Dexmedetomidine

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Bi et al., 2019

Type of study: RCT

Setting and country: the West China Second University Hospital (Sichuan

University, Chengdu, Sichuan Province, China)

Funding and conflicts of interest: Science and Technology Department

of Sichuan Province, China

The authors have no conflicts of interest.

Inclusion criteria:

- age (6-48 months),

-American Society of Anesthesiologists (ASA) physical status I or II, - children whom undergone foreign body removal using fiberoptic broncoscopy during August 10 to December 25, 2018

Exclusion criteria:

-patients with congenital disease, -family history of malignant hyperthermia, coagulation disorders, asthma, severe preoperative respiratory impairment, -allergy to anesthetics

N total at baseline: 40

Intervention group: N = 20

Control: N = 20

Important prognostic factors²:

For example

age ± SD:

I: 17.2 ± 6.3 (months)

C: 18.0 ± 6.6 (months)

Sex (male/female):

I: 15/5

C: 14/6

Groups comparable at baseline? Yes, solely not for baseline value Heart rate (beats per minute):

I: 136±21

C: 151±14

Describe intervention (treatment/procedure/test):

In preparation, children were premedicated with atropine at

10 μg·kg ^{− 1} i.v. 30 min before the induction of anesteshia.

At 25 min before the anesteshia,

received intranasal dexmedetomidine at 1 μg·kg ^{– 1}, 25 minutes before anesthesia induction. Operation/procedure:

use of fiberoptic bronchoscopy for removing foreign bodies.

Describe control (treatment/procedure/test):

They were premedicated with atropine at

10 μg·kg ^{− 1} i.v. 30 min before the induction of anesteshia.

The control group received normal

saline at 0.01 ml kg^{− 1}, 25 min before anesthesia induction. Operation/procedure:

use of fiberoptic bronchoscopy for removing foreign bodies.

Length of follow-up:

Until discharge from the postoperative care unit (PACU) for recovery.

Loss-to-follow-up:

Intervention: none

N (%)

Reasons (describe)

Control:

N (%)none

Reasons (describe)

Incomplete outcome data:

Intervention: none

N (%)

Reasons (describe)

Control: none

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety; Parental separation at entrance into operation (N, %):

Excellent; separate easily (score 1)

I: 0 (0%)

C: 0 (0%)

Good; not clinging, whimpers, easy to calm (score 2)

I: 9 (45%)

C: 2 (10%)

Fair; not clinging, cries, not calm with reassurance (score 3)

I: 9 (45%)

C: 10 (50%)

Poor; crying, clinging to their parent (score 4)

I: 2 (10%)

C: 8 (40%)

Mask acceptance; Tolerance of the anaesthetic mask during anaesthesia induction (N, %):

Excellent; unafraid, cooperative, easy acceptance of mask (score 1)

I: 0 (0%)

C: 0 (0%)

Good; slight fear of mask, easy to quite (score 2)

I: 2 (10%)

C: 1 (5%)

Fair; moderate fear, not quite with reassurance (score 3)

I: 9 (45%)

C: 2 (10%)

Poor; terrified, crying, agitated (score 4)

I: 9 (45%)

C: 17 (85%)

(negative) behavioural changes

Not reported

Anxiety score

Not reported

Comments:

Intranasal dexmedetomidine was associated with lower parent–child separation scores, frequency of agitation, and agitation scores. Moreover, it

did not prolong the recovery time.

Ji et al., 2020

Type of study:

RCT

Setting and country:

Longgang District People’s Hospital of Shenzhen, China

Funding and conflicts of interest:

The work was supported by the Shenzhen Project of Science and Technology.

Disclosure of conflict of interest: none

Inclusion criteria:

-children undergoing laparoscopic inguinal hernia repair.

Exclusion criteria:

-bronchial asthma, -history of upper respiratory tract infection within 2 weeks, -allergy to Dex, -arrhythmia, congenital heart disease, -mental illness, -congenital and neurological disorders.

N total at baseline: 82

-Intervention group 1 (2 μg/kg of Dex): 28

-Intervention group 2 (4 μg/kg of Dex): 29

-Control: 25

Important prognostic factors²:

For example

age ± SD:

I1:2 μg/kg of Dex: 4.19±1.54 (years)

I2: 4 μg/kg of Dex: 4.27±1.80 (years)

C: 4.15 ±1.78 (years)

Sex (male/female):

I1 (2 μg/kg of Dex): 19/9

I2 (4 μg/kg of Dex): 21/8

C: 16/9

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Children whom underwent laparoscopic inguinal hernia

repair with elective general anesthesia were selected

I1 (2 μg/kg of Dex): Venous indwelling needles was established before surgery. 2 μg/kg of Dex was used for sublingual administration (pre-operative). After sublingual administration for 1 h, the children were separated from their parents and entered the operating room for sevoflurane treatment. The process (varying dose of sevoflurane for successful Laryngeal Mask Airway (LMA) placement in children during laparoscopic inguinal hernia repair) was repeated until the seventh exchange

points appeared. Conducted by anaesthesiologist.

I2 (4 μg/kg of Dex): Venous indwelling needles was established before surgery. 4 μg/kg of Dex was

used for sublingual administration (pre-operative). After sublingual administration for 1 h, the children were separated from their parents and entered the operating room for sevoflurane treatment. The process (varying dose of sevoflurane for successful Laryngeal Mask Airway (LMA) placement in children during laparoscopic inguinal hernia repair) was repeated until the seventh exchange

points appeared. Conducted by anaesthesiologist.

Describe control (treatment/procedure/test):

Children whom underwent laparoscopic inguinal hernia

repair with elective general anesthesia were selected

Control:

Venous indwelling needles was established before surgery. The children in control group were treated with equal amounts of 0.9% saline (sublingual administration) instead of intervention (pre-operative). After sublingual administration for 1 h, the children were separated from their parents and entered the operating room for sevoflurane treatment. The process (varying dose of sevoflurane for successful Laryngeal Mask Airway (LMA) placement in children during laparoscopic inguinal hernia repair) was repeated until the seventh exchange

points appeared. Conducted by anaesthesiologist.

Length of follow-up:

24 months of follow-up.

Loss-to-follow-up:

Intervention:

N (%): none

Reasons (describe)

Control:

N (%): none

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%) None

Reasons (describe)

Control:

N (%) None

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety; Parental separation satisfaction* (N, %):

I1: 18 (64.3%)

I2: 29 (100%)

C: 2 (8.0%)

Mask acceptance; Mask acceptance satisfaction** (N, %):

Fear but easy to accept a mask/ quiet to accept a mask (score 3/4)

I1: 13 (46.4%)

I2: 26 (89.7%)

C: 0 (0%)

(negative) behavioural changes

Not reported

Anxiety score

Not reported

Comments:

In total, three groups were studied. 2 intervention groups in which different doses of Dex (respectively:

I1: 2 μg/kg of Dex (n=28) and I2: 4 μg/kg of Dex (m=29) were administered. The third group was the control group.

*Parental separation satisfaction: scoring/rating not reported

**Paediatric mask acceptance scoring:

1-2 points indicated dissatisfaction,

and 3-4 points indicated satisfaction.

1 = aggressive and angry state did not accept a mask

2 = fear and not easy to accept a mask

3 = fear but easy to accept a mask

4 = quiet to accept a mask.

Lee-Archer et al., 2020

Type of study:

RCT

Setting and country:

Griffith University, Brisbane, QLD, Australia

Funding and conflicts of interest:

This work was carried out with the support

of a grant from the Australian and New Zealand College

of Anaesthetists.

Conflict of interest: not reported

Inclusion criteria:

-children aged 2-7 years

- Booked for day-case surgical and radiological

procedures

Exclusion criteria:

-significant comorbidities (ASA physical status 3 or above)

-allergy to dexmedetomidine

-antihypertensive medication

-existing behavioural problems (e.g. under the care of a paediatrician for behavioural problems, or currently taking medications for behavioural issues or ADHD)

-if the child was assessed as requiring premedication by the attending anaesthetist on the day of surgery

-surgery less than 10 min duration

N total at baseline: 247

Intervention: 82

Control: 84

Important prognostic factors²:

Median (IQR[range])

I: 4(3-6[2-7])

C: 4(3-5[2-7])

Sex:

I: 62% M

C: 66 % M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Forty minutes before the procedure, children received a nasal spray. Children received respectively 2 or 4 µg.kg^-1 intranasal dexmedetomidine via a mucosal atomisation device. Then children were accompanied to the operating theatre, and an anaesthetist induced general anaesthesia using an IV method. After induction, anaesthesist will administer an intravenous solution over 10 min. children in the intraoperative dexmedetomidine group will receive 1 µg.kg^-1 of dexmedetomidine made up in a solution of 0.9% saline to a concentration of 1 µg.ml^-1.

Describe control (treatment/procedure/test):

Forty minutes before the procedure, children received a nasal spray. Children in the control group received a nasal spray of the same volume of saline prepared by an intensive care nurse that appeared identical to the study drug. Then children were accompanied to the operating theatre, an anaesthetist induced general anaesthesia using an IV method. After induction. Anaesthesist will administer an intravenous solution: children receive the same volume of 0.9% saline made up by an intensive care nurse to look identical to the study drug.

Length of follow-up:

28 days

Loss-to-follow-up:

Intervention:

N (%) none reported

Reasons (describe)

Control:

N (%) none reported

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%) 3 (3.7%)

Reasons (describe)

Unable to contact family

Control:

N (%) 6 (7.1%)

Reasons (describe)

Unable to contact family

Outcome measures and effect size (include 95%CI and p-value if available):

Anxiety score; Child Anxiety at induction using the Modified Yale Pre-operative Anxiety Scale (mYPAS) at baseline and induction

(median (IQR [range]), N (%):

Baseline anxiety

I: 23 (23-23[23-100])

C: 23 (23-23[23-83])

Anxiety at induction

I: 23 (23-40[23-100])

C: 23(23-52[23-100])

High anxiety at induction (mYPAS >30) (N, %):

I: 27 (33%)

C: 29 (34%)

(negative) behavioural changes: the Post-Hospitalisation Behaviour Questionnaire for Ambulatory Surgery (PHBQ-AS) at different time points* (Mean, SD; N, %):

Day 3

I: 3.05 (0.24)

C: 3.06 (0.33)

Day 3

Improvement in behaviour

I: 6 (8%)

C: 8 (10%)

No change in behaviour:

I: 35 (45%)

C: 30 (39%)

Worse, presence of negative behaviour change:

I: 37 (47%)

C: 40 (51%)

Day 14

Improvement in behaviour

I: 5 (7%)

C: 8 (12%)

No change in behaviour:

I: 35 (52%)

C: 32 (46%)

Worse, presence of negative behaviour change:

I: 28 (41%)

C: 29 (42%)

Day 28

Improvement in behaviour

I: 7 (11%)

C: 9 (14%)

No change in behaviour:

I: 32 (52%)

C: 29 (45%)

Worse, presence of negative behaviour change:

I: 23 (37%)

C: 27 (41%)

Mask acceptance

Not reported

Separation anxiety

Not reported

Comments:

Study showed that there was no difference in the prevalence of behaviour change 3 days after simple day

case procedures in healthy children aged 2–7 years when

dexmedetomidine was administered either before or

during surgery

-scoring mYPAS not reported

-Patients were allocated to three different groups. One group received Dex intra-operative, and thus was not defined as either intervention or control group, explaining the difference in N total at baseline and the N in respectively the I and C group.

*PHBQ-AS:

‘no change in behaviour’: score = 3, ‘presence of negative behaviour change’: score > 3, and ‘improvement in behaviour’: score < 3.

Lin et al., 2016

Type of study:

RCT

Setting and country:

Academic medical center, the Zhongshan

Ophthalmic Center in China

Funding and conflicts of interest: supported by the Fundamental Research

Funds for the Central Universities of China and

Science and Technology Program of Guangzhou, China.

Conflicts of interest: not reported

Inclusion criteria:

-children 1 to 8 years -weight 9 to 38 kg -ASA physical status I or II -undergoing cataract surgeries

Exclusion criteria:

-known adverse reactions to DEX -neurologic illness -developmental delay -previous anesthesia experience -parentall refusal -moderate upper tract infection

N total at baseline: 90

Intervention:30

Control: 30

Important prognostic factors²:

(age ± SD):

I : 4.04±1.68

C: 4.15±1.58

Sex (male/female):

I : 15/15

C: 15/15

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Premedication with a single dose of intranasal dexmedetomidine (2 μg/kg of DEX) for children undergoing cataract surgery with sevoflurane anaesthesia. Patients received 1 μg/kg of DEX intranasally. A masked research assistant dropped half of the volume of the solution into each nostril

45 minutes before induction of anaesthesia, and the patient remained in the lying supine position for at least 2 minutes to facilitate DEX absorption. All of the patients were sedated after intranasal DEX treatment.

Describe control (treatment/procedure/test):

Patients received intranasally normal Saline (placebo) before undergoing cataract surgery with sevoflurance anaesthesia. A masked research assistant dropped half of the volume of the solution into each nostril 45 minutes before induction of anaesthesia. None of the children were sedated after the administration of Saline.

Length of follow-up:

Loss-to-follow-up:

none

I:

N (%) 0

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

none

I:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety

Not reported

(negative) behavioural changes

Not reported

Anxiety score

Not reported

Mask acceptance

Mask induction score (median, range)

I: 2 (1-3)

C: 3 (1-3)

Comments:

-No clinical trial number reported

The advantages

induced by a single dose of DEX were achieved without delaying emergence time or causing severe complications

-three groups were composed, also a group with a dose of dexmedetomidine (1 μg/kg of DEX), however this was considered a relatively low dose and thus not considered as a intervention group.

mask induction score (3-point scale) 1 = calm, cooperative or asleep;

2 = moderate fear of the mask, cooperative with reassurance;

and 3 = combative, crying.

A mask induction score of 3 was considered unsatisfactory. A score of 1 or 2 was regarded a successful response to premedication.

Midazolam

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Aykut et al., 2018

Type of study: RCT

Setting and country:

University hospital, Turkey

Funding and conflicts of interest:

Both not textually mentioned

Inclusion criteria:

/

Exclusion criteria:

ASA III-IV -diagnosis of psychiatric disorders, -use of drugs during recruitment, -history of emergent procedures, -lack of research data.

N total at baseline: 64

Intervention: 32

Control: 31

Important prognostic factors²:

For example

age ± SD:

[mean ± SD, min-max (n)]

I: 6.03 ± 1.49 (3-8)

C: 5.97 ± 1.38 (4–8)

Sex (M/F)

I: 22/10

C: 20/11

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

Intervention was 0.5 mg kg^–1 oral midazolam premedication; N = 31. Then received anesthesia, and then underwent day-case tonsillectomy and/or adenoidectomy.

Describe control (treatment/procedure/test):

No premedication; N = 32. No placebo provided. Received normal usual care, thus anesthesia, and then underwent day-case tonsillectomy and/or adenoidectomy.

Length of follow-up:

post-operative (outcome measure: postoperative pain).

Loss-to-follow-up:

Intervention: 1

N (%) 3.23%

Reasons (describe) lack of ERS, and CPRS-48 data.

Control: none

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention: 1

N (%)

Reasons (describe) lack of ERS, and CPRS-48 data.

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Mask acceptance: reactions to mask response* (N, %):

Mask response – unresponsive

I: 27 (84.4%)

C: 5 (16.1%)

Mask response – responsive

I: 5 (15.6%)

C: 26 (83.9%)

Separation anxiety

Not reported

Anxiety score

Not reported

(negative) behavioural changes

Not reported

Comments

Premedication with midazolam enabled preoperative sedation, and

increased the acceptance

of mask placement

No clinical trial number registered

Mistake detected: wrong referring textually first phrase in text ‘3. Results’ (article) to the numbers included in the intervention and control group. Further textual/table reference to the number patients included in I and C was correct

*the article did not explain/define the subcategories ‘mask response-responsive’ and ‘mask response-unresponsive’

El batawi, 2015

Type of study:

RCT

Setting and country:

in an accredited private hospital in

Jeddah, Saudi Arabia (UAE) during 2012

Funding and conflicts of interest:

Source of Support: Nil.

Conflict of Interest: None declared.

Inclusion criteria:

-healthy, -ASA I children whom underwent DGA due to lack of cooperative behavior to a degree that might impact the quality of dental treatment and/or due to the extensive amount of needed dental procedures were selected.

Exclusion criteria:

-history of allergy to midazolam, -history of post-anesthesia ED, -children with ASA scores >1, -children with special needs whenever their condition was thought to affect their pre – or postoperative behaviour.

N total at baseline: 78

Intervention: 39

Control: 39

Important prognostic factors²:

For example

age ± SD: (age(years))

I: 5.4±1.4

C: 5.6 ± 1.2

Sex (M/F):

I: 18/21

C 22/17

Groups comparable at baseline?

yes

Describe intervention (treatment/procedure/test):

Children were premedicated with 0.5 mg/kg of oral midazolam in 20 ml of 10% sodium citrate solution, 30 minutes prior to induction. Premedication was done 10-15 min prior to separation from parents and 20-25 min prior to intubation.

Procedure: children undergoing dental rehabilitation under general anesthesia

Describe control (treatment/procedure/test):

Children were premedicated with 20 ml of plain 10% sodium citrate solution (placebo). Premedication was done 10-15 min prior to separation from parents and 20-25 min prior to intubation.

Procedure: children undergoing dental rehabilitation under general anesthesia

Length of follow-up:

until discharge from the hospital

Loss-to-follow-up:

Intervention: none

N (%)

Reasons (describe)

Control : none

N (%)

Reasons (describe)

Incomplete outcome data: none

Intervention:

N (%)

Reasons (describe)

Control: none

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety using the Parental Separation Anxiety Scale (PSAS) (N, %):

Acceptable separation (score 1-2):

I: 26 (66.7%)

C: 3 (7.9%)

Unacceptable/difficult separation (score 3-4):

I: 13 (33.3%)

C: 36 (92.3%)

Mask acceptance* (Mean±SD):

I: 1.7 ± 0.76

C: 2.2 ± 0.72

Anxiety score

Not reported

(negative) behavioural changes

Not reported

Comments:

No clinical trial number registered

*Mask acceptance using the Mask Acceptance Scale (MAS), a 3-point scale. Scale of 1 (easy) to 3 (very difficult).

Solely Mean and SD were provided of the MAS, not rating per answer category was provided.

Eskandarian et al., 2015

Type of study:

RCT, double-blind

Setting and country:

Department of Paediatric Dentistry, Dental School,

Shiraz University of Medical Sciences, Shiraz, Iran

Funding and conflicts of interest:

Both not mentioned

Inclusion criteria:

-uncooperative patients (ASA physical status I or II); -aged

2-4 years -who were scheduled for general anaesthesia

for dental treatment

Exclusion criteria:

Not reported

N total at baseline: 60

Intervention: 29

Control: 31

Important prognostic factors²:

For example

age ± SD (months):

I: 38.03±7.5

C: 37.74±8.7

Sex: not reported

I: % M

C: % M

Groups comparable at baseline?

Not reported

Describe intervention (treatment/procedure/test):

Group A (intervention) received

0.2 mg/kg intranasal midazolam as preanaesthetic

medication (the

measured amount of midazolam was dropped equally

into the child’s nose, meanwhile the mother held the child in her lap, trying to keep her/him quiet and still),

before general

anaesthesia about 20 minutes before entering the

operating room for undergoing dental procedures.

Describe control (treatment/procedure/test):

group B (control) received the same volume (0.2 mg/kg)

of intranasal normal saline solution (placebo) (the

measured amount of normal saline

was dropped equally

into the child’s nose, meanwhile the mother held the

child in her lap, trying to keep her/him quiet and still) before general

anaesthesia about 20 minutes before entering the

operating room for undergoing dental procedures.

Length of follow-up:

Until discharge from hospital

Loss-to-follow-up:

Intervention:

N (%) none

Reasons (describe)

Control:

N (%) none

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%) none

Reasons (describe)

Control:

N (%) none

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety; child-parent separation (N, %):

Excellent; patient unafraid, cooperative, asleep (score 1)

I : 16 (55.2%)

C: 5 (16.1%)

Good; slight fear of crying, quiet with reassurance (score 2)

I: 9 (31.0%)

C: 8 (25.8%)

Fair; moderate crying, not quiet with reassurance (score 3)

I: 3 (10.3%)

C: 8 (25.8%)

Poor; crying, need for restraint (score 4)

I: 1 (3.4%)

C: 10 (32.3%)

Mask acceptance

Not reported

Anxiety score

Not reported

(negative) behavioural changes

Not reported

Comments:

- No clinical trial number registered

Kaviani et al., 2014

Type of study:

RCT

Setting and country:

The surgical operating room at the School of Dentistry,

Isfahan University of Medical Sciences, Isfahan, Iran.

Funding and conflicts of interest:

This study was financially supported by vice[1]chancellery of research of School of Dentistry, Isfahan

University of Medical Sciences, Isfahan, Iran.

The authors of this manuscript certify that they have no

financial or other competing interest concerning this

article

Inclusion criteria:

-healthy (ASA I, Frankel -), -age 4-10 years.

Exclusion criteria:

Not reported

N total at baseline: 62

Intervention: 30

Control:32

Important prognostic factors²:

For example

age [mean (max; min]):

I: 5.797 (6; 5.7)

C: 5.797 (5.8;5.7)

Sex:

not reported

I: % M

C: % M

Groups comparable at baseline?

Unclear, solely age reported as baseline characteristic.

Describe intervention (treatment/procedure/test):

Children of test groep received 20 ml orange juice containing 0.5 mg/kg of oral midazolam. Children were separated from their parents 20 minutes later.

Receive dental treatment under general anesthesia. The children under study were then laid on the

Operating table. . At the end of anesthesia, the children were transferred to the recovery room and were monitored.

Describe control (treatment/procedure/test):

Control group received orange juice without any medication (placebo). Children were separated from their parents 20 minutes later. The children under study were then laid on the operating table. The children under study were then laid on the

Operating table. . At the end of anesthesia, the children were transferred to the recovery room and were monitored.

Length of follow-up:

Not specified but until post operative

Loss-to-follow-up:

Intervention: none

N (%)

Reasons (describe)

Control:

none

N (%)

Reasons (describe)

Incomplete outcome data:

none

Intervention:

N (%)

Reasons (describe)

Control:

none

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety; Parental separation (PSAS) (N, %):

Difficult separation (child cried and could not be easily reassured but not clinged to parents; when cried and clinged to parents (score 3 and 4):

I: 11 (36.7%)

C: 30 (93.8%)

Acceptable separation (easy separation; child whimpered but was easily reassured and not clinging) (score 1 and 2)

I: 19 (63.3%)

C: 2 (6.3%)

Mask acceptance

Not reported

Anxiety score

Not reported

(negative) behavioral changes

Not reported

Comments:

- No clinical trial number registered

 -oral midazolam premedication is effective for comfortable separation of

children from parents

Kurdi et al., 2016

Type of study:

RCT

Setting and country:

Reported in text as ‘ at our hospital from January 1, 2014, to December 31, 2014’. Department of Anaesthesia,

Karnataka Institute of Medical

Sciences, Hubli, Karnataka,

India.

Funding and conflicts of interest:

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Inclusion criteria:

-ASA I and II, -age 5-15years,

Exclusion criteria:

-Children with

a history of psychiatric disorders, -on anti‑psychotic

drugs, -language or communication difficulties, -sleep disorders, -renal or hepatic derangement, -low

intelligence quotient, -colour blindness, -abnormalities

of the right and left hands which precluded them from

performing the finger tapping test (FTT)

N total at baseline: 100

Intervention (A): 25

Control (D): 25

Important prognostic factors²:

For example

age ± SD (Mean, SD)

I: 11.04±2.92

C: 9.16±2.62

Sex (male/ female):

I : 12:13

C : 11:14

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

The drug was given to the patient in thee pre‑induction room by a doctor. Oral midazolam (preservative free)

0.5 mg/kg was given 45–60 min, respectively, before induction to children undergoing an elective procedure. The majority of the surgeries were related to the ear, nose

and throat, hypospadiasis and hernias.

Midazolam was mixed with freshly drawn raw liquid honey.

Describe control (treatment/procedure/test):

The drug was given to the patient in thee pre‑induction room by a doctor. A placebo via similar looking measuring cups to the child was provided to the child. The placebo was a volume of 5 ml of multivitamin

Syrup. No other pre‑medication was given. The placebo was given 45–60 min, respectively, before induction to children undergoing an elective procedure. The majority of the surgeries were related to the ear, nose

and throat, hypospadiasis and hernias.

Length of follow-up:

our study ended

with intravenous cannulation irrespective of whether

the surgery took place or not

Loss-to-follow-up: none

Intervention: 0

N (%)

Reasons (describe)

Control: 0

N (%)

Reasons (describe)

Incomplete outcome data: none

Intervention:

N (%): 0

Reasons (describe)

Control: none

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Anxiety score using the Modified Yale Pre‑operative Anxiety Scale (mYPAS)* at different time points (Mean, SD)

Before pre-medication:

I (A): 44.20 ± 10.65

C: 49.68 ± 8.15

30 min after pre-medication:

I: 35.40 ± 9.49

C: 49.88 ± 7.24

60 min after pre-medication:

I: 29.28 ± 6.02

C: 40.88 ± 7.83

Separation anxiety; Parental separation behaviour * (N, %)

Free of anxiety

I: 22 (88%)

C: 0 (0%)

Mask acceptance

Not reported

(negative) behavioral changes

Not reported

Comments:

- No clinical trial number registered

-4 study arms: two groups assessed the effect of different doses of melatonine

- Results showed that oral midazolam 0.5 mg/

kg produced effective anxiolysis.

*The YPAS‑m total score was calculated.

Higher scores indicated

more anxiety

**separation scores: not reported how calculated or score, study solely stated: ‘’the parental

separation score used in our study was different from

the scores used in other studies where the mYPAS

was used for evaluation of parental separation’’.

Singla et al., 2021

Type of study:

RCT: A randomised, double-blind, placebo-controlled study

Setting and country:

Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, India. Children enrolled and randomized from July 2019 and January 2020

Funding and conflicts of interest:

-Financial support and sponsorship: this work was supported by the

Department of Anaesthesia and Intensive Care, Post Graduate

Institute of Medical Education and Research, Chandigarh, India.

- conflict of interest: none.

Inclusion criteria:

-children aged 3 to 8 years, -ASA I or II, -scheduled for elective ambulatory procedure under general anaesthesia

Exclusion criteria:

-children scheduled for emergency procedures, -those with neurological disease, -neurodevelopmental anomalies, -mental retardation, -hearing impairment.

N total at baseline: 135 enrolled.

Sample size calculation performed

Intervention: 45

Control: 45

Important prognostic factors²:

For example

age ± SD:

I: 5.1±1.7

C: 5.2±1.9

Sex: (n, %)

I: 30 (70%) M

C: 32 (73%) M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Children received oral midazolam 0.3 mg kg^-1. oral midazolam was reconstituted by mixing the calculated dose of intravenous midazolam in 3 to 5 ml of plain honey. The calculated dose was administered 45 min prior to anaesthesia induction in a syringe by an anaesthesia resident trainee not involved in the conduct of the anaesthesia or the assessment of study outcomes. During mask induction,

parental presence in the operating room was ensured

in all groups. Type of surgery: urogenital, ophthalmology, superficial.

Describe control (treatment/procedure/test):

Plain honey (3 tot 5 ml) was used as placebo. The calculated dose was administered 45 min prior to anaesthesia induction in a syringe by an anaesthesia resident trainee not involved in the conduct of the anaesthesia or the assessment of study outcomes. . The calculated dose was administered 45 min prior to anaesthesia induction in a syringe by an anaesthesia resident trainee not involved in the conduct of the anaesthesia or the assessment of study outcomes. During mask induction,

parental presence in the operating room was ensured

in all groups. Type of surgery: urogenital, ophthalmology, superficial.

Length of follow-up:

Post-operative

Loss-to-follow-up:

Intervention:

N (%): 2 (4.44%)

Reasons (describe): Did not receive allocated intervention surgery rescheduled (n = 2)

Control:

N (%) 1 (2.22%)

Reasons (describe): Excluded from analysis- deviation from study

Protocol (n = 1).

Incomplete outcome data:

Intervention:

N (%)

none

Reasons (describe)

Control:

N (%)

none

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Anxiety score using preoperative anxiety (mYPAS) at different time points

Before pre-medication, anxiety in pre-operative ward (median [IQR])

I: 23.3 [23.3 to 31.7], n=43

C: 23.3 [23.3 to 23.3], n=44

Number of highly anxious children (mYPAS >=30) (n, %)

I: 13 (30%)

C: 9 (20%)

After arrival inside operating room (median [IQR])

I: 23.3 [23.3 to 40.0]

C: 23.3 [23.3 to 27.9]

Number of highly anxious children (mYPAS >=30) (n, %)

I: 18 (42%)

C: 10 (23%)

Mask acceptance; Patient compliance with mask induction using ICC* (median [IQR])

I: 0 [0 to 1.0]

C: 0 [0 to 1.0]

Number of children with perfect induction (ICC score = 0) (N, %)

I: 28 (65%)

C: 28 (64%)

Separation anxiety

Not reported

(negative) behavioral changes

Not reported

Comments

- midazolam, melatonin and placebo are the groups studied.

-Oral midazolam premedication

did not decrease the risk of emergence delirium

*The compliance to mask induction was

assessed using the Induction Compliance checklist

(ICC). Solely stated that score ; children with ICC=0 were deemed to have perfect mask

induction.

Min et al., 2016

Type of study:

RCT

Setting and country:

Yale-New Haven

Children’s Hospital between January 2003 and September 2008, Verenigde Staten.

Funding and conflicts of interest:

- Financial Support and Sponsorship: This work was supported by grant from the National Institute of Health

[R01HD37007-01, Bethesda, MD].

- Conflicts of Interest: None of the authors have any conflicts of interest to disclose.

Inclusion criteria:

-children between 3-12 years,

Exclusion criteria:

-a

history of chronic illness including obstructive sleep apnea, -prematurity (less than 36 weeks

gestational age),- and developmental delay

N total at baseline: 70

Intervention: 38

Control: 32

Important prognostic factors²:

For example

age ± SD:

I:

C:

Sex:

I: % M

C: % M

Groups comparable at baseline?

not reported: demographic characteristics were compared between full sample (n=70) and a subsample of (n=46) children. However, not between intervention and comparison group

Describe intervention (treatment/procedure/test):

Participants were recruited and informed consent and assent were obtained 5-7 days prior to surgery when parents and their children attended a preadmission visit at the surgery center. The visit consisted of preparation by child life specialists, nurses and anaesthesiologists as well as a tour of the operating rooms.

an experimental group who received both

acetaminophen and midazolam (0.5mg/kg midazolam

with 15mg/kg acetaminophen) administered orally preoperatively (n = 38) appr. 20 minutes prior to the expected start time for surgery. Children were separated from their parents and brought into the operating room. Surgery included patients undergoing elective outpatient tonsillectomy and adenoidectomy. Anesthesia was induced

using oxygen-nitrous oxide and sevoflurane administered via a scented mask.

Describe control (treatment/procedure/test):

Participants were recruited and informed consent and assent were obtained 5-7 days prior to surgery when parents and their children attended a preadmission visit at the surgery center. The visit consisted of preparation by child life specialists, nurses and anaesthesiologists as well as a tour of the operating rooms.

a control group who

received preoperative acetaminophen only (15mg/kg acetaminophen) (n = 32) appr. 20 minutes prior to the expected start time for surgery. Surgery included patients undergoing elective outpatient tonsillectomy and adenoidectomy. Children were separated from their parents and brought into the operating room. Anesthesia was induced

using oxygen-nitrous oxide and sevoflurane administered via a scented mask.

Length of follow-up:

Until one week post-surgery (for a total of six measurements)

Loss-to-follow-up:

Intervention:

N (%) none

Reasons (describe)

Control:

N (%)

1 (3%)

Reasons (describe) discontinued intervention

Incomplete outcome data:

Intervention:

N (%)

30 (79%)

Reasons (describe)

N=22 excluded from analyses (no actigraph data), and n=8 excluded from analyses (outlier data).

Control:

N (%) 28 (87.5%)

Reasons (describe)

Excluded from analysis (no actigraph data) n=24, and excluded from analysis (outlier data), n=4.

Outcome measures and effect size (include 95%CI and p-value if available):

Anxiety score; Percentage of Children with Increased Post-operative Sleep Anxiety (using the PHBQ)* at different timepoints (N, %)

Postop day 1:

I: 1 (2.6%)

C: 6 (18.8%)

Postop day 2:

I: 5 (13.2%)

C: 7 (21.9%)

Postop day 3:

I: 4 (10.5%)

C: 5 (15.6%)

Postop day 4:

I: 4 (10.5%)

C: 8 (25.0%)

Postop day 5:

I: 5 (13.2%)

C: 6 (18.8%)

Postop week 1:

I: 3 (7.9%)

C: 6 (18.8%)

Mask acceptance

Not reported

(negative) behavioral changes

Not reported

Separation anxiety

Not reported

Comments

-clinical trial number not reported

 Under the conditions of the present study, we found that children who received midazolam

prior to surgery exhibited slightly better post-operative sleep changes compared with

children who did not receive midazolam.

*The Post Hospitalization Behavior Questionnaire (PHBQ),

only

the sleep anxiety scale was used as a measure of negative post-operative sleep changes

Nadri et al., 2018

Type of study:

RCT

Setting and country:

Loresten University of

Medical Sciences Teaching Hospital, Khoramabad, Iran

Funding and conflicts of interest:

-Funding: the Research Deputy of Lorestan University of Medical Sciences for their assistance and support in the

approval and funding of this study.

-The authors declare no conflict of interest.

Inclusion criteria:

-patients with ASA I or II, -those scheduled for circumcision, adenotonsillectomy, and hernia repair. -children aged 3-9 years

Exclusion criteria:

-patients having history of several chronic disease (prematurity, severe mental retardation, visual and auditory disorders, and previous cognitive).

N total at baseline: 93

Intervention: 31

Control: 31

Important prognostic factors²:

For example

age ± SD:

I: 6.5±1.4

C: 6.6±1.5

Sex (male/female):

I: (15/15)

C: (15/15)

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

45 minutes before surgery; oral midazolam (0.5 mg/kg) was administered to patients in

group intervention. The prodrug administration was carried out in the waiting room by an independent observer.

Anesthetic was administered and constantly maintained in a standardized manner for all patients, before

Surgery. Children were scheduled for circumcision, adenotonsillectomy, and hernia repair

Describe control (treatment/procedure/test):

45 minutes before surgery: normal saline (3 mL) as placebo was administered to patients in group C.

Prodrug administration was carried out in the waiting room by an independent observer.

Anesthetic was administered and constantly maintained in a standardized manner for all patients, before

Surgery. Children were scheduled for circumcision, adenotonsillectomy, and hernia repair

Length of follow-up:

6 months

Loss-to-follow-up:

Intervention: not reported

N (%)

Reasons (describe)

Control: not reported

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)not reported

Reasons (describe)

Control: not reported

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Anxiety score; eotional scores * (Mean, SD):

I: between 3.97 ± 0.6 to 1.7 ± 0.5

C: between 3.45 ± 1.17 to 2.745 ± 0.997

Emotional scores at different time points

Baseline

I: Thrashing (score 4)

C: Crying (score 3)

30 min before induction of anesthetic

I: Thrashing (score 4)

C: Calm (score 2)

20 minutes before induction

I: Calm (score 2)

C: Calm (score 2)

10 minutes before induction

I: Calm (score 2)

C: Calm (score 2)

Face mask:

I: Apprehensive (score 1)

C: Calm (score 2)

Separation anxiety

Not reported

Mask acceptance

Not reported

(negative) behavioral changes

Not reported

Comments:

-No clinical trial number mentioned

-n=31 patients were included in a third group – patients whom were given Promethazine

*Emotional state scale scores:

1. Apprehensive

2. Calm

3. Crying

4. Thrashing

Midazolam, Dexmedetomidine

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Gupta et al., 2021

Type of study: RCT

Setting and country: the Medical College, Jammu, Jammu and Kashmir, India

Funding and conflicts of interest:

The authors have no conflicts of interest.

Inclusion criteria:

-2-8 years

-Undergoing elective surgery under general anesthesia

Exclusion criteria:

- patients with nasal pathology/infection

-allergy to any study drugs

N total at baseline: 105

Intervention group (M): N = 35

Intervention group (D): N = 35

Control: N = 35

Important prognostic factors²:

Age (years) ± SD:

I (M): 5.47 ± 2.01

I (D): 5.46 ± 2.01

C: 5.57 ± 2.09

Sex (male/female):

I (M): 17/18

I (D): 19/16

C: 18/17

Groups comparable at baseline?
Yes

Group M: 35 patients receiving midazolam 0.2 mg/ kg, 0.5 ml in each nostril, 40 minutes before induction of anesthesia

Group D: 35 patients receiving dexmedetomidine 1 µg/kg, 0.5 ml in each nostril, 40 minutes before induction of anesthesia

Group C: 35 patients receiving normal saline as placebo, 0.5 ml in each nostril, 40 minutes before induction of anesthesia

Length of follow-up:

Not reported

Loss-to-follow-up & incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety
Not reported

Mask acceptance

Mean ± SD

I (M): 2.63 ± 0.88

I (D): 3.91 ± 0.44
C: 1.54 ± 0.66

P<0.001 (ANOVA)

(negative) behavioural changes

Not reported

Anxiety score

Not reported

Comments:

Face mask acceptance (100% oxygen for 3 minutes) by the child was noted according to 5-point scale; 1= combative, crying; 2= moderate fear of mask, not easily calmed; 3= cooperative with reassurance; 4= calm, cooperative; 5= asleep, steal induction. Score 3 or more were considered satisfactory

Dexmedetomidine, Clonidine

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Sidhu et al., 2015

Type of study: RCT

Setting and country:

A tertiary-care hospital, India

Funding and conflicts of interest:

The authors have no conflicts of interest.

Inclusion criteria:

-2-9 years
-ASA I and II

-Undergoing elective surgery under general anesthesia

Exclusion criteria:

- patients any upper respiratory tract infection

-allergy to any study drugs

-organ dysfunction, cardiac arrytmias, prolonged PR interval, atrioventricular blocks, G-6-PD deficiency, congenital heart disease,
- intellectual disability
- prematurity

N total at baseline: 105

Intervention group (D): N = 35

Intervention group (C): N = 35

Control: N = 35

Important prognostic factors²:

Age (years) (median):

I (D): 6 (2-9)

I (C): 5 (2-9)

C: 5 (2-9)

Sex (male/female):

I (D): 31/4

I (C): 23/12

C: 6/5

Groups comparable at baseline?
Yes

Group I received 2 μg/kg intranasal dexmedetomidine (100 μg/ml intravenous preparation; dexmedetomidine hydrochloride, Neon Laboratories Limited, India)

Group II received 3 μg/kg intranasal clonidine (150 μg/ml intravenous preparation; clonidine hydrochloride, Neon Laboratories Limited, India)

Group III received intranasal 0.5 ml normal saline

Length of follow-up:

12 h after surgery

Loss-to-follow-up & incomplete outcome data:

No loss to follow-up, all patients received the allocated intervention

Outcome measures and effect size (include 95%CI and p-value if available):

Separation anxiety
Not reported

Mask acceptance

Not reported

(negative) behavioural changes

Not reported

Anxiety score

Satisfactory anxiolysis achieved

I(D): 88.5%

I(C): 60%

C: 8.6

(p=0.001)

Comments:

The primary outcome measures were proportion of children with satisfactory anxiolysis (score of ≤35 on modified Yale scale)

Dexmedetomidine

Study reference

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Bi et al., 2019

Definitely yes;

Reason: patients were randomly assigned to the two groups, using a simple computerized randomization method.

Definitely yes;

Concealed envelope method was used.

Probably yes;

Double-blind RCT: the doctor whom administered the intervention/placebo was unaware of patient randomization. Additionally, the outcome parameters were assessed by another doctor whom was also unaware of patient randomization. Further blinding not reported

Definitely yes;

No loss to follow-up

Definitely yes

Reason: all relevant outcomes were reported.

Definitely yes

Reason: No other problems noted

Some concerns

Ji et al., 2020

Probably yes;

Reason:

Patients were divided into three groups by random number method.

Probably no;

Reason:

Not reported

Probably no;

Reason:

Outcomes were measured by another anaesthesiologist. Blinding of patients, health care providers, data collectors and analysts: not reported, however not likely to have affected findings.

Definitely yes;

Reason:

Loss-to follow-up did not occurred in both intervention as control group.

Definitely yes

Reason:

All relevant outcomes were reported.

Definitely yes

Reason:

No other problems noted

Some concerns

Lee-Archer et al., 2020

Definitely yes;

Reason:

Randomization in permutated blocks using an online randomisation system

definitely yes;

Reason:

Children were randomly allocated

to one of three groups in a 1:1:1 ratio in

permutated blocks using an online randomisation system

Definitely yes;

Reason:

The researcher, those assessing the outcomes of the study , parents, anaesthetists, and children were blinded to group allocation. Outcome measure such as negative behaviours, these questionnaires were administered by a blinded researcher at days 3, 14 and 28 post surgery.

Only nurses involved in the

drug preparation will be aware of the group allocation.

Probably no;

Reason:

Loss to follow-up did occur, was however disproportionate between intervention and control group (respectively 3.7% and 7.1%) .

Definitely yes

Reason:

All relevant outcomes were reported.

Definitely yes

Reason:

No other problems noted

LOW

Lin et al., 2016

Definitely yes

Reason:

Randomized using a computer-generated randomization program.

Probably no

Reason:

Not reported.

Probably no

Reason:

Single-blind trial: anaesthetist who was blinded to the type

of premedication used. Patients and perhaps other health care providers could be aware of allocated groups since children were sedated after DEX intervention, and not sedated after saline (control) group. This could have resulted in bias. Blinding of data collectors and analysts, and outcome assessors: not reported.

Definitely no

Reason:

No loss to follow-up in either intervention or control group occurred.

definitely yes

Reason:

All relevant outcomes were reported.

Definitely yes

Reason:

No other problems noted

Some concerns

Midazolam

Study reference

Was the allocation sequence adequately generated?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Definitely yes (low risk of bias)…

Definitely no (high risk of bias)

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes (low risk of bias)…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Aykut, 2018

Probably no

Reason: then study population was randomized selected, yet no information about randomization procedure.

Probably no

Reason: no information provided about allocation

Probably no

Reason: no information was provided about potential blinding.

Definitely yes

Reason: loss to follow up was infrequent.

N = 1 participant was excluded, reason: due to lack of data in the intervention group.

Probably yes

Reason: All relevant outcomes were reported

Probably no

Reason:

--mistake detected: wrong referring (in text ‘3. Results’) to the numbers included in the intervention and control group.

-No clinical trial number provided

- Funding and conflicts of interest were both not textually mentioned

HIGH

El batawi, 2015

Probably no,

Reason: During the interviews prior to the operation, the anaesthetist randomly allocated

the children to one of the two groups using the

stratified random selection method (procedure which is unknown).

Probably no:

Reason: allocation could be modified by biostatistician whom made some alterations to ensure

that the two groups had no statistically significant

demographic differences.

Definitely yes,

Reason: double-blinded study. Premedication was given by a blinded anaesthesia assistant. Additionally, scoring (outcomes) was done by two

independent and blinded members of the team.

Not reported whether patients, data analysts, etc. were blinded.

Probably yes

Reason: loss to follow up was infrequent N= 1 participant was excluded, reason: due to lack of data in the intervention group.

Definitely yes

Reason: all relevant outcomes were reported

Probably no,

Reason:

- El Batawi was the only author of this article

-No clinical trial number provided

-Source of Support/funding was provided, ‘’Nil’’, however unknown source.

-Conflict of Interest: None declared.

HIGH

Eskandarian et al., 2015

Probably no

Reason: The children were

allocated randomly into two groups, randomization is unknown.

Probably no

Reason: children were randomly allocated, not described how.

Probably yes

Reason:

All investigators, medical staff, assistants and parents

were blinded to the drug administered. Dentist whom performed all procedures; not known if blinded. Not reported whether data collectors and analysts were blinded

Definitely yes

Reason: loss to follow up was infrequent :no loss to follow-up occurred

Definitely yes

Reason: all relevant outcomes were reported

Probably no

Reason:

- no clinical trial number provided

-funding and conflict of interests: not known

Some concerns

Kaviani et al., 2014

Probably yes

Reason:

The

children were divided into the test and the control

groups, using the stratified random selection method

Probably no

Reason:

No information about concealment of allocation.

Probably no

Reason:

Study states to be ‘triple-blinded’.

Children were blinded (received drink with either midazolam or placebo). No information was provided about the other two blinded groups.

Definitely yes

Reason: loss to follow up was infrequent :no loss to follow-up occurred

Definitely yes

Reason: all relevant outcomes were reported

Probably yes,

Reason:

-no clinical trial number provided

Some concerns

Kurdi et al., 2016

Probably yes

Reason:

Patients were randomly assigned to four

Groups A, B, C and D (n = 25 patients/group) according

to a computer‑generated list.

Probably no

Reason:

Pharamacist posted in the department did the randomization and decided the group the patient belonged to. He informed the group to the pre-induction room anaesthesiologist who administered the drugs orally.

Probably yes

Reason:

double‑blind placebo controlled study was conducted. Both the patient and the

investigator (who assessed the primary and secondary study outcomes) were unaware of the identity of the

administered drug. Participants likely unaware whether received placebo or midazolam. Not reported whether health care provider (surgeon etc.) were blinded.

Definitely yes

Reason:

loss to follow up was infrequent :no loss to follow-up occurred

Probably no

Reason:

separation scores (secondary study outcome): Not reported how it was measured, yet presented quantified results of separation scores (percentages).

Probably yes

Reason:

-no clinical trial number provided

-4 groups were compared, study primarily aimed to assess effect of different doses of melatonin.

Some concerns

Singla et al., 2021

Definitely yes

Reason:

The individuals were enrolled and randomised into three

groups based on a computer-generated block randomisation.

Definitely yes

Reason:

The block randomisation process was with the allocation sequence concealed in

sequentially numbered, opaque, sealed envelopes. The allocation sequence was de-coded only after completion of the study.

Definitely yes

Reason:

The patients, attending anaesthesiologists and outcome assessors were blinded to study outcomes. Not reoprted whether others were blinded.

Probably yes

Reason:

Minor loss to follow-up in intervention group (n=2) and in control group (n=1), additionally reasons for loss to follow-up were specified: respectively Did not receive allocated intervention surgery rescheduled, and, Excluded from analysis-deviation from study

Protocol

Definitely yes

Reason: all relevant outcomes were reported

Definitely yes

Reason: No other problems noted

LOW

Min et al., 2016

Probably no

Reason:

Using a simple randomization procedure,

children were randomly assigned to a control or an experimental group. Not reported which method.

Probably no

Reason: not reported.

Probably no

Reason:

Parents of children who were

assigned to the experimental group were notified regarding administration of midazolam as

well as a general description of its sedative properties. Can be assumed children blinded since all children

received the same anesthetic technique and analgesics. Other health care professional or data analysts, blinding not reported.

Definitely yes

Reason: solely one case of loss-to follow-up reported.

Probably no

Reason: all relevant outcomes were reported.

-no clinical trial number mentioned

-The sample in the current

study was drawn from a larger randomized controlled trial examining the effects of 4

preoperative interventions

-unsure if groups were comparable at baseline since this was not reported.

-although loss to follow-up was minimal, during analysis substantial amount was excluded (a.o. due to no actigraph data, or outlier data) (respectively 87.5 % and 79% in the control and intervention group)

HIGH

Nadri et al., 2018

Probably no

Reason:

Randomization not described: solely ‘’ We included 31 patents in each of the 3 groups to account for

likely dropouts’’.

Probably no

Reason:

Not reported

Probably yes

Reason:

The RCT is double-blind.

Probably independent observer was blinded, as well as the patients.

Not specifically reported whom.

Probably no

Reason: loss to follow-up not reported

Probably no

Reason: all relevant outcomes were reported.

Comments:

-no clinical trial number reported

-three groups were compared in this study

-minimal descriptive quantified results presented regarding outcome measure ‘emotional state’’

HIGH

Midazolam, Dexmedetomidine

Study reference

Was the allocation sequence adequately generated?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Definitely yes (low risk of bias)…

Definitely no (high risk of bias)

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes (low risk of bias)…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Gupta, 2021

Probably no

Reason: then study population was randomized selected, yet no information about randomization procedure.

Probably no

Reason: no information provided about allocation

Probably no

Reason: no information was provided about potential blinding.

Probably no

Reason: loss to follow up was not reported

Probably yes

Reason: All relevant outcomes were reported

Definitely yes

Reason: No other problems noted

HIGH

Dexmedetomidine, Clonidine

Study reference

Was the allocation sequence adequately generated?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Definitely yes (low risk of bias)…

Definitely no (high risk of bias)

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes (low risk of bias)

…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes (low risk of bias)…

Definitely no (high risk of bias)

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Sidhu, 2015

Definitely yes

Reason:

The individuals were enrolled and randomised into three

groups based on a computer-generated block randomisation.

Definitely yes

Reason:

The block randomisation process was with the allocation sequence concealed in

sequentially numbered, opaque, sealed envelopes. The allocation sequence was de-coded only after completion of the study.

Probably yes

Reason:

Not reported who was blinded in this double-blinded study

Definitely yes

Reason:

No loss-to follow-up

Definitely yes

Reason: all relevant outcomes were reported

Definitely yes

Reason: No other problems noted

LOW