Comparative study between intranasal dexmedetomidine and intranasal ketamine as a premedication for anxiolysis and sedation before pediatric general anesthesia

This study compared dexmedetomidine versus ketamine as regard sedation and anxiolysis produced by giving them through intranasal route to pediatric patients undergoing adenotonsillectomy. This study was double-blinded randomized comparative prospective interventional clinical study done in Ain Shams University Hospital (El Demerdash Hospital) on 76 pediatric patients who underwent adenotonsillectomy, and they were randomly allocated equally into two main groups; group D received 2 μg/kg intranasal dexmedetomidine and group K received 5 μg/Kg intranasal ketamine 30 min before the operation, and the aim of this study was to compare the efficacy of intranasal dexmedetomidine versus intranasal ketamine for anxiolysis and sedation to alleviate stress, agitation, and anxiety in children before general anesthesia and for promoting good level of sedation for them. Results of this study as regards sedation level that was assessed by modified Ramsay sedation score showed that there was statistically significant difference between both groups at 10, 20, and 30 min from intranasal application of the drug (P value < 0.05), the median (IQR) of sedation score at 10, 20, and 30 min preoperative in group D was (2 (2 – 2)), (3 (3 – 4)), (4 (4 – 5)) compared to (2 (2 – 3)), (3 (2 – 3)), (4 (3 – 4)) in group K respectively which revealed that there was better and effective sedation in group D more than in group K, this difference was statistically significant but clinically insignificant as both drugs produced an acceptable level of sedation and decreased the level of anxiety in children. Both drugs produce effective and favorable sedation level with superiority to dexmedetomidine in sedation scores and time of onset of sedation, and also there was little decrease in heart rate and mean arterial pressure which is favorable during such surgeries; also, there was accepted level of cannulation and parental separation scores, and the parents were highly satisfied with the procedure and were grateful for us due to alleviating stress and anxiety from them and from their children.


Background
Premedication in children is helpful for both separating the child from their parent and reducing the child's stress and anxiety, thus facilitating smooth induction of anesthesia. Furthermore, the drugs given for this purpose should have little effect on hemodynamics and respiration so as to allow the child to recover quickly and to facilitate early discharge without side effects (Jun et al. 2017).
Anxiety of the pediatric patient can add to the challenging nature of procedures performed before induction of general anesthesia. Pharmacologic and non-pharmacologic means of distraction and anxiolysis are commonly used to optimize the patient and family experience as well as to allow for the successful procedure completion. Intranasal medication delivery has been described as safe and effective and provides high patient and provider satisfaction (Neville et al., 2016).
Many drugs can be taken by the intranasal route such as glucocorticoids, nasal decongestants, naloxone, midazolam, ketamine, and dexmedetomidine. The administration of intranasal dexmedetomidine or intranasal ketamine avoids the need for intravenous cannulation and is not associated with an unpleasant sensation in the nasopharynx. It requires little cooperation and is not associated with distressing side effects (Li et al., 2019).
Dexmedetomidine is a selective alpha 2 agonist similar to clonidine, but with higher affinity to the alpha 2 receptor. Dexmedetomidine produces dose-dependent sedation, anxiolysis, and analgesia without respiratory depression. Dexmedetomidine triggers and maintains natural sleeping status without eye movement by stimulating the locus coeruleus in the brain stem, so it increases the activity of inhibitory gamma aminobutyric acid (GABA) neurons in the ventrolateral preoptic nucleus (Liu et al., 2019).
Ketamine is proved to interact with many receptors, including the N-methyl-D-aspartate receptor (NMDA-R) producing a dissociative anesthesia. Ketamine is known to reduce central sensitization to pain, decrease overall opioid utilization, and produce effective sedation level (Reynolds et al., 2017).

Aim of the study
The aim of this study is to compare the efficacy of intranasal dexmedetomidine versus intranasal ketamine for anxiolysis to alleviate stress, agitation, and anxiety in children before general anesthesia and for promoting sedation for them.
Another aim from this study is to prove the adequacy and effectiveness of another safe, effective, easy, and rapid route of administration of drugs and to make the perioperative period non-stressful and uneventful for the pediatric population.

Methods
The study was double-blinded randomized comparative prospective interventional clinical study and was performed at Ain Shams University Hospitals from April 2019 to March 2020. After departmental ethical committee approval and an informed written consent had been taken from the guardians of the pediatric patients, 76 healthy pediatric patients aged between 3 and 6 years of age boys and girls, American Society of Anesthesiology (ASA) physical status I and II undergone elective adenotonsillectomy under general anesthesia. Patients were blindly randomized using their medical record number into two equal groups and subjected to a comparative study. In group D, 38 patients received 2 μg/kg of body weight dexmedetomidine by intranasal route (Lewis & Bailey, 2020); in group K, 38 patients received 5 mg/kg of body weight ketamine by intranasal route (Suvvari et al., 2020) 30 min before operation. The study was completed in duration of 1 year.
Exclusion criteria were refusal of participation in the study by guardians of the patients, Physical status: ASA III or above, children with history of allergy to dexmedetomidine and ketamine, presence of morbidity (cardiovascular, neurological, respiratory, hepatic, and/ or renal problems), children with any abnormal vital signs especially hypotension and/or bradycardia, children having an illness with significant nasal congestion or deviated nasal septum, mentally retarded children, operations with increased duration due to different causes lasting more than 30 min, operations with increased blood loss and operations started with difficult intubation and multiple manipulations of the airway, and finally, difficult cannulation (three trials of cannulation or more) excluded from the study.
In the OR, children were maintained by full monitoring with non-invasive blood pressure, pulse oximetry, ECG, and capnography. Induction of anesthesia with inhalational induction using sevoflurane and fentanyl 1 μg/ kg was given, atracurium 0.5 mg/kg was given; then, intubation was done with a tube appropriate size to the child age, tube fixed to the middle of the chin; capnography was recording then anesthesia maintained with sevoflurane 2% and oxygen 100% till the end of procedure, and they were on volume-controlled mechanical ventilation.
Measurements a) Assessment of the vital signs mean blood pressure, heart rate, respiratory rate, and oxygen saturation preoperative baseline before application of the intranasal drug (0 min), 10 min preoperative after giving the intranasal drug, 20 min preoperative after giving the intranasal drug, at time of induction 30 min after giving the intranasal drug, intraoperative baseline before induction of anesthesia (0 min), 10 min intraoperative after induction of anesthesia, 20 min intraoperative after induction of anesthesia, 30 min intraoperative after induction of anesthesia and postoperative baseline in recovery (0 min), 10 min postoperative in the recovery, 20 min postoperative in the recovery, and 30 min postoperative in the recovery. b) Assessment of the sedation level done by modified Ramsay sedation scores (MRSS) was (Table 1) as follows: Modified Ramsay sedation scores (MRSS) recoded at different time intervals: preoperative baseline, 10 min, 20 min, at time of induction and postoperative 0 min, 10 min, 20 min, and 30 min. c) Assessment of the response to intravenous cannulation done by the Groningen distress rating scale (GDRS) ( Table 2) by an independent observer unaware of the premedication administered: d) Assessment of the response of the child to parental separation using parental separation score (Table 3): e) Assessment of parents' satisfaction score (Table 4) with as follows: f) All children observed postoperative till discharge criteria was met and monitored for presence of sedation, nausea/vomiting, and/or any other complications. g) Vomiting was assessed by number of vomiting episodes.

Statistical package and analysis
Using PASS program, setting alpha error at 5% and power at 80% results from previous study (Gyanesh et al., 2014), showed that the parents satisfaction in dexmedetomidine was 97.3% compared to 92.4% in ketamine group, considering non inferiority study between the two drugs with 10% accepted difference between the two groups. The needed sample is 38 cases per group.

Sample size
Thirty eight patients in each group (total 76 patients) Group D (intranasal dexmedetomidine): 38 patients will receive 2 μg/kg intranasal dexmedetomidine with concentration 100 μg/ml 30 min before the procedure. Group K (intranasal ketamine): 38 patients will receive 5 mg/kg intranasal ketamine with concentration 50 mg/ ml 30 min before the procedure.
The collected data will be revised, coded, and introduced to a PC using Statistical Package for Social Science (SPSS 15.0.1. for windows; SPSS Inc, Chicago, IL, 2001).
Data will be presented as mean and standard deviation (± SD) for quantitative prometric data. Suitable analysis will be done according to the type of data obtained. P < 0.05 will be considered significant.

Demographic data
Statistical analysis for the demographic data for two groups revealed that there was no statistically significant difference between the two groups (P value > 0.05) ( Table 5) Vital signs Heart rate When comparing heart rate changes after intranasal application of the drug, we observed that at the baseline before giving the drug there was no statistically significant difference (P value > 0.05) between the two groups. At 10 and 20 min after giving the drug, there was statistically significant difference between the two groups (P value < 0.05), and also at 30 min, the difference between two groups became statistically highly significant (P value < 0.01) as here we observed gradual decrease in heart rate in group D and little increase in heart rate or stationary heart rate in group K. Intraoperatively, the changes was statistically insignificant. Postoperatively, the difference was statistically significant (P value < 0.05) ( Table 6).

Mean arterial pressure
On behave of mean arterial pressure (MAP) in our study, we observed that the results was statistically insignificant at baseline before giving the drug (P value > 0.05); at 10, 20, and 30 min, the results between two groups was statistically significant (P value < 0.05) with mean arterial pressure (MAP) lower in group D than that in group K.  The results revealed that the difference intraoperatively and postoperatively was statistically insignificant (P value > 0.05), with generally lower values of mean arterial pressure (MAP) in group D compared to group K (Table 7).

Respiratory rate (RR)
Results of study including respiratory rate revealed statistically insignificant results at baseline (P value > 0.05); at 10, 20, and 30 min from giving the drug, there was statistically significant difference (P value < 0.05).
The results showed little decrease in respiratory rate in both groups with more decrease in group D making the difference statistically significant and clinically insignificant.
The results also showed no statistically significant difference between both groups intraoperatively as respiratory rate was set by the anesthesiologist and patient on mechanical ventilation on fixed preset respiratory rate.
Also postoperatively, the results were statistically insignificant between both groups (Table 8).

Arterial oxygen saturation
Results of the study revealed that there was no statistically significant difference between both groups as regards oxygen saturation (P value > 0.05) through all the stages of evaluating the drug preoperative after intranasal application of drug, intraoperative, and postoperative in recovery.  The least saturation recorded in group D was 95% and 96% in group K which there was no needed intervention in both groups (Table 9).

Modified Ramsay sedation score
Results of this study as regards sedation level that was assessed by modified Ramsay sedation score showed that there was statistically significant difference between both groups at 10, 20, and 30 min from intranasal application of the drug (P value < 0.05); the results revealed that there was better and effective sedation in group D more than in group K; this difference was statistically significant but clinically insignificant as both drugs produced an acceptable level of sedation and decreased the level of anxiety in children.
By observing the results regarding the sedation scores, we also observed that the time to reach better sedation level in patients was shorter with dexmedetomidine when compared to ketamine, and this denotes that the onset time of sedation and anxiolysis in patients premedicated with dexmedetomidine was rapid than patients premedicated with ketamine.
Postoperatively in the recovery room, the difference between both drugs was statistically insignificant (P value > 0.05), and also, the effect may be masked by the effect of residual inhalational anesthetics and narcotics given intraoperatively (Table 10).
Cannulation score, parental separation score, parental satisfaction score, and vomiting: Results of this study as regards cannulation score which was assessed by Groningen distress rating scale showed that there was no statistically significant difference between both groups (P value > 0.05) with median (IQR) score in group D (1 (1 -2)) versus (1 (1 -2)) in group K. As regards parental separation score was statistically insignificant with Median (IQR) score in group D (1 (1 -1)) versus (1 (1 -2)) in group K. As regards parental satisfaction the results also was statistically insignificant with Median (IQR) score (5 (4 -5)) in group D versus (4.5 (4 -5)) in group K. Two patients only (5.3%) in group D experienced vomiting in recovery area compared to 4 patients (10.5%) in group K (Table 11).
Induction of anesthesia was standardized for all patients starting with inhalational induction using sevoflurane, after that fentanyl 1 μg/kg and atracurium 0.5 mg/kg were given so as not to make an effect on different groups and different patients, and all patients were completely relaxed and were on volume-controlled ventilation so most of results after induction of anesthesia was statistically non-significant.

Discussion
Results of this study revealed statistically significant increase in sedation score in children premedicated with