br J Clin Pharmacol 2003;56:691–3. 20. Scheinin H, Karhuvaara S, Olkkola KT, Kallio A, Anttila M, Vuorilehto L, Scheinin M. Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine. Clin Pharmacol Ther 1992;52:537–46. 21. Scheinin H, Jaakola ML, Sjo¨vall S, AliMelkkila¨ T, Kaukinen S, Turunen J, Kanto J. Intramuscular dexmedetomidine as premedication for general anesthesia. A comparative multicenter study. Anesthesiology 1993;78:1065–75. 22. Virkkila M, Ali-Melkkila T, Kanto J, Turunen J, Scheinin H. Dexmedetomidine as intramuscular premedication for day-case cataract surgery. A comparative study of dexmedetomidine, midazolam and placebo. Anaesthesia 1994;49:853–8. 23. Yuen VM. Dexmedetomidine: perioperative applications in children. Paediatr Anaesth 2010;20:256–64. 24. Haenggi M, Ypparila H, Hauser K, Caviezel C, Korhonen I, Takala J, Jakob SM. The
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effects of dexmedetomidine/remifentanil and midazolam/remifentanil on auditoryevoked potentials and electroencephalogram at light-to-moderate sedation levels in healthy subjects. Anesth Analg 2006;103:1163–9. Kang JG, Lee SM, Lim SW, Chung IS, Hahm TS, Kim JK, et al. Correlation of AEP, BIS and OAA/S scores under stepwise sedation using propofol TCI in orthopedic patients undergoing total knee replacement arthroplasty under spinal anesthesia. Korean J Anesthesiol 2004;46:284–92. Yuen VM, Hui TW, Irwin MG, Yuen MK. A comparison of intranasal dexmedetomidine and oral midazolam for premedication in pediatric anesthesia: a double-blinded randomized controlled trial. Anesth Analg 2008;106:1715–21. Yolluatakan T, Bombaci E, C ¸ olakoglu S, C ¸ evik B, Berkel Yildirim G. Assessment of sedation: the comparison of BIS with OAA/S and modified Wilson scales: A164. Eur J Anaesthesiol 2004;21:41. Cheung CW, Ying CL, Chiu WK, Wong GT, Ng KF, Irwin MG. A comparison of dexmedetomidine and midazolam for sedation in third molar surgery. Anaesthesia 2007;62: 1132–8.
Address: Nasser Nooh Department of Oral and Maxillofacial Surgery Dental College King Saud University Riyadh Saudi Arabia Tel: +966 556048558 E-mail: [email protected]