Midazolam and Ketamine Effect Administered Through the Nose for Sedation of Children for Dental Treatment

Study Overview
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Brief Summary
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Randomised clinical trial to test the efficacy, safety and cost-effectiveness of sedatives; masked, controlled, parallel design with three arms, phase 4.

Detailed Description
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About 10% of children may have behavioral problems during dental treatment, but the evidence for sedative protocols that benefit the care in pediatric dentistry are still weak. This randomized, masked, controlled, parallel design study aims to evaluate the efficacy, safety and cost-effectiveness of intranasal sedation with ketamine / midazolam in healthy children aged 2 to 6 years old. Children will be selected among those with dental decay that do not allow dental treatment to be performed, and need at least two restorations under local anesthesia and rubber dam isolation. It is estimated a preliminarily a sample of 84 children equally divided into three groups: A) Ketamine (4.0 mg / kg up to 100 mg) + midazolam (0.2 mg / kg, maximum 5 mg) intranasally; B) ketamine (4.0 mg / kg up to 100 mg) + midazolam (0.5 mg / kg, maximum 20 mg) orally; C) midazolam (1.0 mg / kg, maximum 20 mg) orally. The hypothesis is that ketamine / midazolam combination, administered intranasally, it constitutes an effective sedative regime, safe and cost-effective for use in pediatric dentistry in the public service. The primary endpoint is the behavior of the child. Secondary endpoints are: sedative administration acceptance, procedure memory and salivary cortisol levels within each intervention group. Additionally, we will evaluate: the occurrence of pain and associated changes in facial expressions with potentially painful stimuli in children sedated for dental care; caregivers and paediatric dentists' stress and perception about sedation; adverse events that occur during and after administration of sedatives; cost-effectiveness of the sedative protocols. The experimental design is planned to minimize systematic and random errors and to contribute to higher level of evidence in future systematic reviews. The outcomes of this study have potential impact on public and private health practice, and may support institutional guidelines dealing with this theme.

Official Title
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Efficacy, Safety and Cost-effectiveness of Intranasal Sedation With Ketamine and Midazolam in Pediatric Dentistry: a Randomized Clinical Trial

Conditions
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Child Behavior, Dental Caries

Intervention / Treatment
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* Drug: Intranasal ketamine
* Drug: Oral ketamine
* Drug: Intranasal midazolam
* Drug: Oral midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: American Society of Anesthesiologists I (healthy) or II (mild and controlled systemic disease such as persistent asthma) Small risk of airway obstruction (Mallampati less than 2 or tonsillar hypertrophy occupying less than 50% of the oropharynx) No medical history of neurological or cognitive changes Absence of facial deformities Term birth No use of drugs that may impair cognitive functions At least two teeth with cavities without pulp involvement, requiring dental restoration under local anesthesia and rubber dam Exclusion Criteria: Positive or definitely positive behavior (Frankl et al, 1962) in a dental treatment session conducted by the research team

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Intranasal administration of ketamine (4.0 mg/kg, max. 100 mg) and midazolam (0.2 mg/kg, max. 5 mg) | Drug: Intranasal ketamine<br>* Ketamine injectable solution in a concentration of 50.0 mg/mL administered into the nose with an atomizer; dose of 4.0 mg/kg, maximum 100.0 mg<br>* Other names: Ketamin S, Cristalia, São Paulo, Brazil;Drug: Intranasal midazolam<br>* Midazolam injectable solution in a concentration of 5.0 mg/mL administered into the nose with an atomizer; dose of 0.2 mg/kg, maximum 5.0 mg<br>* Other names: Dormire injectable solution, Cristalia, São Paulo, Brazil;|
| Active Comparator: Comparator<br>Oral administration of ketamine (4.0 mg/kg, max. 100 mg) and midazolam (0.5 mg/kg, max. 20 mg) | Drug: Oral ketamine<br>* Ketamine injectable solution in a concentration of 50.0 mg/mL via oral route; dose of 4.0 mg/kg maximum 100.0 mg<br>* Other names: Ketamin S, Cristalia, São Paulo, Brazil;Drug: Oral midazolam<br>* Midazolam oral solution in a concentration of 2.0 mg/mL via oral route; dose of 0.5 mg/kg, maximum 5.0 mg when associated with ketamine; dose of 1.0 mg/kg, maximum 20.0 mg when give as a solely agent<br>* Other names: Dormire oral solution, Cristalia, São Paulo, Brazil;|
| Active Comparator: Control<br>Oral administration of midazolam (1.0 mg/kg, max. 20 mg) | Drug: Oral midazolam<br>* Midazolam oral solution in a concentration of 2.0 mg/mL via oral route; dose of 0.5 mg/kg, maximum 5.0 mg when associated with ketamine; dose of 1.0 mg/kg, maximum 20.0 mg when give as a solely agent<br>* Other names: Dormire oral solution, Cristalia, São Paulo, Brazil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Child's behavior measured by an observational scale | Children's behavior assessed by OSUBRS (Ohio State University Behavioral Rating Scale) in digital videos recorded during the administration. Scores: 1 - quiet, 2 - cry with movement, 3 - movement without cry; 4 - struggling. Satisfactory behavior means more than 60% of score 1 during the entire appointment. | Participants will be followed for the duration of the dental session, an expected average of 40 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptance of sedative administration measured by an observational scale | Acceptance of the sedative administration, assessed by OSUBRS (Ohio State University Behavioral Rating Scale) minute by minute in digital videos recorded during the administration. Scores: 1 - quiet, 2 - cry with movement, 3 - movement without cry; 4 - struggling. | Participants will be assessed for the duration of the sedative administration, an expected average of 3 minutes | 
| Participants' stress according to salivary cortisol | Occurrence of stress during dental procedure, assessed by salivary cortisol in children, their accompanying parent and the dentist in charge; the ELISA test will determine changes in cortisol level during dental treatment | Change from baseline in the salivary cortisol at an expected average of 40 minutes | 
| Pain measured by the FLACC Pain Assessment Tool | Occurrence of pain and associated changes in body expressions with potentially painful stimuli in children sedated for dental care | Participants will be followed in video files for the duration of the dental session, an expected average of 40 minutes | 
| Caregivers' and dentists' perceptions on sedation measured by a Visual Analogue Scale | Perception of caregivers and dentists on sedation, through self-report | During and soon after the dental session | 
| Child's perceptions on sedation through a semi-structured interview | Child's perception concerning the dental treatment under sedation | One week after the dental session | 
| Memory of the dental procedure at the immediate post-operative period measured by a validated test | Memory of the dental procedure, according to test with figures validated in Brazil. Amnesia will be reported if children do not recall the figures showed after sedative administration | Participants will be assessed for the recall of the dental procedure, at a time point of 20 minutes (average) after the end of the dental procedure | 
| Memory of the dental procedure after 24 hours measured by a validated test | Memory of the dental procedure, according to test with figures validated in Brazil. Amnesia will be reported if children do not recall the figures showed after sedative administration | Participants will be assessed for the recall of the dental procedure, at a time point of 24 hours (average) after the end of the dental procedure | 
| Adverse events during the dental procedure | Occurrence of adverse events assessed by the World SIVA tool; adverse events will be categorised into minor, sentinel and major | Participants will be followed for the duration of the dental session, an expected average of 40 minutes | 
| Post-operative adverse events | Occurrence of adverse events while child is in the recovery room and after discharge, assessed by the World SIVA tool; adverse events will be categorised into minor, sentinel and major | 24 hours | 
| Cost analysis | Cost-effectiveness of different sedation protocols according to the methodology of health technologies assessment; the cost of each intervention will be compared | One year and a half | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dental caries, Moderate sedation