









































Volume 5 - No. 4 2017

Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 5 - No. 4 2017 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 23

Efficacy of Intranasal Dexmedetomidine as a Preoperative Anxiolytic in Children: A 
Systematic Review

Eric R. Wood, MSNA, CRNA

Affiliation:
University of Alabama

Funding/Conflict of Interest Disclosure: 
None declared

KEYWORDS: dexmedetomidine, premedication, anxiety, intranasal, children

INTRODUCTION

Preoperative anxiety and fear affect up to 60% of pediatric patients and can lead to enuresis and delayed recovery from 
surgery.1,2 Ten percent of children with high preoperative anxiety go on to experience emergence delirium in the recovery 
room.2 Moreover, anxiety can increase stress for patients and their families and can delay the induction of anesthesia and the 
start of surgery.2 Of those children who experience preoperative anxiety, 50% will continue to exhibit negative behavior changes 
at 2 weeks after surgery.1,2 Negative behavior changes continue in 20% of children at 6 months and in 7.5% of children at 1 
year.1,2 The most common negative behavior responses include separation anxiety, eating problems, nightmares, aggression 
toward authority, and temper tantrums.1,2 Problems with eating and sleeping may be attributable to the fact that children 
with increased preoperative anxiety often experience a more painful and slower recovery than those with low anxiety levels.2 
Predictors of preoperative anxiety include increased parental anxiety, a low activity level, a less sociable temperament, and a 
history of poor-quality medical encounters.1 It is important to identify these at-risk children so that anesthesia providers can 
mitigate the negative effects by reducing or preventing preoperative anxiety.
Anesthesia providers commonly administer preoperative sedatives that help to reduce anxiety for the child and expedite 
anesthesia induction and surgery.3-5 Midazolam, a benzodiazepine receptor agonist that causes sedation and amnesia, is the 
most common premedication for children,4-7 and its benefits include a short duration of action and a reduction in the incidence 
of postoperative vomiting.7 Midazolam is most commonly delivered to children by the oral route, but this method has several 
disadvantages, including restlessness, cognitive impairment, and respiratory depression.6,8 Use of midazolam is hampered by 
low bioavailability that results in a slow onset and a bitter aftertaste that can reduce compliance to as low as 45%.9 Ketamine 
is another popular premedication that causes dissociative anesthesia, sedation, and analgesia in children.4,5,10 Side effects of 
ketamine include nausea and vomiting, excessive salivation, nystagmus, and psychological disturbances such as emergence 
delirium.10

Dexmedetomidine (DEX) is a highly selective alpha-2 adrenergic agonist that produces sedation, analgesia, and anxiolysis 
without causing respiratory depression.11 Other benefits of DEX include its ability to increase glomerular filtration and 

Abstract
Preoperative anxiety is a common problem in pediatric patients that can have many negative effects; oral premedications 
(eg, midazolam) are often used to reduce anxiety and improve compliance. Dexmedetomidine (DEX) is an alpha-2 recep-
tor agonist that can be given intranasally to children as a premedication and may be useful as an anxiolytic. In this system-
atic review of the PubMed, CINAHL, Ovid, and Cochrane Library databases, the efficacy of intranasal dexmedetomidine 
(IN DEX) was compared with that of oral midazolam for relieving preoperative anxiety among pediatric surgical patients. 
Three trials were assessed: 2 of these trials concluded that IN DEX was a superior anxiolytic for use in children; the third 
showed that there was no significant difference. More rigorous research that includes a larger sample size and an objective 
measurement tool is needed before drawing conclusions.

AEJ



Anesthesia eJournal                         www.anesthesiaejournal.com
Volume 5 - No. 4 2017 Page 24

to decrease salivation, intraocular pressure, and the shivering 
threshold.12 Preliminary studies report that DEX is effective 
for the prevention and treatment of postoperative emergence 
delirium,13-15 and there is a growing trend among anesthesia 
providers to deliver DEX by the intranasal (IN) route. The 
bioavailability of intranasal dexmedetomidine (IN DEX) is high 
(65%), and it does not cause discomfort when administered by 
this route.12,16 The nasal mucosa offers better absorption, faster 
onset, and better compliance without gastric stimulation, painful 
needle sticks, or a high risk of aspiration.10,17 IN DEX has shown 
promise as an alternative to oral agents for premedication in 
children.
The purpose of this systematic review was to identify whether 
there was a difference in anxiety levels among pediatric patients 
who received IN DEX or oral anxiolytics as premedication.

METHODS

Search strategy and trial selection
The following databases were searched during the period from 
September 25, 2016, to October 31, 2016: PubMed (National 
Library of Medicine), CINAHL (EBSCO), Cochrane Database 
of Systematic Reviews (The Cochrane Collaboration), and Ovid. 
The Medical Subject Headings (MeSH) terms used in the search 
strategy were as follows: dexmedetomidine, premedication, 

anxiety, intranasal, and children. All searches were initially 
performed without restrictions. The results were then moved 
to RefWorks (ProQuest) and checked for duplications, which 
were removed. Titles and abstracts of randomized controlled 
trials (RCTs) were screened for historical significance. As 
premedication via the intranasal route is a relatively new 
technique, the results were restricted to articles published within 
the past 5 years.

Inclusion and exclusion criteria
Articles were required to meet the following inclusion criteria: 
(1) have an RCT design, (2) be original research comparing 
premedication with IN DEX to a single oral premedication, (3) 
report anxiety or behavior before induction of anesthesia as a 
primary outcome, and (4) examine pediatric patients aged 2 to 
12 years with an American Society of Anesthesiologists physical 
status of I to II18 and who were undergoing elective surgery. 
Studies were excluded if they examined children with mental or 
physical deficiencies, chronic pain, or any condition that placed 
them in a physical status category above II. Titles and abstracts 
were screened for the inclusion and exclusion criteria. Full texts 
were then retrieved for any publication that met the defined 
criteria. A flow diagram of the study search algorithm is shown in 
Figure 1.

Figure 1. Search Algorithm



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Volume 5 - No. 4 2017 Page 25

RESULTS
Description of the included studies
Three studies were included in the final analysis. The 
characteristics of the studies by Yuen et al,19 Ghali et al,20 and 
Linares Segovia et al21 are summarized in Table 1. All studies 
compared premedication with IN DEX to premedication with 
oral midazolam and used preoperative anxiety at the time of 
transferring the child from the parent to the operating room as 
the primary outcome. In the studies by Yuen et al and Linares 
Segovia et al, the participants were given a premedication 60 
min before the induction of general anesthesia.19,21 However, in 
the trial by Ghali et al, one group of participants was given IN 
DEX 60 min before the induction of general anesthesia, whereas 
another group of participants was given oral midazolam 30 min 
before the induction of general anesthesia.20

Measurement of anxiety
Anxiety was measured differently in the studies. In an older study 
by Yuen et al, the participants were given premedication 60 min 
before the induction of general anesthesia; the authors measured 
anxiety by evaluating behavior at parental separation by using a 
4-point Likert-type behavior scale (a score of 1 indicated “calm 

and cooperative” and a score of 4 indicated “crying or resisting”).19 
By contrast, both Ghali et al and Linares Segovia et al utilized 
the validated modified Yale Preoperative Anxiety Scale (mYPAS) 
to evaluate anxiety at the time of transfer to the operating 
room.20-22 The mYPAS, which can be performed by an observer in 
less than 1 min,20 contains 22 items within 5 categories.20,21 The 
categories include activity, emotional expressivity, state of arousal, 
vocalization, and use of adults.20,21 Scores range from 23 to 100, 
with an increased score indicating an increased anxiety state.20

Primary conclusions
At the time of parental separation, Yuen et al found no significant 
difference in behavior scores between the oral midazolam group 
and the 2 IN DEX dose groups (P = 0.771).19 In contrast, Ghali 
et al and Linares Segovia et al found that the patients in the 
IN DEX group had significantly lower anxiety levels than did 
patients in the oral midazolam group (P = 0.029 and P = 0.036, 
respectively).20,21 Similarly, Linares Segovia et al found that at 
60 min after receiving premedication, anxiety was significantly 
lower among children who received IN DEX than among those 
who received oral midazolam (P = 0.001).21 A risk analysis also 
showed that IN DEX reduced the risk of anxiety by 28% at 60 
min.21

Table 1. Characteristics of the included studies

Study Design Intervention No. Age, y 

(mean)

Sex (M/F) PS

Linares 

Segovia et al21 

Prospective, 

randomized, double-

blind controlled trial

a. DEX 1 mcg/kg IN 60 min 

before induction

b. Midazolam 0.5 mg/kg PO 60 

min before induction

a. 52

b. 56

a. 4

b. 4

a. 24/28

b. 32/24

I

Ghali et al20 Prospective, 

randomized, double-

blind controlled trial

a. DEX 1 mcg/kg IN 60 min 

before induction

b. Midazolam 0.5 mg/kg PO 30 

min before induction

a. 60

b. 60

a. 8.2

b. 8.1

a. 34/26

b. 28/32

I

Yuen et al19 Prospective, 

randomized, double-

blind controlled trial

a. DEX 1 mcg/kg IN 60 min 

before induction

b. DEX 0.5 mcg/kg IN 60 min 

before induction

c. Midazolam 0.5 mg/kg 30 min 

before induction

a. 32

b. 32

c. 32

a. 6.1

b. 6.8

c. 6.4

a. 30/2

b. 29/3

c. 30/2

I or 

II

Abbreviations: DEX, dexmedetomidine; IN, intranasal; PO, by mouth; PS, American Society of Anesthesiologists physical status.



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Volume 5 - No. 4 2017 Page 26

Additional outcome measures
Two of the studies measured anxiety at the time of induction as 
an additional primary outcome.20,21 In the study by Yuen et al, 
there was no significant difference in behavior scores at induction 
of general anesthesia among the 3 groups (P = 0.148).19 The 
results of the study by Linares Segovia et al differed with those 
of the Yuen et al study, concluding that patients who received 
IN DEX experienced significantly less anxiety at induction of 
anesthesia than did those who received oral midazolam (P = 
0.04).21

In addition to these primary outcomes, all 3 studies also 
examined the hemodynamic effects of the premedications 
as secondary outcomes.19-21 The methods of hemodynamic 
assessment and the statistically significant findings of each study 
are shown in Table 2. Although all studies found that IN DEX 
produced statistically significant hemodynamic changes, there 
were no clinically significant adverse effects.

Risk of bias
In all of the studies, the authors implemented random selection 
methods to ensure a low risk of selection bias.19-21 Although 
the participants understood that they were undergoing a minor 
surgical procedure, researchers in all of the studies used double-
blinding to minimize the risks of both performance bias and 
detection bias.19-21 Ghali et al and Linares Segovia et al used the 
validated mYPAS to assess anxiety,20,21 whereas Yuen et al used a 
Likert-type scale.19 The scale did not include a midpoint, which 
can force a biased response (positive or negative).19,23 Yuen et al 
and Ghali et al performed a power analysis and met their sample 
goal.19,20 Linares Segovia et al performed a power analysis and 
calculated that a sample of 75 participants was needed per group 
(n = 150); however, the researchers were only able to enroll 108 
patients.21 Thus, sampling bias limited our ability to draw useful 
conclusions from the results of that study.

Table 2. Significant hemodynamic findings

Study Method spO2 HR BP

Linares 

Segovia 

et al21

HR, SpO2, and BP were 

measured at baseline 

and every 15 min after 

drug administration

SpO2 decreased 

1.5% at 30 min in 

the DEX group (P = 

0.001)

SpO2 decreased 

1.2% at 15 min 

in the midazolam 

group (P = 0.001)

HR decreased by 8 bpm 

at 45 min in the DEX 

group (P = 0.001)

MAP decreased by an 

average of 5 mm Hg at 30 

min in the DEX group (P 

= 0.005)

Ghali et 

al20

HR, SpO2, and BP were 

measured at baseline 

and every 10 min after 

drug administration

No statistically 

significant findings

At transfer to OR, HR 

was significantly less in 

the DEX group (85 bpm) 

than in the midazolam 

group (96 bpm) (P = 

0.036)

At transfer to OR, SBP 

was significantly less 

in the DEX group (92 

mm Hg) than in the 

midazolam group (105 

mm Hg) (P = 0.032)
Yuen et 

al19

HR, SpO2, and BP were 

measured at baseline 

and every 15 min after 

drug administration

No statistically 

significant findings

HR decreased by 

11.1% and 16.4% from 

baseline in group D0.5 

and group D1 at 60 min, 

respectively

SBP decreased by 14.1% 

at 60 min in group D1

Abbreviations: BP, blood pressure; bpm, beats per minute; D0.5, 0.5 mcg/kg IN DEX; D1, 1 mcg/kg IN DEX; DEX, 
dexmedetomidine; HR, heart rate; IN, intranasal; MAP, mean arterial pressure; OR, operating room; SBP, systolic BP; SpO2, oxygen 
saturation.



DISCUSSION AND LIMITATIONS
There was no consensus among the 3 studies regarding the 
superiority of IN DEX over oral midazolam as a preoperative 
anxiolytic.19-21 All of the studies measured anxiety with subjective 
scales, which increased the likelihood of inconsistency. Whereas 
Yuen et al utilized a 4-point behavior scale to assess anxiety, 
the other studies used the mYPAS.19 Ideally, all of the studies 
would have utilized the same validated scale. Nevertheless, it 
is noteworthy that the study by Yuen et al, which found no 
significant differences between therapies, used a simplistic 4-point 
behavior scale to assess anxiety.19 Moreover, the outcomes in that 
study were simply reported as “satisfactory” or “unsatisfactory” 
without either term being defined, and with no mean behavior 
scores being documented.19 We think it is fair to say that this 
method was less rigorous,19 and that the trials by Ghali et al and 
Linares Segovia et al were more reliable as demonstrated by their 
reproducibility with similar methods.20,21

None of the studies evaluated the onset time or peak effect 
of the administered drugs. In all of the studies, IN DEX was 
administered 60 min before induction of general anesthesia.19-21 
The average time a pediatric patient spends in the preoperative 
holding area is less than 50 min.24,25 Ideally, the authors would 
have given the medication within this average time (ie, 30–45 
min before induction).

Although there is a great deal of clinical data concerning the 
use of DEX in children, its use has not been approved for 
premedication, which is still an off-label indication. Anesthesia 
providers must always consider the risks and benefits when 
selecting a medication, and this should be no different in the case 
of IN DEX. However, the results of this analysis indicate that IN 
DEX was safe and may be especially useful when an anesthesia 
provider is concerned about emergence delirium, analgesia, or 
compliance.

In conclusion, this systematic review was performed to compare 
the efficacy of IN DEX with that of oral midazolam as a 
preoperative anxiolytic in children. Three RCTs were selected and 
critically reviewed, but the results were inconclusive. Because the 
studies by Ghali et al and Linares Segovia et al were more reliable 
and used similar methods,20,21 we think it is fair to conclude that 
the evidence favors IN DEX having beneficial effects. An ideal 
study would be one with a large sample size and an objective 
measurement tool in which IN DEX is administered 30 to 45 
min before induction of general anesthesia. While IN DEX 
appears to be a safe and effective alternative to oral midazolam, 
additional rigorous studies are needed before any practice 
recommendations can be made.

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