Comparison of Intranasal Dexmedetomidine and Midazolam as Premedication in Pediatric Surgical Patients: A Prospective, Randomized Double-Blind Study.

INTRODUCTION: To relieve anxiety and fear is a major concern for pediatric anesthesiologist, and intranasal dexmedetomidine seems to be better alternative to midazolam to provide sedation and allay anxiety in children. AIMS AND
OBJECTIVES: We compare the sedative effects, anxiety level, successful child-parental separation, and hemodynamic parameters of either intranasal dexmedetomidine or midazolam as a premedication in children undergoing pediatric surgery. SETTING AND
DESIGN: This is a prospective, randomized, double-blind study conducted on 60 patients belonging to the American Society of Anesthesiologists Physical Status Classes I and II, undergoing pediatric surgical procedures with the use of intranasal dexmedetomidine and midazolam as premedication.
MATERIALS AND METHODS: Sixty children were randomly allocated into two groups of 30 each: dexmedetomidine group received intranasal dexmedetomidine (1 μg.kg-1), and midazolam group received intranasal midazolam (0.2 mg.kg-1), 30 min before induction. The sedation score, anxiety score, and successful child-parent separation were recorded till 30 min of drug administration, and then, the child was taken to the operating room (OR). STATISTICAL ANALYSIS: The Statistical Software, namely Statistical Package for the Social Science 17.0, was used for the analysis of the data. A P < 0.05 was considered statistically significant.
RESULTS: Children premedicated with intranasal dexmedetomidine achieved significantly lower sedation score (P < 0.001), lower anxiety levels (P = 0.001), and easier child-parent separation (P = 0.003) than children who received intranasal midazolam.
CONCLUSION: Intranasal dexmedetomidine was associated with lower sedation levels, lower anxiety levels, and easier child-parent separation at the time of transferring patients to the OR than children who received intranasal midazolam. Copyright:

INTRODUCTION

The most common challenge facing in the operating room (OR) by pediatric anesthesiologists is to facilitate smooth induction of anesthesia for children to minimize the distress among the children. This is usually accomplished by the administration of a sedation before transfer to the OR.[1] Anxiety and fear due to parental separation are major challenges in pediatric anesthesia. Hence, the aim of preanesthetic medication in children was to decrease the anxiety and psychological trauma and also to facilitate the induction of anesthesia without delaying the recovery. Hence, many drugs have been tried so far to find out the appropriate sedative agent and the best route of administration of these drugs in children. Hence, the used premedicant should have an acceptable, nontraumatic route of administration to avoid further stress to the children. Currently, the most commonly used drugs for these purposes are midazolam, ketamine, transmucosal fentanyl, and/or meperidine.[2]

Among the various routes of drug administration for pediatric sedation, intranasal route seems to be more reliable way to administer preanesthetics and sedatives to children because of its relatively easy route with rapid onset of action and high bioavailability due to bypassing the first-pass hepatic metabolism and the high vascularity of the airway mucosa[3] as compared to intravenous (i.v.) route. Furthermore, it has the advantages of being well tolerability, not requiring patient cooperation, and does not have pungency or an unpleasant taste.

In the pediatric patients, midazolam is a mainstay of sedation as they provide anxiolysis, amnesia, and sedation and also have hypnotic, anticonvulsant, and muscle-relaxant properties. Most commonly administered routes of midazolam are oral, i.v., or intramuscular, and the newer addition to this is intranasal. Midazolam are routinely given as orally to allay anxiety in children before the placement of i.v. lines.[4]

There was continuous effort to find out premedicant which has easy route of administration, less traumatic, less pungent, and minimal respiratory depression properties and provides good sedation, anxiolysis, amnesia, and analgesia for children. Dexmedetomidine is selective α2 receptor agonist; its selective α2 adrenoceptor agonist exhibits sedative, anxiolytic, analgesic, and hypnotic effects; and these properties render dexmedetomidine suitable for analgesia and sedation during the perioperative period.[5]

The aim of our study was to compare the sedative effects, anxiety level, successful child–parental separation, and hemodynamic parameters of either intranasal dexmedetomidine or midazolam as a premedication in children's undergoing pediatric surgery.

MATERIALS AND METHODS

After institutional ethical committee approval and informed written consent, 60 children of either sex of American Society of Anesthesiologists (ASA) Physical Status Classes I and II between age group of 2 and 12 years, scheduled for elective pediatric surgical procedure under general anesthesia, were enrolled in this prospective double-blinded, randomized study. Patients were excluded from the study including child refusal, allergy to studied drugs, any psychiatric illness, upper respiratory tract infection, nasal obstruction (mass), epistaxis, nasal congestion, sinusitis, and any higher neurological problems.

All patients were randomly assigned into two equal groups (n = 30) using sealed envelope based on computer-generated random numbers. Group M (n = 30): Children received intranasal midazolam (0.2 mg.kg−1), 30 min before induction. Group D (n = 30): Children received intranasal dexmedetomidine (1 μg.kg−1), 30 min before induction. All the patients were examined a day before surgery, after explaining anesthetic plan, proper fasting status, and current medication to concerned guardian, and informed written consent was obtained. All children were evaluated fulfilling full medical history, clinical examination with body weight, and airway assessment.

All study drugs were prepared by the investigator anesthesiologists and were administered by other observer, and attending anesthesiologists were blinded to the given drug and responsible for further assessment and management of the patient. Child was premedicated in the preoperative holding room in the presence of their parent. Baseline heart rate (HR), oxygen saturation (SpO2), and blood pressure (BP) were measured before drug administration. Intranasal drug was dripped into the both nostril using 1 mL syringe with the child in the recumbent position. HR, SpO2, and BP were measured every 5 min after drug administration until transfer to operation theater. Preoperative sedation was assessed using modified Ramsay sedation scale at the time of administration of drug followed by readings every 5 min for 30 min and at the time of transfer to operation room by blinded observer and sedation score was evaluated with 6-point scale as 1 = does not respond to mild prodding or shaking; 2 = responds only mild prodding or shaking; 3 = eyes closed but arousable to light glabellar tap or responds only after name is called loudly or repeatedly; 4 = semi-asleep but responds to commands only; 5 = awake, cooperative, oriented, and tranquil; and 6 = anxious agitated, restless. Behavioral score (anxiety score) was evaluated every 5 min with a four-point scale: 1 = cooperative and calm, 2 = anxious but could be reassured, 3 = anxious and could not be reassured, and 4 = resisting or crying.[6] In our study, successful parental separation was defined as when the patients were calm and sedated, were not crying and agitated, and allowed smooth induction.

After 30 min, each child was shifted to the OR and induction with general anesthesia was performed after attachment of routine baseline monitor in the form of noninvasive BP, electrocardiography, pulse oximetry, and capnography. i.v. catheter was secured in the ventral aspect of the left forearm before induction and child's sedation, behavioral/anxiety score, and successful parental separation were noted. In all children, preoxygenation with face mask using 100% oxygen was performed for 5 min and induced with injection propofol 2 mg.kg−1 body weight, injection fentanyl 2 μg.kg−1 of body weight, and injection vecuronium 0.1 mg.kg−1 of body weight. After proper bag and mask ventilation for 5 min, the child intubated with proper size-cuffed endotracheal tube, and after confirmation of capnography, the child was checked for bilateral equal air entry on auscultation, and then, the patient put on controlled ventilation. Maintenance of anesthesia was done using O2:N2O in the ratio of 50%:50% and sevoflurane. After the completion of the surgery, anesthetic gases were discontinued till it comes to 0% and replaced with 100% oxygen at the flow rate of 6 L/min for 3–5 min. After proper suctioning of tube, the patient was extubated with the use of injection neostigmine 50 μg.kg−1 and injection glycopyrrolate 10 μg.kg−1; then, the patient was transferred to the postanesthetic care unit for monitoring of vital signs till discharge to the ward. All children were given i.v. paracetamol (10 mg.kg−1 body weight) for postoperative analgesia.

Sample size was calculated using sealed envelope sample size calculator by taking type I error (α error) =5% and β error of 20%, power of the study (1 − β) = 80% was estimated to get a minimum expected difference in sedation state at parent separation between two groups of approximately 30% to yield a total sample size of 53 cases. To make provision for dropouts of 10% -15% cases was expected. Therefore, a total of 60 cases are required for the study (30 in each group). The statistical analysis of data was done using Statistical Package for the Social Science (SPSS, Inc., Chicago, IL, USA) program version 17. Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as absolute numbers and percentage. The comparison of normally distributed continuous variables between the groups was performed using unpaired Student's t-test. Repeated measurements’ data were analyzed using paired t-test. Nominal categorical data between the groups were compared using Chi-square test or Mann–Whitney test as appropriate. P < 0.05 was considered statistically significant at confidence interval of 95%.

For statistical analysis, sedation score was categorized as being satisfactory when rated between 1 and 4 and unsatisfactory when rated 5 or 6. Behavioral/anxiety score was categorized as being satisfactory when rated between 1 and 2 and unsatisfactory when rated 3 and 4.

The primary outcome of our study was to assess the sedative effects of studied drugs used as premedication in pediatric patients.

The secondary outcome was to access anxiety level, successful parental separation, and hemodynamic changes among the children who received studied drug as premedication.

RESULTS

Figure 1 shows consort flow diagram of patients of the study. Of 70 patients, 60 completed the study successfully. Both groups were comparable with respect to age, sex, weight, and ASA classification [Table 1] and found to be statistically insignificant (P > 0.050). In both groups, HR was found to be statistically significant (<0.013) until 30 min of drug administration [Table 2]. In both groups, systolic BP (SBP) and diastolic BP (DBP) were comparable and found to be statistically insignificant (>0.076) [Tables 3 and 4]. Sedation score was significantly lower in the dexmedetomidine group when compared to midazolam group (P < 0.001) at 5, 10, 15, 20, 25, and 30 min after drug administration [Table 5]. In Group D, anxiety score was significantly lower than Group M (P = 0.001) at 5, 10, 15, 20, and 30 min after administration of drug [Table 6]. In Group D, 29 out of 30 (96.7%), and in Group M, 20 out of 30 (66.7%) showed successful parental–child separation and found to be statistically significant (P = 0.003) [Table 7]. However, there was no episode of bradycardia and hypotension in both groups. Three children out of 60 had experienced single episode of vomiting and get subsided without any treatment.

Figure 1

Consort flowchart of patient studied

Table 1

Comparison of demographic data

Parameters	Group D	Group M	P
Age (months)	59.13±35.932	49.60±18.969	0.204
Weight (kg)	17.70±6.742	15.50±4.183	0.134
Sex (male/female)	17/13	16/14	0.154
ASA (I/II)	28/2	28/2	-

Data presented as mean±SD or number or percentage P<0.05 considered as significant. SD=Standard deviation, ASA=American Society of Anesthesiologists

Table 2

Comparison of heart rate between groups

Time interval	Mean±SD		t	P
	Group D	Group M
HR baseline	108.77±20.686	109.50±22.551	−0.131	0.896
HR 5 min	95.20±20.679	109.70±22.890	−2.575	0.013
HR 10 min	89.87±17.577	109.50±22.604	−3.756	<0.001
HR 15 min	85.77±15.409	107.53±22.104	−4.425	<0.001
HR 30 min	84.00±14.047	109.13±20.382	−5.561	<0.001

Data presented as mean±SD. P<0.05 considered as significant. P<0.001 considered as highly significant. SD=Standard deviation, HR=Heart rate

Table 3

Comparison of systolic blood pressure between groups

Time interval	Mean±SD		t	P
	Group D	Group M
SBP baseline	113.37±13.614	111.43±14.699	1.989	0.088
SBP 5 min	112.07±9.659	107.30±10.755	1.806	0.076
SBP 10 min	106.40±10.698	106.13±11.953	0.091	0.928
SBP 15 min	102.27±10.405	107.20±10.591	−1.820	0.074
SBP 30 min	97.07±9.972	107.70±11.540	−3.819	<0.001

Data presented as mean±SD. P<0.05 considered as significant. P<0.001 considered as highly significant. SD=Standard deviation, SBP=Systolic blood pressure

Table 4

Comparison of diastolic blood pressure between groups

Time interval	Mean±SD		t	P
	Group D	Group M
DBP baseline	72.73±11.650	70.33±9.140	0.888	0.378
DBP 5 min	67.40±7.859	68.73±6.362	-0.722	0.473
DBP 10 min	63.33±7.327	68.60±8.767	-2.525	0.014
DBP 15 min	61.30±6.944	65.63±7.005	-2.406	0.019
DBP 30 min	60.00±7.446	68.07±8.534	-3.901	<0.001

Data presented as mean±SD. P<0.05 considered as significant. P<0.001 considered as highly significant. SD=Standard deviation, DBP=Diastolic blood pressure

Table 5

Comparison of sedation score between groups

Variables	Mean±SD		t	P
	Group D	Group M
MRS baseline	5.50±0.682	5.53±0.507	−0.215	0.831
MRS 5 min	3.20±0.847	4.03±0.809	−3.898	<0.001
MRS 10 min	2.90±0.845	3.97±0.890	−4.761	<0.001
MRS 15 min	2.80±0.925	3.90±0.923	−4.612	<0.001
MRS 20 min	2.57±0.817	3.87±0.937	−5.727	<0.001
MRS 25 min	2.50±0.820	3.87±0.937	−6.011	<0.001
MRS 30 min	2.50±0.820	3.87±0.937	−6.011	<0.001

Data presented as mean±SD. P<0.05 considered as significant. P<0.001 considered as highly significant. SD=Standard deviation, MRS=Modified Ramsay sedation score

Table 6

Comparison of anxiety score between groups

Variables	Mean±SD		t	P
	Group D	Group M
BS baseline	3.47±0.629	3.53±0.507	−0.452	0.653
BS 5 min	1.30±0.535	2.07±0.828	−4.261	<0.001
BS 10 min	1.20±0.551	1.87±0.900	−3.462	0.001
BS 15 min	1.17±0.461	1.83±0.928	−3.481	0.001
BS 20 min	1.17±0.461	1.80±0.925	−3.357	0.001
BS 25 min	1.17±0.461	1.80±0.925	−3.357	0.001
BS 30 min	1.13±0.434	1.80±0.925	−3.574	0.001

Data presented as mean±SD. P<0.05 considered as significant. P<0.001 considered as highly significant. SD=Standard deviation, BS=Behavioral score

Table 7

Comparison of successful parental separation between two groups

Successful parental separation	Group D, n (%)	Group M, n (%)
No	1 (3.3)	10 (33.3)
Yes	29 (96.7)	20 (66.7)
Total	30 (100)	30 (100)

χ2=9.017, P=0.003. Data presented as percentage. P<0.05 considered as significant

DISCUSSION

Pediatric anesthesia always presents with major challenge as it deals with psycho-biologically vulnerable age group. Despite reassurance by parents, surgeons, and anesthetists, a large number of children still remain anxious preoperatively and an equal number of children suffer from postoperative maladaptive behaviors[7] even a week after surgical experience. Although several behavioral modalities such as coping, modeling, play therapy, use of dolls and toys for distraction, and parental presence during induction have been practiced to reduce anxiety, none of these methods have been satisfactorily effective and practicable. Hence, premedication is required to alleviate anxiety and fear, allow smooth separation from parents, and allow easy acceptance of needle prick for i.v. cannulation and anesthesia induction. This prospective, randomized, double-blind, controlled study compared the intranasal administration of dexmedetomidine (1 μg.kg−1) and midazolam (0.2 mg.kg−1) as premedication in children of age group between 2 and 12 years, posted for elective pediatric surgery under general anesthesia. Intranasal dexmedetomidine premedication for children attained satisfactory and significant sedation and lower behavioral change with better parental separation than those who premedicated with intranasal midazolam. Among various routes of administration, intranasal application is a relatively noninvasive, convenient, and easy route of administration and results in a faster onset of action as well as reduces first-pass metabolism.[89] Hence, we have chosen to administer midazolam and dexmedetomidine intranasally as premedication to allay anxiety and to provide sedation in pediatric patients. Intranasal dexmedetomidine produces significant sedation in healthy adults and in children aged between 2 and 12 years.[89]

In the present study, demographic profile between two groups was comparable. Children in the dexmedetomidine group achieved significant lower sedation score (P < 0.001) and lower anxiety score (P = 0.001) till 30 min after drug administration in comparison to midazolam group. Furthermore, the more percentage of children (96.7%) were satisfactorily separated from parents in the dexmedetomidine group when compared to the midazolam group and found to be clinically and statistically significant (P = 0.003). Our study was supported by Kumar et al.[10] study of efficacy of intranasal dexmedetomidine versus oral midazolam for pediatric premedication and concluded that intranasal dexmedetomidine at dose of 1 μg.kg−1 produces superior sedation and behavioral score at separation and induction to oral midazolam in pediatric patients. Similar result was observed by Ghali et al.[11] they concluded that intranasal dexmedetomidine (1 μg.kg−1) is a better choice for preanesthetic medication than oral midazolam (0.5 mg.kg−1) in children scheduled for adenotonsillectomy and was associated with lower anxiety levels, lower sedation levels, and easier parent separation during transferring patients to the OR than children who received oral midazolam. Our result was further strengthened by Yuen et al.[1213] they concluded that children were more sedated during parental separation and at induction of anesthesia after intranasal dexmedetomidine (0.5 μg.kg−1) than oral midazolam (0.5 mg.kg−1). Furthermore, Patel et al.[14] concluded that children who were premedicated with intranasal dexmedetomidine had lower sedation scores and easier parent separation than children who received intranasal midazolam. In contrast to the present study, Akin et al.[15] and Schmidt et al.[16] concluded that intranasal midazolam (0.2 mg.kg−1) and dexmedetomidine (1 μg.kg−1) were equally effective in decreasing anxiety at parental separation. This could have resulted from the different scale used for sedation and anxiety assessment and age group included in the study.

In our study, HR between two groups was found to be statistically significant (P < 0.001) and decrease of HR was more in Group D than Group M. This can be explained by the fact that dexmedetomidine is known to cause decrease in sympathetic outflow and circulating catecholamine levels and would therefore be expected to cause a decrease in HR, and our study was supported by similar result of Sundaram and Mathian.[17] There was no significant difference of SBP and DBP between groups was found at any interval of time except at 30 min. Contrary to our results, Sundaram and Mathian[17] found that decreased SBP and DBP from baseline after administration of premedication.

How dexmedetomidine and midazolam provide sedation and allay anxiety is not known exactly. In case of dexmedetomidine, best possible mechanism might be the site of action at locus coeruleus in the central nervous system primarily and seems to provide sedation, anxiolysis, and analgesia without respiratory depression.[18] Primary action of benzodiazepine (BZD) is to facilitate the binding to GABA -A receptor in cerebral cortex especially in the limbic system, thalamus and hypothalamus which enhances the membrane conductance of chloride ions and leads to a change in membrane polarization that inhibits normal neuronal function, that might be the cause of sedation, anxiolysis and antegrade amnesia.[19]

Limitations of our study were that we could not assess the sedative effects of both drugs postoperatively and effects of dexmedetomidine premedication on analgesic requirements during the surgery. Our study is lacking the peak sedative effects of studied drugs. Further study is required to match the child–parent separation at the time of peak sedative effect of studied drugs.

CONCLUSION

Intranasal dexmedetomidine was associated with lower sedation levels, lower anxiety levels, and easier child–parent separation at the time of transferring patients to the OR without significant side effects than children who received intranasal midazolam. Intranasal dexmedetomidine seems to be better alternative than midazolam to provide sedation in pediatric patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.