Dexmedetomidine, a selective -2 agonist with anxiolytic,

Pediatric Anesthesiology Section Editor: Peter J. Davis The Effect of Intraoperative Dexmedetomidine on Postoperative Analgesia and Sedation in Pediatric Patients Undergoing Tonsillectomy and Adenoidectomy Olutoyin A. Olutoye, MD,* Chris D. Glover, MD,* John W. Diefenderfer, BS, Michael McGilberry, RN, Matthew M. Wyatt, MD, Deidre R. Larrier, MD,* Ellen M. Friedman, MD,* and Mehernoor F. Watcha, MD* BACKGROUND: The immediate postoperative period after tonsillectomy and adenoidectomy, one of the most common pediatric surgical procedures, is often difficult. These children frequently have severe pain but postoperative airway edema along with increased sensitivity to the respiratory-depressant effects of opioids may result in obstructive symptoms and hypoxemia. Opioid consumption may be reduced by nonsteroidal antiinflammatory drugs, but these drugs may be associated with increased bleeding after this operation. Dexmedetomidine has mild analgesic properties, causes sedation without respiratory depression, and does not have an effect on coagulation. We designed a prospective, double-blind, randomized controlled study to determine the effects of intraoperative dexmedetomidine on postoperative recovery including pain, sedation, and hemodynamics in pediatric patients undergoing tonsillectomy and adenoidectomy. METHODS: One hundred nine patients were randomized to receive a single intraoperative dose of dexmedetomidine 0.75 g/kg, dexmedetomidine 1 g/kg, morphine 50 g/kg, or morphine 100 g/kg over 10 minutes after endotracheal intubation. RESULTS: There were no significant differences among the 4 groups in patient demographics, ASA physical status, postoperative opioid requirements, sedation scores, duration of oxygen supplementation in the postanesthetic care unit, and time to discharge readiness. The median time to first postoperative rescue analgesic was similar in patients receiving dexmedetomidine 1 g/kg and morphine 100 g/kg, but significantly longer compared with patients receiving dexmedetomidine 0.75 g/kg or morphine 50 g/kg (P 0.01). In addition, the number of patients requiring 1 rescue analgesic dose was significantly higher in the dexmedetomidine 0.75 g/kg group compared with the dexmedetomidine 1 g/kg and morphine 100 g/kg groups, but not the morphine 50 g/kg group. Patients receiving dexmedetomidine had significantly slower heart rates in the first 30 minutes after surgery compared with those receiving morphine (P 0.05). There was no significant difference in sedation scores among the groups. CONCLUSIONS: The total postoperative rescue opioid requirements were similar in tonsillectomy patients receiving intraoperative dexmedetomidine or morphine. However, the use of dexmedetomidine 1 g/kg and morphine 100 g/kg had the advantages of an increased time to first analgesic and a reduced need for additional rescue analgesia doses, without increasing discharge times. (Anesth Analg 2010;111:490 5) Dexmedetomidine, a selective -2 agonist with anxiolytic, sedative, and analgesic properties, has been shown to decrease postoperative analgesic or opioid consumption in adults. 1 5 This drug has been used in children undergoing postoperative mechanical ventilation, cardiac catheterization, magnetic resonance imaging (MRI), endoscopic, and other minor procedures. 6,7 However, its From the Departments of *Pediatrics, Anesthesia, and Otolaryngology, Texas Children s Hospital, Baylor College of Medicine, Houston, Texas. Accepted for publication March 31, 2010. Supported by intramural departmental sources. Disclosure: The authors report no conflicts of interest. Address correspondence and reprint requests to Olutoyin A. Olutoye, MD, Texas Children s Hospital, 6621 Fannin St., Suite A-300, MC 2-1495, Houston, TX 77030. Address e-mail to oao@bcm.edu. Copyright 2010 International Anesthesia Research Society DOI: 10.1213/ANE.0b013e3181e33429 usefulness as an analgesic in the pediatric population has not yet been well established. Tonsillectomy and adenoidectomy, one of the most common surgical procedures in this patient population, is usually indicated for the management of recurrent pharyngotonsillitis and obstructive sleep apnea. The immediate postoperative period after tonsillectomy and adenoidectomy is often difficult because these children frequently have severe pain, but edema of the operative site may result in transient worsening of obstructive symptoms and hypoxemia. In addition, children with obstructive sleep apnea are particularly sensitive to the respiratory-depressant effects of perioperative opioids such as morphine. 8,9 Nonsteroidal antiinflammatory drugs reduce opioid consumption but may be associated with increased bleeding after this operation. 10 Dexmedetomidine has mild analgesic properties, causes sedation without respiratory depression, and does not have an effect on 490 www.anesthesia-analgesia.org August 2010 Volume 111 Number 2

coagulation. It has sympatholytic effects that can result in decreased arterial blood pressure and heart rate, which may be of concern in anesthetized children with a ratedependent cardiac output. 7,11 This study was designed to determine the effects of intraoperative dexmedetomidine on postoperative recovery including pain, sedation, and hemodynamics in pediatric patients undergoing tonsillectomy and adenoidectomy. METHODS This prospective, randomized, double-blind study was conducted in 109 pediatric patients undergoing tonsillectomy and adenoidectomy, after receiving approval from both the Baylor College of Medicine IRB and the Food and Drug Administration (investigational new drug, IND# 79,290). In addition, we obtained written informed consent from the legal guardian and, when appropriate, assent from the child older than 7 years. Children between the ages of 3 and 12 years with ASA classification of I or II were eligible for inclusion in the study. Exclusion criteria were a body mass index more than the 95th percentile for age, ASA classification III or more, and the presence of confirmed severe obstructive sleep apnea by a polysomnograph test. Patients with a history of snoring or sleep-disordered breathing, but without a polysomnogram test, were included. After consent was obtained, children were randomized to 1 of 4 groups based on a computer-generated random number to receive a single IV dose of (a) dexmedetomidine 0.75 g/kg, (b) dexmedetomidine 1 g/kg, (c) morphine 50 g/kg, or (d) morphine 100 g/kg intraoperatively. Doses of dexmedetomidine were chosen to exceed those from a previous pilot study in which patients who received dexmedetomidine 0.5 g/kg IV intraoperatively during tonsillectomy and adenoidectomy did not demonstrate a decrease in postoperative rescue analgesic requirements compared with morphine 50 g/kg. 12 After a preoperative fasting period of a minimum of 6 hours, all patients received a standardized anesthetic regimen that included premedication with oral midazolam 0.5 mg/kg (maximum of 10 mg), and induction with sevoflurane and nitrous oxide in oxygen via facemask. Endotracheal intubation was facilitated with 0.5 mg/kg atracurium. The study drug was administered over a 10-minute period immediately after endotracheal intubation. Anesthesia was maintained with sevoflurane and nitrous oxide in oxygen, adjusted to maintain heart rate and arterial blood pressure within 20% of preinduction levels. No additional opioid, acetaminophen, or propofol was used during the procedure. Intraoperative dexamethasone 0.5 mg/kg (maximum dose of 20 mg), IV antibiotics, and ondansetron 0.15 mg/kg (maximum of 4 mg) were administered per routine intraoperative management of tonsillectomy and adenoidectomy patients at our institution. All patients received a lactated Ringer solution infusion for fluid maintenance and deficit replacement. Replacement of calculated fluid deficit was commenced in the operating room and completed in the postanesthetic care unit (PACU). Neuromuscular blockade was antagonized with neostigmine 0.07 mg/kg and glycopyrrolate 0.01 mg/kg at the end of the operation and anesthetic gases were discontinued. The trachea was extubated when patients were awake as defined by eye opening, purposeful movement, or response to command. The child was then transported to the PACU with supplemental oxygen. Oxygen administration was continued after extubation until the patient was awake and could sustain room air saturations 95% for 5 minutes. Duration of oxygen requirement was recorded as the time from tracheal extubation to cessation of oxygen supplementation in the PACU. Data for each individual patient were obtained by 1 of 2 observers who were blinded to patient assignment. Routine vital signs, Ramsay sedation score, 13 and Children s Hospital of Eastern Ontario Pain Scale 14 score were measured and recorded on arrival in the PACU at 5, 10, and 15 minutes, and then every 15 minutes until the child was discharged. Patients with a Children s Hospital of Eastern Ontario Pain Scale score 8 received morphine 25 g/kg IV at 10-minute intervals until the score was 8. Patients in the PACU who were crying, restless, disoriented, unresponsive to the parent s voice, with nonpurposeful thrashing movements requiring additional personnel to prevent bodily harm, and inconsolable even after parental presence, rescue analgesia and additional measures of comfort were considered to have emergence agitation. 15,16 Patients were considered ready for discharge from the PACU when they attained an Aldrete score 17 of 9 or more and were free from pain, nausea, and vomiting. The duration of surgery and anesthesia, time to first postoperative rescue analgesic, amount of rescue analgesic received, need for antiemetics, and total duration of PACU stay were also recorded. Statistical Analysis The primary outcome measure was the amount of postoperative rescue morphine required for analgesia during the patient s stay in the PACU. Secondary outcome measures were the time to first analgesic rescue, the number of patients who needed more than 1 analgesic rescue dose, the degree of sedation as determined by the Ramsay sedation score, oxygen requirement, heart rate, respiratory rate, time to discharge readiness, along with the incidence of emergence agitation and postoperative nausea and vomiting. Sample size calculation was based on the following assumptions. (1) The primary end point was the amount of morphine required in the PACU. (2) In a previous pilot study, there were no differences noted in postoperative rescue morphine administered to patients receiving dexmedetomidine 0.5 g/kg or morphine 50 g/kg. 12 We therefore assumed the rescue analgesic requirements in the morphine 50 g/kg group in the current study would be similar to those in the dexmedetomidine 0.5 g/kg group in the pilot study (rescue analgesic requirement: 46.75 25 g/kg morphine). (3) We assumed that the rescue analgesic requirements in the group receiving dexmedetomidine 1 g/kg would be 50% less than in the morphine 50 g/kg group. This was based on the adult study by Arain et al., 1 which showed a 66% reduction in postoperative opioid consumption in patients who had received this dose of dexmedetomidine compared with a group receiving morphine 80 g/kg. We thought it would be reasonable to base our power analysis on a more conservative estimate of a August 2010 Volume 111 Number 2 www.anesthesia-analgesia.org 491

Dexmedetomidine in Pediatric Tonsillectomy and Adenoidectomy Table 1. Demographic Data and Recovery Data in the Four Study Groups Dexmedetomidine (0.75 g/kg) Dexmedetomidine (1 g/kg) Morphine (50 g/kg) Morphine (100 g/kg) No. of patients 26 27 30 26 Age (y) 6.3 6.6 6.3 6.3 Male/female 8/18 11/16 15/15 10/16 Duration of surgery (mean SD) (min) 22.0 8.4 21.3 9.7 22.8 7.6 25.9 9.5 Duration of anesthesia (mean SD) (min) 48.0 19.3 44.7 10.8 43.3 9.7 49.5 13.3 Rescue morphine ( g/kg) (mean SD) 45.2 30.8 37.0 25.4 43.3 23.6 36.5 31.0 Morphine rescue doses (n) 0 dose 6 3 1 4 1 dose 2 14 13 14 1 dose 18 10* 16 8* Mean duration of oxygen supplementation (min SD) 17 11 19 12 20 19 18 14 Mean time to discharge readiness (min SD) 115 0.04 116 0.03 117 0.03 122 0.06 Emergence agitation, n (%) 5 (19) 4 (15) 4 (13) 1 (4) Nausea, n (%) 2 (8) 0 0 3 (11.5) Vomiting, n (%) 0 0 0 2 (8) All 4 groups were similar in patient demographics, operative timeline, and postoperative course. * P 0.05 versus dexmedetomidine 0.75 g/kg. 50% reduction in opioid use compared with a group receiving a smaller intraoperative dose of morphine (50 g/kg) than in the study by Arain et al. Based on these assumptions, we calculated that a sample size of 26 would have an 80% power of detecting a difference at a 0.05 level of significance. Data are presented as mean SD, numbers, and percentages. The postoperative opioid requirement, time to first analgesic rescue dose, and time to discharge readiness were compared using parametric 1-way analysis of variance (ANOVA) or the nonparametric Kruskal-Wallis test, after testing for normal distribution and equal variance. The numbers of patients who required more than 1 rescue analgesic dose in the PACU were compared by a 2 test. The Ramsay sedation scores and heart rate over time were compared among groups using the 2-way repeatedmeasures ANOVA. When indicated by a significant F statistic (ANOVA) or H statistic (Kruskal-Wallis) 0.05, specific significant differences were isolated using the Holm-Sidak and Dunn s methods, respectively. P values 0.05 were considered statistically significant. RESULTS One hundred ninety-four patients who qualified for the study were approached and 109 consented to participate, and 85 refused. The 109 patients were randomized after obtaining consent, and all were included in the analysis. All procedures were performed by 1 of 4 otolaryngologic surgeons with an even distribution of cases among the 4. There were no differences among the groups of patients with regard to age, gender, duration of surgery and anesthesia, the time to tracheal extubation, duration of oxygen supplementation in the PACU, and time to discharge readiness (Table 1). There were no significant differences in the mean amount of supplemental rescue opioid required among the 4 groups (Table 1). However, the median time to first postoperative rescue analgesic was significantly longer in the dexmedetomidine 1 g/kg and morphine 100 g/kg groups compared with the dexmedetomidine 0.75 g/kg and morphine 50 g/kg groups (P 0.01) (Fig. 1). In Figure 1. Kaplan-Meier curves for median time to first rescue opioid administration. Horizontal line indicates time at which 50% of patients in each medication group received the first postoperative dose of morphine. Dex dexmedetomidine. addition, the number of patients requiring 1 rescue analgesic dose was significantly higher in the dexmedetomidine 0.75 g/kg group compared with the dexmedetomidine 1 g/kg ( 2 4.293, P 0.03) and morphine 100 g/kg ( 2 6.231, P 0.013) groups, but not the morphine 50 g/kg group ( 2 0.885, P 0.347). There were no significant differences in the postoperative respiratory rate, oxygen saturation, or duration of supplemental oxygen therapy among the 4 groups. Eightyfive percent of the enrolled patients had at least 2 of 3 symptoms of obstruction: gasps while sleeping, snoring, and mouth breathing. None of these children exhibited signs of airway obstruction, prolonged oxygen requirement, or required unanticipated hospital admission after surgery. There were no differences in the preoperative heart rate among the groups, but 2-way repeated-measures ANOVA revealed a significantly slower postoperative heart rate in patients who received dexmedetomidine compared with patients who received morphine (Fig. 2). These differences were statistically significant at 5, 10, 15, and 30 minutes after arrival in the PACU. The Ramsay sedation score in the PACU decreased over time in all 4 groups, but there were no significant intergroup differences in sedation in the PACU over time using 2-way repeated-measures ANOVA (Fig. 3). By 60 minutes 492 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

Figure 2. Postoperative heart rate over time. Chart depicting postoperative heart rate compared with preoperative values. Patients receiving dexmedetomidine (Dex) had significantly slower heart rates compared with those who received morphine. Those who received morphine 50 or 100 g/kg had significantly increased heart rate in the first 15 minutes in the recovery room compared with preoperative values. 0 min arrival in the recovery room; preoperative (pre-op) baseline values. #P 0.002 dexmedetomidine 0.75 g/kg versus both morphine 100 and 50 g/kg. P 0.002 dexmedetomidine 1 g/kg versus both morphine 100 and 50 g/kg. *P 0.001 morphine 50 and 100 g/kg versus preoperative heart rate. P 0.001 versus preoperative heart rate. Figure 3. Ramsey sedation scores over time in the postanesthesia care unit (PACU). Sedation scores decreased over time in all groups. Dex dexmedetomidine. in the PACU, patients in all 4 groups had a mean Ramsay score 4. There were also no differences among the 4 groups in the incidence of emergence agitation. There were no unanticipated hospital admissions for analgesia, airway management, prolonged supplemental oxygen requirement, or emesis management and no patient required readmission for recurrent tonsillar bed bleeding. Of the 109 patients, 5 had nausea and 2 of these had associated emesis in the PACU, but no patient required admission for this complication. DISCUSSION This study was designed to determine the postoperative rescue opioid requirement among tonsillectomy and adenoidectomy patients receiving 2 different doses of dexmedetomidine (0.75 or 1 g/kg) and 2 different doses of morphine (50 or 100 g/kg). Our primary result demonstrated that there were no significant differences in postoperative morphine requirements among the 4 different treatment groups. We did demonstrate differences in 2 secondary outcomes: time to first analgesia, and number of children requiring 1 dose of morphine in the PACU. The time to first analgesia was longer and the number of children who required 1 dose of morphine in the PACU were decreased in the dexmedetomidine 1.0 g/kg and morphine 100 g/kg groups compared with the other groups (dexmedetomidine 0.75 g/kg and morphine 50 g/kg). Dexmedetomidine is a potent -2 agonist with an affinity for receptors that is 8 times greater than that of clonidine. The primary analgesic effect of dexmedetomidine is mediated via activation of the -2 receptors on the dorsal horn of the spinal cord and also by inhibition of substance P. 18 Adult studies have shown that intraoperative use of dexmedetomidine decreases postoperative opioid consumption. 1,19 However, this reduction in opioid requirement has been recently shown in only 1 pediatric study in which IV dexmedetomidine was used. 20 Reduction in opioid requirement was also noted in 2 studies in which dexmedetomidine was administered in children as a caudal analgesic. 21,22 The failure to show a statistically significant difference in the primary outcome in our study is related to the fact that the differences in opioid rescue requirements among the high-dose and low-dose dexmedetomidine and morphine groups was 17%, suggesting that the effect size was much lower than that assumed in the sample size calculation. Post hoc sample size calculations show that 200 patients per group would be required to August 2010 Volume 111 Number 2 www.anesthesia-analgesia.org 493

Dexmedetomidine in Pediatric Tonsillectomy and Adenoidectomy show a statistically significant difference between dexmedetomidine 1 g/kg and morphine 50 g/kg. The difference in effect size noted in our study may be related to differences in patient population (pediatric versus adult) and/or surgical procedure (adenotonsillectomy versus major inpatient surgery). Based on the small differences among the postoperative rescue opioid requirements for dexmedetomidine 0.5 g/kg used in the pilot study, and dexmedetomidine 0.75 and 1 g/kg used in this study, there may not be a dose response for dexmedetomidine and postoperative analgesic requirements. We did not obtain time-related pain scores or data on oral opioid use after discharge. Therefore, we cannot comment on the possibility that there was a doserelated residual analgesic effect of the intraoperative study drug on the time-related area under the pain curve after discharge. Previous studies have investigated the use of alternative non-opioid drug regimens for tonsillectomy and adenoidectomy including -2 agonists. 8 These drugs provide adequate analgesia without causing respiratory depression typically associated with opioid therapy. The perioperative use of the -2 agonist clonidine in pediatric adenotonsillectomy has been associated with findings of increased sedation and conflicting results on its effect on postoperative opioid consumption. 23,24 In our study, a single intraoperative dose of dexmedetomidine did not significantly increase sedation in the PACU, the time to tracheal extubation, discharge readiness, duration of supplemental oxygen requirement, or unanticipated hospital admission compared with the morphine groups. Our results suggest that benefits to administration of larger doses of dexmedetomidine for intraoperative analgesia in the studied patient population are limited to the secondary outcomes of a reduced frequency of additional rescue medications and the time to first rescue analgesia. It is important, however, to note that we studied a relatively healthy patient population and excluded children with documented sleep apnea by polysomnography because we were concerned that the use of a more rigid, fixed dose of morphine or dexmedetomidine required in the study protocol may subject these children to unacceptably greater risks for postoperative respiratory complications. In our institution, the threshold for ordering a polysomnogram varies among surgeons and is usually reserved for those with severe sleep apnea or an uncertain diagnosis of sleep-disordered breathing. Our local institution criteria for considering a diagnosis of sleep-disordered breathing include, but are not limited to, a history of snoring, mouth breathing, and periods of apnea while asleep, 25 and 85% of the enrolled patients had at least 2 of these symptoms. None of these children exhibited signs of airway obstruction, prolonged oxygen requirement, or required unanticipated hospital admission after surgery. A recent study suggested airway obstruction was decreased when dexmedetomidine was used for sedation for MRI scans in children with sleep apnea, compared with propofol. 26 However, the patients were not randomized in this study. It is also unclear if data from children undergoing nonpainful procedures such as MRI can be applied to the tonsillectomy patient population. An appropriately powered randomized controlled trial comparing dexmedetomidine and the current standard opioid regimen needs to be performed in children with documented sleep apnea by polysomnography to determine whether the incidence of airway obstruction is reduced after tonsillectomy. In the absence of such a study, we would urge caution in the use of dexmedetomidine in children with documented sleep apnea. Other potential side effects of concern with the use of dexmedetomidine include severe bradycardia. 27 29 This was not observed in any patient in our study, although patients who received dexmedetomidine had a slower heart rate over time compared with those who received morphine. We agree that dexmedetomidine should be used cautiously in patients with a critically ratedependent cardiac output because increased side effects may be observed. 11 As reported in 1 study, the benefit of dexmedetomidine administration just before the end of adenotonsillectomy procedures was a decreased incidence of emergence agitation compared with a placebo group. 30 In our study, the incidence of postoperative emergence agitation was similar after a single dose of dexmedetomidine or morphine given at induction. In summary, this prospective, randomized, doubleblind study suggests that total postoperative rescue opioid requirements were similar in tonsillectomy patients receiving intraoperative dexmedetomidine or morphine. However, the use of dexmedetomidine 1 g/kg and morphine 100 g/kg had the advantages of an increased time to first analgesic and a reduced need for additional rescue analgesia doses in the PACU. AUTHOR CONTRIBUTIONS OAO helped with study design, conduct of study, data analysis, and manuscript preparation; CDG, DRL, and EMF helped with conduct of study and manuscript preparation; JD and MM helped with conduct of study; MMW helped with data analysis; MFW helped with conduct of study, data analysis, and manuscript preparation. ACKNOWLEDGMENTS The authors thank Dean Andropoulos, MD, for encouragement and assistance with this study. The assistance of O Brien Smith, PhD, Tara McCartney, RPh, Carla Giannoni, MD, Marcelle Sulek, MD, recovery room nurses, and Stephen Stayer, MD, is also greatly appreciated. REFERENCES 1. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg 2004;98:153 8 2. 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 3. Al-Metwalli RR, Mowafi HA, Ismail SA, Siddiqui AK, Al- Ghamdi AM, Shafi MA, El-Saleh AR. Effect of intra-articular dexmedetomidine on postoperative analgesia after arthroscopic knee surgery. Br J Anaesth 2008;101:395 9 4. Tufanogullari B, White PF, Peixoto MP, Kianpour D, Lacour T, Griffin J, Skrivanek G, Macaluso A, Shah M, Provost DA. Dexmedetomidine infusion during laparoscopic bariatric surgery: the effect on recovery outcome variables. Anesth Analg 2008;106:1741 8 494 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

5. Unlugenc H, Gunduz M, Guler T, Yagmur O, Isik G. The effect of pre-anaesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patientcontrolled morphine. Eur J Anaesthesiol 2005;22:386 91 6. Lubisch N, Roskos R, Berkenbosch JW. Dexmedetomidine for procedural sedation in children with autism and other behavior disorders. Pediatr Neurol 2009;41:88 94 7. Mason KP, Zgleszewski SE, Prescilla R, Fontaine PJ, Zurakowski D. Hemodynamic effects of dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth 2008;18: 393 402 8. Englelhardt T, Steel E, Johnston G, Veitch DY. Tramadol for pain relief in children undergoing tonsillectomy: a comparison with morphine. Paediatr Anaesth 2003;13:249 52 9. Brown KA, Laferriere A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia. Anesthesiology 2004;100:806 10 10. Moiniche S, Romsing J, Dahl JB, Tramer MR. Nonsteroidal antiinflammatory drugs and the risk of operative site bleeding after tonsillectomy: a quantitative systematic review. Anesth Analg 2003;96:68 77 11. Hammer GB, Drover DR, Cao H, Jackson E, Williams GD, Ramamoorthy C, Van Hare GF, Niksch A, Dubin AM. The effects of dexmedetomidine on cardiac electrophysiology in children. Anesth Analg 2008;106:79 83 12. Olutoye O, Kim T, Giannoni C, Stayer S. Dexmedetomidine as an analgesic for pediatric tonsillectomy and adenoidectomy. Paediatr Anaesth 2007;17:1007 8 13. McGrath PJ, Johnson G, Schillinger J. CHEOPS: a behavioral scale for rating postoperative pain in children. Adv Pain Res Ther 1985;9:395 402 14. Ramsay MA, Savage TM, Simpson BR. Controlled sedation with alphaxalone-alphadolone. BMJ 1974;2:656 9 15. Cole JW, Murray DJ, McAllister JD, Hirshberg GE. Emergence behaviour in children: defining the incidence of excitement and agitation following anaesthesia. Paediatr Anaesth 2002; 12:442 7 16. Voepel-Lewis T, Malviya S, Tait AR. A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit. Anesth Analg 2003;96:1625 30 17. Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg 1970;49:924 34 18. Tobias JD. Dexmedetomidine: applications in pediatric critical care and pediatric anesthesiology. Pediatr Crit Care Med 2007;8:115 31 19. Bulow NM, Barbosa NV, Rocha JB. Opioid consumption in total intravenous anesthesia is reduced with dexmedetomidine: a comparative study with remifentanil in gynecologic videolaparoscopic surgery. J Clin Anesth 2007;19:280 5 20. Al-Zaben KR, Qudaisat IY, Al-Ghanem SM, Massad IM, Al- Mustafa MM, Al-Oweidi AS, Abu-Halaweh SA, Abu-Ali HM, Saleem MM. Intraoperative administration of dexmedetomidine reduces the analgesic requirements for children undergoing hypospadius surgery. Eur J Anaesthesiol 2010;27:247 52 21. El-Hennawy AM, Abd-Elwahab AM, Abd-Elmaksoud AM, El-Ozairy HS, Boulis SR. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. Br J Anaesth 2009;103:268 74 22. Saadawy I, Boker A, Elshahawy MA, Almazrooa A, Melibary S, Abdellatif AA, Afifi W. Effect of dexmedetomidine on the characteristics of bupivacaine in a caudal block in pediatrics. Acta Anaesthesiol Scand 2009;53:251 6 23. Reimer EJ, Dunn GS, Montgomery CJ, Sanderson PM, Scheepers LD, Merrick PM. The effectiveness of clonidine as an analgesic in paediatric adenotonsillectomy. Can J Anaesth 1998;45:1162 7 24. Fazi L, Jantzen EC, Rose JB, Kurth CD, Watcha MF. A comparison of oral clonidine and oral midazolam as preanesthetic medications in the pediatric tonsillectomy patient. Anesth Analg 2001;92:56 61 25. Schwengel DA, Sterni LM, Tunkel DE, Heitmiller ES. Perioperative management of children with obstructive sleep apnea. Anesth Analg 2009;109:60 75 26. Mahmoud M, Gunter J, Donnelly LF, Wang Y, Nick TG, Sadhasivam S. A comparison of dexmedetomidine with propofol for magnetic resonance imaging sleep studies in children. Anesth Analg 2009;109:745 53 27. Mason KP, Zgleszewski S, Forman RE, Stark C, DiNardo JA. An exaggerated hypertensive response to glycopyrrolate therapy for bradycardia associated with high-dose dexmedetomidine. Anesth Analg 2009;108:906 8 28. Candiotti KA, Bergese SD, Bokesch PM, Feldman MA, Wisemandle W, Bekker AY, for the MAC Study Group. Monitored anesthesia care with dexmedetomidine: a prospective, randomized, double-blind, multicenter trial. Anesth Analg 2010; 110:47 56 29. Gerlach AT, Murphy CV. Dexmedetomidine-associated bradycardia progressing to pulseless electrical activity: case report and review of the literature. Pharmacotherapy 2009;29:1492 30. Guler G, Akin A, Tosun Z, Ors S, Esmaoglu A, Boyaci A. Single-dose dexmedetomidine reduces agitation and provides smooth extubation after pediatric adenotonsillectomy. Paediatr Anaesth 2005;15:762 6 August 2010 Volume 111 Number 2 www.anesthesia-analgesia.org 495