Sevoflurane Associated With Oral Midazolam and Ketamine for Dental Sedation
Condition: Dental Anxiety
Study type: Interventional
Phase: Phase 2

Summary: 
      There is still extensive debate on the best method of controlling the behavior of preschool
      children during dental treatment. Protective stabilization, moderate sedation and general
      anesthesia are advanced behavior control techniques indicated for the dental treatment of
      early childhood caries and offer advantages and disadvantages during the procedure or
      immediately after. Many children with early childhood caries require invasive dental
      treatment. According to the final report of a large epidemiological survey on the oral
      condition of Brazilians, five-year-old children had an average of 2.43 primary teeth with
      caries and fewer than 20% of these had been treated in 2010. This disease also remains a
      public health problem in most developed countries; 19.5% of 2-5-year-old American children
      have untreated cavities.

      There is, however, a lack of the ideal sedative. Such drugs must, on the one hand, control
      the behavior of integral form, provide amnesia, minimizing physical discomfort, distress and
      pain, and, on the other, safeguard security, with minimal effect on the cardio-respiratory
      function, minimizing the occurrence of adverse events, as well as allowing the return of the
      patient to a State that allows high safely. The investigators thus performed this prospective
      study with the aim to assess the occurrence of adverse events during dental treatment and in
      the first 24 hours after sedation with midazolam, ketamine and sevoflurane in children aged
      four to six years. Our hypothesis was that no differences in adverse events among different
      association of drugs could be found.
    

Detailed description: 
      Twenty one children aged 46-81 months (mean 62.8 months) completed a randomized clinical
      trial and were followed-up for adverse events from a total of 37 children (27 were excluded
      because of being outside the age range of the survey, did not present negative behavior or
      had have prior dental treatment). These children were classified as ASA PS 1 or 2, and were
      referred to the Dental Sedation Study Center (NESO) of the Federal University of Goiás School
      of Dentistry by public health services.

      In this clinical trial, randomized controlled type triple-blind, two groups of children
      received specific interventions: a) MC group: composed of children undergoing sedation for
      association of midazolam and ketamine per oral, and placebo (oxygen) by inhalation; b) MCS:
      group composed of children undergoing sedation for association of midazolam and ketamine per
      oral, and inhaled sevoflurane. Inclusion criteria were: 1) age of four to six years (until
      the end of the dental procedures); 2) children ASA I or II; 3) need for restorative procedure
      at least a deciduous tooth; 4) patent airway and nasal effective breathing and 5) inadequate
      behavior in previous dental treatment. Exclusion criteria were 1) previous experience of
      dental treatment under sedation or 2) having completed seven years during data collection.
      Sample size was calculated based on primary study with 18 children, which were included in
      the final sample. In this, through two-tailed hypothesis test, it was found that the
      occurrence of adverse events in the first 24 hours after sedation for dental treatment
      presented proportion of 87.5% for the MC Group and proportion of 30% for the MCS Group, which
      if defined that, to achieve the probability of 80% of the study to detect a difference in a
      level of significance of 5%, we would need a sample of 10 participants for each group (n =
      20). On the day of treatment, upon arriving at the clinic, after checking healthiness of
      children and NPO protocols, the child accompanied by their parent/guardian were redirected to
      a drug delivery room, where the anesthesiologist or the pediatrician prepared medications in
      a disposable syringe and administered the drugs: midazolam-Dormire ® (Cristália, São Paulo,
      Brazil), at a dose of 0.5 mg/kg (maximum dose 20 mg) and ketamine-Ketamin ® (Cristália, São
      Paulo, Brazil), at a dose of 3 mg/kg (maximum 50 mg). After 15 minutes, they were redirected
      to the dental office and vital signs were monitored (Infinity ® Vista XL (Drägerwerk AG &
      co., Lubeck, Germany). According to the randomization, the child received only oxygen or a
      mixture of oxygen and sevoflurane-Sevocris ® (Cristália, São Paulo, Brazil), provided through
      an anesthesia workstation (Fabius ® Plus - Drägerwerk AG & co., Lubeck, Germany). Such gases
      were provided through a mask placed over the nose of the child (Dynomite ® Nasal Hood -
      Matrx-Parker Instrument, Hatfield, USA) and analysed using an anesthetic gas analyser (Let's
      ® -Drägerwerk AG & co., Lubeck, Germany). Initially, the child received the 100% oxygen at a
      flow rate of 5 l/min, for 5 minutes. After this period, if the child had been randomized to
      the MCS Group, sevoflurane was added in an initial concentration of 0.1%, with 0.1% increment
      every 30 seconds, until a final expired concentration between 0.3 and 0.4 %. In cases where
      the child had been randomized to the MC Group (without sevoflurane), the anesthesiologist
      simulating the supply of sevoflurane, but the child received only 100% oxygen. After 15
      minutes of placing the nasal mask and supply of gases, the pediatric dentist dental treatment
      began as planned.

      At the end of each procedure, post-operative recommendations (written protocol) were given to
      parents/guardians. On the day following treatment, telephone contact was made to
      parents/guardians to gather information about possible adverse events in 24 hours following
      procedure. In both groups, during the sessions, children's behavior was evaluated through the
      Houpt scale, with an observer previously calibrated and masked. The scoring system suggested
      by Houpt et al. for this purpose included four scales: sleep scale (awake - score 1; asleep -
      score 2), crying scale (hysterical crying that demands attention - score 1; continuous,
      persistant crying that makes treatment difficult - score 2; intermittent, mild crying that
      does not interfere with the treatment - score 3; no crying - score 4), movement scale
      (violent movement, interrupting treatment - score 1; continuous movement make treatment
      difficult - score 2; controllable movement that does not interferes with the treatment -
      score 3; no movement - score 4) and overall behavior scale (aborted, no treatment rendered -
      score 1; poor, treatment interrupted, only partial treatment completed - score 2; fair,
      treatment interrupted, but eventually all completed - score 3; good, difficult but all
      treatment performed - score 4; very good, some limited crying or movement - score 5;
      excellent, no crying or movement - score 6). The evaluations were performed during all the
      treatment sessions. The scores were established in accordance with the Houpt Scale every
      minute of the session, and in three specific moments of the dental treatment (at the time of
      anesthesia, at the time of use of high rotation and at the end of treatment), in addition to
      the overall evaluation. For calibration, the examiner watched five minutes videos of three
      patients during the clinical examination. The same videos were watched by a researcher as a
      gold standard, in order to assess the correlation between the examiners. There was
      concurrence intra and inter examiner, obtaining values of kappa 0.9 and 0.8, respectively.

      After the child was considered eligible to participate in the survey and your legal guardian
      have agreed with their participation, the same was assigned at random to a group. The
      randomization plan of children in groups was prepared through the website Randomization.com
      (http://www.randomization.com).

      The data were analyzed using the Statistical Package for Social Sciences (SPSS for Windows,
      version 19.0 SPSS Inc. Chicago, IL, USA), having the following variables: a) dependents
      (occurrence of adverse events in 24 hours following procedure; occurrence of intraoperative
      adverse events; child's Behavior) and b) independents (gender; age; weight; dose of oral
      sedatives; need for physical restraint; duration of the session; recovery time; heart rate;
      oxygen saturation).

      According to the distribution of the data obtained for the analysis Mann-Whitney test,
      Pearson's Chi-square and Fisher test were used. The choice of these non-parametric tests were
      due to the characteristics of the data of the study, which did not present normal
      distribution. Adopted as significance level for the statistical tests applied a value of 5%
      (p < 0.05).
    

Intervention name(s): Midazolam, Ketamine and Sevoflurane; Midazolam and Ketamine
Intervention type(s): Drug; Drug
Intervention description(s): The combination of these three drugs were administered for the children of the intervention group in a attempt to improve the behavioral control. Midazolam and ketamine orally, sevoflurane inhaled.; The combination of these two drugs were administered orally for the children of the control group.
Other intervention name(s): Midazolam, Dormire ® (Cristalia Lab, Sao Paulo, Brazil); Ketamine, Ketamin ® (Cristalia Lab, Sao Paulo, Brazil); Sevoflurane, Sevocris ® (Cristalia Lab, Sao Paulo, Brazil); Midazolam, Dormire ® (Cristalia Lab, Sao Paulo, Brazil); Ketamine, Ketamin ® (Cristalia Lab, Sao Paulo, Brazil)
Intervention MeSH terms: Midazolam; Ketamine; Sevoflurane
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Supportive Care