Evaluation of intranasal Midazolam spray as a sedative in pediatric patients for radiological imaging procedures.

CONTEXT: Preoperative anxiety and uncooperativeness experienced by pediatric patients are commonly associated with postoperative behavioral problems. AIMS: We aimed to evaluate the efficacy and safety of intranasal Midazolam as a sedative in a pediatric age group for radiological imaging procedures and to note onset of sedation, level of sedation, condition of patient during separation from parents and effect on the cardio-respiratory system. SETTINGS AND
DESIGN: Randomized double-blinded study. SUBJECTS AND METHODS: Fifty patients of the pediatric age group of American Society of Anesthesiologist grade 2 and 3 who came for any radiological imaging procedures were studied. Patients were randomly allocated to receive, intranasally, either Midazolam 0.5 mg/kg (group A N = 25) or normal saline (group B N = 25) in both nostrils (0.25 mg/kg in each) 15 min before the procedure. Time for onset of sedation and satisfactory sedation, sedation score, separation score, hemodynamic changes and side-effects were recorded. STATISTICAL ANALYSIS USED: Student's t-test.
RESULTS: Intranasal Midazolam group had a significantly shorter time for onset of sedation and satisfactory sedation. Mean sedation score and mean separation score at 10 min and 15 min intervals were significant in intranasal Midazolam as compared with normal saline (P < 0.001).
CONCLUSIONS: Intranasal Midazolam 0.5 mg/kg is safe and effective and provides adequate sedation for easy separation from the parents and reduced requirement of intravenous supplementation during radiological imaging procedures without any untoward side-effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Sedation has become more common for children undergoing radiological imaging procedures. The benefits of providing adequate procedural sedation include decreasing patient anxiety and emotional trauma, decreasing parental emotional discomfort and facilitating ease and/or completion of the procedure.

A desirable sedating agent in children should have a rapid onset with a short duration of action, good patient and parent acceptance, predictable results and rapid recovery, and should be free from any serious side-effects.

Midazolam is a sedating agent frequently used in children. Although not analgesic, the advantageous properties of Midazolam include anxiolysis, sedative, amnesia, hypnotic, anticonvulsant, and muscle relaxant.[1234]

Midazolam has been used for sedation by intramuscular (IM),[567] rectal,[8910] oral[111] and sublingual routes,[1213] but each has its own advantages and disadvantages. IM administration, although effective, is not well accepted by children because children have a natural fear for syringes and needles, and also causes distressing pain to children. The rectal administration is associated with unpredictable absorption and discomfort to the child. The oral route, although now most popular, allows a bioavailability of Midazolam of only 15-27%.[14] Therefore, a larger dose is required and the peak effect is also delayed.[115] Bitter taste is also a limiting factor and cause for rejection as well as low compliance.[13] Sublingual route is more beneficial in this regard. But, for a desired effect, the drug must be held under the tongue for at least 30 s.[16] This requires cooperation, and that is difficult to achieve in pediatric patients.

Nasal administration of medication is emerging as a promising method of delivering medication directly to the blood stream. Intranasal Midazolam has got some advantages. Midazolam can be rapidly absorbed through the nasal mucosa, resulting in a rapid and reliable onset of action, avoidance of painful injection ease of administration and predictability and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver.[171819]

Considering these aspects, the current study was planned to evaluate the effect of Midazolam spray through the nasal route as a sedative in pediatric patients for radiological imaging procedures.

SUBJECTS AND METHODS

After obtaining institutional ethical committee approval and written informed parental consent, randomly selected 50 patients of the pediatric age group of American Society of Anesthesiologist (ASA) grade 2 and 3 who came for any kind of radiological imaging procedures were included in the study. We selected children weighing less than 10 kg because they are more susceptible to separation anxiety as their understanding is limited.

Exclusion criteria were:

Weight >10 kg

General contraindications for the use of Midazolam (i.e., myasthenia gravis, allergic reactions)

Presence of otorhinolaryngeal diseases (e.g., rhinitis, nasal polyposis)

Children with respiratory and cardiac diseases or having upper respiratory tract infection.

All patients were brought to the reception area of the radiological imaging center along with parents and were randomly allocated into one of two groups. Venous cannulation was performed after applying eutectic mixture of local anesthetics (EMLA) cream in all patients before giving any drug for safety reasons.

Group A: Received Midazolam 0.5 mg/kg through intranasal spray in both nostrils (0.25 mg/kg in each) in a semirecumbent position 15 min before the radiological imaging procedure.

Group B: Received normal saline through intranasal spray in each nostril in a semirecumbent position 15 min before the radiological imaging procedure.

A patient response to drug administration was noted. Heart rate, respiratory rate, and oxygen saturation were recorded before and at 5, 10, and 15 min after administration of the drug. Degree of sedation was assessed before and at 5, 10, and 15 min using the sedation score. Separation and induction score was noted during separation from parents at 5, 10, and 15 min. Time for onset of sedation and onset of satisfactory sedation were also noted.

Sedation score[17]

Agitated: Clinging to parent/crying

Alert: Anxious, not clinging to parent, may whimper but not cry

Calm: Sitting or lying comfortably with eyes open

Drowsy: Eyes closed but responding to verbal or tactile stimulation

Asleep: Does not respond to minor stimulation.

Separation and induction score[20]

Excellent: Patient unafraid, cooperative, asleep

Good: Slight fear or crying, quit with reassurance

Fair: Moderate fear or crying but not quite with reassurance

Poor: Crying, need for restraint.

All patients were brought to the radio imaging chamber. Inj. ketamine 1-2 mg/kg intravenously was given to the children if they were not adequately sedated. Repeat doses of Inj. ketamine were given when patients moved during the procedure. Heart rate, respiratory rate, and oxygen saturation were recorded during the procedure.

Patients were followed-up in the recovery room after the procedure up to 2 h for complications like nausea, vomiting, excessive sedation, or respiratory depression.

All the data were statistically analyzed by applying Student's t-test for analysis in between the two groups for various parameters. The results were considered significant if the P value was < 0.05.

RESULTS

Fifty pediatric patients with less than 10 kg weight who came for radiological imaging procedures were studied. There were no significant differences between groups in age, sex, or weight distribution [Table 1]. Duration of radiological imaging procedure was almost similar in both groups. Majority of the patients had imaging procedure lasting from 15 to 45 min [Table 2].

Table 1

Demographic data

Table 2

Duration of procedure

Onset of sedation and onset of satisfactory sedation noted was in the intranasal Midazolam group while no sedation was noted in the control group [Table 3].

Table 3

Onset of sedation and onset of satisfactory sedation

There was a significant difference in the mean sedation score and mean separation score in the Midazolam group as compared with the placebo group at 10 and 15 min intervals (P value < 0.05) [Table 4].

Table 4

Mean sedation score and mean separation scores: Comparison in the two groups

Both groups were found to be comparable with respect to heart rate and respiratory rate changes. There was a significant decrease in pulse rate 15 min after intranasal Midazolam as compared with group B (P-value < 0.05). There was a significant decrease in the respiratory rate in Group A as compared with Group B at 10 and 15 min intervals (P value < 0.05) [Table 5].

Table 5

Mean and standard deviation of heart rates and respiratory rates in the two groups

In the intranasal Midazolam group, eight of 25 patients undergoing CT scan did not require intravenous (IV) ketamine supplementation, and 16 patients undergoing MRI required IV ketamine, but the dose and frequency of administration were much less as compared with the placebo group [Table 6].

Table 6

Supplementary IV ketamine requirement for sedation

No patients developed bradycardia or hypoxemia after administration of intranasal Midazolam.

DISCUSSION

Conscious sedation is one of the most important measures to help pediatric patients cooperate with the radiological imaging procedure. The term “conscious sedation” means that the patient is able to maintain his/her airway and respond appropriately to physical stimulation and verbal commands while sedated. For this purpose, Midazolam is often used because its pharmacological properties are superior to other benzodiazepines (fast onset, better tissue compatibility, controllability of effect, short duration of action, short elimination half-life). Administering these drugs IM or IV, although effective, is not well accepted by children because children have a natural fear for syringes and needles, and these modes of administration also cause pain, which itself is distressing to children. The oral route can be used, but there are certain disadvantages attributed to it, like slower onset of action, requirement of a larger dose, erratic absorption, unpalatibility, lesser bioavailability and hepatic first-pass metabolism.

To circumvent the above-said problems, intranasal route is an option. The nasal mucosa is supplied by a rich network of blood vessels that facilitate relatively rapid and predictable absorption of drug, no risk of stimulation of gastric secretion (and hence less risk of aspiration), better bioavailability and no hepatic first-pass metabolism. Also, this is not associated with pain of a needle prick.

We therefore designed this randomized controlled study to evaluate the efficacy and safety of intranasal Midazolam as a sedative in 50 pediatric patients of comparable age, weight, and sex of ASA grade 2 or 3 for radiological imaging procedures.

We studied intranasal Midazolam in the dose of 0.5 mg/kg and compared with intranasal saline. This study has demonstrated that the intranasal Midazolam group is effective and safe in reducing anxiety and as a sedative in pediatric patients, which is comparable with the study of Harcke et al.,[21] who studied the effectiveness of intranasal Midazolam 0.2 mg/kg as a sedative in pediatric patients undergoing radiological imaging procedures. In 88% of the patients, intranasal Midazolam demonstrated a positive effect, while in 12% patients it was ineffective. There was a noticeable change in the behavior of the patient that facilitated the procedure being performed after giving intranasal Midazolam. They found that intranasal Midazolam was effective and safe in reducing the anxiety and stress that accompanied the radiological imaging procedures.

The mean time for onset of sedation and satisfactory sedation were 7.04 ± 1.4 min and 10.04 ± 1.88 min, respectively, for the intranasal Midazolam group, and there was no sedation in the control group till IV ketamine was given. Our study was comparable with the study done by Trivedi et al.,[22] who compared the effects of intranasal Midazolam versus sublingual Midazolam in pediatric patients undergoing MRI and found that the mean time for onset of sedation was 7.3 ± 0.8 min for the intranasal group. Similar findings were seen with the Alex et al.[23] study, which compared the efficacy of intranasal and oral Midazolam as a premedication in pediatric patients. The mean time for onset of sedation and satisfactory sedation were 8.63 ± 1.5 min and 11.3 ± 1.8 min, respectively, for the intranasal Midazolam group. Another study done by Shashikiran et al.,[24] in which they compared intranasal Midazolam and IM Midazolam, found that the intranasal route showed a significantly faster pharmacodynamic profile in terms of faster onset.

In our study, mean sedation and mean separation score at 10 min and 15 min intervals were highly significant for the intranasal Midazolam group (P value < 0.05). Most of the patients in the Midazolam groups became either calm or drowsy (sedation scale score 3 or 4), which helps in easy separation of the child from their parents. Similar results were seen in the study of Bhakta et al.,[25] who evaluated the efficacy of intranasal Midazolam for preanesthetic sedation in pediatric patients of 2-5 years of age scheduled for minor elective surgery. Patients were divided into three equal groups to receive intranasal normal saline, 0.2 mg/kg intranasal Midazolam or 0.3 mg/kg intranasal Midazolam. Statistically significant changes in the level of sedation were found in both intranasal Midazolam group compared with the control group by 10 min. Parental separation was significantly easier, and mask acceptance rate was also found to be significantly higher in the Midazolam group while in the control group, many of the patients became alert and accepted the mask only after persuasion during induction.

In our study, we found that this route of administration reduced the necessity for IV sedation and, if required, the doses of supplement were much less in the intranasal Midazolam group as compared with the placebo group. This result was comparable with the study done by Harcke et al.,[21] who found that MRI procedures required pentobarbital and chloral hydrate as an IV supplementation along with intranasal Midazolam while CT scan procedures were carried out with intranasal Midazolam and did not require IV supplementation.

In our study, none of the patients in the intranasal Midazolam group became excessively sleepy during the study period. Clinically evident respiratory depression or apnea during the study period did not occur in any group. Oxygen saturation was maintained above 97% in both groups during the study period. This proved that Midazolam used intranasally in this dose range is quite safe, which was reported in the study done by Bhakta et al., who found that only one patient became asleep who responded to minor stimulation and no other patient in the Midazolam group became excessively sleepy during the study period.

In our study, we used an atomized intranasal Midazolam delivery device that was very effective and safe in providing conscious sedation and anxiolysis to children. Lane et al.,[26] used atomized intranasal Midazolam spray at a dose of 0.4 mg/kg for minor procedures in the pediatric emergencies. They concluded that atomized intranasal Midazolam is effective in providing anxiolysis.

We conclude from our study that intranasal Midazolam in a dose of 0.5 mg/kg is safe and effective, and provides adequate sedation for easy separation from the parents, co-operation from children and reduced requirement of IV supplementation during radiological imaging procedures without any untoward side-effects.