Egyptian Journal of Anaesthesia

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/teja20

Effectiveness and safety of Ketamine and Midazolam

mixture for procedural sedation in children with mental
disabilities: A randomized study of intranasal versus
intramuscular route

Sanaa Farag Wasfy, Rasha Mahmoud Hassan & Reham Mustafa Hashim

To cite this article: Sanaa Farag Wasfy, Rasha Mahmoud Hassan & Reham Mustafa Hashim
(2020) Effectiveness and safety of Ketamine and Midazolam mixture for procedural sedation in
children with mental disabilities: A randomized study of intranasal versus intramuscular route,
Egyptian Journal of Anaesthesia, 36:1, 16-23, DOI: 10.1080/11101849.2020.1727669

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EGYPTIAN JOURNAL OF ANAESTHESIA
2020, VOL. 36, NO. 1, 16–23
https://doi.org/10.1080/11101849.2020.1727669

RESEARCH ARTICLE

Effectiveness and safety of Ketamine and Midazolam mixture for procedural

sedation in children with mental disabilities: A randomized study of intranasal
versus intramuscular route
Sanaa Farag Wasfy, Rasha Mahmoud Hassan and Reham Mustafa Hashim
Anesthesia, ICU and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt

ABSTRACT ARTICLE HISTORY

Background: Sedation outside the operating room is challenging especially for mentally Received 4 January 2020
disabled children. The intravenous sedation is an effective way of drug administration, but it Accepted 2 February 2020
is difficult to insert. The intramuscular route still has fear of injection. The intranasal route can KEYWORDS
be an effective, needleless, and painless approach for procedural sedation. Intranasal Midazolam;
Methods: 40 children with a mental disability aged from 4–12 years classified as ASA class I and intranasal Ketamine;
II were included after parents’ approval for procedural sedation. They were divided into two sedation score; parents’
groups; IN who received intranasal Midazolam 0.2 mg/kg and Ketamine 5 mg/kg and group IM satisfaction
who received the same dose intramuscularly. The heart rate, oxygen saturation and mean
arterial blood pressure were recorded. We used the Pediatric Sedation State Scale to assess the
level of sedation of children. Also, the satisfaction of the parents and complications were
recorded.
Results: The onset of sedation showed no statistical difference between the two groups while
the duration of sedation and the time of discharge from the post-anesthesia care unit were
significantly higher in the IM group. The sedation score was statistically higher in the IM group
at 10 minutes while in 20 and 30 minutes it showed no statistically significant difference with
comparable sedation state. Parents of IN group showed a statistically significant higher level of
satisfaction.
Conclusion: Midazolam and Ketamine mixture given through the nasal route with nasal
atomization device is a needleless approach and as effective and safe as an intramuscular
route for procedural sedation in mentally disabled children.

1. Introduction patient. The intranasal route is an important alternative

route because it is a painless and needleless approach
Sedoanalgesia decreases the need for general anesthe-
with rapid drug absorption from nasal mucosa reach-
sia outside the operating room. The intravenous route
ing the cerebrospinal fluid and bypassing the first-pass
is the standard way of sedation, but its use can be
metabolism in the liver [5].
limited in uncooperative mentally disabled children.
The intranasal route has a comparable time of onset
Active Physical restraint of these children causes emo-
of action to the intravenous route, but higher doses are
tional trauma for both parents and children. Children
needed to offset incomplete absorption from the
with mental developmental delays account for 2%–3%
mucosa of the nose [6,7]. Using mucosal atomization
of the general population. Thirty to forty percent of
devices solve this problem as they simply administer
these children may come to the anesthesiologist for
intranasal drugs up to 1ml in each nostril and provide
various therapeutic and diagnostic procedures [1].
smaller drug particle size of 30–100 microns leading to
Oral sedation can be used in these patients but it
higher bioavailability, and higher patient satisfac-
has various disadvantages as delayed onset of action,
tion [7,8].
bitter taste, postoperative nausea and vomiting [2,3],
Intranasal midazolam for sedation of children was
and the need for the addition of different types of
first described by Wilton et al [3]. Nasal midazolam
flavored syrup or honey according to the preference
dose can range from 0.1–0.5 mg/kg. Intranasal mida-
of the patient. Some children may refuse to take such
zolam is an efficient sedative in mild to moderate
oral drugs up to spitting it. On the other hand, intra-
irritable children, but for more challenging children,
muscular sedation is an easy effective way of adminis-
the addition of stronger sedative drug is advised [9].
tration [4], and it is preferred due to its rapid onset of
Ketamine is commonly used as a premedication and
action and higher predictability of the duration, how-
recently can be used in children via the nasal route. It is
ever, phobia of the pain of injections must be consid-
used as a nasal spray in the management of adult cases
ered as a disadvantage in this vulnerable pediatric

CONTACT Reham Mustafa Hashim [email protected]; [email protected] 7 Abd El Magied Seliem St., Kobry Alkobba, Cairo
11766, Egypt
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
 EGYPTIAN JOURNAL OF ANAESTHESIA 17

with resistant depression. In literature, Variable doses palsy. They were classified according to the American
and frequencies of intranasal ketamine are noticed Society of Anesthesiology (ASA) physical status into
with the single-dose ranged from 2 to 10 mg/kg [10]. Classes I and II. Children aged 4 to 12 years. All were
In our institute, we give either oral Midazolam or scheduled for short procedures (30 minutes or less)
intramuscular Ketamine followed by sevoflurane or pro- under sedation in remote areas as a dental clinic,
pofol for pediatric procedural sedation. Nasal burn unit, oncology department, MRI, CT, or who
Midazolam Ketamine mixture has not been tried despite came to the emergency department for small wounds
being a feasible choice with many possible advantages. suturing or reduction of a fracture.
A combination of ketamine and midazolam causes dee- We excluded cases after parents’ refusal, who showed
per sedation and the less dysphoric reaction of keta- cooperation and readiness for venous access insertion or
mine. We claim that the usage of the technique of nasal patients with existing venous access. Also, children with
sedation is a good possibility that may promise to over- known allergy to the drugs under study, liver or renal
come the combative behavior of mentally retarded organ dysfunction, suspected difficult airway or difficult
patients presented for medical procedures. cannulation. Patients with congenital heart disease,
So this study will evaluate the efficacy and safety of severe respiratory illness, increased intracranial tension
the administration of ketamine midazolam mixture or intraocular pressure, severe trauma, significant nasal
through the intranasal route in comparison with the discharge or obstruction were also excluded from the
intramuscular route for procedural sedation in men- study.
tally disabled children outside the operating room. The selected patients were randomized and allocated
using an automated method dividing them into two
study groups. Fasting for at least six hours was fulfilled
2. Materials and methods by all patients. It was not possible to blind the parents or
This study was a comparative prospective randomized the anesthesia team about the type of intervention. The
study applied in our Anesthesia department-University surgeon and the nurse or the assistant who recorded the
Hospitals from March 2019 to November 2019. Once we data of patients were blinded about the route of drug
got the approval of the Ethical Committee of Ain Shams administration. Patients were divided into two groups:
University, we selected patients who referred from the Group IN received midazolam (0.2 mg/kg) in addi-
pediatric outpatient clinic, the Radiology department, tion to ketamine (5 mg/kg) intranasally [8,9]. In cases
and/or after admission to the emergency room. Written that needed a small dose, an insulin syringe was used,
consents following the ethical regulations were taken then the drugs diluted with normal saline to reach 2ml.
from the parents/guardians who were informed about The calculated dose was divided inside the two nostrils
the sedation protocol with no intended effort to get equally using the intranasal mucosal LMA, MAD atomi-
their approval. After Ain Shams University’s ethical zation device (Figure 1) with the help of the parents.
approval, the proposal has been registered in the Half of the dose in the form of midazolam (0.1 mg/kg)
ClinicalTrials.gov Identifier: NCT03860831. + ketamine (2.5 mg/kg) can be given again after
We included in this study 40 children with mental 10 minutes in cases that showed no or unsatisfactory
disability due to autism, Down syndrome or cerebral response.

Figure 1. Intranasal LMA, MAD atomization device.

18 S. F. WASFY ET AL.

For group IM intramuscular midazolam (0.2 mg/kg) After the end of the procedure, patients were trans-
in addition to ketamine (5 mg/kg) was given in the ferred to the post-anesthesia care unit (PACU) under
gluteal region. Also, half of the dose midazolam full noninvasive monitoring till recovery, then trans-
(0.1 mg/kg) + ketamine (2.5mg/kg) can be repeated ferred to a nearby area for another 2 hours before
once by the same route after 10 minutes if the child home discharge.
showed little or no response. After the recovery of the patients, parents were
Physical restraint was applied with the help of the asked to rate their overall satisfaction by using
parents during drug administration in the 2 groups if a simple image of 5 points Likert scale [12] (Figure 2).
needed. Venous cannula was inserted when parents’
separation was possible after drug administration in
2.1. Primary outcome
both groups.
Heart rate (HR), Oxygen saturation (Spo2), and mean effectiveness of sedation.
arterial blood pressure (MBP) was continuously mon-
itored and recorded every 5 min after parents’ separa-
2.2. Secondary outcome
tion for 60 minutes. Local anesthesia was given in
painful procedures if possible. onset, duration of sedation, adverse effects, parents’
Sedation level after 10, 20 and 30 min were evalu- satisfaction.
ated by the Pediatric Sedation State Scale (PSSS) [11] as
follows:
2.3. The endpoint of the study
● State 5: Movement impedes procedure and if our technique failed to sedate the patients, general
requires forceful immobilization. anesthesia by inhalational sevoflurane was used to
● State 4: Movement requires gentle immobiliza- perform the procedure.
tion to maintain certain positioning
● State 3: Facial expression of pain.
● State 2: Quiet, not moving, no frown, no verbali-
3. Sample size justification
zation of complaint (ideal state). After setting, alpha error at 5% and power at 80% using
● State 1: Deeply asleep with normal vital signs but the E power program, results from a pilot study
requires airway monitoring. showed that the mean recovery time for the nasal
● State 0: Deeply asleep with abnormal physiologic group was 20 minutes while for intramuscular it was
parameters that require acute intervention (e.g., 30 minutes with a common standard deviation of 40.
O2saturation <90%, hypotension or bradycardia). Based on this the needed sample size is 20 cases per
group.
Intravenous ketamine 0.5-1mg/kg was given if
needed due to prolongation of the procedure.
Respiratory events as airway obstruction and desatura-
4. The statistical analysis
tion of less than 92% were treated by jaw thrust and We used a standard SPSS software package version 21
oxygen supplementation, apnea or laryngeal spasm (Chicago, IL) for statistical analysis. The numerical data
were managed with endotracheal intubation. are presented as mean ± standard deviation (SD) and
Wheezing was recorded and properly managed with differences between groups were compared using the
bronchodilators and steroids. Bradycardia less than 80 independent Student’s t-test, data not normally dis-
bpm or increased secretions was treated by atropine tributed were compared using Mann-Whitney test
(0.01–0.02 mg/kg). Emergency cart and drugs were and are presented as median (IQR) and categorical
available for hemodynamic and respiratory instability. variables were analyzed using the χ2 test or Fisher

Figure 2. A simple image of 5 points Likert scale for parents’ satisfaction.

 EGYPTIAN JOURNAL OF ANAESTHESIA 19

exact test and are presented as number and percen- Concerning the onset of sedation, there was no statis-
tage (%). All P values are two-sided. P < 0.05 is con- tical difference between the two groups while there was
sidered statistically significant. a statistically prolonged sedation in the IM group. Time to
discharge from the PACU showed a statistically significant
difference between the two groups where the IN group
5. Results was discharged earlier than the IM group as noted in
The present work was conducted on 40 children with Table 4.
mental disabilities undergoing procedural sedation. Concerning the sedation score, patients in the IM
They were divided into two groups; Group IN received group achieved a higher sedation state at 10 minutes
intra-nasal Midazolam 0.2 mg/kg + Ketamine 5 mg/kg than the patients in the IN group and comparable
while group IM received the same dose of Midazolam sedation state at 20 and 30 minutes (Table 5) (Figure 5).
and Ketamine yet with IM injection (Figure 3). Prolonged recovery time recorded the higher compli-
Patients’ characteristics were similar in both groups cation incidence being recorded in 3 cases with all follow-
with no statistical significance (Table 1) ing IM group. Overall, we found no statistically significant
Four children representing 20% of the IN group difference between the IN and IM groups regarding the
required a second dose after 10 minutes to reach the rate and types of complications (Table 6). Regarding par-
desired level of sedation. However, in the IM group, one ents’ satisfaction; group IN showed higher significance
case representing 5% needed the second injection. regarding the very satisfied scale with p-value 0.041
Regarding the type of procedures done to our (Table 7).
patients, we found no statistical difference between the
two groups. In dental procedures, continuous suction
6. Discussion
and rubber dam were used to avoid aspiration (Table 2).
Comparing the changes in heart rate, mean arterial In literature, there is a huge variation in both locally and
blood pressure, respiratory rate and oxygen saturation, internationally usage of sedative drugs and their route of
differences among both groups were statistically not administration for procedural sedation in children [13–
significant (Table 3) (Figure 4). 15]. Most of the anesthesiologists prefer intravenous

Figure 3. Consort flow chart.

20 S. F. WASFY ET AL.

Table 1. Demographic data of the patients. Table 4. Onset and duration of sedation.
Variables Group IN (n = 20) Group IM (n = 20) p-value Group IN Group IM
Age (years) 7.3 + 2.54 6.24 + 3.06 0.235 (n = 20) (n = 20) P-value
Weight (kg) 23.1 + 5.49 21.76 + 6.52 0.482 The onset of sedation 8.6 ± 3.69 7.24 ± 1.8 0.139
ASA (I/II) 10/10 12/8 0.524 (min)
Sex (M/F) 11/9 12/8 0.538 Duration of sedation 35.1 ± 4.81 46.29 ± 6.94 < 0.001*
Age and weight data are presented as mean ±SD. (min)
P > 0.05 is considered statistically non-significant. Time to discharge 70.35 ± 10.18 93.5 ± 11 < 0.001*
from PACU (min)
Data are presented as mean ±SD.
P > 0.05 is considered statistically non-significant.

Table 2. Types of procedures in both groups.

Procedure IN group IM group route due to the possibility to titrate the dose and to
Dental 5 6
MRI and CT 5 5
predict the drug action [14], but Children with mental
Suturing 1 1 disabilities who already suffer from their injury and illness,
Burn dressing 2 1 should be protected from more discomfort and iatrogenic
Fundus examination 1 2
Lumbar aspiration 0 1 pain caused by intravenous access insertion [16].
Fracture reduction 1 2 Iatrogenic needle phobia in handicapped children is
Audiometry 2 1
Upper GIT endoscope 1 0 usually due to prior exposure for vaccinations, previous
Pediatric ECHO 2 1 medical interventions, or repeated procedures in chronic
Total 20 20
cases. Those patients should have adequate sedation and
analgesia to avoid emotional factors that can increase
Table 3. Mean ± S.D of vital data for the two groups. their perception of pain [17].
Vital Data Group IN (n = 20) Group IM (n = 20) p-value Many studies evaluated intranasal sedation as pre-
MAP (mmHg) 94.85 ± 5.22 94.5 ± 4.32 0.779 operative premedication in normal healthy children
HR (bpm) 102.85 ± 5.49 101.7 ± 6.2 0.52
RR (n/min) 21.4 ± 1 21.35 ± 1 0.858
[7,18] but to our knowledge, no study compared intra-
SpO2 (%) 97.1 ± 1.41 97.3 ± 1.71 0.71 nasal route versus intramuscular route for procedural
P > 0.05 is considered statistically non-significant. sedation in combative mentally disabled children.

Figure 4. Mean arterial blood pressure (MAP), Mean heart rate, and oxygen saturation for the two groups during study time.
 EGYPTIAN JOURNAL OF ANAESTHESIA 21

Table 5. Sedation score.

Time Group IN (n = 20) Group IM (n = 20) p-value
10 min. 3 (3–4) 2 (2–3) < 0.001
20 min. 2 (1–2) 1 (1–2) 0.268
30 min. 1 (1–2) 1 (1–2) 0.433
Data are presented as median (IQR).
P > 0.05 is considered statistically non-significant.

Figure 5. The sedation score at 10, 20 and 30 minutes in both groups. The middle black solid line represents the median sedation
score, the upper and lower margins of each box represent IQR, the upper margin of the box is the maximum value.

Table 6. The rate of complications in the study groups.

Type of complication IN group IM group p-value nasal atomization device was effective as an intramus-
Laryngospasm 0 0 1 cular route for procedural sedation in children with
Cough 1 0 1
Increase secretion 1 2 1
mental disabilities due to autism, Down syndrome
Vomiting 1 0 1 and cerebral palsy. This intranasal mixture was well
Emergence reaction 1 0 1 tolerated without major side effects.
Prolonged recovery time 1 3 0.605
Lethargy 0 1 1 The onset of sedation in our study was 8.6 + 3.69 min-
utes in the intranasal group and 7.24 + 1.8 minutes in
the intramuscular group. We suspected that the intra-
Table 7. Parents’ overall satisfaction. nasal route will be faster in onset but the results showed
Group IN Group IM p-value
that the difference was statistically insignificant this is
Very unsatisfied 0 (0%) 2 (10%) 0.487
Unsatisfied 1 (5%) 4 (20%) 0.342 maybe because parts of the drugs have been swallowed
Neutral 4 (20%) 6 (30%) 0.716 or coughed in spite of using the nasal atomization
Satisfied 5 (25%) 5 (25%) 1
Very satisfied 10 (50%) 3 (15%) 0.041
device due to the use of physical strain in highly unco-
Data are presented as numbers and percentages. operative patients. Khatavkar and Bakhshi’s study [19]
P > 0.05 is considered statistically non-significant. showed comparable results as the onset time of seda-
tion was 10.16 ± 3.50 min. they gave nasal midazolam
0.15 mg/kg + ketamine 1 mg/kg as drops for premedi-
This study showed that a mixture of midazolam and cation in children undergoing major surgeries. Taking
ketamine were given through the nasal route with into consideration that our onset was faster due to the
22 S. F. WASFY ET AL.

higher dose used to produce procedural sedation and As regards the parents’ satisfaction, both groups
analgesia, not for premedication. In contrast, Buonsenso were almost similar with a higher incidence of a very
et al [20] studied the effect of intranasal midazolam satisfied scale in the IN group using Likert scale and this
0.5mg/kg in combination with 2mg/kg ketamine in chil- is almost similar to Malia L., et al [25] who also used
dren undergoing gastric aspirates for suspected tuber- Likert scale for assessment of parents’ satisfaction while
culosis found that the mean of the onset time of using intranasal midazolam during an emergency. We
sedation was 22.9 minutes. This difference could be used this simple scoring system due to the presence of
due to the higher ketamine dose we used in comparison illiterate parents and the difficult circumstances they
to their dose. were in with handling these children. More sophisti-
Also, Saeed Majidinejad et al [21] found that ade- cated questionnaires are available but would have
quate sedation through oral route was achieved in been difficult to be completed by the parents
32.87 ± 10.18 minutes after receiving 0.2 mg/kg mid-
azolam and 5 mg/kg ketamine in 33 children sched-
uled for brain CT. 7. Conclusion
We used LMA mucosal atomization device as recom-
Intranasal Midazolam and Ketamine mixture given
mended by Pandey et al [22] instead of nasal dropper or
through the nasal route with nasal atomization device
syringe used by Gyanesh P et al [23] because atomization
showed a similar effect as the intramuscular route for
devices minimize drug volume and maximize drug con-
procedural sedation. It also shortens the time needed
centration, which increases the bioavailability of the
for discharge with no difference in the incidence of
drugs.
complications. So, It is considered an adequate alter-
In Pandey et al study [22] thirty-four uncooperative
native in children with mental disabilities.
children received intranasal ketamine 6mg/kg either as
drops or atomized nasal spray in two different dental
visits. There was a statistically significant difference
8. Limitation of the study
regarding the onset of sedation between the two meth-
ods of administration as the onset of action was more Many evaluators assessed the depth of sedation and
rapid with a mean duration of 5.13 minutes in the behavior parameters so interobserver reliability could
atomized group. not be tested, this is due to the distribution of this
A comparison of the level of sedation between differ- number of patients over different departments.
ent studies is difficult due to the implementation of multi- Randomization was done but we didn’t stratify pro-
ple scores of pediatric sedation. In spite of that, we claim cedures to painful/non-painful procedures.
that higher levels of sedation were achieved in our study We didn’t also follow up with the patients’ late
in comparison with Khatavkar and Bakhsh [19] who used recovery after home discharge.
a sedation scale adapted from Wilton and Colleagues [3].
We used Pediatric Sedation State Scale (PSSS) [11] and the
results showed that the IM group achieved a higher score 9. Recommendations
of sedation at 10 min point than the IN group and the
Multicenter research is needed to study a Larger popula-
same level of sedation at 20 and 30 min.
tion with other mental disabilities. studying other seda-
Intramuscular midazolam, ketamine, and glycopyrro-
tives and different doses may also support our results.
late for pediatric sedation in the emergency department
were investigated by JOHN W et al [24]. The discharge
time from the recovery area averaged 76 minutes which Competing interests
is less than our average time of discharge time in the IM
group 93 min. this is related to the difference of doses The authors declare that they have no competing interests
and type of our patients and their response to these and no conflict of interest.
sedative drugs. The average discharge time in the IN
group was 70 minutes which is significantly shorter
than the IM group. Our results as regards the IN group Declaration of interest
are very close to Buonsenso et al [20] who had an average We agree that all copyright ownership is transferable to the
duration of sedation 71.5 minutes in the intranasal group. Egyptian Journal of Anesthesia when the manuscript is
Regarding complications or vital data changes, our accepted for publication in EJA.
results are in line with the findings of the previous We certify that the submitted article will not constitute
“Redundant Publication”.
studies [22–24]. There were no major side effects. Also,
This study is not previously published nor submitted else-
children’s pulse rate, mean arterial blood pressure, where and the methods employed respect the Helsinki
respiratory rate, and oxygen saturation levels did not Declaration of 1975, as revised in 1983.
change significantly throughout the sedation period. No Funds, sponsorship or financial support to be disclosed.
 EGYPTIAN JOURNAL OF ANAESTHESIA 23

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