A Comparison of Intranasal Dexmedetomidine and Oral
`Midazolam for Premedication in Pediatric Anesthesia: A
`Double-Blinded Randomized Controlled Trial
`
`Vivian M. Yuen, MBBS, FANZCA,
`FHKCA, FHKAM
`
`Theresa W. Hui, MBBS, FANZCA,
`FHKCA, FHKAM
`
`Michael G. Irwin, MBChB, MD,
`FRCA, FHKCA, FHKAM
`
`Man K. Yuen, MBBS, FANZCA,
`FHKCA, FHKAM
`
`BACKGROUND: Midazolam is the most commonly used premedication in children. It
`has been shown to be more effective than parental presence or placebo in reducing
`anxiety and improving compliance at induction of anesthesia. Clonidine, an ␣
`2
`agonist, has been suggested as an alternative. Dexmedetomidine is a more ␣
`2
`selective drug with more favorable pharmacokinetic properties than clonidine. We
`designed this prospective, randomized, double-blind, controlled trial to evaluate
`whether intranasal dexmedetomidine is as effective as oral midazolam for pre-
`medication in children.
`METHODS: Ninety-six children of ASA physical status I or II scheduled for elective
`minor surgery were randomly assigned to one of three groups. Group M received
`midazolam 0.5 mg/kg in acetaminophen syrup and intranasal placebo. Group D0.5
`and Group D1 received intranasal dexmedetomidine 0.5 or 1 ␮g/kg, respectively,
`and acetaminophen syrup. Patients’ sedation status, behavior scores, blood pres-
`sure, heart rate, and oxygen saturation were recorded by an observer until
`induction of anesthesia. Recovery characteristics were also recorded.
`RESULTS: There were no significant differences in parental separation acceptance,
`behavior score at induction and wake-up behavior score. When compared with
`group M, patients in group D0.5 and D1 were significantly more sedated when they
`were separated from their parents (P ⬍ 0.001). Patients from group D1 were
`significantly more sedated at induction of anesthesia when compared with group
`M (P ⫽ 0.016).
`CONCLUSIONS: Intranasal dexmedetomidine produces more sedation than oral mi-
`dazolam, but with similar and acceptable cooperation.
`(Anesth Analg 2008;106:1715–21)
`
`One of the challenges for pediatric anesthesiologists
`
`is to minimize distress for children in the operating
`room (OR) environment and to facilitate a smooth
`induction of anesthesia. This is often accomplished by
`prior administration of a sedative drug before transfer
`to the OR. Midazolam is the most commonly used
`drug for this purpose.1,2 Premedication with midazo-
`lam has shown to be more effective than parental
`presence or placebo in reducing anxiety and improv-
`ing compliance at induction of anesthesia.3,4 The benefi-
`cial effects of midazolam include sedation, anxiolysis,
`and reduction of postoperative vomiting.4 –9 A recent
`evidence-based clinical update has shown that oral
`
`From the Department of Anesthesiology, Queen Mary Hospital,
`University of Hong Kong, Hong Kong.
`Accepted for publication January 23, 2008.
`Presented at the “Gilbert Brown Prize Session” of the 2007
`Annual Scientific Meeting of the Australian and New Zealand
`College of Anaesthetists.
`Address correspondence and reprint requests to: Dr. Vivian M.
`Yuen, Department of Anaesthesiology, University of Hong Kong,
`Room 424, K Block, Queen Mary Hospital, Pokfulam Rd, Hong
`Kong. Address e-mail to vtang131@hku.hk.
`Copyright © 2008 International Anesthesia Research Society
`DOI: 10.1213/ane.0b013e31816c8929
`
`Vol. 106, No. 6, June 2008
`
`midazolam 0.5 mg/kg is effective in reducing both
`separation and induction anxiety in children, with
`minimal effect on recovery time.10 However, the ac-
`ceptability of oral midazolam by pediatric patients is
`only 70%.11 Other undesirable effects including rest-
`lessness, paradoxical reaction, and negative postop-
`erative behavioral changes have made it a less than
`ideal premedication.12–14 Although amnesia is consid-
`ered an advantage by some authorities, it has also
`been regarded as a possible disadvantage by others.15
`Clonidine, an ␣
`2-agonist, has been suggested as an-
`other option for premedication in children16 and pre-
`vious studies have shown it to be equally as effective
`as midazolam.17–19 Oral clonidine premedication has
`also been shown to reduce the incidence of sevoflurane-
`induced emergence agitation.20 Dexmedetomidine is a
`newer ␣
`2-agonist with a more selective action on the
`␣
`2-adrenoceptor and a shorter half-life. Its bioavailability
`is 81.8% (72.6–92.1%) when administered via the buccal
`mucosa.21 Yuen et al., in a randomized, crossover evalu-
`ation of healthy adult volunteers, demonstrated that
`intransal 1 and 1.5 ␮g/kg dexmedetomidine produces
`sedation in 45–60 min and peaks in 90–105 min. In
`addition, they observed only a modest reduction of
`heart rate (HR) and arterial blood pressure (BP).22
`
`1715
`
`Hospira, Exh. 2022, p. 1
`
`

`
`The purpose of this investigation was to test the
`hypothesis that intranasal dexmedetomidine is as
`effective as oral midazolam for preoperative anxi-
`olysis and sedation in children before induction of
`anesthesia.
`
`METHODS
`Subjects and Study Protocol
`After approval from the our local IRB and written
`informed consent from the patients’ parents or legal
`guardian, 96 children of ASA physical status I or II,
`aged between 2 and 12 years, scheduled to undergo
`elective minor surgery, were enrolled in this prospec-
`tive, randomized, double-blind, controlled trial. In
`appropriate instances when the child was mature
`enough to understand and discuss the need for pre-
`medication, patient assent was also obtained. Exclu-
`sion criteria included known allergy or hypersensitive
`reaction to dexmedetomidine or midazolam, organ
`dysfunction, cardiac arrhythmia or congenital heart
`disease, and mental retardation.
`Children were randomly allocated to one of the
`three groups by drawing lots. Since previous study of
`healthy adults has shown that the mean onset time for
`significant sedation after 1 ␮g/kg intranasal dexme-
`detomidine was approximately 45–60 min,22 all chil-
`dren received intranasal medication or placebo at
`approximately 60 min before induction of anesthesia.
`Oral medication or placebo was given at 30 min before
`induction of anesthesia. Group M received 0.5 mg/kg
`oral midazolam, up to a maximum 15 mg (5 mg/mL
`parenteral preparation) in 20 mg/kg acetaminophen
`syrup, and up to 1 g and 0.4 mL intranasal placebo
`(normal saline). Group D0.5 and Group D1 received
`intranasal dexmedetomidine at 0.5 ␮g/kg and 1
`␮g/kg, respectively, and 20 mg/kg oral acetamino-
`phen syrup. Intranasal dexmedetomidine was pre-
`pared from the 100 ␮g/mL parenteral preparation
`(Hospira®) in a 1-mL syringe; 0.9% saline was added
`to make a final volume of 0.4 mL. All study drugs
`were prepared by an independent investigator not
`involved in the observation or administration of anes-
`thesia for the children. Observers and attending anes-
`thesiologists were blinded to the study drug given.
`Children had premedication in the preoperative
`holding area in the presence of one parent. All chil-
`dren received EMLA® cream unless contraindicated.
`Baseline HR, oxygen saturation (Spo2), and BP were
`measured before any drug administration. Intranasal
`drug was dripped into both nostrils using a 1-mL
`syringe with the child in the recumbent position. HR,
`Spo2, and BP were measured before and every 15 min
`after intranasal drug administration until transfer to
`the OR. Sedation status was assessed by a blinded
`observer every 5 min with a 6-point sedation scale,
`which was modified from the Observer Assessment of
`Alertness and Sedation Scale (Table 1). Behavior was
`evaluated every 5 min with a 4-point behavior score
`
`Table 1. Evaluation Scale
`
`6
`
`4
`5
`
`Sedation scores
`1
`Does not respond to mild prodding or shaking
`2
`Responds only mild prodding or shaking
`3
`Responds only after name is called loudly or
`repeatedly
`Lethargic response to name spoken in normal tone
`Appear asleep but respond readily to name
`spoken in normal tone
`Appear alert and awake, response readily to name
`spoken in normal tone
`Behavior scores
`1
`Calm and cooperative
`2
`Anxious but reassurable
`3
`Anxious and not reassurable
`4
`Crying, or resisting
`Wake-up behavior scores
`1
`Calm and cooperative
`2
`Not calm but could be easily calmed
`3
`Not easily calmed, moderately agitated or restless
`4
`Combative, excited, disoriented
`
`(Table 1). A parent was allowed to accompany the
`child at induction if the child refused to be separated
`from his/her parent. The duration of premedication
`was approximately 60 min; however, it could be longer
`or shorter depending on the schedule of the OR.
`Sedation status and behavior were evaluated by the
`attending anesthesiologist at induction using the same
`scale. Mode of induction (IV versus inhalation) was
`decided by the attending anesthesiologist. The airway
`was maintained with a facemask or laryngeal mask
`airway throughout
`the operation. Anesthesia was
`maintained with isoflurane and 60% nitrous oxide in
`oxygen. Regional anesthesia was administered when-
`ever it was appropriate. When surgery was finished,
`the child was placed in the recovery position and
`allowed to wake up naturally in the postanesthesia
`care unit (PACU). Behavior at awakening was evalu-
`ated with a four-point wake-up score (Table 1). Time
`taken for readiness to be discharged from the PACU
`was recorded.
`
`Outcome Measures
`The primary end-points were behavior and seda-
`tion status at separation from the parent and at
`induction of anesthesia. Secondary end-points in-
`cluded systolic BP (SBP) and HR changes, wake-up
`behavior, and time until ready for discharge from the
`PACU. Standard discharge criteria were used in the
`PACU. Patients were discharged from the PACU to
`the ward when they were awake, with reasonable
`control of pain and with vital signs within 20% of
`baseline values. Observations of sedation status and
`vital signs, including HR and Spo2, were made at 5
`min and BP at 15 min intervals until the patient was
`ready to be discharged.
`
`Power Analysis
`In a previous study, about 70% of children demon-
`strated satisfactory sedation within 30 min of 0.5
`
`1716
`
`Intranasal Dexmedetomidine Pediatric Premedication
`
`ANESTHESIA & ANALGESIA
`
`Hospira, Exh. 2022, p. 2
`
`

`
`Table 2. Patients’ Demographic Data
`
`Age (yr)
`Body weight (kg)
`Sex, M:F
`Type of induction, gas: IV
`Type of surgery
`High ligation hydrocele/orchidopexy
`Excision lymph nodes or lumps
`Circumcision/other penile surgery
`Cystoscopy/colonoscopy/EUA
`Duration of surgery (min)
`Time from premedication to induction (min)
`Values in mean ⫾ SD 关range兴 or no. (%).
`EUA ⫽ examination under anesthesia.
`
`Group M
`(n ⫽ 32)
`6.4 ⫾ 3.0 关2–12兴
`24.1 ⫾ 8.6
`30:2
`12:20
`
`Group D0.5
`(n ⫽ 32)
`6.8 ⫾ 3.1 关2–12兴
`25.5 ⫾ 11.9
`29:3
`13:19
`
`Group D1
`(n ⫽ 32)
`6.1 ⫾ 2.7 关2–12兴
`21.6 ⫾ 5.8
`30:2
`9:23
`
`2 (6.3%)
`6 (18.8%)
`20 (62.5%)
`4 (12.5%)
`27.7 ⫾ 10.1 关10–50兴
`70.5 ⫾ 15.7 关40–105兴
`
`2 (6.3%)
`4 (12.5%)
`24 (75%)
`2 (6.3%)
`29.5 ⫾ 9.0 关15–50兴
`61.7 ⫾ 23.3 关20–120兴
`
`5 (15.6%)
`3 (9.4%)
`21 (65.6%)
`3 (9.4%)
`33.4 ⫾ 14.1 关15–85兴
`68.0 ⫾ 18.1 关40–110兴
`
`P
`0.615
`0.228
`0.857
`0.553
`
`0.657
`
`0.117
`0.180
`
`mg/kg oral midazolam6; hence, a sample size of 96 (32
`patients per group) provided 80% power at 0.05 level of
`significance to detect a 35% difference in the proportion
`of children who attain satisfactory sedation between oral
`midazolam and intranasal dexmedetomidine.
`
`Statistical Methods
`Sedation, behavior, and wake-up behavior scores
`were analyzed by Kruskal–Wallis test. When a signifi-
`cant result was obtained, the Mann–Whitney U-test
`was applied for post hoc pairwise comparisons. Cat-
`egorical data were analyzed by ␹2 test. The adjusted P
`value was applied to the post hoc pairwise compari-
`sons for nonparametric and categorical data. The
`adjusted P value for the 0.05 level of significance was
`0.017. Hemodynamic variables including BP and HR
`were analyzed by ANOVA. When a significant result
`was obtained, the Tukey test was applied for post hoc
`pairwise comparisons. The changes of BP and HR
`from baseline among the three groups were tested by
`Kruskal–Wallis t-test. The statistical software used
`was SPSS 15.0 for Windows (SPSS Inc., USA).
`For statistical analysis, sedation scores were catego-
`rized as being satisfactory when rated between 1 and
`4 and unsatisfactory when rated 5 or 6. Behavior
`scores and wake-up scores were categorized as satis-
`factory when they were 1 or 2, and unsatisfactory
`when they were 3 or 4.
`
`RESULTS
`Patients
`Demographic characteristics for all patients are
`summarized in Table 2. Patients in the three groups
`were comparable with respect to age, weight, gender,
`type of surgery, duration of surgery, and type of
`induction.
`Five of 96 (5.2%) children resisted intranasal drug
`administration and 1 of 91 (1%) resisted oral medica-
`tion. Five children (1 in group D0.5 and 4 in group D1)
`did not take the oral medication (placebo) because
`they were too sleepy. No child complained of pain or
`discomfort with intranasal drug administration. The
`
`children who resisted the medication were also in-
`cluded in the analysis.
`
`Assessment of Sedation and Behavior at Separation and
`at Induction
`The median sedation scores at separation from the
`parent were 6, 3, and 1.5 for groups M, D0.5, and D1,
`respectively. The sedation scores of children from
`group D0.5 and group D1 were significantly different
`from that of group M at separation from parents (P ⫽
`0.001 and ⬍0.001). Moreover, 21.9%, 59.4%, and 75%
`of the children from groups M, D0.5, and D1 achieved
`satisfactory sedation at separation from parents. There
`were significantly more children in groups D0.5 and
`D1 who achieved satisfactory sedation when compared
`with group M (P ⫽ 0.002 and ⬍0.001, respectively)
`(Table 3). The median sedation scores at induction were
`6, 5, and 4 for groups M, D0.5, and D1, respectively.
`Group D1 patients were significantly more sedated
`than group M at induction of anesthesia (P ⫽ 0.009).
`At induction of anesthesia, 18.8%, 40.6%, and 53.1%
`of
`the children from groups M, D0.5, and D1,
`respectively, were satisfactorily sedated. Signifi-
`cantly more children from group D1 achieved satis-
`factory sedation when compared with group M (P ⫽
`0.004) (Table 3).
`There was no evidence found for a difference in
`behavior scores at separation from parents and at
`induction of anesthesia among the three groups. All
`children except one in group M and two in group D0.5
`had satisfactory behavior at separation from parents
`(P ⫽ 0.771) (Table 3). Most children had satisfactory
`behavior at induction of anesthesia with no evidence
`of a difference among groups (P ⫽ 0.148) (Table 3).
`The proportion of children who had satisfactory be-
`havior at separation from parents, but became dis-
`tressed at induction of anesthesia, were 0%, 3.3%, and
`18.8% from groups M, D0.5, and D1, respectively.
`Although there was a tendency for more children who
`had received dexmedetomidine to develop unsatisfac-
`tory behavior at induction of anesthesia, and the P
`
`Vol. 106, No. 6, June 2008
`
`© 2008 International Anesthesia Research Society 1717
`
`Hospira, Exh. 2022, p. 3
`
`

`
`Table 3. Distribution of Behavior and Sedation Status at Parental Separation and at Induction, Proportion of Children Who Had
`Change of Behavior and Sedation from Satisfactory to Unsatisfactory at Induction, Time Ready for Discharge from Postanesthetic
`Care Unit (Minutes)
`
`Successful parental separation
`Yes
`No
`Sedation at separation from parent
`Satisfactory
`Unsatisfactory
`Behavior at induction
`Satisfactory
`Unsatisfactory
`Sedation at induction
`Satisfactory
`Unsatisfactory
`Change of behavior at induction from satisfactory
`to unsatisfactory
`n/total (%)
`Change of sedation at induction from Satisfactory
`to Unsatisfactory
`n/total (%)
`Values in number (%) or mean ⫾ SD.
`* Significantly different between Group M and Group D1 at 0.05 level.
`† Significantly different between Group M and Group D0.5 at 0.05 level.
`
`Table 4. Sedation Scores in Different Age Groups
`
`Age 2–5
`Baseline
`Separation from parent
`At induction
`
`Age 6–9
`Baseline
`Separation from parents
`At induction
`
`Group M
`(n ⫽ 15)
`
`6 关6–6兴
`6 关6–6兴
`6 关6–6兴
`
`Group M
`(n ⫽ 10)
`
`6 关6–6兴
`5.5 关4.75–6兴
`6 关5–6兴
`
`Group M
`(n ⫽ 7)
`
`Age 10–12
`Baseline
`Separation from parent
`At induction
`Values in median 关IQR兴.
`* Significantly different between Group M and Group D0.5 at 0.05 level.
`† Significantly different between Group M and Group D1 at 0.05 level.
`
`6 关6–6兴
`6 关1–6兴
`6 关1–6兴
`
`Group M
`
`Group D0.5
`
`Group D1
`
`31 (96.9%)
`1 (3.1%)
`
`7 (21.9%)
`25 (78.1%)
`
`31 (96.9%)
`1 (3.1%)
`
`6 (18.8%)
`26 (81.3%)
`
`30 (93.7%)
`2 (6.3%)
`
`19 (59.4%)
`13 (40.6%)
`
`29 (90.6%)
`3 (9.4%)
`
`13 (40.6%)
`19 (59.4%)
`
`32 (100%)
`0 (0%)
`
`24 (75%)
`8 (25%)
`
`26 (81.3%)
`6 (18.8%)
`
`17 (53.1%)
`15 (46.9%)
`
`P
`
`0.771
`
`⬍.001*†
`
`0.148
`
`0.016*
`
`0/31 (0)
`
`1/30 (3.3)
`
`6/32 (18.8%)
`
`0.012
`
`1/7 (14.3)
`
`6/19 (31.6)
`
`7/24 (29.2)
`
`0.828
`
`Group D0.5
`(n ⫽ 13)
`
`Group D1
`(n ⫽ 15)
`
`6 关6–6兴
`2 关1–5兴
`2 关1–5兴
`
`Group D0.5
`(n ⫽ 12)
`
`6 关6–6兴
`2.5 关1.25–5.75兴
`6 关4.25–6兴
`
`Group D0.5
`(n ⫽ 7)
`
`6 关6–6兴
`5 关3–6兴
`6 关5–6兴
`
`6 关6–6兴
`1 关1–2兴
`2 关2–6兴
`
`Group D1
`(n ⫽13)
`
`6 关6–6兴
`2 关1–6兴
`6 关3–6兴
`
`Group D1
`(n ⫽ 4)
`
`6 关6–6兴
`2 关1.25–2兴
`4.5 关2.5–5.75兴
`
`P
`
`0.393
`⬍.001*†
`⬍.001*†
`
`P
`
`0.287
`0.122
`0.691
`
`P
`
`1.000
`0.112
`0.527
`
`value from ␹2 test was 0.012, post hoc pairwise com-
`parisons did not reveal any significant difference
`among the three groups. Of the children from groups
`M, D0.5, and D1, respectively, 14.3%, 31.6%, and 29.2%
`were awoken by the transfer from the preoperative
`holding area to the OR. There was a tendency for more
`children who had received dexmedetomidine to
`awaken during this transfer, although these differ-
`ences were not statistically significant (P ⫽ 0.828)
`(Table 3).
`The median behavior score and sedation score were
`further analyzed with the children divided into three
`
`different age groups, age 2–5, age 6–9, and age 10–12
`yr. The median behavior scores at baseline, at separa-
`tion from parent, and at induction were not different
`among the children from groups M, D0.5, and D1 in all
`age groups. The median sedation scores of group D0.5
`and D1 were significantly different from that of group
`M at separation from parent and at induction in
`children of age 2–5 yr (Table 4). In age Group 2–5 yr,
`the median sedation scores at separation from parent
`were 6, 5, and 2 from group M, D0.5, and D1,
`respectively (P ⬍ 0.001). For the same age group, the
`median sedation scores at induction of anesthesia
`
`1718
`
`Intranasal Dexmedetomidine Pediatric Premedication
`
`ANESTHESIA & ANALGESIA
`
`Hospira, Exh. 2022, p. 4
`
`

`
`children from groups M, D0.5, and D1, respectively,
`were included in this analysis.
`There were significant group and time effects on
`SBP (P ⫽ 0.025 and ⬍0.001, respectively). There was
`no significant group ⫻ time interaction (P ⫽ 0.085).
`Post hoc analysis showed that SBP decreased signifi-
`cantly in group D1 when compared with group M
`(P ⫽ 0.004). Moreover, SBP decreased with time and it
`was significantly different from baseline at 30 min
`(P ⫽ 0.003), 45 min (P ⬍ 0.001), and 60 min (P ⬍ 0.001)
`after drug administration in group D1 (Figure 1). The
`SBP was reduced by 14.1% at 60 min in group D1.
`There was also a significant time effect on HR (P ⬍
`0.001) and group ⫻ time interaction (P ⬍ 0.001). The
`group effect on HR was not significant (P ⫽ 0.102).
`Post hoc analysis showed that HR decreased signifi-
`cantly with time in group D0.5 (P ⬍ 0.001) and group
`D1 (P ⬍ 0.001). The HR became significantly reduced
`from baseline at 45 and 60 min after drug administration
`in group D0.5 (P ⫽ 0.006 and ⬍0.001, respectively). The
`HR became significantly reduced from baseline at 45 and
`60 min after drug administration in group D1 (P ⬍ 0.001)
`(Fig. 2). It was decreased by 11.1% and 16.4% from
`baseline in group D0.5 and group D1 at 60 min, respec-
`tively, after drug administration.
`
`DISCUSSION
`Sedative and Anxiolytic Effects
`This prospective, double-blind, randomized, con-
`trolled trial compared intranasal dexmedetomidine
`and oral midazolam as premedication in healthy chil-
`dren between 2 and 12-yr-of-age. Children premedi-
`cated with 1 ␮g/kg of intranasal dexmedetomidine
`attained more significant and satisfactory sedation at
`parental separation and at induction of anesthesia
`than those patients who received oral midazolam. Al-
`though patients premedicated with 0.5 ␮g/kg dexme-
`detomidine were initially effectively sedated, these
`children were aroused more easily with external
`stimulation. Hence, the 0.5 ␮g/kg dose may not be
`adequate for children. Most children tolerated the
`intranasal and oral study drugs. Previous studies
`have shown that intranasal administration is an
`effective way to administer premedication and se-
`dation to children.23–25 It is a relatively easy and
`noninvasive route with a high bioavailability. How-
`ever, cooperation is still required and it may be
`more difficult in younger children. Oral administra-
`tion may be even more difficult in uncooperative
`children. Unlike conventional gabaminergic seda-
`tive drugs, such as midazolam, dexmedetomidine’s
`site of action in the central nervous system is
`primarily in the locus coeruleus where it induces
`electroencephalogram activity similar to natural
`sleep.26 It is, therefore, not surprising that external
`stimulation should facilitate arousal. Patients are
`also less likely to become disorientated and unco-
`operative. A recent study has demonstrated that
`
`© 2008 International Anesthesia Research Society 1719
`
`Figure 1. Mean systolic blood pressure ⫾ sd during the
`premedication period.
`
`Figure 2. Mean heat rate ⫾ sd during the premedication
`period.
`
`were 6, 2, and 2 for group M, D0.5, and D1, respec-
`tively (P ⬍ 0.001). These differences were not observed
`in older children (Table 4).
`Nine children receiving midazolam were noted to
`become euphoric or restless after premedication, but
`none after dexmedetomidine. As this paradoxical behav-
`ior was not prospectively sought in our observations as
`a priori outcome variable, it was not statistically tested.
`
`Respiratory and Hemodynamic Effects
`Overall, we did not observe any clinically signifi-
`cant effects of the study drugs on Spo2 and no child
`had a reduction of Spo2 to below 95% during the
`observation period after premedication.
`The mean SBP and HR during the premedication
`period are shown in Figures 1 and 2. Only children
`who stayed for more than 60 min after premedica-
`tion were included in the analysis of SBP and HR
`during the premedication period by repeated mea-
`sures of ANOVA. Consequently 25, 19, and 18
`
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`
`75% and 92% of adult healthy volunteers attained
`significant sedation after 1 and 1.5 ␮g/kg intranasal
`dexmedetomidine, respectively.22 In this investiga-
`tion, we have shown that 75% of
`the children
`attained a satisfactory level of sedation after 1 ␮g/kg
`intranasal dexmedetomidine. Moreover, 70.8% of
`these sedated patients allowed IV or inhaled induction
`without showing signs of distress or awakening. The
`doses of 0.5 and 1 ␮g/kg intranasal dexmedetomidine
`were chosen in this preliminary investigation in order
`to evaluate the lowest effective dose. Although 0.5
`␮g/kg intranasal dexmedetomidine produced effec-
`tive sedation at parental separation, it was not effec-
`tive when the children were transferred to the OR.
`Subgroup analysis revealed that children from age
`group 2–5 yr seemed to be more sedated with intra-
`nasal dexmedetomidine. However, the lack of a sig-
`nificant sedative effect of intranasal dexmedetomidine
`in age groups 6–9 and 10–12 could be real or due to an
`inadequate sample size. Since this study was not
`designed to investigate the sedative effect of intranasal
`dexmedetomidine in different age groups, we cannot
`draw a conclusion on this. Future studies could ad-
`dress the sedative effect of intranasal dexmedetomi-
`dine on children of varying ages. The reported seda-
`tive effects of midazolam are quite variable.
`Effective sedation has been reported to range from
`39% to 75%27–30 when a parenteral preparation was
`used for oral administration. In two different stud-
`ies, commercially prepared oral midazolam has
`been shown to produce satisfactory sedation in 97%
`and 81% of children.5,9 Our study has shown that
`only 21.9% of children receiving 0.5 mg/kg of oral
`midazolam were sedated. The great variability may be
`due to a difference in study design, different carrier
`vehicle for midazolam, and different bioavailabities of
`the midazolam preparation.
`Although previous studies have documented the
`effectiveness of oral midazolam as a preoperative
`anxiolytic,3,4,10,30 –32 our behavior scoring system did
`not allow us to evaluate the anxiety level of children.
`We have shown in this investigation that the behavior
`of children at separation from parents and at induc-
`tion of anesthesia were similar in children who received
`oral midazolam and intranasal dexmedetomidine based
`on our behavior scale. Although oral midazolam did not
`produce significant sedation in our subjects, it could
`have produced significant anxiolytic and/or amnesic
`effects. It is also uncertain if the sedative effect of
`intranasal dexmedetomidine is associated with any an-
`xiolytic effect. The use of other validated anxiety scales
`such as the modified Yale Preoperative Anxiety Scale33
`would allow evaluation of the change in anxiety level of
`children after premedication and to delineate the seda-
`tive effect from anxiolytic effect.
`
`Hemodynamic Effects
`␣
`2-Agonists produce a modest reduction in BP and
`HR. When dexmedetomidine is infused as an IV bolus
`
`at doses ranging from 0.25 to 2 ␮g/kg over 2 min in
`healthy volunteers,34 it causes a dose-dependent de-
`crease in BP ranging from 14% to 27%. When clonidine
`was given as premedication, it was shown to effec-
`tively attenuate the cardiovascular responses to tra-
`cheal intubation in children undergoing induction of
`anesthesia.18,19 In a recent study comparing midazo-
`lam, clonidine, and dexmedetomidine for premedica-
`tion in children, both clonidine and dexmedetomidine
`were shown to reduce mean BP and HR before and
`during surgery.17 In a pharmacokinetic study of IV
`dexmedetomidine in children, it was shown that 0.66
`and 1 ␮g/kg IV dexmedetomidine given over 10 min
`produced a significant reduction of HR (⬍15% com-
`pared with baseline) and SBP (⬍25% compared with
`baseline).35 Munro et al.36 reported that the reduction
`of blood pressure and HR were ⬍20% of baseline in
`children who were sedated with an initial dose of 1
`␮g/kg IV dexmedetomidine, followed by a mainte-
`nance infusion during cardiac catheterization. In this
`study, we have shown that preoperative 0.5 and 1
`␮g/kg intranasal dexmedetomidine reduces HR and
`blood pressure in healthy children during the first
`hour after drug administration.
`
`Limitations of this Study
`We did not evaluate the onset time and peak effect of
`the two doses of intranasal dexmedetomidine or the
`blood concentrations. The onset time of 1 and 1.5 ␮g/kg
`intranasal dexmedetomidine was about 45 min with a
`peak effect at 60–105 min after intranasal dexmedetomi-
`dine in healthy adults.22 In this study, the premedication
`period was 60 min for intranasal dexmedetomidine;
`however, some children were transferred to the OR
`slightly earlier in order not to interfere with the normal
`OR schedule. If a longer premedication period had been
`allowed, possibly more subjects could have attained
`satisfactory sedation at separation from parents and at
`induction of anesthesia.
`The sedation produced by dexmedetomidine dif-
`fers from other sedatives as patients may be easily
`aroused and cooperative. Some children who were
`premedicated with dexmedetomidine became dis-
`tressed when they were aroused at the induction of
`anesthesia, despite being very much sedated at the
`time of parental separation. Anesthetic technique may
`need to be adjusted to provide optimal conditions for
`induction in children sedated with dexmedetomidine.
`
`CONCLUSION
`Although midazolam is the most commonly used
`premedication in children, it may not be the most
`suitable preoperative sedative and anxiolytic in all
`children and in all circumstances. Finley et al.37 have
`shown that children with impulsive traits did not
`benefit from midazolam premedication. In this study,
`we have shown that 1 ␮g/kg intranasal dexmedeto-
`midine is another technique for producing sedation in
`
`1720
`
`Intranasal Dexmedetomidine Pediatric Premedication
`
`ANESTHESIA & ANALGESIA
`
`Hospira, Exh. 2022, p. 6
`
`

`
`children and it causes no discomfort during adminis-
`tration. Intranasal drug administration is relatively
`quick, simple, and may have benefits over transmu-
`cosal routes or rectal administration, which requires
`more patient cooperation. We have established that
`this route is feasible for dexmedetomidine administra-
`tion and future studies could now be directed to
`further evaluate the effect of this interesting drug on
`various outcome measures including preoperative
`anxiety levels, induction time, emergence excitation,
`postoperative analgesic requirements, and postopera-
`tive behavior disturbances.
`In summary, 1 ␮g/kg intranasal dexmedetomidine
`produces significant sedation in children between 2
`and 12-yr-of-age. Behavior of the children at parental
`separation and at induction of anesthesia was compa-
`rable to children who received oral midazolam. The
`hemodynamic effects of the two doses of intranasal
`dexmedetomidine were modest.
`
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