Any surgery or anesthesia is a stress for any child as well as for the parents. Depending on the developmental maturity, age, or past surgical experiences, children develop the sense of insecurity when they are separated from their parents for the induction of aaesthesia [1]. Preoperative anxiety can result in a variety of maladaptive behavior (postoperative pain, night enuresis, sleep disturbances etc) and can largely affect the smoothness of induction and emergence from anesthesia [2-3]. Midazolam provides anterograde amnesia, reduced anxiety, and rapid onset of sedation and reduced postoperative behavioral changes when used as premedicant in children. Clonidine reliably produces preoperative sedation and anxiolysis in children. Furthermore, it has analgesic properties, decreases volatile anesthetic requirements and improves perioperative hemodynamics of the patient [4-5]. Premedicant drugs can be administered through various routes. Amongst these, Drug administration through intranasal route offers the advantage of rapid, easy, painless and virtually complete absorption due to high mucosal vascularity [6]. 

Till date few studies have been conducted comparing the efficacy of midazolam and clonidine as intranasal premedicants and many have recommended further evaluation. The rationale of conducting the present study was to compare the safety and efficacy of these drugs when used as premedicants via the intranasal route in paediatric patients.

This randomized, double blind controlled trial study was conducted prospectively in a tertiary care centre of North India over a period of one year after approval from the Institutional Ethical Committee (PHARMA/2010/2/541). The participants were 105 children of age between 3-7 years of either gender, belonging to ASA grade 1 and 2 who were scheduled for elective orodental surgeries under general anesthesia. Children with upper respiratory tract infection, allergy to any of the study drugs, any congenital anomaly, and refusal to participate by the parents were excluded from the present study. A written informed consent was taken from the parents of the participating children. Preoperatively, children were kept fasting for 6 hours. The study drugs were reconstituted according to per kilogram of body weight dosage and divided into two aliquots of equal volume for administration in both the nostrils. Variables like heart rate, mean arterial blood pressure (MAP), SpO2, degree of sedation were measured before administering the study drug. Each patient was randomly assigned to one of the three study groups:

• Group 1: 35 patients receiving midazolam 0.2 mg/kg, 0.5 ml in each nostril, 40 minutes before induction of anesthesia

• Group 2: 35 patients receiving clonidine 3 μg/kg, 0.5 ml in each nostril, 40 minutes before induction of anesthesia

• Group 3: 35 patients receiving normal saline as placebo, 0.5 ml in each nostril, 40 minutes before induction of anesthesia

To generate the random allocation sequence randomization was done using a computer generated random number table. Adequate allocation concealment was done to prevent selection bias using sequentially numbered, sealed and opaque envelopes that contained the code of the group which were opened only when the consent to participate in the study was obtained. Data was recorded by another observer who was blinded to the group allocation. The patients as well as the post anesthesia care unit staffs were also unaware of the group assignment. The code was broken after completion of the study and statistical analysis. To ensure blinding, drugs were administered into each nostril by an independent observer not involved in the study with dropper in supine position after which the subjects were immediately shifted to lateral position, and then their nostril was pinched. The code was broken after completion of the study and statistical analysis. Heart rate, mean blood pressure (MAP), SpO2, degree of sedation were measured every 10 minutes till 30 minutes according to the 5- point sedation scale: 1 = Agitated (clinging to parent/crying); 2 = Alert (aware, may whimper but not clinging/crying); 3 =  Calm (sitting or lying comfortably with spontaneous eye opening), 4 = Drowsy ( sitting or lying comfortably with eyes closed but responding to minor stimulation); 5  = Asleep (eyes closed, arousable but does not respond to minor stimulation). Then the child was taken inside the operating room and intravenous line with 5% dextrose started. The reaction to i.v. cannulation was recorded according to 4-point scale: 1 = fight without success; 2 = fight with success; 3 = minor resistance; 4 = no resistance. Score 3 and 4 was considered satisfactory.  Routine monitors were then attached to the child and HR, MAP, SpO2 and degree of sedation were noted at 40 minutes.  Once the sedation score of 2–3 was achieved the child was shifted to the operating room. One hundred percent oxygen was given by face mask for 3 minutes. Child’s face mask acceptance was noted according to 5-point scale; 1 = combative, crying; 2 = moderate fear of mask, not easily calmed; 3 = cooperative with reassurance; 4 = calm, cooperative; 5 = asleep, steal induction. Score 3 or more were considered satisfactory. The patient was induced with injection propofol 2 mg/kg. Tracheal intubation was done after administration of atracurium 0.5 mg/kg. Anesthesia was maintained with nitrous oxide 66%, oxygen 33% and isoflurane. Intraoperatively, vitals were recorded every 10 minutes. For analgesia, injection paracetamol 10 mg/kg intravenous was given. Any intraoperative complications were noted and treated accordingly.  At the end of the surgery, residual neuromuscular blockade was reversed by injection neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Level of postoperative sedation was assessed using a 3- point scale: 1 = agitated, crying; 2 = crying but easily consoled; 3 = calm/asleep. Postoperatively, patient was assessed at 10 minutes for one hour interval using the same scale.

The primary outcome of the study was to evaluate the efficacy of intranasal midazolam and clonidine as premedicants to provide sedation and anxiolysis by a noninvasive route. The secondary outcomes were to compare their effects on hemodynamics, reaction to intravenous cannulation, mask acceptance, postoperative sedation and assess any side effects, if any.

Sample size

Based on a pilot study on 25 subjects conducted in our institute, we calculated that at least 30 patients would be required per group for an experimental design incorporating two equal sized groups, with β = 0.2 and α = 0.05. However, to minimize any effect of possible drop outs, we elected to recruit 35 patients per group into the study. 

Statistical Analysis

Data was analyzed with the help of computer software SPSS version 17.0 for windows. Difference in mean values of sedation score and hemodynamic variables was assessed by One- way Analysis of Variance (ANOVA). Statistical significance of qualitative variables was assessed by chi-square test. Intergroup comparisons were made post-hoc by Bonferroni’s t-test. p-value <0.05 was considered statistically significant. All ‘p’ values reported were two- tailed.

All children enrolled in the study completed the analysis. All groups were comparable in terms of age, sex, weight and duration of surgery. In our study, 10 minutes after the study drug was given children experienced sedation (Table 1). Using ANOVA, sedation score at 10 minutes was highly significant (p<0.001) when compared to control group (group 1 vs 3 and group 2 vs 3) but it was statistically insignificant between midazolam and clonidine group (group 1 vs group 2). At 20, 30 and 40 minutes, the difference in sedation score was highly significant between all the groups (p<0.001). 

Table 1: Sedation Score after Giving Premedication   (Mean±Sd)

Table 2: Heart Rate Changes (Beats/Min) after Giving Premedication (Mean±Sd)

Table 3: Mean Arterial Blood Pressure Changes (Mmhg) after Giving Premedication (Mean±Sd)

Table 4: Reaction to Intravenous Cannulation and Mask Acceptance Score

Table 5: Intraoperative Heart Rate (Beats/Minute) Changes at Various Time Intervals from the Start of Surgery (Mean±Sd)

Table 6: Intraoperative Mean Blood Pressure (Mmhg) Changes at Various Time Interval from the Start of Surgery (Mean±Sd)

Table 7: Postoperative Sedation Score (Mean± SD)

After the premedication was given, the heart rate and mean MAP decreased more in clonidine than midazolam group from baseline values at various time intervals with no change seen in control group (Table 2, 3). At 10, 20, 30 and 40 minutes after giving premedication, the decrease in heart rate was statistically insignificant between midazolam and clonidine group but statistically highly significant (p<0.001) for MAP amongst all the three groups.

The mean reaction to intravenous cannulation score and mask acceptance score was highest for clonidine followed by midazolam and control group (Table 4). The difference in the scores was statistically highly significant among all the three groups (p<0.001). Intraoperative hemodynamic parameters of the patients in all the three groups are shown in (Table 5, 6).

Sedation score for the three groups was assessed postoperatively at various intervals from emergence till one hour. The difference was found to be statistically highly significant amongst the groups (p<0.001) at all the time intervals being highest for clonidine followed by midazolam and control group (Table 7). Side effects such as bradycardia, hypotension or excessive sedation were not noted in either of the groups. Only 2 patients in midazolam group reported teary eyes which did not need any pharmacological intervention.

Hospital admission, syringes, needles, fear of separation from parents, operating equipments, operation theatre lights, face masks and intravenous cannulation may accentuate anxiety in children. [2]. Preoperative anxiety can largely affect the smoothness of induction, emergence from anesthesia and the psychological and emotional state of the child. An ideal premedicant drug is anxiolytic, analgesic, sedative and amnestic. A number of pharmacological agents like melatonin, opioids (morphine, pethidine, fentanyl); barbiturates; phenothiazines (promethazine), chloral and related agents (chloral elixirs and triclofos), NSAIDS (diclofenac, piroxicam), anticholinergics (atropine, scopalamine), antiemetics, ranitidine, ketamine etc are being used as premedicant [7-10]. Midazolam, an imidazobenzodiazepine, is a sedative and an anesthetic agent. It facilitates the inhibitory effects of GABA by binding to a specific site on the GABAA receptor resulting in anxiolysis, sedation, anticonvulsant and skeletal muscle relaxant effects [4].

Clonidine is a mixed α1 and α2 agonist with a predominant α2 action (α2:α1 = 220: 1). Its primary effect is sympatholysis by stimulating inhibitory neurons in the medullary vasomotor centre. Sedative effects of clonidine are due to inhibition of pontine locus coeruleus which is an important source of sympathetic nervous system innervation of forebrain and a vital modulator of vigilance. It calms down the patient so that he can be aroused easily to full consciousness. The quality of sedation produced by clonidine is therefore different from drugs that act on GABA receptors. Stimulation of α₂ adrenergic inhibitory neurons in the medullary vasomotor center results in decrease in sympathetic activity which is manifested as peripheral vasodilation and decrease in blood pressure and heart rate. This is the reason preoperatively and intra operatively a declining trend in hemodynamic parameters of the patients was seen more in clonidine than midazolam group. 

The present study showed that preoperative sedation, intravenous cannulation, mask acceptance and postoperative wake up score was better in children receiving intranasal clonidine as premedicant than midazolam. 

In our study, children experienced sedation 10 minutes after the study drug was administered. The sedation achieved with clonidine was more than midazolam and it increased significantly at 20, 30 and 40 minutes. Hence, parentral separation of the child was easier with clonidine than midazolam. Satisfactory sedation at parentral separation in our study was seen in 22.86% children of midazolam and in 68.57% of clonidine group. During transfer to the operating room, 14% of the children who received midazolam and 20% of children who received clonidine had woken up. These findings were in accordance with other studies of who found out that the sedation score after intranasal midazolam premedication started increasing at 10 minutes and this increase persisted till 30 minutes [12-14]. The result is also in consistence with those obtained by Sundaram AM et al who found 28.3 % of children to be satisfactorily sedated at parentral separation with intranasal midazolam 0.2 mg/kg as premedication [15].They reported 16.7 % children to have woken up during transfer to the operation theatre. However, Bhakta et al found 80% of the children to be easily separated from their parents after intranasal midazolam 0.2 mg/kg [14]. This difference in result may be due to the fact that in their study midazolam was only compared to placebo resulting in bias towards midazolam. Similarly, Sidhu GK et al in their study found satisfactory sedation and anxiolysis in 60 % and 25.7% of the children receiving 3 μg/kg of intranasal clonidine, respectively [16].

In contrast to our findings, the study conducted by Qteshat BS stated that oral midazolam was preferred by child’s parents as it was superior to clonidine in relieving preoperative anxiety and shortening the time of separation from parents [17]. But their study did not include the parameters like child’s mask acceptance and reaction to i.v. cannulation.

Intravenous cannulation was best achieved wih clonidine followed by midazolam and control group.This could be explained by the study conducted by Maaly AM et al who found clonidine better than midazolam in decreasing stress response and achieving better level of sedation [18]. When compared with control, children were less agitated during mask induction when they were premedicated with midazolam or clonidine. However, mask acceptance was better with clonidine than midazolam. This was in accordance to other studies [14,19]. Our study was contrary to the findings of Fazi et al who concluded midazolam to be superior to clonidine with less anxiety at parentral separation and easiear mask induction [20].

Clonidine caused a significant decrease in heart rate and blood pressure as compared to midazolam and control group. However, the effect on hemodynamic parameters was little and no pharmacological intervention was required.  This was supported by previous studies that reported mean blood pressure to be significantly decreased in the clonidine premedication group (63±7 mmHg) as compared to midazolam (69±10 mmHg) [14, 17, 20]. Clonidine produces its clinical effects by binding to α₂ receptors which are of three subtypes- alpha 2A (sedation, analgesia and sympatholysis); alpha 2B (vasoconstriction, antishivering); alpha 2C (responsible for neuromodulation) [21]. Sedative effects of clonidine are due to inhibition of alpha2 receptors that are densely located in pontine locus coeruleus which is an important source of sympathetic nervous system innervation of forebrain and a vital modulator of vigilance. The result is a calm patient who can be easily aroused to full consciousness. Stimulation of α₂ adrenergic inhibitory neurons in the medullary vasomotor center results in decrease in sympathetic activity which is manifested as peripheral vasodilation and decrease in blood pressure and heart rate. This is the reason preoperatively and intra operatively a declining trend in hemodynamic parameters of the patients was seen more in clonidine than midazolam group. 

Finally, postoperative sedation score was highest in clonidine and lowest in control group. Children were either calm cooperative or could be easily consoled in the postoperative period.  This was in accordance with the previous studies that found better wake up score and significantly lower emergence agitation in clonidine than midazolam [11, 19, 20, 22].

Limitations

It was a single centre study. Further studies with higher sample size would be required to establish the usefulness of intranasal clonidine and midazolam efficacy as preoperative anxiolytics.

Compared to midazolam, intranasal clonidine provides higher sedation level, better mask acceptance and better response to intravenous cannulation. Hence, intranasal clonidine is superior to intranasal midazolam for premedication in paediatric patients.

Acknowledgements

None

Declaration of Interests: 

None

Funding: 

Nil

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