Comparison of two intravenous sedation techniques for use in pediatric dentistry: A randomized controlled trial Porównanie dwóch technik dożylnej sedacji w stomatologii dziecięcej – randomizowane badanie kliniczne

Material and methods. The study was performed on 40 healthy uncooperative children aged 2–6 years. They were equally and randomly divided into 2 groups: group D – intravenous dexmedetomidine with a loading dose of 1 μg/kg body weight (b.w.), which was followed by 0.2 μg/kg b.w./h via continuous infusion; and group K – intravenous ketamine 2 mg/kg b.w. with atropine 0.01 mg/kg b.w. Vital signs, recovery time and adverse effects were all recorded. Behavior was also evaluated using the Ohio State University Behavioral Rating Scale (OSUBRS).


Introduction
Uncooperative behavior is the greatest challenge faced by pediatric dentists in daily practice. It can be a barrier to completing dental treatment or providing quality care. 1,2 Generally, most of the children showing a lack of coope ration or fears should be managed by behavioral mana gement techniques (BMTs). However, the use of phar macological methods, like conscious sedation or general anesthesia, is required in some children who are unable to tolerate dental procedures despite the use of all gentle psychological methods. 3,4 Among the drugs used for conscious sedation, one can mention ketamine, which is a phencyclidine derivative and provides amnesia and dissociative sedation, associated with an analgesic effect by blocking NmethylDaspartate receptors, without the loss of consciousness when given in appropriate doses. 5 When ketamine is administered alone intravenously, it produces an adequate sedative effect. However, it may have different side effects, 5 including hal lucinations and nightmares during the recovery, 6 as well as nausea, vomiting and excessive salivation, which may lead to potential coughing and laryngospasm. 7 Dexmedetomidine is a potent, highly selective alpha2 agonist that has sedative and analgesic effects. 8 It acts on adrenoceptors in many tissues, including the nervous, car diovascular and respiratory systems. 9 When dexmedeto midine is administered within the recommended doses provided by the clinical guidelines, it results in dosedepen dent analgesia with no accompanying respiratory depres sion. 10 Some researchers even claim that the results of the action of dexmedetomidine resemble normal sleeping due to its alpha2 agonist effect on the sympathetic system. 11 Although there has been a lot of research on various drugs used individually and/or in sort of a combination (a cocktail) to achieve sedation in children, the 'golden' sedative drug -with better outcomes, a higher impact (but unquestionably safe) and with fewer side effects -is still being sought. 12 Consequently, the present random ized controlled study was conducted to evaluate the ef ficacy and safety of intravenous sedation with dexme detomidine in comparison with ketamine administered with atropine in uncooperative children aged 2-6 years during dental treatment. It is worth mentioning that this age group is widely considered to be the most difficult to manage in pediatric dentistry.

Material and methods
In this randomized controlled study, ethical and licens ing approvals were obtained from the related specific re view board (the number of the ethical approval is 2088, dated October 7 th , 2017, and all parents gave informed written consent. This trial was carried out from Novem ber 2017 to January 2019. The study consisted of 40 healthy (according to the American Society of Anesthesiology (ASA) scale, ASA I) children aged 2-6 years, requiring dental treatment (pulpo tomy) under conscious sedation for exhibiting negative and definitely negative behavior on the Frankl scale. 13 Each child was assessed by a pediatric dentist prior to the sedation procedure. Moreover, preoperative medical questionnaires were completed by the children's parents or guardians with the help of the dentist.
The exclusion criteria embraced any children with known allergy to the drugs used, and children with respi ratory infections or any systemic disease.
All the children were requested to fast preoperatively for 6 h (solid foods and nonhuman milk), 4 h (human milk) and 2 h (water and clear liquids). 14 Baseline heart rate (HR), oxygen saturation (SpO 2 ) and blood pressure (BP) were recorded before any drug administration, at a 10minute interval and at the end of the dental proce dure. 14 An intravenous (IV) line was inserted before the start of conscious sedation using EMLA TM cream (Astra Zeneca, Wilmington, USA).
The children were randomized into 2 equal groups -group D and group K -using a computergenerated table of random numbers.
The children in group D received intravenous dexme detomidine with a loading dose of 1 µg/kg b.w. adminis tered over 10 min, followed by 0.2 µg/kg b.w./h dexmedeto midine as continuous infusion using a syringe pump, until the desired level of sedation was achieved. 15 Dexmedeto midine was prepared and diluted with 0.9% sodium chlo ride saline to obtain the required concentration (4 µg/mL); then, it was gently shaken to mix it well prior to admini stration. 15 In group K, the children received intravenous keta mine hydrochloride 2 mg/kg b.w. along with atropine 0.01 mg/kg b.w.
After the drug administration, the dental procedure was initiated and completed by an experienced pediatric dentist. All sedation procedures were handled by 1 anes thetist and all dental procedures were performed by 1 ex perienced pediatric dentist.
The sedation onset and recovery time were recorded, and also the behavior of each child during treatment was assessed by an external assessor using recorded videos according to the Ohio State University Behavioral Rating Scale (OSUBRS) ( Adverse events were noted, if any existed, and then the children were discharged when full consciousness was re gained and all vital signs were within normal ranges. The parents were contacted by telephone approx. 24 h post operatively to check for any complications experienced by the children. Data analysis was performed using the Mann-Whitney Utest and Student's ttest. The statistical package used for all data was IBM SPSS Statistics for Windows, v. 21 (IBM Corp., Armonk, USA). Statistical significance was defined as p < 0.05.

Results
A total of 40 healthy children aged 2-6 years completed the study protocol and the dental procedures. They were comparable with respect to the demographic data ( Table 2). With regard to age, weight, gender, and type of procedure, the differences were not statistically significant. Through out the procedures and during the recovery, no episodes of oxygen desaturation, hypotension, airway obstruction, or bradycardia were noted in any of the children. Oxygen saturation was SpO 2 > 97% in both groups.
The mean OSUBRS scores for both groups are pre sented in Table 3. There were statistically significant dif ferences between the 2 intravenous sedation groups in the mean OSUBRS scores as recorded by the external as sessor during treatment (Table 3). Group D showed bet ter behavior than group K (p = 0.03; the Mann-Whitney Utest).
In this study, the mean recovery time for dexmedetomi dine was shorter than that for ketamine (15.13 ±2.4 min and 17.93 ±2.5 min, respectively) ( Table 2). However, there were no statistically significant differences according to Student's ttest; the pvalue for this comparison was 0.12 (nonsignificant).
No serious side effects were noted, either during the procedures or in the recovery room. Also, no late compli cations were reported by the children's parents in the 24 h following the operation in either group.

Discussion
The ideal sedative for the outpatient dental clinic would be effective, easy to titrate, fast in onset and offset, pre dictable in response, able to preserve the airway tone, and inexpensive. Most importantly, it should exhibit minimal cardiovascular or respiratory effects, and minimal risk of the central nervous system (CNS) depression.
Dexmedetomidine has been shown to possess some of the desirable properties mentioned. Despite these ex cellent attributes, data regarding the use of dexmedetomi dine in pediatric dentistry is still limited. 17 Based on the present investigation, there is promising potential in the use of intravenous sedation techniques to overcome children's interfering behavior in the dental of fice. The outcomes of the present study indicate that both the intravenous sedation protocols used in this trial (with dexmedetomidine or with ketamine along with atropine) could provide effective and safe sedation for children undergoing outpatient dental procedures, still dexme detomidine resulted in superior sedation in comparison with ketamine. Most children in the dexmedetomidine group (55%) showed quiet behavior and no movement, i.e., score 1 according to OSUBRS. This superiority can be attributed to the pharmacological sedative and anal gesic effects of dexmedetomidine. 18 In a previous study by Hall et al., the authors reported that alpha2 agonists behaved differently from other sedatives due to their unique characteristics that make their action in inducing sedation closer to normal sleep, yet obtaining the level of consciousness sufficient to respond to orders. 8 This is consistent with the results obtained in the present study.
There is no research in the dental field comparing the use of intravenous dexmedetomidine to ketamine with atropine. This is the first comparative study of its kind, Group D -administered dexmedetomidine; group K -administered ketamine along with atropine; SD -standard deviation. led to an earlier awakening than ketamine, this difference was not statistically or clinically significant. The addition of atropine as an adjunct to intravenous ketamine seda tion in children prevents the occurrence of complications and adverse effects.

ORCID iDs
especially with the dosage mentioned. Therefore, the re sults of the present study could not be compared with any other. Studies that resemble the present one the most were conducted in the medical field, and compared dexmedeto midine to ketamine alone. In our study, the use of dexme detomidine led to an earlier recovery than ketamine, but this difference was not clinically or statistically significant. However, intravenous dexmedetomidine has a longer time of onset, and ketamine has the advantage of having a quicker onset. Similar results were found in a study con ducted by Gyanesh et al., who reported that children in the dexmedetomidine group had an earlier awakening and discharge than those in the ketamine group, but this differ ence was statistically nonsignificant. 19 Dexmedetomidine is a potent centrallyacting alpha2 agonist, and its action is characterized by easy titrating and a quick recovery from sedation, actually mimicking some aspects of natural sleep, 8,20 as the drug has a short halflife of 1.5-3 h after administering the intravenous doses, and because the main site of action of dexmedeto midine is the locus ceruleus rather than the cerebral cor tex in the CNS. 8,20,21 In the present study, the results of recovery time for ketamine were consistent with the clinical pharmacoki netics and pharmacodynamics of ketamine. It is an an esthetic that has a short acting time, so it is used mainly in children and elderly adults for short procedures. The later halflife of ketamine (beta phase) is 2.5 h, making the awakening from anesthesia fast. 22,23 In our study, no patients experienced serious adverse events in either of the sedation groups, nor did any re quire the termination of the procedure or the administra tion of any emergency medications. This finding supports the aspect of safety relating to the use of intravenous dex medetomidine, 24,25 and it is in accordance with the find ings of several other studies that utilized intravenous dex medetomidine. 26 It also confirms the benefit of the prophylactic coad ministration of atropine (an anticholinergic) as an adjunct to intravenous ketamine sedation in children. This is con sistent with many studies, which have reported that atro pine counters the effects of some sedatives, like ketamine, and reduces hypersalivation, excessive secretion from the respiratory tract, nausea, and vomiting, [27][28][29] which are the most common complications related to the use of keta mine. 6,7,30

Conclusions
In summary, both dexmedetomidine and ketamine pre sented satisfactory and good sedation, and were effective in behavior management in children undergoing outpa tient dental procedures, but intravenous sedation with dexmedetomidine proved to be more effective than that with ketamine. Although intravenous dexmedetomidine