Intranasal Fentanyl, Midazolam and Dexmedetomidine as Premedication in Pediatric Patients.

BACKGROUND: Surgery is a very stressful experience for patients. Children are the most susceptible to fear, anxiety, and stress due to their limited cognitive capabilities and dependency. In children, pharmacologic agents are frequently used as premedication to relieve the fear of surgery, to make child-parental separation easy, and to carry out a smooth induction of anesthesia. We conducted this study to compare the efficacy of intranasal fentanyl, midazolam, and dexmedetomidine as premedication in pediatric patients.
MATERIALS AND METHODS: The present study was conducted prospectively on 75 patients in the age group of 2-6 years of either sex of the American Society of Anesthesiologists physical Class I or II admitted in Guru Nanak Dev Hospital, attached to Government Medical College Amritsar, scheduled to undergo surgery under general anesthesia. The patients were divided into three groups of 25 each. Group F received intranasal fentanyl 1.5 μg/kg body weight, Group M received intranasal midazolam 0.3 mg/kg body weight, and Group D received intranasal dexmedetomidine 1 μg/kg body weight as nasal drops 50 min before surgery.
RESULTS: Children who received intranasal fentanyl and intranasal midazolam had early onset of anxiolysis and sedation as compared to dexmedetomidine. In child-parent separation, quality of induction was better with fentanyl and dexmedetomidine as compared to midazolam. Intravenous cannulation score was best achieved with fentanyl as premedicant. Postoperative sedation was better with dexmedetomidine as compared to fentanyl and midazolam.
CONCLUSION: Onset of action of fentanyl and midazolam is early as compared to that of dexmedetomidine. However, fentanyl provided better conditions for induction and emergence than midazolam. With dexmedetomidine onset of action was delayed and duration of action was prolonged which helped child to remain calm and sedated even after the surgery.

INTRODUCTION

The preoperative period is a stressful event for the majority of individuals undergoing surgery. Children suffer from severe anxiety and apprehension when they are separated from their parents or family members for the induction of anesthesia. There are several nonpharmacological means to minimize child's anxiety like preadmission visits showing videos and preoperative clinic visits by the anesthesiologist to establish rapport with the child. Pharmacological agents are more efficient to provide sedation and promote smooth induction. The ideal premedicant for children should:[1]

Be available in a preparation that is readily accepted by the children

Have a rapid onset

Provide anxiolysis with mild sedative effects

Be free of side effects

Provide a rapid recovery and return to alertness postoperatively.

The administration of medications in pediatric patients is not always an easy task. The majority of children are premedicated via the oral route (80%), followed by intranasal route (8%), the intramuscular route (6%), and the rectal route (3%).[2] The relatively rapid delivery of drug to the bloodstream and the central nervous system (CNS) after intranasal administration produces effective sedation with minimal patient discomfort, making it a popular option.[3] Midazolam is a short-acting benzodiazepine that produces anxiolytic, amnestic, hypnotic, anticonvulsant, and skeletal muscle relaxant effects. Fentanyl is a potent, synthetic opioid analgesic with a rapid onset, and short duration of action.[4] It is a strong agonist at the mu opioid receptors. Dexmedetomidine is a highly selective α2 agonist. While most often administered as a continuous infusion in the intensive care unit, dexmedetomidine is increasingly being studied as an alternative to standard agents for intranasal administration.

There are very few studies comparing intranasal fentanyl, midazolam, and dexmedetomidine as premedication in children. Hence, considering all these aspects, the present study was conducted to compare these three drugs in children as premedication via intranasal route.

MATERIALS AND METHODS

After obtaining approval from the Institutional Ethics Committee, and an informed and written consent from parents or guardians of the patients, the present study was conducted prospectively in a double-blind manner on 75 patients in the age group of 2–6 years of either sex of the American Society of Anesthesiologists (ASA) physical status Class I and II admitted in Guru Nanak Dev Hospital, attached to Government Medical College Amritsar, scheduled to undergo surgery under general anesthesia.

Exclusion criteria

Children physical status ASA Classes III and IV

Children with a history of:

Upper airway disease

CNS dysfunction

Cardiovascular dysfunction

Gastrointestinal disorders which may affect drug absorption.

Allergy to the drugs under study

All children who refused to take the premedication

Patients with any intranasal pathology or children with any congenital anomaly.

Preanesthetic check up

Preanesthetic checkup including a detailed history and thorough general physical examination of the patient was carried out a day before surgery and was recorded.

All the children were investigated preoperatively for:

Hemoglobin

Bleeding time

Clotting time

Complete urine examination: macroscopic and microscopic

Any specific investigation if required

The weight of the patient was recorded.

All the patients were kept nil by mouth: 3 h for clear fluids and 6 h for solids and milk.

Study design

This was a prospective randomized double-blind study because neither the participants nor the observers (who collected the data) knew that which drug was being used. The patients were divided into three groups of 25 each in a random and unbiased manner. The first group (Group F) received intranasal fentanyl, second group (Group M) received intranasal midazolam, and the third group (Group D) received intranasal dexmedetomidine. Sample size was calculated based on the onset of anxiolysis and sedation with 5% alpha error and keeping 20% beta error. The sample size of 20 patients per group was required. Hence, we used a sample of 25 patients in each group.

Statistical analysis was performed using Student's “t” test and Chi-square test. P < 0.05 was considered statistically significant. A computer-generated a list of numbers accomplished by a research member was used for drug allocation. This list was concealed in opaque sealed envelopes that were numbered and opened sequentially after obtaining consent from children's parents/guardian. The person who was not involved in any other part of the study obtained the envelopes and then prepared the premedication drugs to be studied.

Technique

Group F (n = 25): The patients were given intranasal fentanyl 1.5 μg/kg body weight as nasal drops, 50 min before surgery

Group M (n = 25): The patients were given intranasal midazolam 0.3 mg/kg body weight 50 min before surgery as nasal drops

Group D (n = 25): The patients were given intranasal dexmedetomidine 1 μg/kg body weight as nasal drops, 50 min before surgery. Intranasal drugs were dripped into both the nostrils using a 1 ml syringe with the child in the recumbent position and plunger was pushed.

Heart rate, blood pressure, respiratory rate, oxygen saturation levels, sedation, and anxiety levels were noted at the time of administration of premedication and then monitored continuously. Readings were recorded every 10 min until the time patient attained sedation score of 2 or 3. Once the sedation score of 2–3 was achieved the child was transferred to the operating room. Any side effects such as hypotension, bradycardia, hypoxemia, apnea, nasal irritation, vomiting, itching, and any other was looked for.

The child was taken inside the operation theater. Intravenous line was started and reaction to intravenous cannulation was noted. Injection glycopyrrolate 5 mcg/kg body weight was given intravenously. 100% oxygen was given via facemask and the mask acceptance by the child was noted. Preoxygenation for 3 min with 100% oxygen was done. 8% inhaled concentration of sevoflurane was administered with the Jackson-Rees circuit for induction. Muscle relaxant vecuronium 0.1 μg/kg body weight was used to facilitate endotracheal intubation. Maintenance of anesthesia was done with (50:50) O2:N2O with sevoflurane 1%–2% and an intermittent dose of injection vecuronium 0.08 mg/kg body weight intravenously. All patients received rectal acetaminophen suppository for postoperative analgesia. In the end, sevoflurane was discontinued plus N2O was switched off. Neuromuscular blockade was reversed with glycopyrrolate 0.01 mg/kg body weight and neostigmine 0.04 mg/kg body weight intravenously. The child was extubated after suctioning of oral cavity and return of protective reflexes and after adequate neuromuscular recovery and regular respiratory rate was achieved.

Monitoring

Hemodynamics was monitored continuously – In the preoperative period, readings were noted every 10 min for up to 50 min of administration of premedication or until the sedation score of 2 or 3 was achieved (whichever was earlier) Continuous monitoring was done in the intraoperative period and postoperative period (0–2 h).

Level of preoperative anxiolysis was evaluated as:

Crying, very anxious

Anxious, not crying

Calm but not cooperative

Calm, cooperative or asleep.

Anxiolysis score >3 was considered as satisfactory.

Level of preoperative sedation will be evaluated as:

Awake

Drowsy

Asleep.

Sedation score of >2 was considered as satisfactory.

Parental separation of the child was noted with child-parent separation score[5]

Patient fearful and crying; not quieted with reassurance

Patient slightly fearful and/or crying; quieted with reassurance

Patient unafraid, cooperative or asleep.

Quality of induction was assessed as:

Combative/crying

Moderate fear of mask, not easily calmed

Cooperative with reassurance

Calm, cooperative

Asleep.

Mask induction score of >3 was regarded as satisfactory.

Reaction to intravenous cannulation was assessed:

Fight without success

Fight with success

Minor resistance

No reaction.

Emergence score

Excellent (quiet)

Good (occasional crying)

Fair (crying, but able to be quieted)

Poor (thrashing, unable to be quieted).

Postoperative sedation was monitored for 2 h after surgery at an interval of 15 min.

Awake

Drowsy

Asleep.

Any side effect or complication in the perioperative period was noted, for example,

Nasal irritation or congestion

Respiratory depression (SpO2 < 95% OR respiratory rate <16 breaths/min)

Itching

Shivering

Nausea or vomiting

Blurred vision

Bad taste

Watering of eyes

Increased salivation.

The observations were recorded on the pro forma, and the results were statistically analyzed in the three groups.

RESULTS

The three groups were comparable regarding age, sex, duration, and type of surgery they underwent.

Demographic data

Demographic data are shown in Table 1.

Table 1

Demographic data

Preoperative heart rate

In Group F, M, and D heart rate decreases at 10, 20, 30, 40, and 50 min from the baseline (0 min), but statistically significant fall (P < 0.05) is seen in Group F, only at 10 and 20 min, when compared to Group M and Group D. As very few number of patients were left at 50 min, the statistical test were not applied. Fall in heart rate was observed at 30 min in Group D, but it was statistically insignificant (P > 0.05).

Preoperative systolic blood pressure

In Group F, M, and D systolic blood pressure decreases at 10, 20, 30, 40 and 50 min from baseline (0 min), but statistically significant fall (P < 0.05) is seen in Group M at 10 min and 20 min when compared to Group F and Group D. At 40 min Group D shows statistically significant fall (P < 0.05) in systolic blood pressure when compared to Group M. As very few number of patients were left at 50 min, the statistical test were not applied.

Preoperative diastolic blood pressure

In Group F, M and D diastolic blood pressure decreases at 10, 20, 30, 40, and 50 min from baseline (0 min), but statistically significant fall (P < 0.05) is seen in Group F only at 10 min when compared to Group M. As very few number of patients were left at 50 min, the statistical test were not applied.

Respiratory rate in preoperative period

In Group F, respiratory rate falls at 10, 20, 30, and 40 min from baseline (0 min). Fall is statistically significant (P < 0.05) at 10 and 20 min when compared to Group M. Fall in RR in Group F is also statistically significant (P < 0.05) when compared to Group D at 30 min. In Group M, statistically significant fall (P < 0.05) is seen at 20 min when compared to Group D. As very few number of patients were left at 50 min, the statistical test were not applied.

O2 saturation in preoperative period – No significant fall is seen in any of the groups.

Onset of anxiolysis

Onset of anxiolysis [Figure 1]

The mean onset of anxiolysis in Group F was 13.6 ± 7.00 min

The mean onset of anxiolysis in Group M was 12.80 ± 6.13 min

The mean onset of anxiolysis in Group D was 23.20 ± 8.52 min

The difference of onset of anxiolysis between Group M/D and F/D is statistically

Significant (P < 0.05).

Onset of sedation

Onset of sedation [Figure 2]

In Group F the mean onset of sedation was 21.20 ± 5.25 min

In Group M the mean onset of sedation was 21.20 ± 8.32 min

In Group D the mean onset of sedation was 32.00 ± 5.77 min.

The results were seen to be statistically significant (P < 0.05) between Group M/D and F/D.

Parental separation score

Parental separation score [Figure 3]

The difference in mean parental separation score was statistically significant (P < 0.05) between Group F/M and M/D.

The difference in mean parental separation score was statistically insignificant (P > 0.05) between Group F/D.

Quality of induction and mask acceptance

Quality of induction and mask acceptance [Figure 4]

The difference in mean score was statistically significant (P < 0.05) between Group F/M and M/D and statistically insignificant between Group F/D (P > 0.05).

Reaction to intravenous cannulation

Reation to intravenous cannulation [Figure 5]

The statistically significant (P < 0.05) difference was seen in a mean score of reaction to I/V cannulation in Group F/M, M/D, and F/D.

Postoperative sedation

The difference in the mean post-operative sedation score was found to be statistically significant (P < 0.05) at 0, 15, 30, and 45 min between Group M/D and F/D.

DISCUSSION

The principal effect of opioid receptor activation is a decrease in neurotransmission.[6] Opioids act as agonists at specific opioid receptors at presynaptic and postsynaptic sites in the CNS (mainly the brainstem and spinal cord) as well as in the periphery.[7] A single dose of fentanyl administered IV has a more rapid onset and shorter duration of action than morphine. The greater potency and more rapid onset of action reflect the greater lipid solubility of fentanyl compared with that of morphine, which facilitates its passage across the blood-brain barrier. Similarly, the short duration of action of a single dose of fentanyl reflects its rapid redistribution to inactive tissue sites such as fat and skeletal muscles, with an associated decrease in the plasma concentration of the drug.[8]

Benzodiazepines appear to produce all their pharmacologic effects by facilitating the actions of gamma-aminobutyric acid (GABA).[9] The short duration of action of a single dose of midazolam is due to its lipid solubility, leading to rapid redistribution from the brain to inactive tissue sites as well as rapid hepatic clearance. Midazolam undergoes rapid absorption from the gastrointestinal tract and prompt passage across the blood-brain barrier.

Dexmedetomidine is a highly selective α2-adrenergic agonist. Unlike opioids and other sedatives such as propofol, dexmedetomidine can achieve its effects without causing respiratory depression. Dexmedetomidine induces sedation by decreasing activity of noradrenergic neurons in the locus ceruleus in the brain stem, thereby increasing the activity of inhibitory GABA neurons in the ventrolateral preoptic nucleus.[10] Rapid IV administration or bolus has been associated with slow heart rate (bradycardia) and low blood pressure (hypotension) due to peripheral α2-receptor stimulation.

In our study, fentanyl and midazolam had the earlier onset of anxiolysis and sedation as compared to dexmedetomidine which was statistically significant (P < 0.05). The mean onset of anxiolysis in Group F was 13.6 ± 7.00 min.

The mean onset of anxiolysis in Group M was 12.80 ± 6.13 min

The mean onset of anxiolysis in Group D was 23.20 ± 8.52 min

In group F the mean onset of sedation was 21.20 ± 5.25 min

In group M the mean onset of sedation was 21.20 ± 8.32 min

In group D the mean onset of sedation was 32.00 ± 5.77 min.

The results of our study also corresponds with the results of study conducted by Sheta et al., in 2014, in which it was concluded that the median onset of sedation was significantly earlier in Group M (intranasal midazolam 0.2 mg/kg) than in Group D (intranasal dexmedetomidine 1 μg/kg). In Group M it was 15 min (10–25 min). In Group D, it was 25 min (20–40 min), P = 0.001.[11]

With regard to child-parent separation in our study, fentanyl and dexmedetomidine provided better parental separation than midazolam (P < 0.05).

Ghali et al., in their study found the statistically significant difference (P < 0.05) in parental separation between children who received intranasal dexmedetomidine 1 μg/kg (Group D) and oral Midazolam 0.5 mg/kg (Group M) at approximately 60 and 30 min, respectively before induction of anesthesia. Child parental separation was easier in children who received intranasal dexmedetomidine than in children who received oral midazolam.[12]

Quality of induction of anesthesia and mask acceptance was significantly better in fentanyl and dexmedetomidine as compared to midazolam.

Reaction to intravenous cannulation score was best observed in the fentanyl group. Our results are also in accordance to the work of Tarek which compared Midazolam syrup versus Midazolam syrup Plus Fentanyl Lozenge and proved Midazolam plus Fentanyl Lozenge to be superior in reducing apprehension at IV cannulation and improving mask acceptance.[13]

Owing to their shorter duration of action fentanyl and midazolam failed to provide post-operative sedation in our study while dexmedetomidine provided arousable sedation even after the completion of surgery which kept the children calm and cooperative in the recovery area.

Hemodynamics remained stable in all the three groups and none of the patient suffered from any drug-related side effect which required any pharmacological or other therapeutic intervention.

CONCLUSION

Intranasal fentanyl in a dose of 1.5 μg/kg is better than intranasal midazolam 0.3 mg/kg and intranasal dexmedetomidine 1 μg/kg as far as premedication is concerned because of its early onset of action, better anxiolysis, deeper levels of sedation, easy child-parent separation and shorter duration of action. However, owing to long duration of action of dexmedetomidine it keeps the child calm and sedated for longer durations of time period postoperatively.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.