Year : 2009 | Volume
: 27 | Issue : 1 | Page : 9--16
Comparison of oral midazolam with a combination of oral midazolam and nitrous oxide-oxygen inhalation in the effectiveness of dental sedation for young children
AM Al-Zahrani1, AH Wyne2, SA Sheta3,
1 Specialist Pediatric Dentist, Security Forces Hospital, Makkah Al-Mukarrama, Saudi Arabia
2 Associate Professor/Consultant, Pediatric Dentistry, King Saud University College of Dentistry, Riyadh, Saudi Arabia
3 Associate Professor/Consultant, Anesthesiology, King Saud University College of Dentistry, Riyadh, Saudi Arabia
A H Wyne
PO Box 60169, Riyadh 11545
Aim: To compare the effectiveness of 0.6 mg/kg oral midazolam sedation alone and a combination of 0.6 mg/kg oral midazolam plus nitrous oxide-oxygen inhalation sedation, in controlling the behavior of uncooperative children during dental treatment. Study Design: The study had a crossover design where the same patient received two different sedation regimens, that is, oral midazolam 0.6 mg/kg and oral midazolam 0.6 mg/kg with nitrous oxide-oxygen inhalation during two dental treatment visits. Materials and Methods: Thirty children (17 males and 13 females) were randomly selected for the study, with a mean age of 55.07 (± 9.29) months, ranging from 48 - 72 months. A scoring system suggested by Houpt et al. (1985) was utilized for assessment of the children«SQ»s behavior. Results : There was no significant (p > 0.05) difference in the overall behavior assessment between the two sedation regimens, that is, oral midazolam alone and oral midazolam plus nitrous oxide-oxygen. However, the combination of midazolam and nitrous oxide-oxygen showed significantly (p < 0.05) superior results as compared to midazolam alone, in terms of controlling movement and crying during local anesthesia administration and restorative procedures. Conclusion: Compared to oral midazolam alone, a combination of oral midazolam and nitrous oxide inhalation sedation appears to provide more comfort to pediatric dental patients and operators during critical stages of dental treatment.
|How to cite this article:|
Al-Zahrani A M, Wyne A H, Sheta S A. Comparison of oral midazolam with a combination of oral midazolam and nitrous oxide-oxygen inhalation in the effectiveness of dental sedation for young children.J Indian Soc Pedod Prev Dent 2009;27:9-16
|How to cite this URL:|
Al-Zahrani A M, Wyne A H, Sheta S A. Comparison of oral midazolam with a combination of oral midazolam and nitrous oxide-oxygen inhalation in the effectiveness of dental sedation for young children. J Indian Soc Pedod Prev Dent [serial online] 2009 [cited 2020 Dec 3 ];27:9-16
Available from: https://www.jisppd.com/text.asp?2009/27/1/9/50810
Dental treatment of pediatric patients with behavioral problems is an extremely challenging task. Psychological behavior management techniques alone are not always adequate for soliciting the patients' cooperation. Therefore, a definite need remains for pharmacological remedies for the problem. A variety of oral sedative agents have been used for managing uncooperative young dental patients.  Midazolam, one such agent, is a relatively newer generation benzodiazepine, with a wide toxic/therapeutic ratio and safety margin. , It does not produce prolonged sedation that is associated with other benzodiazepines, such as, diazepam.  When taken orally, midazolam is rapidly absorbed in the gastrointestinal tract and produces its peak effects in a relatively shorter time of about 30 minutes, with a half-life of about 1.75 hours.  When administered in doses between 0.5 to 0.75 mg/kg of body weight, oral midazolam has been found to be a useful sedative agent for pediatric dental patients. , Midazolam has also been shown to enhance anterograde amnesia when used preoperatively in pediatric patients. , However, Midazolam is a short-acting anxiolytic agent  with a short duration of action, ,, which makes its use limited for shorter and simpler dental procedures only. Hence, it is desirable to find a second agent, which in combination with midazolam, can add its own desirable effects (sedation and analgesia) to the clinical situation.
Sedation by inhalation of nitrous oxide with oxygen has become increasingly popular, pioneered principally by Langa.  Inhaled nitrous oxide also produces anxiolytic and mild analgesic effects.  However, inhalation sedation used alone may prove difficult or impossible in the treatment of very fearful children because of their refusal to accept the nasal mask. ,
Several studies have reported the efficacy and safety of using nitrous oxide in combination with other sedative drugs in uncooperative children. ,,,,,, Nitrous oxide has also been reported to potentiate the sedative effects of benzodiazepines. , However, the effectiveness of nitrous oxide on oral midazolam sedation, and safety of combining oral midazolam and nitrous oxide-oxygen have rarely been studied. The aim of the present study is to compare the effectiveness of 0.6 mg/kg oral midazolam sedation alone with a combination of 0.6 mg/kg oral midazolam and nitrous oxide-oxygen inhalation in controlling the behavior of uncooperative children during restorative dental treatment.
Materials and Methods
The study protocol was reviewed and approved by the Ethics Committee of the College of Dentistry Research Center, and then the College of Graduate Studies, King Saud University. The study had a crossover design where the same patient received two different regimens that is, oral midazolam 0.6 mg/kg and oral midazolam 0.6 mg/kg with nitrous oxide inhalation during the two dental treatment visits. The dental treatment was provided by the same operator during the two visits.
Thirty patients were randomly selected through screening of the sedation waiting list of dental patients in the pediatric dentistry clinics of the King Saud University College of Dentistry, Riyadh, Saudi Arabia.
The inclusion criteria are given below:
Age between four and six yearsASA - I Category  Child's weight within the normal rangeNo previous dental treatmentBehavior category: Frankl  Scale #2 (negative: reluctant to accept treatment and some evidence of Negative attitude, not profound)Needing bilateral restorative treatment in lower archNo cognitive impairment
Following were the exclusion criteria:
Those who needed pulp therapy or extractionsPatients who had recently used medications such as erythromycin or anticonvulsants that may interfere with the pharmacokinetics of midazolam  Children with any condition that predisposes them to airway obstruction or difficulties (such as, adenoid hyperplasia, nasal septum problems, enlarged turbinates or nasal polyp)
The selected children were called for further assessment of medical and dental history, clinical/radiographic examination, and confirmation of behavior category. Verbal and written explanations of the procedures were provided to the parents of the selected children. A written consent was obtained from the parent for participation of their child in the study. Preoperative written instructions (with verbal reinforcement) were given to the parents, including emphasis on nothing per mouth at least 6 hours before the appointment. The parents were advised to call for cancellation of sedation appointment if the child got unwell.
Midazolam was prepared in syrup form in King Saud University College of Pharmacy. The syrup was prepared in a concentration of 2 mg/ml, with a stability of 30 days, if kept refrigerated. The syrup consisted of intravenous midazolam (ampoules of [email protected] 15 mg/3 ml, F. Hoffinan - La Roche Ltd, Basel, Switzerland) and a dye-free flavored diluent. The diluent consisted of sorbitol 45 g, sucrose 15 g, saccharine 0.2 g, sodium benzoate 0.15 g, citric acid 2 g, and distilled water 100 ml. Then, 45 ml of the diluents and 30 ml of intravenous midazolam were mixed to obtain a final preparation, which had the strength of midazolam as 2 mg/ml. The nitrous oxide and oxygen source was a relative analgesia unit (Matrx Digital Quantiflex, MDM, New York, USA).
All the patients were examined by the anesthetist (SAS), on the day of sedation, for medical clearance. The patients with upper respiratory tract infection and/or nasal discharge on the day of sedation were postponed. Subsequently, the patient's body weight was taken with the help of an electronic weighing scale. Baseline blood pressure, heart rate, and oxygen saturation were recorded. The dose of midazolam was calculated for the child and the appropriate quantity was given in a cup. The degree of drug acceptability was recorded. The treatment was to be postponed, if a child expectorated all or part of the drug (actually no such case occurred). After administration of midazolam, the child waited in a quiet room with his/her parents and signs of onset of sedation were observed and recorded every 5 minutes. The following sedation onset signs  were observed:
Glazed lookDelayed eye movementLack of muscle coordinationSlurred speechSleep
After 30 minutes of drug administration, the patient was moved to a sedation room, carried by his/her parent, with the guidance of a trained clinical assistant. Before starting the dental procedure, the child was asked to select and name one of the three pictures (cat, car or a flower), for the purpose of evaluating the amnesic action of the drug. Next, a pulse oximeter (Vitalmax 800 Monitoring Equipment: Pace Tech. Inc., Clearwater, FL 34615) clip was attached to the child's big toe of the right foot. The blood pressure cuff was wrapped to the left arm by a trained assistant. The patient was immobilized using a papoose board with pedi-wrap (Olympic, Medical Group, Seattle, WA). One of the parents remained present in the sedation room, but was instructed to be passive.
A mouth prop (Molt) was placed and topical anesthesia (Benzocaine 20%) was applied for 2 minutes followed by local anesthesia (2% lidocaine with epinephrine 1:100,000) in one of the lower quadrants. Local anesthesia was administered once, not exceeding the maximum recommended dosage (4.4 mg/kg). Rubber dam was applied and the required restorative treatment accomplished. The required procedures such as class I, II, III, IV, V restorations, preventive resin restorations and fissure sealants were completed using glass ionomers, compomers, composite resins or amalgam.
The same protocol, as on the first visit, was followed for treatment on the other side, but with addition of nitrous oxide inhalation. First, 100% oxygen was delivered via a flavored nasal mask, and then nitrous oxide was gradually added, up to 30-50%, titrated to the patient's need. The required restorative treatment was accomplished. At the end of the dental procedure, 100% oxygen was given for 3 minutes before removal of the nasal mask. The time interval between the appointments was one week.
All the hemodynamic parameters were monitored continuously during the course of the treatment. The hemodynamic parameters were also recorded at the beginning of the procedure, for every 10 minutes, during the course of the treatment, end of the treatment, in the recovery room, and before discharge. At the end of the dental procedure, the child was transferred to a quiet room and monitored for recovery. The child was discharged when he/she fulfilled the discharge criteria (ability to maintain a standing posture, absence of dizziness or disorientation, and acceptable vital signs). Before discharge, the patient was asked about the picture he/she had selected. Post-sedation instructions were given to the parents. Parents were instructed to give clear liquids slowly and juice only after 2 hours from discharge to avoid vomiting. Parents were advised to observe the child for the rest of the day. They were advised not to allow the child to play with sharp objects or walk on the stairs alone. The parents were provided with a telephone number in case of any query.
Amnesia Test  : The child was shown pictures of three familiar objects (cat, car, and a flower) and asked to select one of the pictures before starting the dental procedure. At the time of discharge, the child was asked which picture he/she had selected. The child was asked again about it after 24 hours, at the time of the follow-up phone call to the parents.
Assessment of the Sedation: A scoring system suggested by Houpt et al .  was utilized for this purpose. The system included the following scales:
Sleep ScaleCrying ScaleMovement ScaleOverall Scale
An experienced observer (AHW) assessed and recorded all the behavioral and hemodynamic parameters. The evaluations were carried out at the following times:
During placement in the Papoose BoardAt mouth prop insertionDuring administration of local anesthesiaDuring treatment in the selected quadrant
All the data were entered into the computer and analyzed using the Statistical Program for Social Sciences (SPSS, Version 12). Frequency tables and cross tabulations were generated. The effectiveness of sedation (sleep, movement, crying, and overall behavior) of the two regimens was compared using the Wilcoxon signed ranks test. The same test was also used to compare amnesia between the two regimens. The paired t test was used to compare the working time of the two regimens.
Thirty children (17 males and 13 females) were selected for the study, with a mean age of 55.07 (±9.29) months. The age ranged from 48 - 72 months. The body weight of the children ranged from 13 - 24 kilograms with a mean weight of 17.45 (±3.46) kilograms.
Most of the children accepted oral midazolam readily both during the first visit (86.7%) and the second visit (83.3%), with others accepting it with only some hesitation. There was no case of drug rejection. Nitrous oxide was administered in concentrations ranging from 30 to 50% according to the patient's need. The mean concentration of nitrous oxide used was 37.8% (±4.29). There were no problems in acceptance of the nasal mask.
In all children, on both visits, dental treatment was started after 30 minutes of midazolam administration. The mean onset times for various sedation markers during both visits are shown in [Table 1].
Most of the children were not able to recall the selected picture. For first visit, 23 (76.7%) patients, and for the second visit, 24 (80%) patients were unable to recall the selected picture, with no significant difference in amnesia between the two visits ( P = 0.56).
The mean working time (the time from bringing the patient to the operating room until the planned dental procedures were completed) was 33.3 (±5.5) minutes for the first visit and 33.2 (± 5.9) minutes for the second visit. The difference was not statistically significant ( P = 0.97).
Only one patient reached deep sleep on both visits and that occurred only in the beginning of dental treatment [Table 2]. During local anesthesia administration, the percentage of children who were fully awake was more (36.7%) with oral midazolam alone as compared to oral midazolam plus nitrous oxide (16.7%). During the restorative treatment 30% of the children were fully awake with midazolam as compared to 10% with midazolam plus nitrous oxide. Most of the children were drowsy on both visits during various phases of dental treatment. There was a significant difference during the local anesthesia administration stage ( p = 0.05) and during the restorative procedures ( p = 0.05), where midazolam plus nitrous oxide showed more sleep (drowsiness) than midazolam alone.
In most of the patients, movement did not interrupt dental treatment on both visits [Table 3]. However, a significant ( p 0.05) difference was observed between the two visits during local anesthesia administration and restorative procedures. During local anesthesia administration the children sedated with oral midazolam alone exhibited significantly more ( p = 0.02) movement than those sedated with oral midazolam plus nitrous oxide. Similarly, during restorative procedures, children during oral midazolam alone exhibited significantly more ( p = 0.02) movement than oral midazolam plus nitrous oxide sedation. Violent movements were rare (3.3%) and occurred only with oral midazolam alone.
The scores of crying in most of the children on both visits were either intermittent crying or no crying [Table 4]. The percentage of children with "no crying" was higher on the second visit compared to the first visit, but significant difference ( p = 0.05) was only observed during administration of local anesthesia. On both visits, there was no hysterical crying during various phases of dental treatment.
Evaluation of overall behavior
Only one (3.3%) child was labeled as having behavior score "excellent" with midazolam alone compared to seven (23.3%) with midazolam plus nitrous oxide sedation [Table 5]. Most of the patients showed good or very good behavior in both groups; with no poor behavior or treatment aborted. The overall behavior of the children was divided into two categories: acceptable behavior (excellent behavior, very good, and good behavior) or unacceptable behavior (fair behavior, poor behavior, and where treatment had to be aborted) [Table 5]. Overall, acceptable behavior was observed in 76.6% children sedated with oral midazolam alone and in 79.9% children sedated with oral midazolam plus nitrous oxide. However, the difference was not significant ( p = 0.13). When the behavior score of each child was compared, between the two visits, the behavior improved in 56.7% of the cases; remained the same in 16.7% of the cases, and deteriorated in 26.6% of the cases. It was noted that the improvement and deterioration, however, remained limited within the same overall categories, that is, acceptable behavior and unacceptable behavior.
The present study has attempted to test the efficacy of combining oral midazolam with nitrous oxide - oxygen inhalation in controlling the behavior of uncooperative children during dental treatment. Oral midazolam (0.6 mg/kg) alone and in combination with nitrous oxide - oxygen inhalation seems to be an effective and suitable sedative agent for young dental patients who need minimal restorative treatment (The safety aspects of combining oral midazolam and nitrous oxide are being published separately).
The Houpt  Sedation Rating Scale was used to assess the efficacy of sedation because of its demonstrated reliability, simplicity in data interpretation, and frequent successful previous use by various studies. ,,,,,, The lower arch was used for the purpose of standardization and to administer local anesthesia, for reducing repeated stressful situations during dental treatment.
Midazolam has a disagreeable taste that is difficult to mask.  Children may refuse to swallow the drug or may expectorate some of it. The clinician then becomes uncertain about how much of the drug has actually been ingested by the child. Various homemade preparations to mask the bad taste have been suggested. ,, The present study utilized a special preparation of midazolam sweetened with sorbitol, sucrose, and saccharine, which made it palatable for children; with no case of drug expectoration during the study.
Previous studies have reported a sedation onset time ranging from 15 - 40 minutes for oral midazolam. McMillan et al .,  in1992, in their dose-related study, reported that time taken to reach maximum sedation when using midazolam 0.5 mg/kg was 15 - 30 minutes. Silver et al ., in 1994, found that the length of time between administering the oral midazolam and starting treatment varied from 15 minutes to 40 minutes.  The present study utilized "30 minutes" waiting time before starting treatment. However, the mean times of onset of various sedation signs in the present study indicated that a shorter waiting time of 20 - 25 minutes could be utilized for clinical purposes.
Amnesia after sedation is considered a positive side effect of sedative agents, especially in uncooperative patients, because memory of any unpleasant aspects of the dental procedures is lost. The results of the present study indicated a strong amnesic affect of oral midazolam on most of the children. However, the amnesic affect was not enhanced by the addition of nitrous oxide - oxygen to midazolam. The results of the present study are in agreement with previous studies, which reported amnesia in 50 - 80% of the children after medical or dental procedures, under oral midazolam sedation. ,,,
The sleep scale in the present study indicated that most of the children were drowsy on both visits during various phases of dental treatment. However, a combination of oral midazolam and nitrous oxide seemed to work better during administration of local anesthesia and restoration. A study of comparison between midazolam/N 2 O and diazepam/N 2 O in autistic children showed that midazolam/N 2 O was more effective during local anesthesia administration. 
Undesirable body movements did not reach the level of interrupting dental treatment during both visits. However, there were significantly less movements with the midazolam/N 2 O combination than with midazolam alone during local anesthesia administration and restorative procedures. In addition, violent movement, although rare, occurred only with oral midazolam alone. The study in autistic children also showed that midazolam/N 2 O combination was more effective in controlling movements during dental treatment. 
There was no case of hysterical crying in both visits. The crying level was generally higher in midazolam-alone visits as compared to midazolam/N 2 O visits. However, the difference reached a significant level ( p et al .  has also reported that the midazolam/N 2 O combination showed greater success in the early phases of treatment when the patient was exposed to several painful stimuli.
There were no significant differences in the overall behavior between oral midazolam alone and oral midazolam plus nitrous oxide sedation. However, the midazolam/N 2 O combination did work better during stressful situations, such as, local anesthesia administration and cavity preparation. It is in agreement with the previous studies, , where midazolam/N 2 O combination was more effective (than oral midazolam alone) in regulating patient behavior at the time of increased stimulation in children.
There was no statistically significant ( P > 0.5) difference in the overall behavior of children (undergoing dental treatment) who had been administered oral midazolam (0.6 mg/kg) alone and oral midazolam (0.6 mg/kg) plus nitrous oxide - oxygen sedation.
However, sleep (drowsiness) scores were significantly ( P P P <0.05) less when oral midazolam plus nitrous oxide was administered as compared to midazolam alone during local anesthesia administration.
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