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Year : 2019  |  Volume : 13  |  Issue : 2  |  Page : 370-375  

Comparative study of oral midazolam syrup and intranasal midazolam spray for sedative premedication in pediatric surgeries

1 Department of Anaesthesiology, ERA's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
2 Department of Anaesthesiology, Super Speciality Cancer Institute, Lucknow, Uttar Pradesh, India

Date of Web Publication28-May-2019

Correspondence Address:
Shirin Parveen
Department of Anaesthesia, 1st Floor, Hospital Building, ERA's Lucknow Medical College, Sarfarazganj, Lucknow - 226 003, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aer.AER_182_18

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Introduction: Midazolam is a water-soluble benzodiazepine which is frequently administered by intravenous and oral routes. Its nasal spray has become recently available. Materials and Methods: In this study, after obtaining clearance from the ethical committe, 66 patients between the age group of 4 and 10 years comparable in demographic variables were randomly allocated into two groups of 33 each. Group “O” received oral midazolam (0.5 mg/kg) 20 min before induction. Group “N” received intranasal midazolam (0.2 mg/kg) 20 min before induction. The heart rate and blood pressure (systolic, diastolic, and mean) and oxygen saturation (SPO2) were recorded.Statistical Analysis Used: The statistical analysis was done using SPSS (Statistical Package for the Social Sciences) version 15.0 software. The values were represented in number (%) and mean±sd. Results: Satisfactory sedation scores were better in nasal spray group than oral group. Satisfactory ease of induction scores, recovery times, and postanesthesia recovery scores were better in the nasal spray group than in the oral group. Conclusion: Nasal midazolam spray is acceptable and is a good alternative to oral midazolam as premedication in the pediatric population.

Keywords: Children, midazolam, premedication

How to cite this article:
Mehdi I, Parveen S, Choubey S, Rasheed A, Singh P, Ghayas M. Comparative study of oral midazolam syrup and intranasal midazolam spray for sedative premedication in pediatric surgeries. Anesth Essays Res 2019;13:370-5

How to cite this URL:
Mehdi I, Parveen S, Choubey S, Rasheed A, Singh P, Ghayas M. Comparative study of oral midazolam syrup and intranasal midazolam spray for sedative premedication in pediatric surgeries. Anesth Essays Res [serial online] 2019 [cited 2021 Jun 18];13:370-5. Available from:

   Introduction Top

A surgical intervention even in these days brings fears, apprehensions, a frightening experience of being put under the knife, to the patient and his family, when one of the youngest ones (children) are affected the level of fear and stress is multiple times.

Sedation in children is administered to control their behavior and to allow the safe completion of the procedure.

Midazolam is a benzodiazepine medication having calming effects and is commonly used as sedative premedicant in the preoperative holding area to adults and children who get anxious or distressed during medical procedures or before surgery.[1]

Intramuscular (i.m) injections are painful and frightening to the patients, each of the routes has its own merits and demerits, but oral and intranasal routes were preferred for pediatric sedation.[2],[3],[4],[5],[6],[7]

This study was planned to compare the sedation level, anxiety level, acceptance of drug, drug response, hemodynamic changes, recovery, and complications of oral midazolam syrup and intranasal midazolam spray used for preanesthetic sedation in children.

   Methodology Top

After obtaining clearance from Institutional Ethics Committee a total of 66 children aged 4–10 years, scheduled for elective surgery under general anesthesia were recruited in this study. The patient with a history of allergy to midazolam, the patient suffering from respiratory system dysfunction such as rhinorrhea, bronchial asthma, nasal polyps, and those with central nervous system dysfunction such as epilepsy or raised Intracranial tension were excluded from the study.

Sample size is calculated on the basis of variation in recovery time in the two groups using the formula n = (Zα + Zβ)2 (σ12 + σ22) / d2

Where σ1 = 4.19, σ2 = 9.36 the SD of recovery time in the two group, d = mean (σ1, σ2), Type I error α = 5 % Type II error β = 10 % for detecting result with 90 % power of study. Data Loss = 10 %. The minimum sample size comes out to be n = 33 each group.

Computer generated randomization done for allocation in two equal groups of 33 children each. Thirty-three patients received oral Midazolam (0.5 20 min before induction of anesthesia and were classified as Group O while rest 33 patients received intranasal Midazolam spray (0.2 20 min before the induction of anesthesia were classified as Group N.

These recruited pediatric patients were visited a day before surgery for preanesthetic review. The patient was kept nil orally according to internationally accepted criteria before surgery. Written and Informed consent was obtained from the parents or legal guardian of the patients.

On the day of surgery, premedication was carried out by an anaesthesia resident in pre operative room, who was not involved in the recording of parameters.

  • Oral midazolam 0.5 min before induction – In “Group O”
  • Midazolam spray 0.2 min before induction – In “Group N”

Patients were shifted to the operating room; monitors were attached.

(After using midazolam in both group patient was sedated enough and become coperative to allow us to take an i.v injection access comfortably)

Intravenous (i.v) injection glycopyrrolate 4 μ and i.v injection fentanyl 2 μ were given prior to induction.

Induction was carried out by i.v injection propofol 2

Intubation was carried out following relaxation with i.v injection Vecuronium 0.1 (loading dose) followed by endotracheal tube placement of appropriate size.

The maintenance of anesthesia was carried out by using – oxygen (50%), nitrous oxide (50%), and sevoflurane in titrated doses.

i.v injection paracetamol was given at a dose of 15

At the conclusion of surgery, on return of respiratory efforts reversal was carried out by using i.v injection neostigmine 50 μ and i.v injection glycopyrrolate 10 μ

The patient was extubated after thorough suctioning and thereafter oxygenated with 100% oxygen for 5 min and shifted to postoperative ward once fully stable.

The parameter noted was as follows:

  1. Sedation was evaluated using Ramsay sedation score every 10 min for 60 min. Excessive sedation was defined as a score >4.[8]

    • Score at 20 min was noted for comparative evaluation.

  2. Ease of induction[9] was labeled as:

    • Excellent: Patient unafraid, cooperative, and asleep;
    • Good: Patient slightly afraid and/or crying but quieted with reassurance;
    • Fair: Patient moderately afraid, crying and not quieted with reassurance;
    • Poor: Patient crying and in need of restraint.

  3. Level of recovery was labeled as:

    • Unable to move extremities voluntarily or on command, nonresponsive and with a temperature less than 35°C or more than 37°C
    • Unable to move extremities voluntarily or on command but responding to painful stimuli and with a temperature range of 35–37°C
    • Able to breathe deeply and cough effectively, can move extremities voluntarily or on command, fully awake and with a temperature range of 35–37°C.

  4. Adverse effects:

    • Hypotension (defined by decrease in mean arterial pressure below 20% of baseline)
    • Bradycardia (heart rate <60 beats/min)
    • Respiratory depression was defined as respiratory rate <10 breaths/min, Dyspnea/Apnea.

  5. Onset time: The onset time was considered when a sedation score of 2 or above was achieved

  6. Recovery time: It was the time when the status of the patient was comparable to Ramsay Score 1, i.e., the child was fully alert.

   Results Top

The range of Ramsay Sedation Score in Group O was 1–4 while in Group N was 2–4. The median Ramsay Sedation Score of Group N (3.0) was higher than Group O (2.0). The mean Ramsay Sedation Score of Group N (3.21 + 0.49) was found to be statistically significantly higher (P < 0.001) than Group O (2.18 + 0.53).

The range of ease of induction score was 2–4 in Group O and 1–4 in Group N. Ease of induction score of Group O (median: 3.00; mean: 2.85 + 0.51) was found to be higher than that of Group N (median: 2.00; mean: 2.15 + 0.62), and the difference in ease of induction score of Group O and Group N was found to be statistically significant (P < 0.001).

The range of level of recovery in Group O was 1–3 while in Group N was 2–3. The level of recovery of Group N (median 3.00; mean: 2.73 + 0.45) was found to be higher as compared to Group O (median: 2.00; 1.97 + 0.47), and the difference in level of recovery between Group O and Group N was found to be statistically highly significant (P < 0.001).

At baseline (T0), differences in none of the above hemodynamic variables of Group O and Group N were found to be statistically significant. Oxygen saturation level in both the groups at baseline was found to be similar (100.00+0.00).

   Discussion Top

Interactions with health-care providers are stressful experiences for children. Due to the stress and the anxiety, it provokes, minor procedures often require mild-to-moderate sedation.

Intranasal and oral transmucosal (buccal and sublingual) delivery of sedative medications offer alternatives that provide some advantage over the conventional methods in properly selected minor procedure: they are faster than oral or rectal forms and also less painful than i.m injection forms.

Among different medications available, the midazolam (a benzodiazepine), has become the most frequently used preanesthesia medication given to children scheduled for surgery.[10] Midazolam has a number of beneficial effects when used as premedication in children: sedation, fast onset, and limited duration of action.[11] Despite having a number of beneficial effects, some recent studies have reported untoward side effects such as restlessness, paradoxical reaction, cognitive impairment, amnesia, and respiratory depression.[12],[13] Although oral midazolam has been found to be effective for day-to-day anesthetic requirements in children[14] yet there are instances where oral Midazolam is not acceptable to some children owing to sensory acceptability concerns. In previous studies, several alternate routes including oral and nasal routes have been suggested to have almost an equal efficacy and acceptability. In the present study, we made an attempt to compare oral and nasal routes in terms of sedation score and the overall ease of inducing general anesthesia in pediatric patients.

For this purpose, a prospective observational study was carried out in which a total of 66 children scheduled to undergo elective surgery under general anesthesia were enrolled [Table 1].
Table 1: Between group comparison of demographic profile

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In both groups, hemodynamic parameters remained under control throughout the evaluation period and did not show a significant difference between the two groups. Oxygen saturation also remained absolute throughout the procedure in both groups [Figure 1]. Although some studies have reported restlessness and respiratory depression as the possible side effects associated with Midazolam, however in the present study, no such incidence was noted. The findings thus suggest that both the routes were hemodynamically safe for use among children. Similar to the results of the present study, all the studies reviewed by us did not report hemodynamic instability as an associated feature of either of two routes of administration. In a step further, Özmert et al. (2016) showed a comparable and stable hemodynamic profile for oral, intranasal, and rectal routes for Midazolam administration. In fact, in a study Tyagi et al. (2012) while comparing i.v and oral Midazolam too did not report hemodynamic instability as a concern. It seems that the reported side effects of restlessness and respiratory depression are just incidental and do not have empirical basis at least for oral and intranasal route as observed in the present study and confirmed by findings in previous studies.
Figure 1: Hemodynamic variables

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In the present study, the sedation scores [Table 2] were found to be significantly higher in nasal Midazolam Group (median score 3; mean 3.21) as compared to oral group (median score 2; mean 2.18). Compared to the present study, Yildirim et al.[15] did not find a significant difference in sedation scores of oral and nasal routes. Similar to the present study, Verma et al.[16] also found better sedation scores in nasal group as compared to oral group. In the present study, mean scores were 3.21 and 2.18 (difference 1.03) respectively in nasal as compared to oral group. Similar to the present study, Raval and Gunga[17] also found higher scores for nasal (3.06) as compared to oral (2.96) but found the difference to be much lower (0.1) that observed in the present study (1.03). Abhishek et al.[18] in their study while using a different scoring system for sedation, also found the performance of nasal group to be better than oral group (86% vs. 83%) but did not find a significant difference between two groups. However, Nainegali et al.[19] also reported results comparable to the present study and reported 20-min postadministration sedation scores in nasal group to be significantly higher as compared to that in oral group. In their study, the difference in mean scores of two groups was 0.58 at 20 min interval. On reviewing the literature, we did not find a single study citing the better outcome of oral as compared to nasal route. Nasal absorption is generally faster and probably deeper than oral absorption, and that is why in the present study, the sedation scores in nasal group were higher as compared to that in oral group. The bioavailability and peak plasma levels of midazolam are highly dependent on the selected routes. Midazolam has an oral bioavailability of only about 40%–50% because it is subject to first-pass metabolism in the intestine and liver. Peak plasma levels of oral midazolam are reached rapidly, within 1–2 h. With i.m injection sedative effects are present within 15 min and peak between 30 and 60 min after i.m injection. i.m midazolam has bioavailability >90%. Through nasal route, its bioavailability is reported to be higher through the latter, midazolam is rapidly absorbed directly into systemic circulation, with a bioavailability of 55%–83%.[20],[21] After nasal administration, midazolam Cmax has been reported to be 182 ng/ml within 12.6 min, thus showing that not only bioavailability but also the onset is also faster through intranasal route.[22]
Table 2: Between group comparison of Ramsay Sedation Score (Mann-Whitney U-test)

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In the present study, median scores for ease of induction [Table 3] were higher in oral group (Median 3; mean 2.85) as compared to nasal group (median 2; mean 2.15), thus showing a significant difference between two groups. One of the barriers behind the use of oral Midazolam is its bitter taste. Although in 1988, the FDA approved a syrup with a more pleasant taste and a lower pH than the i.v formulation thus increasing its bioavailability yet it has failed to be acceptable to children at least when other routes are available. Similar to our study, Yildirim et al.[15] also reported nasal route to be more acceptable as compared to oral route. Verma et al.[16] also made a similar study. However, Raval and Gunga[17] and Nainegali et al.[19] on the other hand reported a better acceptability of oral as compared to nasal route. Musani and Chandan[23] on the other hand did not report a difference in acceptability grade of both groups. Ease of induction and acceptability are basically sensory perceptions which are subjective to different populations and might vary from patient to patient. However, most of the studies denote nasal Midazolam to be better accepted and easily inducible as compared to oral Midazolam and findings of the present study coincided with these observations.
Table 3: Between group comparison of ease of induction score (Mann-Whitney U-test)

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In the present study, the level of recovery scores [Table 4] was significantly higher in nasal group (median 3.00; mean 2.73) as compared to oral group (median 2; mean 1.97), thus indicating that recovery characteristics were better in nasal as compared to oral group. Observations to similar effect were also made by Verma et al.,[16] however, Raval and Gunga[17] found recovery scores to be similar in both groups. On the other hand, Fallahinejad Ghajari et al.[24] reported both recovery time and quality (represented by sleepy face) to be poor in nasal as compared to oral groups. The findings in the present study thus reinforce and endorse the findings made by Verma et al.[16] Nasal administration is often accompanied with the possible uncomfortable feeling for patients which can sometimes be associated with anxiety and fear, even though the discomfort linked to nasal route can be reduced by preadministration of a lidocaine puff.[25] However, in the present study, no such requirement was felt. One of the reasons for the better recovery scores in nasal group in our study could be a higher proportion of children >5 years of age. Fallahinejad Ghajari et al.[24] who reported poor response for nasal spray conducted their study in uncooperative children and that too in relatively younger age of 3–6 years. Raval and Gunga[17] also has an age range of 2–10 years. In contrast, in the present study, the age range started from 4 to 10 years with majority of patients being >5 years of age.
Table 4: Between group comparison of level of recovery (Mann-Whitney U-test)

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In the present study, both onset and recovery times were found to be significantly lower in intranasal as compared to intraoral group. Findings to similar effect have also been reported by Verma et al.[16] and Musani and Chandan[23] However, Fallahinejad Ghajari et al.[24] have reported a longer recovery time in intranasal group as compared to oral group.

In some previous studies, the impact of the selection of route has also been shown on the discharge time. Davis et al.[26] reported that intranasally administered midazolam in doses of 0.2–0.3 mg/kg showed satisfactory sedation in terms of parent–child separation and satisfactory ease of induction in 70% of patients and did not prolong recovery time or hospital discharge time. Several studies reported that orally administered midazolam is associated with delayed discharge,[27],[28] although a prolongation of recovery time for oral route was noticed in present study too yet no such impact on hospital discharge time was noticed.

Oral route is the preferred method in greater than 90% of pediatric patients that are premedicated.[29] Patient and parent preference for oral administration may partly explain this as some patients who were approached to participate in this study refused to do so because they had a strong preference for oral midazolam as opposed to intranasal administration. Although it would have been interesting, however, we did not collect data on those patients or parents who refused to participate. It was a small group of subjects and was a parental decision because of previous experiences with oral midazolam. In some cases, it could be due to parental or children's aversion to intranasal administration of drugs. In such circumstances, they should be given alternative routes of the administration of midazolam agreeable to them.

The present study thus showed that nasal route is a better choice as compared to oral route in terms of early onset, better sedation, induction, and recovery scores, the findings of the present study are in agreement with most of the literature. A previous study[30] in which 205 patients of whom 89% required laceration repair were reviewed. They found that aerosolized intranasal midazolam was effective in almost 95% of the patients and that just over 5% required additional sedation (generally ketamine) for the procedure to be completed. There were no adverse events from the midazolam. The findings of the present study also indicated no need for additional sedation in either of two groups, thus establishing the usefulness of intranasal route over oral route in terms of onset time, sedation quality, acceptability, and recovery time.

   Conclusion Top

The present study was carried out to compare the efficacy of Midazolam administered by oral and intranasal routes as premedicants in terms of sedation score and the overall ease of inducing general anesthesia in pediatric patients. In conclusion, on the basis of our study, we found that use of intranasal midazolam spray over oral midazolam should be preferred as it has almost similar hemodynamic effects but early onset, better sedation, induction and higher level of recovery than oral midazolam.

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   References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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