Introduction
Preanesthetic medication in paediatric patients is well known to be a challenge for anaesthesiologists. Premedication in pediatric population helps to produce a relaxed state with reduced anxiety and increased compliance as well as to ease separation from parent and allowing the patient to tolerate and co-operate with the necessary procedure.1, 2, 3, 4 The aims of preanesthetic medication in pediatric population include decreasing fear, anxiety and facilitation of a smooth anesthetic induction5, 6 and preventing postoperative psychological sequel. Intranasal administration has shown to be very effective, easy, non-invasive route with high bioavailability and rapid onset of action due to the high vascularization of the nasal mucosa.7
A γ-amino-butyric acid (GABA) receptor inhibitor, Midazolam is the most widely employed sedative drug in children as a premedication. It is known to provide effective sedation, anxiolytic effect, and of antero-grade amnesia of varying degrees.8, 9 A recent clinical study shows that a dose of 0.2 mg/kg midazolam is effective in reducing both induction anxiety and separation from parent, with no effect on recovery time.10, 11
A newer alpha 2-agonist, Dexmedetomidine has more selective action on the alpha 2-adrenoceptor and has a short half-life.12, 13 its bioavailability is around 80% when given via the nasal mucosa. Dexmedetomidine usage in paediatric population as preanesthetic is increasing because of its huge safety profile.14 We hypothesized that dexmedetomidine can be used as an alternative to midazolam for intranasal premedication in children. This prospective randomized double-blind study was conducted to compare the efficacy of dexmedetomidine and midazolam as intranasal premedication in children undergoing tonsillectomy. The primary outcome was determined with correlation to preoperative sedation, response of child to parental separation, mask induction, and the incidence and severity of postoperative agitation. Secondary outcomes studied hemodynamic stability of both drugs.
Materials and Methods
This was a prospective double blinded study conducted after obtaining approval from institutional ethical committee. This study included children of age 6 to 12 years with ASA physical status I posted for tonsillectomy. Informed written consent was obtained from the parents of the patients after explaining the study protocol to them. Patients with known allergy to any of the study drugs, recent upper respiratory tract infection/ lower respiratory tract infection, congenital heart disease, mental retardation, or neurobehavioral problems were excluded from the study. Children were randomly assigned using simple randomization procedure (random numbers generated by computer) to 1 of 2 treatment groups. Intranasal study medication was given 60 min before inducting anaesthesia to all the children.
Patient in group M (50) received 0.2mg/kg of midazolam administered intranasally as nasal drop using 1ml insulin syringe and similarly group D (50) received 1µg/kg of dexmedetomidine administered intranasally as nasal drops using 1ml insulin syringe.
An investigator who doesn’t have role in the giving anaesthesia was made to prepare the drug mixture. Anaesthesiologists attending the patients and the observers were blinded.
Pre-operative assessment
A blinded observer was made to assess the sedation status once in 10 min with a six- point sedation scale as shown in Table 1 and every 10 min the level of anxiety was evaluated using a four – point scale as shown in Table 2.
During anesthesia
All patients received general anaesthesia induced nasally by nitrous oxide, oxygen (50:50) and sevoflurane 2% via a primed face mask. The degree of mask acceptance was assessed using three-point Mask Induction scale. Standard ASA monitors (NIBP, ECG, SPO2) were connected.
Post-operative
At the end of surgery with adequate routine precautions post op agitation was assessed using a 3-point scale shown in Table 4. Postoperative agitation score after 10 min of extubation.
Statistical analysis
Sample size was calculated based on a study by Akin A et al.15 who mentioned that 82.2% of Group M and 60% of Group D (P = 0.01) achieved satisfactory mask induction. Taking this study as an example for calculating, in which a sample of 45 patients in each group provided 80% power at a 0.05 level of significance. We recruited 50 patients in each group in case of possible dropouts. The numerical data were compared using unpaired Student's t-test and reported as mean ± standard deviation. For sedation and anxiety scores nonparametric Mann-Whitney U-Test was used. Categorical variables were compared by Chi-square test and reported as median with interquartile range (IQR) and also numbers and percentages. For assessing statistical significance, a P value of 0.05 or less was set. Statistical Analysis was done using Epi info 3.5.4.
Results
During the entire study period, a total number of hundred patients met inclusion criteria and were involved in the study. The two groups selected were more or less similar with regard to demographic characters like age, weight, gender, duration of surgery, duration of anaesthesia, and extubation time. The mean age in group dexmedetomidine 9.00 + 2.11 years and group midazolam was 8.98 + 2.18 years suggesting both the group had comparable demographic characteristics (p=0.962). In this study 52% were male and 48% female in group dexmedetomidine and 60% were male and 40% female in group midazolam, suggesting both the group had comparable demographic characteristics.
hows the mean of Duration of Surgery, Anaesthesia, extubation time in group Dexmedetomidine is 34.24, 47.44, 8.1 and group midazolam is 34.58, 47.04,8, suggesting mean value of both the group is comparable.
As shown in Table 4, separation from parent, a satisfactory sedation was achieved in 86% and 68% of patient in dexmedetomidine and midazolam respectively p (0.03). Mask induction was satisfactorily achieved by 84% and 70% of patient in dexmedetomidine and midazolam respectively p (0.09). In terms of post op agitation score there is no difference in both the group p (0.30).
hows that the Sedation score were statistically lower in dexmedetomidine group compared to midazolam group at the 50th and 60thmin after administered of drug and separation. The anxiety score is equal in both the group there is no statistically significant between the groups.
Haemodynamic parameters
In the dexmedetomidine group a 13.41% reduction was seen in Heart Rate compared with midazolam group there was 7.56% decrease at the end of 60th minute. In our study, heart rate was significantly reduced in dexmedetomidine group when compared to midazolam group from the 20th minute continuously intraoperatively. Peripheral oxygen saturation never went below 95% in any group in the preop, intraop and postop periods.
There was modest decrease in Blood pressure (13.19%) in dexmedetomidine group and 10.46% in midazolam group. There was no statistical significance in between groups both during preoperative and intraoperative period.
No patient developed hypotension, hypoxia during the time between administration of pre op medication and initiation of anaesthesia induction. None of the patient developed laryngospasm in the both groups.
Table 1
Modified observer’s assessment of Alertness/sedation score
Table 2
Anxiolysis score
|
Score |
Criteria |
|
1 |
Calm and cooperative; |
|
2 |
Anxious but could be reassured; |
|
3 |
Anxious and could not be reassured |
|
4 |
Crying or resisting |
Table 3
Mean duration of surgery, anaesthesia and extubation time
Table 4
Separation from parents, quality of mask induction and agitation score
Table 5
Preoperative sedation and anxiety score (median IQR)
Discussion
In this study, we intend to compare the effects of administering dexmedetomidine and midazolam via intranasal route on mask induction and satisfactory sedation upon separation from parents in children undergoing tonsillectomy and found that premedication with 1μg/kg of intranasal dexmedetomidine was superior to 0.2 mg/kg of intranasal midazolam in decreasing anxiety at parenteral separation. However, both drugs seem to have equal effectiveness in terms of achieving satisfactory sedation throughout mask induction.
Most frequently used drug as a premedication is Midazolam. The main drawback of using midazolam via intranasal route is that it causes an unfavourable irritation within the nasal cavity. Hence, the nasal route of administering midazolam isn’t encouraged in regular practice. However, there are numerous studies that suggest that giving midazolam intranasally is best tolerated by children than its oral administration.16
Walbergh et al. studied the plasma concentration of Midazolam in children following intranasal administration and concluded that intranasal midazolam rapidly achieved sedative plasma concentration.
Malinovsky et al. studied the effect of intranasal, rectal and oral route on plasma midazolam concentration and observed that adequate sedation occurred within 10 min by giving midazolam intranasally.
As dexmedetomidine poses anxiolytic, sedation analgesic and sympatholytic properties, it’s a useful adjunct for premedication, especially for patients vulnerable to preoperative stress. Yuen et al. studied the sedative and analgesic effect of intranasal dexmedetomidine and concluded that intranasal route is more effective, well tolerated and convenient for the administration of dexmedetomidine.
L Kumar in 2017 has compared nasal instillation of Dexmedetomidine with oral Midazolam in various types of paediatric surgeries and has shown that both are effective premedication in paediatric practice.17
Another study clearly shows that intranasal 1 and 1.5 µg/kg doses of dexmedetomidine have similar effects on volunteers. Yuen et al reported that 1 µg/kg of dexmedetomidine is more effective in their study which compared 0.5 and 1 µg/kg intranasal doses. In children with burns, Talon et al. preferred using large doses of intranasal dexmedetomidine (such as 2 µg/kg) for preoperative premedication. Taking these references into consideration we choose 1 µg/kg dose of dexmedetomidine in our study. Davis et al. found that there’s no difference in effects while using both 0.2 and 0.3 mg/kg intranasal midazolam. Numerous other studies have shown to use intranasal dose of midazolam of 0.2 mg/kg. The dose that we have used in our study was firm in light of these studies. Yuen et al. study shows that the sedative effect of intranasal dexmedetomidine is observed after 45–60 min while the best sedative effect occurs at 90–105 min in healthy volunteers. In a study of paediatric patients by the same authors, this duration was accepted approximately 60 min.18 For intranasal midazolam Satisfactory separation from the parents has been found between 25 to 30 min19 because midazolam has the benefit of being a fast-acting drug. In our study the time taken for onset of both drugs utilized was different, we kept the preoperative sedation time to be 60 min. In this investigation, it shows that 86% of paediatric patients in dexmedetomidine group attained a satisfactory sedation compared to 68% in midazolam group. Moreover 84% of those sedated patients allowed mask induction without signs of distress and awakening.
We may have seen the best sedative effect in the midazolam group if we had used the upper doses of 0.3mg/kg. In a previous study which compared the effects of Clonidine, dexmedetomidine, and midazolam as premedication in children proved that Oral preparation of midazolam is superior to clonidine, and oral dexmedetomidine with faster onset of sedation, higher sedation score, lower anxiety score, and greater number of children with easy separation and excellent mask acceptance.20 Additionally, administering intranasal dexmedetomidine (0.5 and 1µg/kg) preoperatively shown to reduce Heart rate and Blood pressure in healthy children during the first hour. The reduction in SBP and HR seen after giving 1 µg/kg of dexmedetomidine was 14.1% and 16.4%, respectively. In our study with dexmedetomidine, reduction in Systolic Blood Pressure was 13.19% and Heart Rate was 13.14%. These levels in comparison with midazolam group was 10.46% and 7.56%. In a study conducted by yuen et al also showed there was decrease in SBP & HR after 1μg/kg of dexmedetomidine was 14.1% and 16.4% respectively.
Postoperative agitation score, both the groups had better score and there’s no statistical significance.
We found that there were no clear differences among both the groups with relevance to adverse effects, emergence from anaesthesia, or follow-up. The foremost limitation seen in this trail is that the timing of the drug administration, since peak onset of both the drug varied. So, fixing premedication time of both groups is also the reason for the difference and dose of midazolam could also be inadequate. The three- or four-point scales used in this study is unvalidated still, which again is considered as a limitation. There were some difficulties we encountered in evaluating paediatric patients while using these scales. For instance, if the child was crying but not combative, we found it hard to make a decision what rating to provide on the mask induction scale. More valid scales are to be used.
Conclusion
In our study we found that intranasal dexmedetomidine is a much better sedative than intranasal Midazolam so it can be preferred as a premedicant in young children. However, in providing satisfactory condition during mask induction, both the drugs midazolam and dexmedetomidine are equally effective.