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

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

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

Study Overview

• Status: Completed
• Conditions: Dental Caries; Child Behavior
• Intervention / Treatment: Drug: Intranasal ketamine; Drug: Intranasal midazolam; Drug: Oral ketamine; Drug: Oral midazolam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Goias
    • Goiania, Goias, Brazil, 74605220
      • Dental School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 6 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Intranasal administration of ketamine (4.0 mg/kg, max. 100 mg) and midazolam (0.2 mg/kg, max. 5 mg)	Drug: Intranasal ketamine; 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; Other Names: Ketamin S, Cristalia, São Paulo, Brazil; Drug: Intranasal midazolam; 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; Other Names: Dormire injectable solution, Cristalia, São Paulo, Brazil
Active Comparator: Comparator; Oral administration of ketamine (4.0 mg/kg, max. 100 mg) and midazolam (0.5 mg/kg, max. 20 mg)	Drug: Oral ketamine; Ketamine injectable solution in a concentration of 50.0 mg/mL via oral route; dose of 4.0 mg/kg maximum 100.0 mg; Other Names: Ketamin S, Cristalia, São Paulo, Brazil; Drug: Oral midazolam; 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; Other Names: Dormire oral solution, Cristalia, São Paulo, Brazil
Active Comparator: Control; Oral administration of midazolam (1.0 mg/kg, max. 20 mg)	Drug: Oral midazolam; 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; Other Names: Dormire oral solution, Cristalia, São Paulo, Brazil

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universidade Federal de Goias
• Collaborators: Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Investigators: Principal Investigator: Luciane R Costa, DDS, MS, PhD, Professor

Publications and helpful links

General Publications

• Sado-Filho J, Viana KA, Correa-Faria P, Costa LR, Costa PS. Randomized clinical trial on the efficacy of intranasal or oral ketamine-midazolam combinations compared to oral midazolam for outpatient pediatric sedation. PLoS One. 2019 Mar 11;14(3):e0213074. doi: 10.1371/journal.pone.0213074. eCollection 2019.
• Gomes HS, Miranda AR, Viana KA, Batista AC, Costa PS, Daher A, Machado GC, Sado-Filho J, Vieira LA, Correa-Faria P, Hosey MT, Costa LR. Intranasal sedation using ketamine and midazolam for pediatric dental treatment (NASO): study protocol for a randomized controlled trial. Trials. 2017 Apr 11;18(1):172. doi: 10.1186/s13063-017-1919-2.

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2015
• Primary Completion (Actual): October 11, 2016
• Study Completion (Actual): October 18, 2016

Study Registration Dates

• First Submitted: May 11, 2015
• First Submitted That Met QC Criteria: May 13, 2015
• First Posted (Estimate): May 18, 2015

Study Record Updates

• Last Update Posted (Actual): April 30, 2018
• Last Update Submitted That Met QC Criteria: April 26, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Dental caries; Moderate sedation
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Tooth Demineralization; Tooth Diseases; Dental Caries; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam; Pharmaceutical Solutions
• Other Study ID Numbers: 041530

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD can be available as requested by the scientific journal where the manuscript is gonna be submitted