A comparison of intranasal dexmedetomidine for sedation in children administered either by atomiser or by drops

Original Article doi:10.1111/anae.13407 A comparison of intranasal dexmedetomidine for sedation in children administered either by atomiser or by drops B. L. Li, 1 N. Zhang, 2 J. X. Huang, 1 Q. Q. Qiu, 2 H. Tian, 3 J. Ni, 4 X. R. Song, 4 V. M. Yuen 5 and M. G. Irwin 6 1 Attending, 2 Resident, 3 Associate Consultant, 4 Consultant, Department of Anaesthesiology, Guangzhou Women and Children s Medical Centre, Guangzhou Medical University, Guangzhou, China 5 Consultant, Department of Anaesthesiology, University of Hong Kong Shenzhen Hospital, Shenzhen, China 6 Head and Professor, Department of Anaesthesiology, University of Hong Kong, Hong Kong, China Summary Intranasal dexmedetomidine has been used successfully for sedation in children. A mucosal atomisation device delivers an atomised solution to the nasal mucosa which facilitates rapid and effective delivery of medication to the systemic circulation. We compared intranasal delivery of dexmedetomidine in a dose of 3 lg.kg 1 by either atomiser or drops from a syringe in children < 3 years old undergoing transthoracic echocardiography. Two hundred and seventy-nine children were randomly assigned to one or other group. One hundred and thirty-seven children received dexmedetomidine by atomiser and 142 by drops. The successful sedation rate was 82.5% (95% CI 75.3 87.9%) and 84.5% (95% CI 77.7 89.5%) for atomiser and drops, respectively (p = 0.569). Sedation tended to be less successful in older children (p = 0.028, OR 0.949, 95% CI 0.916 0.983). There were no significant complications. We conclude that both modes of dexmedetomidine administration are equally effective, although increasing age of the child was associated with a decreased likelihood of successful sedation.... Correspondence to: X. R. Song Email: sxjess@126.com Accepted: 18 January 2016 Keywords: atomizer; drops; intranasal dexmedetomidine; paediatric; sedation This article is accompanied by an editorial by Bailey, Anaesthesia 2016; 71: 501 5. Introduction Transthoracic echocardiography is important in evaluating children with suspected cardiac conditions. Although not painful, sedation is often necessary in order to obtain a complete and accurate examination in young children. Dexmedetomidine is a highly selective a2-adrenoreceptor agonist with dose-dependent sedative and mild analgesic effects [1]. It may cause a reduction in heart rate and blood pressure, but there is little evidence that it causes respiratory depression [2]. Administration of dexmedetomidine by the intranasal route has become a popular technique for sedation in children because it is non-invasive, convenient, relatively fast in onset and effective [3 5]. When intranasal dexmedetomidine was administered by drops in doses of 1 lg.kg 1 and 2 lg.kg 1 for pre-medication before surgery in children aged 1 8 years, approximately 53% and 66% of children, respectively, were 522 2016 The Association of Anaesthetists of Great Britain and Ireland

Li et al. Intranasal dexmedetomidine Anaesthesia 2016, 71, 522 528 satisfactorily sedated at the time of anaesthetic induction [3]. When intranasal dexmedetomidine administered by drops was used as a primary sedative for computerised tomography, the success rate with 2 lg.kg 1 and 3 lg.kg 1 was approximately 90% and 93%, respectively [6]. In addition, intranasal dexmedetomidine has been shown to be an effective rescue sedative following failed chloral hydrate sedation in children [7]. We have used intranasal dexmedetomidine as a sedative for transthoracic echocardiography examination in young children. In a series of 115 children the successful sedation rate was 87% when the drug was administered using a mucosal atomisation device (MAD300; Wolf Tory Medical Inc., Salt Lake City, UT, USA) in a dose of 3 lg.kg 1 [8]. Administration of ketamine and midazolam by atomisation is associated with significantly less adverse behaviour compared with administration by drops in children undergoing dental procedures [9, 10]. However, the rate of successful sedation was not affected by the mode of administration in these studies. Unlike midazolam, administration of dexmedetomidine intranasally is not associated with unpleasant taste or sensation. Previous studies comparing atomisation with drops were either retrospective or contained small numbers of patients. We therefore decided to compare the efficacy of intranasal dexmedetomidine when administered by an atomisation device or by drops in young children undergoing transthoracic echocardiography. Methods Following approval by the local research ethics committee written, informed consent was obtained from each parent or legal guardian. Children of ASA physical status 1 3, aged between 2 months and 36 months and scheduled to undergo transthoracic echocardiography examination, were enrolled in the study. Exclusion criteria were known allergy or hypersensitivity to dexmedetomidine, renal or hepatic dysfunction, nasal discharge and learning difficulties. Each child received intranasal preservative-free dexmedetomidine (Jiangsu Hengrui Medicine Co. Ltd., Jiangsu, China) at a concentration of 100 lg.ml 1. They were randomly assigned to one of two groups: an atomiser group or a drops group depending on the mode of administration. Randomisation was stratified by age: infants (2 12 months old); and toddlers (> 12 months old). The randomisation list by blocks of 10 was revealed by an independent investigator using computer-generated randomisation software. Sealed, opaque envelopes were prepared with group assignment. The nurse who was responsible for drug administration opened the envelopes in sequence for each recruited subject. The undiluted drug was drawn up in a 1 ml tuberculin syringe. Children were given intranasal dexmedetomidine in a dose of 3 lg.kg 1 by atomiser or by drops by the nurse who had opened the envelope. All observations and data collection were performed by a nurse or anaesthetist who was blinded as to the method of drug administration. An equal volume of drug was administered to each nostril when the child was in a recumbent position. The drug was administered as quickly as possible to ensure the atomisation effect in the group receiving dexmedetomidine by atomisation while the drug was dripped slowly into the nose in the group receiving dexmedetomidine by drops. The children were encouraged to remain in the recumbent position for 1 2 min in order to maximise drug absorption. Behaviour during intranasal drug administration was evaluated on a fourpoint scale (Table 1). Oxygen saturation (SpO 2 ), heart Table 1 Evaluation scales used in the study. Behaviour scores 1 Calm and cooperative 2 Anxious but reassurable 3 Anxious and not re-assurable 4 Crying, or resisting University of Michigan Sedation Scale (UMSS) 0 Awake/alert 1 Minimally sedated: tired/sleepy, appropriately responds to verbal conversation and/or sounds 2 Moderately sedated: somnolent/sleeping, easily aroused with light tactile stimulation 3 Deeply sedated: deep sleep, arousable only with significant physical stimulation 4 Unarousable Movement scores 1 Not moving 2 Involuntary mild body movement 3 Involuntary moderate body movement 4 Purposeful body movement 2016 The Association of Anaesthetists of Great Britain and Ireland 523

Li et al. Intranasal dexmedetomidine rate (HR) and respiratory rate (RR) were measured at baseline and every 5 min after drug administration until discharge. Non-invasive blood pressure was measured at baseline and every 10 min. However, blood pressure measurement could be omitted before or after the procedure if the child was uncooperative or in distress. Sedation level using the University of Michigan Sedation Scale (UMSS, Table 1) and behaviour scores were recorded before, and every 5 min after, drug administration. Movement during echocardiography was evaluated by a blinded sonographer using a four-point movement score (Table 1). The parent or legal guardian was encouraged to awaken their child by gentle tactile stimulation after the examination had been completed. Discharge criteria included an UMSS score of 0 or 1 and an Aldrete Score of 9 or 10. Successful sedation was defined as a UMSS of 2 4 or if the child tolerated echocardiography examination with no physical restraint. Sedation onset time was the time to attain satisfactory sedation after intranasal drug administration. Waiting time was from the onset of sedation until the time when echocardiography commenced. Wake-up time was from intranasal drug administration until the child attained a UMSS of 0 or 1. Prolonged sedation was defined as the inability of a patient to meet discharge criteria 1 h after completion of the echocardiogram. Bradycardia was defined as more than a 20% reduction in heart rate from baseline or from the lower limit of published normal values for age [11], whichever was lower. Since only a small number of subjects had blood pressure measured at baseline, hypertension or hypotension was defined as a systolic blood pressure of 20% higher or lower than the published normal values for age [11]. Hypoxia was defined as SpO 2 93% or 5% decrease from baseline. The primary outcome was the proportion of children who were satisfactorily sedated, allowing completion of an echocardiographic examination. In a pilot study at our institution, the success rate of 3 lg.kg 1 intranasal dexmedetomidine administered by atomisation device was 87% in a series of 115 children. If we were to show that administration of intranasal dexmedetomidine by drops was non-inferior to atomisation, and we defined administration of dexmedetomidine by drops to be non-inferior when the success rate was, at most, 10% less than that by atomisation, 140 children per group would be associated with an 80% power and a one-sided 97.5% confidence interval. Secondary outcome measures included: depth of sedation; behavioural response to drug delivery; onset time; wake-up time; duration of sedation; movement scores; haemodynamic effects; and adverse events. The difference between the two modes of administration was analysed by logistic regression adjusted for age. The relationship between age and sedation success rate was analysed by logistic regression. The mean sedation onset time, duration of sedation and wake-up time were compared between groups using Mann Whitney U test. Categorical data were analysed by chisquare test. Analysis of sedation onset time, duration of sedation, wake up time, discharge time, sedation scores and movement scores were performed on children who were successfully sedated. The statistical software used was SPSS for Windows version 21.0 (SPSS Inc., Chicago, IL, USA) and a p value of < 0.05 was considered statistically significant. Results Figure 1 shows the CONSORT flow diagram for the 280 patients included in the study. One patient did not complete the study because echocardiography was cancelled after recruitment. One hundred and thirty-seven children received 3 lg.kg 1 intranasal dexmedetomidine via an atomiser and 142 children received intranasal dexmedetomidine by drops. Baseline characteristics and the clinical indications for echocardiography are shown in Table 2. Table 3 shows the primary and secondary outcomes measured. The successful sedation rate was 82.5% (95% CI 75.3 87.9%) and 84.5% (95% CI 77.7 89.5%) in the atomiser and drops groups, respectively. There was a significant decreasing trend in the proportion of successful sedation related to patient age (p = 0.028, OR 0.95, 95% CI 0.92 0.98). The estimated odds of successful sedation decreased by 0.95 for each 1 month increase in age. The median sedation onset times, times from onset of sedation until the procedure commenced, duration of procedure, wake-up times and discharge times were no different between the two 524 2016 The Association of Anaesthetists of Great Britain and Ireland

Li et al. Intranasal dexmedetomidine Anaesthesia 2016, 71, 522 528 Enrollment Assessed for eligibility (n = 382) Excluded (n = 102) Not meeting inclusion criteria (n = 13) Refused to participate (n = 89) Randomised (n = 280) Allocated to intervention (n = 138) Received allocated intervention (n = 138) Did not receive allocated intervention (give reasons) (n = 0) Allocation Allocated to intervention (n = 142) Received allocated intervention (n = 142) Did not receive allocated intervention (give reasons) (n = 0) Lost to follow-up (give reasons) (n = 1) (Echocardiograph cancelled after patient was enrolled) Discontinued intervention (give reasons) (n = 0) Follow-Up Lost to follow-up (give reasons) (n = 0) Discontinued intervention (give reasons) (n = 0) Analysed (n = 137) Excluded from analysis (give reasons) (n = 0) Analysis Analysed (n = 142) Excluded from analysis (give reasons) (n = 0) Figure 1 CONSORT flow diagram of patients included in the study. groups. There were no differences in behaviour scores between the groups at drug administration (p = 0.23) (Table 4). There was also no difference in sedation scores between the two groups during the procedure (p = 0.44) and no difference in movement scores between the two groups during the procedure (p = 0.19). The mean age of children who had successful and failed sedation was 13.4 (95% CI 12.3 14.5) months and 17.5 (95% CI 14.8 20.2) months, respectively. Children who had successful sedation were significantly younger than the children who had failed sedation (p = 0.003). Sedation onset times were not correlated with age in either group (r = 0.029 and r = 0.105 in atomiser and drop groups, respectively) and neither were wakeup times (r = 0.063 and r = 0.051 in atomiser and drop groups, respectively). Wake-up time was positively correlated with the duration of the procedure in both groups with a Pearson correlation coefficient (r) of 0.27 for the atomiser group (p = 0.004) and 0.26 for the drops group (p < 0.004). One patient in each group had prolonged sedation (65 min and 100 min in the atomiser and drops groups, respectively). No patient suffered from bradycardia, but nine patients were hypotensive at some point during the study period, although none required intervention. There were no episodes of oxygen desaturation or respiratory depression. Discussion Since we first reported the feasibility of the technique [5], intranasal dexmedetomidine has been used increasingly for sedation in children undergoing nonpainful procedures [12]. This is the first prospective, randomised trial to compare administration by atomisation with drops. In young children aged 2 months to 3 years the success rate, at a dose of 3 lg.kg 1 was not affected by the mode of administration. Atomisation of intranasal drugs by MAD device produces fine particles (30 100 lm in diameter) and is thought to increase drug absorption and bioavailability [13]. However, previous paediatric studies have shown that it was not superior when it was used to administer midazolam [9] or ketamine [10] in terms of sedation suc- 2016 The Association of Anaesthetists of Great Britain and Ireland 525

Li et al. Intranasal dexmedetomidine Table 2 Baseline characteristics of patients included in the study. Values are median (IQR [range]) or number (proportion). Atomiser group (n = 137) Drops group (n = 142) Age; months 13 (6 20 [2 42]) 13 (7 19 [3 38]) Weight; kg 9 (8 11 [4 15]) 10 (8 11 [4 18]) Sex; male 80 (58%) 90 (63%) Presumed diagnosis Congenital heart 63 (46%) 61 (43%) disease Physical examination 47 (34%) 45 (31%) Kawasaki disease 25 (18%) 33 (23%) Obstructive 1 (0.7%) 0 sleep apnoea Others 1 (0.7%) 3 (2%) ASA physical status; 1:2:3 47: 88: 2 47: 89: 6 cess rate. In a pharmacokinetic study of intranasal diazepam in four dogs, the bioavailability was no different when it was administered by atomisation or by drops [14]. Similarly, in the current study, we have shown that administration by atomisation is not superior to drops when intranasal dexmedetomidine is used in children under 3 years of age. Atomisation of both intranasal midazolam and ketamine was associated with significantly less adverse behaviour in children [9, 10], probably because the smaller particle size is associated with less discomfort during administration. However, the behavioural scores in our study were the same for both groups and this may be related to the fact that administration of intranasal dexmedetomidine is not usually associated with any unpleasant sensation [15]. Table 4 Behaviour, sedation and movement scores of patients included in the study. Values are number (proportion). Atomiser group Drops group p value Behaviour score at (n = 137) (n = 142) drug administration 1 17 (13%) 14 (10%) 0.23 2 70 (51%) 65 (46%) 3 39 (28%) 56 (39%) 4 11 (8%) 7 (5%) UMSS score during (n = 113)* (n = 120)* procedure 1 5 (4%) 7 (6%) 0.44 2 67 (59) 63 (52%) 3 32 (28%) 33 (28%) 4 9 (8) 17 (14%) Movement score (n = 113) (n = 120) during procedure 1 44 (39%) 59 (49%) 0.19 2 60 (53%) 51 (43%) 3 9 (8) 8 (7%) 4 0 2 (2%) *Only those who were successfully sedated were included in the analysis. UMSS, University of Michigan Sedation Scale. The bioavailability of transmucosal dexmedetomidine has been shown to be between 65% and 80% [16, 17] and it is possible that atomisation only offers a marginal improvement compared with drops that does not translate into a significant clinical effect. It is also possible that there is a ceiling effect to dexmedetomidine for sedation and if the ceiling is below 3 lg.kg 1, increasing the dose or optimising absorption would not be associated with an improvement in clinical effect. However, a previous investigation demonstrated that increasing the intravenous dexmedetomidine dose from 2 lg.kg 1 to 3 lg.kg 1 Table 3 Sedation success rate, sedation times and other timings of patients included in the study. Values are proportion (95% CI) or median (IQR [range]). Atomiser group Drops group (n = 137) (n = 142) p value Success rate 82.5% (75.3% 87.9%) 84.5% (77.7% 89.5%) 0.57 (n = 113)* (n = 120)* Sedation onset time; min 15 (14 25 [7 55]) 15 (13 20 [4 45]) 0.54 Time from onset of sedation until procedure commenced; min 10 (5 15 [0 47]) 11 (8 18 [1 38]) 0.07 Duration of procedure; min 5 (3 7 [2 42]) 5 (4 7 [2 30]) 0.57 Time from drug administration until wake up; min 41 (35 50 [19 84]) 42 (35 50 [17 145]) 0.52 Time to wake up after completion of the procedure; min 4 (2 9 [0 61]) 5 (2 8 [0 97]) 0.31 Discharge time; min 45 (40 55 [23 105]) 46 (40 55 [20 150]) 0.48 *Only those who were successfully sedated were included in the analysis. 526 2016 The Association of Anaesthetists of Great Britain and Ireland

Li et al. Intranasal dexmedetomidine Anaesthesia 2016, 71, 522 528 was associated with an increase in sedation success rate in children undergoing magnetic resonance imaging [18]. Another study [1] and a case report [19] have suggested that high doses of intravenous dexmedetomidine produce a general anaesthetic state, hence a ceiling effect may not be an explanation for the lack of difference between atomisation and drops. In order to produce a fine mist using the atomisation device, one needs to apply brisk high pressure to the atomiser. It has been shown in a silicone human nose model that insertion depth, angle of administration as well as head position affect drug deposition [20]. It is possible that obtaining optimal head position and spray angle may improve deposition and bioavailability when using the atomiser, but this is likely to be difficult in paediatric clinical practice. Although transthoracic echocardiography is not painful, complete examination requires the child to be immobile. Most echocardiography studies were completed within 10 min in our centre. For studies as brief as this, intravenous sedation with propofol or midazolam may also be suitable choices but this necessitates intravenous cannulation, careful titration, possible discomfort, repeated dosing and a higher risk of respiratory and cardiovascular adverse events. Chloral hydrate is another commonly used sedative in a number of countries and is associated with a high success rate in young children for echocardiographic studies [21]. However, in a retrospective report that included more than 1000 children, approximately 11% experienced adverse events which included apnoea, airway obstruction, oxygen desaturation, hypercarbia, hypotension, vomiting and prolonged sedation [22]. Approximately 7% of the sedated children in that study required minor medical intervention and 0.5% required major medical intervention which included fluid therapy, oxygenation, bag-mask ventilation and even tracheal intubation. By contrast we did not experience any major adverse events related to intranasal dexmedetomidine sedation in our study and no medical intervention was required in any patient. The majority of our children, including those with suspected congenital heart disease, were of ASA physical status 1 or 2. The effect of dexmedetomidine sedation on children with unrepaired congenital heart disease causing systemic effects would be an interesting area for future research. In our hospital, the cost of using an atomiser for intranasal drug administration is 8.70 (USD12.90, Euro 11.81) while using simple drops is negligible. Although the atomiser may allow easier and quicker drug administration, it may not be cost effective compared with drops. In conclusion, 3 lg.kg 1 intranasal dexmedetomidine administered by either an atomisation device or drops is a feasible choice for sedation of young children undergoing transthoracic echocardiography. Although the safety and efficacy is not affected by the mode of administration, increasing age is associated with a decreased rate of successful sedation whichever mode of administration is used. Acknowledgements We thank J.S.F. Man, Department of Anaesthesiology, University of Hong Kong, for statistical analysis. We also thank J. Miller, Department of Anesthesiology, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Ohio, USA, for making critical revisions of the manuscript. Competing interests No competing interests and no external funding declared. References 1. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000; 93: 382 94. 2. Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesthesia and Analgesia 2000; 90: 699 705. 3. Yuen VM, Hui TW, Irwin MG, et al. A randomised comparison of two intranasal dexmedetomidine doses for premedication in children. Anaesthesia 2012; 67: 1210 6. 4. Yuen VM, Hui TW, Irwin MG, Yao TJ, Wong GL, Yuen MK. Optimal timing for the administration of intranasal dexmedetomidine for premedication in children. Anaesthesia 2010; 65: 922 9. 5. 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. Anesthesia and Analgesia 2008; 106: 1715 21. 6. Li BL, Song XR, Li YQ, Li YM, Liu QX. The effectiveness and safety of intranasal dexmedetomidine and oral chloral hydrate for pediatric CT sedation. Journal of Clinical Anesthesiology 2013; 29: 859 62. 2016 The Association of Anaesthetists of Great Britain and Ireland 527

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