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

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

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.

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.

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

Ketamine injectable solution in a concentration of 50.0 mg/mL via oral route; dose of 4.0 mg/kg maximum 100.0 mg

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

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

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

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

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

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

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, 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

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

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

Cost-effectiveness of different sedation protocols according to the methodology of health technologies assessment; the cost of each intervention will be compared

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

IPD can be available as requested by the scientific journal where the manuscript is gonna be submitted

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.