The study was conducted from July 2009 to June 2010. Ethical approval for this study was provided by the Institutional Ethics Committee. Children of either sex, in age group of 1-10 yr, of American Society of Anesthesiologists (ASA) physical status I and II only, scheduled to undergo minor elective surgical procedures such as hydrocele repair, herniorrhaphy, circumcision or eye surgery were included in this prospective randomized parallel group (with 1:1 allocation ratio) double-blind study after obtaining written informed consent from the parents of these children and additional assent from children over 7 years. The exclusion criteria were: children with rhinopharyngitis or recent upper respiratory tract infection, known allergy or hypersensitivity to clonidine or midazolam, children requiring intravenous induction, cardiac arrhythmias, congenital heart disease, prolonged PR interval, atrioventricular blocks, intrinsic bradycardia, prematurity, mental retardation, raised intracranial pressure, history of convulsions, liver and renal disease, and children refusing to take the whole dose of premedication.

Statistical analysis: Fisher’s Exact test was used to compare proportions. Onset time of sedation and anxiolysis was analyzed by Kaplan Meier survival curve and log rank test. Statistical significance was accepted if P value was less than 0.05. All data were analyzed using Statistical Package for Social Sciences (SPSS)15.0.

As there was no previous study directly comparing intranasal clonidine with intranasal midazolam, a pilot study was done using 10 patients in each group. Proportion of patients with satisfactory anxiolysis was 80% and 100%, respectively. Using this data, and setting alpha at 5% and power at 80%, we needed 35 patients in each group.

A total of 60 patients were enrolled, 30 in each group (23 males in group I and 27 in group II). The demographic profiles of the patients of two groups were similar with median (range) age of 2.5 (1-10) and 4 (1-10) years, respectively in group I and group II. The median (range) duration of surgery was 64 (35-90) and 62 (30-80) minutes in the two groups, respectively. The flow of patients in the study is shown in Fig. 1.

Fig.1 Flow of patients in the study

All the patients in both the groups developed acceptable levels of anxiolysis (anxiety score 3-4) after 30 minutes of drug administration. The secondary outcomes and adverse effects are shown in Table I and Figs. 2 and 3.

TABLE I  Comparison of Secondary Outcomes and Adverse Effects in The Two Groups

Fig. 2 Kaplan-Meier survival curve showing onset of anxiolysis in the two groups. p = 0.7261 (Log rank test).

Fig. 3 Kaplan-Meier survival curve showing onset of sedation in the two groups. p = 0.0208 (Log rank test).

Crying during drug administration, median duration of crying, complaints of nasal stinging and bitter taste were significantly higher in group II (Table I). A higher number of patients in Group I had a mask acceptance score 3-4.

Postoperatively, all the patients in Group I were either calm and cooperative or could be easily consoled (i.e., wake-up scores 1-2) as compared to 53% of patients in Group II (P < 0.001).

This randomized controlled trial compared intranasal clonidine and intranasal midazolam as premedication in children undergoing elective surgery found satisfactory anxiety score in both groups. Mukherjee, et al. [16] found that the onset of anxiolysis after clonidine premedication was 15.8±2.6 minutes whereas Almenrader, et al. [9] reported 23.3±17.2 minutes for the onset of anxiolysis, that was longer than reported in our study. Kogan, et al. [15] found that the maximal anxiolysis was achieved at 20 minutes after intranasal midazolam administration. However, others have reported that intranasal midazolam provided maximal sedation and anxiolysis within 10 minutes after administration [18,19]. The results of our study are broadly in line with the previous studies, with the exception of one [9].

Findings on various drug effect related parameters have varied markedly across various studies. This variation might be due to several factors such as drug dose, preparation, exact mode of administration (single, repeated, patient position, etc.), observer-related factors, patient-related factors, state of nasal mucosa, preoperative information and experience, and even cultural and environmental differences in experiencing and reporting some outcomes. There is a practical limit to the total volume of the drug that can be instilled through the nasal route. Inadvertent swallowing of the drug and subsequent gastric absorption are other potential drawbacks. It has been shown that direct transport of clonidine from the nasal mucosa to systemic circulation can be erratic and unpredictable [11]. Further, atropine was co-administered intranasally in the clonidine group. Nasal atropine has been shown to reduce nasal secretions and mucociliary clearance [20,21], which might have favored nasal clonidine absorption in our study.

As regards the secondary outcome measures, drug acceptance was better in clonidine group than midazolam. Midazolam, either directly or because of its acidic pH, may be responsible for nasal mucosal irritation, thus causing low acceptance [6,15].

Significantly more patients in the clonidine group than in the midazolam group accepted mask satisfactorily. Mask acceptance can be an important composite marker signifying a combination of anxiolysis, lack of fear, drug tolerability and the resultant cooperativeness. Steal induction could be performed in four (13.3%) of the patients in clonidine group as compared to three (10%) in midazolam group. Almenrader, et al. [9] found that steal induction was possible in 60% of the patients whereas Mukherjee, et al. could perform it in 20% of the patients [16]. Although patients were well-sedated, steal-induction could not be performed as patients were waking up during transfer. It is possible that Almenrader, et al. achieved steal induction in 60% cases because they induced children in the parents’ arms in a dimmed and quiet operating room [9].

The onset of sedation was significantly faster in midazolam group as compared to clonidine group in this study but both the groups achieved acceptable sedation levels at 30 min. The onset of sedation after clonidine premedication in our study is consistent with their findings [9,16] but faster compared to few other reports [18,19,22,23]. In contrast, a recent publication compared two dose strengths of an aerosol preparation of nasal clonidine with placebo in a double-blind randomized trial and found that only 55% of the children receiving the higher dose (7-8 µg/kg) were adequately sedated at 30 min after administration of the aerosol [24]. The variations in these study results might be because of several factors mentioned above. It is an interesting and important area for future research.

Finally, patients in clonidine group had significantly better wake up score than midazolam group. Previous reports [9,16] also found that the majority of the patients were either calm and cooperative, or could be easily consoled postoperatively when clonidine was used as premedicant. Other authors also report that clonidine produces more effective early postoperative analgesia, reduces the incidence of postoperative nausea vomiting and shivering, and causes attenuation of postoperative delirium when compared to midazolam and thus produces better wake up score [5,8]. This is consistent with the results obtained in our study. Further, midazolam, a benzodiazepine, causes anterograde and retrograde amnesia, and this has been suggested to be a potential mechanism for causing poorer wake-up score and early postoperative agitation in the midazolam group [5].

We did not study the cognitive functions of the children before and after receiving the drugs. This may be considered a limitation of the study, though our primary focus was on efficacy. Other limitations include a sub-optimal sample size lack of a placebo control group and lack of generalizability of the findings in children undergoing emergency surgery. Further, preoperative anxiety was measured by a previously used scale [15] but not compared with other validated scales [25]. However, these limitations should not invalidate the main conclusions from this study.

In conclusion, intranasal clonidine has been shown to produce comparable level of sedation and effective anxiolysis as nasal midazolam after 30 minutes, but with a better mask acceptance and recovery profile.

Contributors: SM: conception and design, interpretation of results, critical inputs to manuscripts writing; SK: study design, data collection, analysis and interpretation, and manuscript writing; LA: study design, data interpretation and critical inputs to manuscript writing. All authors approved the final version of manuscript.

Funding: None; Competing interests: None stated.