Clinical trial NCT02679781
Conditions: Conscious Sedation
Sponsor: Hadassah Medical Organization
Start date: 2017-03-28; Completion date: 2020-12-15
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The general objective of the study is to compare the efficacy of administering midazolam orally as syrup versus nasally with nasal atomizer. The specific objectives are to measure: 1) acceptability of the medication, 2) effect on behavior, 3) time of onset, 4) maximum working time.

Detailed description:
* Prospective, parallel design
* Study and control group: 100 healthy children (ASA 1), ages: 2-6 years, uncooperative (Frankl 1-2), that needs at least two similar dental treatments. Exclusion criteria: enlarged tonsils (Brodsky's grading scale11 +3 = 50-75% airway obstruction, and +4 = \>75% airway obstruction), upper respiratory tract infection or nasal discharge.
* Randomization: At the first appointment the subjects will assigned randomly to receive oral midazolam or nasal midazolam;
* Sedation: oral midazolam dose is 0.5mg/kg. Nasal midazolam dose is 0.2mg/kg. During treatment 50% nitrous oxide/ 50% oxygen will be administered via nasal hood.
* Acceptability of the medication: compliance in taking the medication will be assessed and recorded as: willingly, coaxed, forced, or failed (not administered).
* Behavior during dental treatment: Houpt scale measures behavior by rating sleep, movement, crying and overall behavior. The degree of alertness, movement and crying will be assessed before, during (every 5 min) and after the operative procedure. The rating will be done by one observer blind to the route of administration. This blind observer will also monitor the pulse and oxygen saturation.

Arms: arm 1: administration of 0.5mg/kg oral midazolam. During dental treatment 50% nitrous oxide/ 50% oxygen will be administered via nasal hood. arm 2: administration of 0.2mg/kg nasal midazolam. During dental treatment 50% nitrous oxide/ 50% oxygen will be administered via nasal hood.
Interventions: intervention 1: oral midazolam intervention 2: nasal midazolam
Intervention descriptions: intervention 1: administration of 0.5mg/kg oral midazolam. During dental treatment 50% nitrous oxide/ 50% oxygen will be administered via nasal hood. intervention 2: administration of 0.2mg/kg nasal midazolam. During dental treatment 50% nitrous oxide/ 50% oxygen will be administered via nasal hood.

Protocol documents:
Prot_SAP_000.pdf: 
 
Nasal versus oral midazolam sedation in routine pediatric dental care 
 
 
NCT02679781 
 
Research protocol 31/01/2016 
 
 
 
 


Background: Conscious sedation is a frequently used behavior management 
technique for providing comprehensive dental treatment to fearful, uncooperative 
young children. It is well documented in the literature that midazolam is safe and 
effective in reducing anxiety and improving behavior in children prior to medical and 
dental procedures1-2. Midazolam can be administered by either enteral or parenteral 
routes. The practice of administering midazolam by either the oral or nasal route is 
becoming rapidly incorporated in routine pediatric dental care. The literature 
regarding the advantages and limitations of using different administration routes for 
midazolam, especially with respect to the ease of administration and patient 
acceptance is controversial1-8. Although the oral route of administration is popular 
among pediatric dentists, confrontation and frustration often arise when children 
refuse to accept the sedative medication. Despite efforts to disguise the taste, children 
can spit or regurgitate the medication when administered orally4. Similar 
contradictions existed in the literature regarding patient acceptance of nasal 
midazolam. Some authors have reported that the nasal route required less patient 
cooperation and was a simple, convenient, noninvasive, painless and reliable 
alternative to oral drug administration2,3. In contrast, other authors reported nasal 
midazolam to be noxious, painful and poorly tolerated3,7,9.  
 
Rationale: Based on previous studies done in our department, the oral route and the 
nasal route are both accepted and used for midazolam administration. Both routes has 
disadvantages, children can spit or regurgitate the medication when administered 
orally because of the bitter taste, nasal midazolam as drops can be painful and poorly 
tolerated. We want to assess the acceptability of nasal spray, which diffuses better 
than drops in the nose.  Most of the studies assessed advantages and limitations of 
using different administration routes for midazolam as premedication before general 
anesthesia. In dental treatment, however, the child needs to receive the premedication 
few times and the tolerance and compliance are crucial for the success of the 
treatment, and can affect the compliance on the next visits. By comparing the 
tolerance and acceptability of these routes of administration and related factors, the 
pediatric dentist will be able to better select the route of administration to his patient. 
 
Study goals and objectives  


The main objective is to compare children's acceptance of midazolam premedication 
orally as syrup and nasally with a spray and to measure parents' satisfaction with these 
two routes of administration. The secondary objective is to examine the effects of 
various variables on the acceptance of premedication, such as age, gender and 
behavior in dental treatment. 
 
Study design 
Randomized controlled study 
 
Methodology 
Intervention: Midazolam premedication prior to dental treatment by means of two 
routes: orally and by nasal spray. The oral midazolam (Midolam 5mg/1ml) dose is 
0.5mg/kg up to a maximum of 10mg. Nasal midazolam is administered with MAD 
Nasal™ Intranasal Mucosal Atomization Device, at a dose of 0.2mg/kg up to a 
maximum of 5mg. During dental treatment, both groups receive 50% nitrous oxide/ 
50% oxygen via a nasal hood.  
Study group: The study inclusion criteria are: healthy children (American Society of 
Anesthesiologists 1), aged 2-6 years, uncooperative (Frankl10 1-2) in a dental 
examination, and in need of at least two similar dental treatments under conscious 
sedation with midazolam. Exclusion criteria are: enlarged tonsils (Brodsky’s11 grading 
scale +3 = 50–75% airway obstruction, and +4 = >75% airway obstruction), upper 
respiratory tract infection and nasal discharge. 
Randomization: Children are assigned by a single trained disinterested investigator to 
one of the groups (oral or nasal midazolam) by simple randomization (flip of a coin). 
Randomization performed after meeting study inclusion criteria.      
Observations and measurements:  
1. Participants' age, gender and weight will be documented.  
2. Acceptability of the medication: compliance in taking the medication will be 
assessed and recorded by the treating dentist as: willingly, coaxed, forced. 
Duration of crying, if any, after taking the medicament will be recorded by an 
observer blind to the route of administration.  
3. Parent's satisfaction will also be recorded by the blind observer. Parents will be 
asked to rank their satisfaction with the premedication administering as high, 


moderate or low. High satisfaction is ranked as 1 point and low is ranked as 3 
points. 
4. Behavior during dental treatment: Houpt12 scale measures behavior by rating 
sleep, movement, crying and overall behavior. Children's overall behavior during 
dental treatment will be rated by observer blind to the route of administration.  
 
Safety considerations 
Midazolam dose do not exceed maximum dose.  
Patients and parents can stop participating in the study at any time. 
In cases of refusal to take the medication or a low cooperation in dental treatment, 
other treatment options will be discussed and offered to the patient.  
 
Follow-up 
Participants will be followed up for two dental visits. 
For each visit they will be followed up in the dental clinic until full recovery from 
sedation. 
 
Data management and statistical analysis 
The information will be stored in a password-protected computer in a locked office, 
anonymously using a coding table. 
Data is analyzed in SPSS software version 25. Descriptive statistics are produced 
using means, standard deviations (SD), ranges, frequencies and percentages. 
Differences according to route of premedication administration are assessed using the 
Mann-Whitney and Kruskal-Wallis tests for the continuous variables, and the Chi-
square tests for the individual variables. A multivariate model for predicting forced 
drug administration is performed using logistic regression. Using Fisher's exact test, 
the correlation is analyzed between the categorical independent variables and the 
dichotomous dependent variable, namely, child's acceptance of the medication in the 
second session. The results considered significant for alpha less than 5%. 
 
Expected outcomes of the study 
By comparing the tolerance and acceptability of these routes of administration and 
related factors, the pediatric dentist will be able to better select the route of 
administration to his patient. 


 
Duration of the project 
Data collection will take one year. For each patient, participation duration is two 
dental visits.  
 
Ethics 
Patients of the Pediatric Dentistry Department that will meet inclusion criteria will be 
offered to participate.  Detailed information in simple non-technical language will be 
provided in advance and parents/guardians of all the patients included in the study 
will be requested to sign an informed consent form. No compensation was provided 
for participation. Patients and parents can stop participating in the study at any time. 
In cases of refusal to take the medication or a low cooperation in dental treatment, 
other treatment options will be discussed and offered to the patient.  
 
 
References: 
1. Kupietzky, A. and Houpt, M.I.: Midazolam: a review of its use for conscious 
sedation of children. Pediatr Dent 15:237-241, July-August 1993. 
2.  Hartgraves, P.M and Primosch, R.E.: An evaluation of oral and nasal 
midazolam for pediatric dental sedation. J Dent Child,61:175-181, May-June 
1994. 
3. Fuks, A.B.; Kaufman, E.; Ram, D. et al: Assessment of two dosages of 
intranasal midazolam for sedation of young pediatric dental patients. Pediatr 
Dent, 16:301-305, July-August 1994. 
4. Primosch RE, Bender F. Factors associated with administration route when 
using midazolam for pediatric conscious sedation. ASDC J Dent Child. 2001 
68(4):233-8, 228. 
5. Kogan A,  Katz J, Efrat R, Eidelman LA. Premedication with midazolam in 
young children: a comparison of four routes of administration. Paediatr 
Anaesth. 2002 Oct;12(8):685-9. 


6. Primosch RE, Guelmann M. Comparison of drops versus spray administration 
of intranasal midazolam in two- and three-year-old children for dental 
sedation.Pediatr Dent. 2005 Sep-Oct;27(5):401-8. 
7. Verma RK,  Paswan A,  De A,  Gupta S. Premedication with midazolam nasal 
spray: an alternative to oral midazolam in children. Anesth Pain Med. 2012 
Spring;1(4):248-51. doi: 10.5812/aapm.4567. Epub 2012 Apr 1. 
8. Fallahinejad Ghajari M, Ansari G, Soleymani AA, Shayeghi S, Fotuhi 
Ardakani F. Comparison of Oral and Intranasal Midazolam/Ketamine 
Sedation in 3-6-year-old Uncooperative Dental Patients. J Dent Res Dent Clin 
Dent Prospects. 2015 Spring;9(2):61-5. doi: 10.15171/joddd.2015.013. Epub 
2015 Jun 10. 
9. Baldwa NM, Padvi AV, Dave NM, Garasia MB. Atomised intranasal 
midazolam spray as premedication in pediatric patients: comparison between 
two doses of 0.2 and 0.3 mg/kg. J Anesth. 2012 Jun;26(3):346-50. doi: 
10.1007/s00540-012-1341-6. Epub 2012 Mar 1. 
10. Frankl SN, Shiere FR, Fogels HR. Should the parent remain with the child in 
the dental operatory? J Dent Child. 1962, 29: 150-163. 
11. Brodsky L. Modern assessment of tonsils and adenoids.Pediatr Clin North 
Am. 1989 Dec;36(6):1551-69. 
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intravenous sedation in child and adolescent dental patients: report of a case 
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