Anaesthesia 2016, 71, 522–528 doi:10.1111/anae.

13407

Original Article
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. Yuen5 and
M. G. Irwin6

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 deliv-
ers an atomised solution to the nasal mucosa which facilitates rapid and effective delivery of medication to the sys-
temic 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 sev-
enty-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 little evidence that it causes respiratory depression [2].

Transthoracic echocardiography is important in evalu-
ating 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 selec-
tive 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
Administration of dexmedetomidine by the intranasal
route has become a popular technique for sedation in
children because it is non-invasive, convenient, rela-
tively fast in onset and effective [3–5]. When intrana-
sal 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, approxi-
mately 53% and 66% of children, respectively, were

522 © 2016 The Association of Anaesthetists of Great Britain and Ireland

Li et al. | Intranasal dexmedetomidine
satisfactorily sedated at the time of anaesthetic induc-
tion [3]. When intranasal dexmedetomidine adminis-
tered 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 seda-
tion 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]. How-
ever, the rate of successful sedation was not affected
by the mode of administration in these studies. Unlike
midazolam, administration of dexmedetomidine intra-
nasally 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 echocardio-
graphy.
Methods
Following approval by the local research ethics com-
mittee written, informed consent was obtained from
each parent or legal guardian. Children of ASA physi-
cal status 1–3, aged between 2 months and 36 months
and scheduled to undergo transthoracic echocardiogra-
phy 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:
© 2016 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2016, 71, 522–528
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 tuber-
culin 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 enve-
lope. All observations and data collection were per-
formed by a nurse or anaesthetist who was blinded as
to the method of drug administration. An equal vol-
ume 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 dexmedeto-
midine by atomisation while the drug was dripped
slowly into the nose in the group receiving dexmedeto-
midine by drops. The children were encouraged to
remain in the recumbent position for 1–2 min in order
to maximise drug absorption. Behaviour during intra-
nasal drug administration was evaluated on a four-
point scale (Table 1). Oxygen saturation (SpO2), 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
523
Anaesthesia 2016, 71, 522–528
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 beha-
viour scores were recorded before, and every 5 min
after, drug administration. Movement during echocar-
diography 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 SpO2 ≤ 93% or ≥ 5% decrease from base-
line.
The primary outcome was the proportion of chil-
dren who were satisfactorily sedated, allowing com-
pletion 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-infer-
ior to atomisation, and we defined administration of
524
Li et al. | Intranasal dexmedetomidine
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 associ-
ated with an 80% power and a one-sided 97.5% con-
fidence 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 adminis-
tration 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 chi-
square test. Analysis of sedation onset time, duration
of sedation, wake up time, discharge time, sedation
scores and movement scores were performed on chil-
dren 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. Base-
line characteristics and the clinical indications for
echocardiography are shown in Table 2.
Table 3 shows the primary and secondary out-
comes 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 propor-
tion 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
© 2016 The Association of Anaesthetists of Great Britain and Ireland
Li et al. | Intranasal dexmedetomidine
Enrollment
Allocated to intervention (n = 138)
Received allocated intervention (n = 138)
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)
Analysed (n = 137)
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 success-
ful 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 wake-
up times (r = 0.063 and r = 0.051 in atomiser and
drop groups, respectively). Wake-up time was posi-
tively 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
© 2016 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2016, 71, 522–528
Assessed for eligibility (n = 382)
Excluded (n = 102)
Not meeting inclusion criteria (n = 13)
Refused to participate (n = 89)
Randomised (n = 280)
Allocation
Allocated to intervention (n = 142)
Received allocated intervention (n = 142)
Did not receive allocated intervention (give
reasons) (n = 0)
Follow-Up
Lost to follow-up (give reasons) (n = 0)
Discontinued intervention (give reasons) (n = 0)
Analysis
Analysed (n = 142)
Excluded from analysis (give reasons) (n = 0)
in the atomiser and drops groups, respectively). No
patient suffered from bradycardia, but nine patients
were hypotensive at some point during the study per-
iod, 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 non-
painful procedures [12]. This is the first prospective,
randomised trial to compare administration by atomi-
sation 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. Atomisa-
tion of intranasal drugs by MAD device produces fine
particles (30–100 lm in diameter) and is thought to
increase drug absorption and bioavailability [13]. How-
ever, previous paediatric studies have shown that it
was not superior when it was used to administer mida-
zolam [9] or ketamine [10] in terms of sedation suc-
525
Anaesthesia 2016, 71, 522–528 Li et al. | Intranasal dexmedetomidine

Table 2 Baseline characteristics of patients included in Table 4 Behaviour, sedation and movement scores of
the study. Values are median (IQR [range]) or number patients included in the study. Values are number
(proportion). (proportion).

Atomiser group Drops group Atomiser Drops

(n = 137) (n = 142) group group p value
Age; months 13 (6–20 [2–42]) 13 (7–19 [3–38]) Behaviour score at (n = 137) (n = 142)
Weight; kg 9 (8–11 [4–15]) 10 (8–11 [4–18]) drug administration
Sex; male 80 (58%) 90 (63%) 1 17 (13%) 14 (10%) 0.23
Presumed diagnosis 2 70 (51%) 65 (46%)
Congenital heart 63 (46%) 61 (43%) 3 39 (28%) 56 (39%)
disease 4 11 (8%) 7 (5%)
Physical examination 47 (34%) 45 (31%) UMSS score during (n = 113)* (n = 120)*
Kawasaki disease 25 (18%) 33 (23%) procedure
Obstructive 1 (0.7%) 0 1 5 (4%) 7 (6%) 0.44
sleep apnoea 2 67 (59) 63 (52%)
Others 1 (0.7%) 3 (2%) 3 32 (28%) 33 (28%)
ASA physical 47: 88: 2 47: 89: 6 4 9 (8) 17 (14%)
status; 1:2:3 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%)
cess rate. In a pharmacokinetic study of intranasal dia- 4 0 2 (2%)
zepam in four dogs, the bioavailability was no different
*Only those who were successfully sedated were included in
when it was administered by atomisation or by drops the analysis. UMSS, University of Michigan Sedation Scale.
[14]. Similarly, in the current study, we have shown
that administration by atomisation is not superior to The bioavailability of transmucosal dexmedeto-
drops when intranasal dexmedetomidine is used in midine has been shown to be between 65% and
children under 3 years of age. Atomisation of both 80% [16, 17] and it is possible that atomisation only
intranasal midazolam and ketamine was associated offers a marginal improvement compared with drops
with significantly less adverse behaviour in children [9, that does not translate into a significant clinical
10], probably because the smaller particle size is asso- effect. It is also possible that there is a ceiling effect
ciated with less discomfort during administration. to dexmedetomidine for sedation and if the ceiling
However, the behavioural scores in our study were the is below 3 lg.kg 1, increasing the dose or optimising
same for both groups and this may be related to the absorption would not be associated with an improve-
fact that administration of intranasal dexmedetomidine ment in clinical effect. However, a previous investi-
is not usually associated with any unpleasant sensation gation demonstrated that increasing the intravenous
[15]. 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 propor-
tion (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
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 atomisa-
tion 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 administra-
tion as well as head position affect drug deposition
[20]. It is possible that obtaining optimal head position
and spray angle may improve deposition and bioavail-
ability 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 com-
pleted within 10 min in our centre. For studies as brief
as this, intravenous sedation with propofol or midazo-
lam may also be suitable choices but this necessitates
intravenous cannulation, careful titration, possible dis-
comfort, repeated dosing and a higher risk of respira-
tory and cardiovascular adverse events. Chloral
hydrate is another commonly used sedative in a num-
ber 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% experi-
enced 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 expe-
rience any major adverse events related to intranasal
dexmedetomidine sedation in our study and no medi-
cal intervention was required in any patient. The
majority of our children, including those with sus-
pected congenital heart disease, were of ASA physical
status 1 or 2. The effect of dexmedetomidine sedation
on children with unrepaired congenital heart disease
© 2016 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2016, 71, 522–528
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 dexmedeto-
midine administered by either an atomisation device
or drops is a feasible choice for sedation of young chil-
dren 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 criti-
cal revisions of the manuscript.
Competing interests
No competing interests and no external funding
declared.
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