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Paediatric anaesthesia

Effectiveness of premedication agents administered prior to nitrous oxide/oxygen

Baygin, Ozgul; Bodur, Haluk; Isik, Berrin

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European Journal of Anaesthesiology: April 2010 - Volume 27 - Issue 4 - p 341-346
doi: 10.1097/EJA.0b013e3283313cdd



Premedication is applied to increase the cooperation of children during applications for medical diagnosis and treatment. When behaviour guidance techniques (e.g. tell–show–do, voice control, nonverbal communication, positive reinforcement, distraction, parental presence) are insufficient during dental treatment in children, sedative premedication, sedation, or general anaesthesia applications may become necessary.1 Pharmacological sedation is employed as an adjunct to behaviour management techniques. Oral and inhalation routes of sedative administration are the most convenient for use in children and are the most popular among paediatric dentists.2 In paediatric dentistry, sedation procedures are required when anxiety or behavioural impairment precludes carrying out dental treatments. However, sedation at the desired level might not be achieved despite administration of various agents.

Several drugs are currently being used for conscious sedation. Oral hydroxyzine is one of the popular sedative agents and is usually used in combination with other drugs like chloral hydrate, meperidine, or midazolam.3 However, dosages and schedules for oral administration of hydroxyzine have varied widely in clinical reports, ranging from 20 to 60 mg taken 45 min to 1 h before treatment.4 Midazolam is one of the most commonly used drugs for sedation in children during procedures. It provides potent sedation, loss of memory and anxiolysis. However, the use of midazolam may be associated with paradoxical reactions (delayed recovery, anxiety, behavioural changes, agitation), and irregular breathing patterns, skipped heartbeats, respiratory failure, and unusual or involuntary muscle movements have been observed rarely in some children.5 Combinations of ketamine and midazolam have been stated to be among the best and safest techniques for sedoanalgesia.6 This combination seems particularly beneficial because the elimination half-life of each agent is approximately the same.7 Nitrous oxide/oxygen (N2O/O2) inhalation is the most frequently used sedation method in paediatric dentistry. The depth of sedation is increased by giving oral sedative premedication agents before the N2O/O2 inhalation in patients with a high anxiety level.1

In paediatric dentistry, although numerous studies have been undertaken using various drug combinations to obtain deliberate sedation, no combination or method producing sufficient sedation in all cases and without any side effects has been identified yet.8

The bispectral index (BIS) is currently used most commonly intraoperatively to monitor the effects of anaesthetic and sedative agents as a means of judging the depth of sedation or anaesthesia. The BIS offers a potential alternative to subjective scales when they do not work well or may not be sufficiently sensitive to evaluate the sedation level.9

The aim of this study is to compare the efficiency of premedication agents used just before N2O/O2 inhalation with that of no oral premedication (solely N2O/O2). BIS data that are used for following the sedation level and haemodynamic data [heart rate (HR) and saturation of oxygen] were observed in addition to Ramsay Sedation Scale (RSS) data.


The present research was approved by Gazi University Faculty of Dentistry Ethics Committee. Sixty children aged between 5 and 8 years, ASA I or II, having no mental or motor retardation, requiring at least two-visit dental treatment, having no sedation or general anaesthesia experience, and incompliant with dental treatment [Frankl Behaviour Scale (FBS) score ≥3]10 (Table 1), were enrolled in the study after obtaining informed parental consent. The participants were seen for their initial examination and it was determined that they definitely exhibited ‘negative’ FBS equal to 3 or ‘definitely negative’ FBS equal to 4 behaviour according to the FBS.

Table 1
Table 1:
Frankl Behavioural Scale

Prior to the sedation, a detailed history was obtained and physical examination was performed. We excluded children who had taken medication within the past 2 weeks before dental treatment, had prior sedation, or had temperament disorder. All children were fasted for 3–5 h before sedation. All the patients were premedicated between 1: 30 and 2: 30 p.m.

One hour before sedation, children were transported to an isolated recovery room near the dental suite. Parental presence was allowed throughout the sedation and postsedation periods.

The children were randomly assigned to one of four groups (n = 15 in each). The treatment regimen according to the study groups was as follows: oral administration of 1 mg kg−1 hydroxyzine hydrochloride suspension (Atarax, Ucb pharma, Istanbul, Turkey) 1 h preoperatively (group I, n = 15); oral administration of 0.7 mg kg−1 midazolam (Dormicum, Roche, Fontenay, France, 15 mg/3 ml) 15 min preoperatively (group II, n = 15); oral administration of 3 mg kg−1 ketamine (Ketalar, Pfizer, Luleburgaz, Turkey) with 0.25 mg kg−1 midazolam (Dormicum) 15 min preoperatively (group III, n = 15); and no oral premedication was administered to the control group (group IV, n = 15).

Study drugs were given by a trained nurse to maintain the double blind nature of the study. Throughout the study period, resuscitation and rapid reaction requirements were present in the clinic.

Topical anaesthesia in the form of benzocaine gel 20% was applied to the dried mucosa adjacent to the tooth. Lidocaine 2% with 1: 80000 adrenaline was then given in a standardized manner to each quadrant just before dental treatment.

Peripheral oxygen saturation (SpO2) and HR were monitored by pulse oximeter (Datex-Ohmeda TuffSAT, GE Healthcare, Chalfont St Giles, UK) during treatment. Following premedication, 40% N2O and 60% O2 was administered to all groups with a nasal mask. The sedation level was monitored by the BIS (BIS XP Aspect, Aspect Medical Systems Inc., Norwood, Massachusetts, USA). The BIS processes the complex EEG waveform into a single number, from 100 to 0. At high values near 100, the patient is awake. At ranges from 60 to 70, about 95% of the patients are considered to be in deep sedation or light hypnotic state (i.e. the range used to maintain sufficient general anaesthesia and amnesia). At ranges from 40 to 60, the patient is unconscious and is said to be in a moderate hypnotic state. Below 40, the patient is said to be in a very deep hypnotic state.11 Based on previous studies, the ideal BIS range of 80–100 for maintaining sufficient sedation in children is the same as for adults.

Sedation was induced in all children using 4–5 l min−1 O2 90% and N2O 10% via nasal mask. The N2O concentration was fractionally increased from 10 to 40% every minute, and dental treatment was performed. If necessary, the head position was adjusted to ensure a clear airway and O2 was administered to maintain an SpO2 higher than 94%.

Time-dependent HR (beats min−1) and SpO2 (%) variables of the patients were recorded as follows: T0, at 15 min after being given the drug; T1, at presedation; T2, at the BIS setting; T3, at the inhalation of N2O; T4, at the start of the operation; T5, at the end of the operation; and T6, at the discontinuation of N2O.

Sedation depth was evaluated as T0, at 15 min after being given the drug; T1, at presedation; T2, at the BIS setting; T3, at the inhalation of N2O; T4, at the start of the operation; T5, at the end of the operation; T6, at the discontinuation of N2O; T7, 5 min later than T6; T8, 10 min later than T6; T9, 30 min later than T6; and T10, 60 min later than T6, according to the RSS12 (Table 2). Data were recorded at 5 min intervals. RSS scores were recorded (as T1 values) 15 min later than oral hydroxyzine hydrochloride suspension premedication in group I, oral midazolam premedication in group II, oral ketamine with midazolam premedication in group III, and in the control group (group IV). The children's sedation success during dental treatment was classified as satisfactory (RSS score at any evaluation point of 2, 3 or 4 and dental treatment performed successfully); mid-level satisfactory (RSS score at any evaluation point of 1, 2 or 3 and treatment performed with difficulty); or unsatisfactory (RSS score at any evaluation point of 1 or 2 and dental treatment not performed due to agitation).

Table 2
Table 2:
Ramsay Sedation Scale

Treatment with general anaesthesia was planned for those children with unsatisfactory sedation.

At the end of the dental treatment, following discontinuation of N2O, 100% O2 was inhaled. One of the researchers, who was blinded to the premedication drug, evaluated every patient during the sedation and postsedation periods. Sixty minutes after discontinuation of N2O, children were evaluated with respect to discharge criteria. Discharge criteria were considered as met if children were alert, oriented, able to stand without support or help, had normal circulatory and respiratory system functions, and were without haemorrhage, vomiting, or nausea complications, and the children were subsequently discharged home. Otherwise, the children were kept under observation until the criteria were met.

Sample size was predetermined by power analysis using RSS scores (α = 0.05 and β = 0.2, SD 0.87, mean difference 1.0, normal two-sided test). The analysis showed that 15 patients per group would be sufficient. HR and SpO2 data were analysed with parametric one-way analysis of variance (ANOVA). If differences were significant, then the Multiple Comparisons Tukey's Honestly Significant Differences (HSD) test was used to compare groups. For statistical analysis of the RSS scores and sedation success variables, the Kruskal–Wallis test was used. If there was a distinction, the Mann–Whitney U-test was used, and a value of P < 0.05 was accepted as indicating a significant difference.


All 60 patients enrolled in the study were evaluated. There were no significant differences between the four groups regarding demographic characteristics (age, sex, body weight; P > 0.05). There were no differences in the anxiety level (measured by the FBS in the first dental examination) between the four groups (P > 0.05; Table 3). There were no differences in the treatment time between the four groups (P > 0.05; Table 3).

Table 3
Table 3:
Patient characteristics, dental treatment time, and scores on the Frankl Behaviour Scale according to groups

Time-dependent SpO2 (Fig. 1) and HR (Fig. 2) mean values in the groups were in the normal clinical range throughout the sedation period. There were no significant differences between the four groups regarding HR (P > 0.05). Time-dependent mean SpO2 values were significantly different in groups I, II, and III when compared with group IV at the T1, T3, and T4 time points (P = 0.001); mean SpO2 values were significantly different in groups II and III compared with group IV at the T2 time point (P = 0.001); and the mean SpO2 values were significantly different in groups I and III compared with group IV at the T5 time point (P = 0.005).

Fig. 1
Fig. 1
Fig. 2
Fig. 2

The sedation level was monitored by the BIS as shown in Fig. 3. Time-dependent mean BIS values were significantly different in groups II and III when compared with group I and group IV at the T2, T3, T4, T5, and T6 time points (P = 0.001).

Fig. 3
Fig. 3

RSS scores according to group are shown in Fig. 4. Comparison of the mean RSS values in groups I, II, and III showed significant differences at the T1 (P = 0.013), T3 (P = 0.046), T4 (P = 0.019), and T5 (P = 0.027) time points when compared with group IV, and group III showed significant differences at the T3 (P = 0.046) and T4 (P = 0.019) time points when compared with groups I and II. Although children were asleep while being transported to the dental unit, at the application of the nasal mask (T3) the children exhibited significantly more excitation in groups I, III, and IV than in group II. With regard to sedation levels, RSS scores were found to be significantly greater in group II than in groups I, III, and IV (P < 0.05). Achievement of sedation in terms of satisfactory/mid-level satisfactory/unsatisfactory was as follows: 13.3/53.3/33.3% in group I; 54/20/26% in group II; 33.3/33.3/33.3% in group III; and 6.7/60/33.3% in group IV. RSS score sedation success is shown in Fig. 5.

Fig. 4
Fig. 4
Fig. 5
Fig. 5

All of the children were followed after cessation of N2O/O2 at 5, 10, 30 and 60 min according to RSS score and all of the children were discharged from hospital when the starting sedation level on the RSS was reached.

Evaluation of side effects according to groups revealed nausea/vomiting (n = 1/2/3/4), cough (4/4/−/−), hiccough (−/1/−/5), enuresis (−/2/−/−), bronchospasm (−/1/−/−), hypersalivation (−/−/8/−), otalgia (−/−/−/2), hallucination (−/−/2/−), and epistaxis (−/−/−/1) in patients in groups I, II, III, and IV, respectively.


In paediatric dentistry, in cases in which cooperation cannot be achieved using psychological techniques because of fear and anxiety, it is imperative to resort to sedation methods that have minimal side effects and are safe and economical both for the child and for the dentist. Voluntary sedation ranks first among such methods. The most frequently used method for voluntary sedation is N2O/O2 inhalation. Even though the N2O/O2 inhalation method is used frequently, it is insufficient in children with a high to very high anxiety level.1 Leelataweewud et al.13 reported that use of N2O/O2 combined with another sedative agent would increase the depth of sedation. Therefore, in our study, sedation with 40% N2O/60% O2 inhalation was applied to the control group without premedication and to the other groups after premedication with oral intake of hydroxyzine hydrochloride, midazolam, or ketamine along with midazolam.

The level of a patient's anxiety and fear and the type and amount of sedative agent used to achieve sufficient sedation are important for the success of sedation. Sedation is achieved with much difficulty after premedication in children with a high level of agitation. Thus, in our study, in all groups, only cases with a high level of anxiety (FBS≥3) were considered.

In clinical studies in dentistry, the dose of hydroxyzine administered has varied.14 Whereas Malamed1 reported the dose of oral hydroxyzine not combined with other agents as 1.1–2.2 mg kg−1, Kupietzky and Blumenstyk14 recommended a dose of 5 mg kg−1. Shapira et al.4 emphasized that when oral hydroxyzine is applied, the planned dose should be calculated according to body weight. In our study, 1 mg kg−1 hydroxyzine hydrochloride was applied based on body weight.

Midazolam, which is a derivative of benzodiazepine, is used frequently in paediatric dentistry.1 In anaesthetic applications in paediatric patients, oral midazolam is reported in a wide range of 0.2–1 mg kg−1.15 Day et al.16 reported that in the high-anxiety level group aged 2.9 ± 1.6 a dose of 0.2–0.3 mg kg−1 and in the age group 5 ± 1 a dose of 0.5–0.7 mg kg−1 midazolam is appropriate for sedative premedication. In the second group of our study, 0.7 mg kg−1 midazolam was applied.

In general, when ketamine is used in low doses to achieve general anaesthesia, it provides sedation. Many researchers6,7,17 have reported that ketamine can be used in combination with benzodiazepines, such as midazolam, and presents an alternative to general anaesthesia for cheap, safe, and effective minor dental treatment. Funk et al.17 applied oral 0.5 mg kg−1 midazolam along with 3 mg kg−1 ketamine and 0.5 mg kg−1 midazolam along with 6 mg kg−1 ketamine to 24 children in the age range of 2–7 and reported that the most effective and safest dose was 0.5 mg kg−1 midazolam along with 3 mg kg−1 ketamine. In the third group of our study, 3 mg kg−1 ketamine along with 0.25 mg kg−1 oral midazolam was applied.

The best approaches in evaluating the level of anxiety and fear and the success of sedation are to use the scales and questionnaires by which a measurement of psychological answers to a situation in a clinical environment can be made.18 The RSS is a reliable method that has been used in many studies to measure sedation level.12,19

Chowdhury and Vargas,3 in a study to assess the success of sedation in 116 paediatric patients aged 2–5 years, reported the combination of 25 mg kg−1 chloral hydrate with 1 mg kg−1 hydroxyzine and with 1 mg kg−1 meperidine as being 90% successful, whereas 0.65 mg kg−1 midazolam was 70% successful. Fraone et al.20 reported that the application of 0.5 mg kg−1 midazolam to 61 paediatric patients in the age groups of 2–3, 3–4, and 4–5 years resulted in a success rate of 42–49%. In our study, a 54% success rate was achieved with 0.7 mg kg−1 midazolam and a 13.3% success rate was achieved with 1 mg kg−1 hydroxyzine hydrochloride. Our study is in agreement with the results of that study.

Silver et al.21 reported that, in 31 participants in the age range of 3–18, 0.3 and 0.5 mg kg−1 midazolam application resulted in 75 and 60% success, respectively. In our study, high doses of midazolam were found to be more successful for sedation. The observed differences in sedation success ratios of the various studies and the present investigation may stem from the different techniques used for behavioural guidance, the age ranges of the children studied, and their different anxiety levels.

It is essential to monitor a patient's vital functions, such as SpO2 and HR during sedation applications.

It is reported that breathing depression may develop during oral midazolam sedation, although infrequently.5 Chowdhury and Vargas3 observed in their study that at the 10th, 30th, and 40th min during the sedation procedure, a higher percentage of children who were given 0.65 mg kg−1 midazolam showed 95% or lower SpO2 compared with children who received the combination of 25 mg kg−1 chloral hydrate with 1 mg kg−1 meperidine. When they evaluated all groups, they reported that they did not observe a period when SpO2 dropped below 90%, and the observed period between 90 and 93% was temporary and these cases were instantly resolved with repositioning of the head and neck. They attributed this to the possibility of erroneous measurements due to the children holding their breath or moving.

When the results of our study were evaluated, SpO2 below 95% was not seen in the majority of cases. In cases in which N2O/O2 was applied with hydroxyzine hydrochloride, midazolam, or ketamine with midazolam, the SpO2 dropped only once for a short period. With repositioning of the patient's head, the SpO2 was brought to a level above 95%.

In our study, in all groups during the N2O/O2 application (T3), HRs were found to be lower when compared with initial values. A possible explanation is that the N2O/O2 combination applied after premedication may have increased the sedation depth. An increase in HRs was observed in patients following N2O/O2 application at the beginning of treatment (T4) in the groups with the local anaesthesia.

Administration of N2O/O2 is widely used to induce both analgesia and sedation and to improve patients' cooperation during dental treatments. It was investigated that BIS scores were decreased by different sedation or hypnosis techniques. Religa et al.22 conducted a study on paediatric patients requiring dental restorations between 3 and 6 years of age who received oral sedation with chloral hydrate or meperidine or hydroxyzine intraoperatively and N2O/O2 was also administered. A significant association was detected between patients' behaviours observed during sedation and the levels of sedation as measured by BIS. Morse et al.23 assessed the use of BIS monitoring in 22 patients undergoing conscious sedation with midazolam or midazolam along with ketamine for dental surgery and found that the BIS values remained close to baseline. In this research, the mean BIS value was 80–100 and it was similar to the results of Morse et al.

Chowdhury and Vargas3 observed two cases of vomiting and balance disorder in the standing position in some children. They did not observe paradoxical agitation after midazolam application.

Needleman et al.24 reported the incidence of vomiting as 8% in their studies when they used chloral hydrate together with hydroxyzine and N2O. Mishra et al.25 reported side effects such as nausea, vomiting, recovery agitation, and breathing depression following oral midazolam premedication at doses of 0.5, 0.75, and 1 mg kg−1. In their study with 3 and 6 mg kg−1 ketamine, Gutstein et al.26 reported a significant increase in saliva secretion.

It was concluded in this study that, for the purpose of achieving conscious sedation, premedication with oral application of 1 mg kg−1 hydroxyzine hydrochloride, 0.7 mg kg−1 midazolam, or 3 mg kg−1 ketamine along with 0.25 mg kg−1 midazolam before N2O/O2 inhalation increases the sedation success rate without causing any serious complications, but the most effective among them is 0.7 mg kg−1 midazolam.


1 Malamed SF. Sedation: a guide to patient management. In: Malamed SF, editor. Oral, rectal and intramuscular sedation: oral sedation, inhalation sedation: techniques of administration. 4th ed. St Louis: Mosby Co; 2003.
2 Houpt M. Pharmacological methods and research issues in the management of child patients. Anesth Prog 1986; 33:25–29.
3 Chowdhury J, Vargas KG. Comparison of chloral hydrate, meperidine, and hydroxyzine to midazolam regimens for oral sedation of pediatric dental patients. Pediatr Dent 2005; 27:191–197.
4 Shapira J, Holan G, Guelmann M, Cahan S. Evaluation of the effect of nitrous oxide and hydroxyzine in controlling the behavior of the pediatric dental patient. Pediatr Dent 1992; 14:167–170.
5 Bozkurt P. Premedication of the pediatric patient: anesthesia for the uncooperative child. Curr Opin Anaesthesiol 2007; 20:211–215.
6 Whitwam JG, McCloy RF. Principles and practice of sedation. 2nd ed. Oxford: UK: Blackwell Science; 1998.
7 Domio EF. Status of ketamine in anesthesiology. Ann Arbor, Michigan: NPP Books; 1990.
8 Matharu L, Ashley PF. Sedation of anxious children undergoing dental treatment. Cochrane Database Syst Rev 2006:CD003877.
9 Davidson A. Monitoring the anaesthetic depth in children: an update. Paediatr Anaesth 2007; 20:236–243.
10 Frankl SN, Shiere F, Fogels HR. Should the parent remain with the child in the dental operatory? J Dent Child 1962; 29:150–163.
11 Sebel PS, Lang E, Rampil IJ, et al. A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect. Anesth Analg 1997; 84:891–899.
12 Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone/alphadolone. BMJ 1974; 2:656–659.
13 Leelataweewud P, Vann WF Jr, Dilley DC, Lucas WJ. The physiological effects of supplemental oxygen versus nitrous oxide/oxygen during conscious sedation of pediatric dental patients. Pediatr Dent 2000; 22:125–133.
14 Kupietzky A, Blumenstyk A. Comparing the behavior of children treated using general anesthesia with those treated using conscious sedation. ASDC J Dent Child 1998; 65:122–127.
15 Cray SH, Dixon JL, Heard CMB, Selsby DS. Oral midazolam premedication for paediatric day case patients. Paediatr Anaesth 1996; 6:265–270.
16 Day PF, Power AM, Hibbert SA, Paterson SA. Effectiveness of oral midazolam for paediatric dental care: a retrospective study in two specialist centres. Eur Arch Paediatr Dent 2006; 7:228–235.
17 Funk W, Jakob W, Riedl T, Taeger K. Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 2000; 84:335–340.
18 Ram D, Mamber E, Chosack A, Fuks AB. The effect of metoclopramide and hydroxyzine in sedation of infants undergoing dental treatment. J Dent Child 1999; 66:49–52.
19 Isik B, Baygin O, Bodur H. Premedication with melatonin versus midazolam in anxious children. Paediatr Anaesth 2008; 18:635–641.
20 Fraone G, Wilson S, Casamassimo PS, et al. The effect of orally administered midazolam on children of three age groups during restorative dental care. Pediatr Dent 1999; 21:235–241.
21 Silver T, Wilson C, Webb M. Evaluation of two dosages of oral midazolam as a conscious sedation for physically and neurologically compromised pediatric dental patients. Pediatr Dent 1994; 16:350–359.
22 Religa ZC, Wilson S, Ganzberg SI, Casamassimo PS. Association between bispectral analysis and level of conscious sedation of pediatric dental patients. Pediatr Dent 2002; 24:221–226.
23 Morse Z, Kaizu M, Sano K, Kanri T. BIS monitoring during midazolam and midazolam-ketamine conscious intravenous sedation for oral surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 94:420–424.
24 Needleman HL, Joshi A, Griffith DG. Conscious sedation of pediatric dental patients using chloral hydrate, hydroxyzine, and nitrous oxide – a retrospective study of 382 sedations. Pediatr Dent 1995; 17:424–431.
25 Mishra LD, Sinha GK, Bhaskar Rao P, et al. Injectable midazolam as oral premedicant in pediatric neurosurgery. J Neurosurg Anesthesiol 2005; 17:193–198.
26 Gutstein HB, Johnson KL, Heard MB, Gregory GA. Oral ketamine preanesthetic medication in children. Anesthesiology 1992; 76:28–33.

anxious children; hydroxyzine hydrochloride; ketamine; midazolam; oral sedation

© 2010 European Society of Anaesthesiology