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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 19-28

Comparison of nebulized fentanyl, midazolam, and dexmedetomidine as a sedative premedication in outpatient pediatric dental surgeries: a randomized double-blind study


Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission22-Apr-2021
Date of Decision02-Jul-2021
Date of Acceptance30-May-2021
Date of Web Publication13-May-2022

Correspondence Address:
MD Marwa M Medhat
Anaesthesia Department, Faculty of Medicine, Zagazig University, Takseem El Moalmeen, Zagazig, 44511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_10_21

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  Abstract 


Background The preoperative time is traumatic for young children undergoing surgery. Parental separation and needle injection increase preoperative anxiety. Preoperative sedation in children is usually administered via the rectal, oral sublingual, and intranasal routes with different degrees of patient acceptance. Nebulized drug is an alternative method of sedation that is relatively easy to set up.
Materials and Methods Thirty nine pediatric patients (2–6) years old scheduled for outpatient dental surgeries were randomly allocated in three groups (13 patients each); group (F) received nebulized fentanyl 2 μg/kg 30 min before surgery, group (M) received nebulized midazolam 0.2 mg/kg 30 min before surgery and group (D) received nebulized dexmedetomidine 2 μg/kg 30 min before surgery. The outcome measures included onset of sedation, parental separation, tolerance to mask induction, reaction to intravenous cannulation and preoperative hemodynamic changes (systolic blood pressure, diastolic blood pressure and heart rate).
Results Children who received nebulized fentanyl and nebulized midazolam had early onset of 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 premedication.
Conclusion Nebulized fentanyl in a dose of 2 μg/kg is better than nebulized midazolam 0.2 mg/kg and nebulized dexmedetomidine 2 μg/kg as far as premedication is concerned because of its early onset of action, deeper levels of sedation, easy child-parent separation and shorter duration of action.

Keywords: dental surgeries, dexmedetomidine, fentayl, midazolam


How to cite this article:
Medhat MM, Abd Elnaby SM. Comparison of nebulized fentanyl, midazolam, and dexmedetomidine as a sedative premedication in outpatient pediatric dental surgeries: a randomized double-blind study. Res Opin Anesth Intensive Care 2022;9:19-28

How to cite this URL:
Medhat MM, Abd Elnaby SM. Comparison of nebulized fentanyl, midazolam, and dexmedetomidine as a sedative premedication in outpatient pediatric dental surgeries: a randomized double-blind study. Res Opin Anesth Intensive Care [serial online] 2022 [cited 2022 Oct 6];9:19-28. Available from: http://www.roaic.eg.net/text.asp?2022/9/1/19/345215




  Introduction Top


The time before operation is traumatic for young children. Pediatric anesthesiologists act strongly to decrease distress for children in the operating room (OR) and to provide a smooth induction of anesthesia [1]. Parental separation and needle injection increase preoperative anxiety. Stress response before operation stimulates the endocrine and sympathetic and parasympathetic systems, which leads to an increase in heart rate (HR), blood pressure, and cardiac excitation [2],[3]. Dental procedures are associated with high rate of fear and anxiety in children [4].

Many drugs have been used as premedication to decrease anxiety, facilitate smooth induction, and easy separation of children from their parents. The premedication especially in children is ideal when it is acceptable with rapid onset, has minimal adverse effects, and rapid postoperative recovery and return to alertness [5],[6].

Fentanyl is a potent analgesic opioid that has a rapid onset and short duration of action [7]. Midazolam is a short-acting benzodiazepine with anxiolytic, amnestic, hypnotic, anticonvulsant, and muscle relaxant actions [8],[9]. Dexmedetomidine is a selective α-2 adrenergic agonist that has both sedative and analgesic effects [10],[11],[12].

Preoperative sedation in children is usually administered via the rectal, oral sublingual, and intranasal routes with different degrees of patient acceptance [13],[14],[15],[16],[17],[18]. Nebulized drug is an alternative method of sedation that is relatively easy to set up, without need for venipuncture, and is associated with high bioavailability of the drug [19],[20].

This study was designed to evaluate and compare the effect and safety of nebulized either fentanyl, midazolam, or dexmedetomidine as a sedative premedication before general anesthesia in the outpatient pediatric dental surgeries. The primary end point is the onset time of sedation based on the Modified Observer’s Assessment of Alertness/Sedation Scale [19]. The secondary end points are level of sedation when the child is first seen in the OR 30 min after using studied drugs, parental separation, tolerance to mask induction, reaction to intravenous cannulation, hemodynamic parameters, respiratory rate, and recovery time.


  Patients and methods Top


Study population

This prospective randomized double-blind study was conducted in Zagazig University Hospitals from February 2020 to August 2020. Approval of Institutional Review Board (IRB) and the parent’s informed written consent were obtained. Our clinical study was registered with ClinicalTrials.gov (NCT04226885).

39 cases allocated into three equal groups, with 13 patients in each one.

Pediatric patients aged 2–6 years old, of either sex, 12–18 kg of body weight, and scheduled for outpatient dental surgeries that were classified as American Society of Anesthesiologists (ASA) I and ASA II were included in this study. Patients with difficult airway; patients with central nervous system dysfunction; patients with advanced cardiovascular, liver, and renal diseases; patients with allergy to any drugs used in this study; patients with any intranasal pathology or congenital anomaly; and patients who refused to take the inhaled premedication were excluded from this study.

Study design

Preoperative assessment

Preoperative visit for all participating patients during their preoperative preparation was done to discuss the goal and end points of the study, to clarify the advantages and possible side effects of the preoperative sedation, and to take an informed consent regarding the procedure from parents. On physical examination, special attention was given to document vital signs and cardiac and chest conditions. All patients were investigated by complete blood picture, coagulation profile, liver functions test, and kidney functions test. Fasting for minimum 6 h for solid and 2 h for free fluids before the operation was confirmed.

The patients enrolled in this study were divided randomly by a computer-generated randomization table into three equal groups: group F (n=13) included patients who were given nebulized fentanyl 2 μg/kg, group M (n=13) included patients who were given nebulized midazolam 0.2 mg/kg, and group D (n=13) included patients who were given nebulized dexmedetomidine 2 μg/kg 30 min before surgery. We used a prospective double-blind study (patients and anesthetist totally blinded to the randomization). An independent investigator not involved in data collection or patients’ anesthesia would give the studied drugs.

Basal blood pressure [systolic and diastolic blood pressure (SBP and DBP)], HR, and respiratory rate were assessed and then monitored continuously in the preoperative period; readings were recorded every 10 min for up to 30 min of administration of the studied drugs.

The calculated dose of the studied drugs was completed to a total volume of 3 ml of 0.9% saline and was administered by a standard venturi mask with a nebulization chamber at a constant flow rate of oxygen, 4–6 l/min for about 8 min.
  1. Time of onset of sedation was assessed when sedation score became 2 or 3. Preoperative sedation was based on the Modified Observer’s Assessment of Alertness/Sedation Scale [19]:
    • 6–appears alert and awake, responds readily to name spoken in normal tone.
    • 5–appears asleep but responds readily to name spoken in normal ton.
    • 4–lethargic response to name spoken in normal tone.
    • 3–responds only after name is called loudly or repeatedly.
    • 2–responds only after mild prodding or shaking.
    • 1–does not respond to mild prodding or shaking.
    • 0–does not respond to noxious stimulus.
  2. Parental separation was assessed by a four-point parental separation anxiety scale [1] as follows: 1=easy separation; 2=whimpers, but is easily reassured and not clinging; 3=cries and cannot be easily reassured, but not clinging to parents; and 4=crying and clinging to parents. Parental separation anxiety scale scores of 1 and 2 signified acceptable separation, whereas scores of 3 and 4 were classified as difficult separation.
  3. Level of sedation was assessed 30 min after administration of the studied drugs, and then, the child was transferred to the OR.
  4. Any adverse effects in the perioperative period such as hypoxia, apnea, and hypotension (SBP is less than 70+ [age in years ×2)], associated with altered peripheral perfusion requiring fluid bolus administration, bradycardia (<60 beats/min requiring atropine administration), nasal irritation in the form of sneezing and runny nose, vomiting, and itching were noted and recorded.


Intraoperative assessment

Intravenous line was done, and reaction to intravenous cannulation was noted and assessed by an anesthesiologist blinded to the studied drugs as follows: poor (uncooperative without success), fair (uncooperative with success), good (minor resistance), or excellent (no reaction) [20]. Atropine 0.01–0.02 mg/kg was given. Preoxygenation for 3 min with oxygen was given via facemask, and the mask acceptance by the child was assessed using a four-point mask acceptance scale (MAS) [1] as follows: 1 (excellent)=unafraid, cooperative, accepts mask easily; 2 (good)=slight fear of mask, easily assured; 3 (fair)=moderate fear of mask, not calmed with reassurance; and 4 (poor)=terrified, crying, or combative. MAS scores of 1 and 2 are considered ‘satisfactory’ mask acceptance but scores of 3 and 4 are considered ‘unsatisfactory’. Face mask induction was carried out using sevoflurane in oxygen, The dial setting was increased by 1% every 2–3 breaths until loss of eyelash reflex. Muscle relaxant rocuronium 0.6 mg/kg was used to facilitate tracheal intubation. Maintenance of anesthesia was done with sevoflurane 1–2% with oxygen/air mixture and an intermittent dose of injection rocuronium 0.075 mg/kg intravenously. At the end, sevoflurane was discontinued.

Neuromuscular blockade was given if needed with intravenous injection of atropine 0.01 mg/kg and neostigmine 0.04 mg/kg. Extubation was done after adequate neuromuscular recovery, return of protective reflexes, and regular respiratory rate were achieved. All patients received rectal acetaminophen 10–15 mg/kg suppository for postoperative analgesia before extubation.

Data collection

The following data were collected:
  1. Patient characteristics: age, sex, weight, and ASA physical status.
  2. Basal SBP and DBP, HR, and respiratory rate levels were assessed and then monitored continuously in the preoperative period; readings were recorded every 10 min for up to 30 min of administration of the studied drugs.
  3. Time of onset of sedation was based on the Modified Observer’s Assessment of Alertness/Sedation Scale.
  4. Parental separation was assessed using patient separation anxiety scale.
  5. Level of sedation was assessed when the child is first seen in the OR 30 min after sedation.
  6. Reaction to intravenous cannulation was recorded
  7. Tolerance of mask induction was assessed using a four-point MAS.
  8. Operative time was recorded.
  9. Recovery time from discontinuation of anesthesia until regaining baseline sedation score was recorded.
  10. Any adverse effects in the perioperative period such as hypoxia, apnea, hypotension, bradycardia, nasal irritation, vomiting, and itching were noted and recorded.


Statistical analysis

Calculation of sample size was based on a previous study of premedication in pediatric patients which compared intranasal Fentanyl, midazolam and dexmedetomidine [7]. At a confidence interval of 95% and power of test 80%. The collected data were statistically analyzed using Statistical Package for the Social Science software (version 20 (SPSS Inc., Chicago, Illinois, USA). Continuous variables with a normal distribution were reported as mean±SD. Categorical variables were summarized as frequencies and percentages. Quantitative data were evaluated using analysis of variance followed by post-hoc test, whereas qualitative data were evaluated by χ

2. P values greater than 0.05 and greater than 0.001 were considered statistically significant and highly statistically significant, respectively.


  Results Top


A total of 39 patients scheduled for outpatient dental surgeries were assessed for eligibility to participate in this study and randomized into three equal groups of 13 patients each ([Figure 1]).
Figure 1 Study flowchart.

Click here to view


As shown in [Table 1], there was no statistically significant difference (P>0.05) between the studied groups regarding age, sex, weight, ASA physical status (I/II), and operative time, ensuring homogeneity of the groups. Recovery time showed statistically significant difference among the three groups (F, M, and D), which was found to be lower in group F.
Table 1 Patient characteristics and clinical data of the studied groups (n=13) for each group

Click here to view


[Figure 2] shows that the HR was comparable at baseline reading in groups F, M, and D and immediately after nebulization. HR decreased at 10, 20, and 30 min from the baseline (0 min), but a statistically significant fall was seen in group D, only at 10 and 20 min, when compared with group M and group D (P<0.05). Fall in HR was also observed at 30 min in group F, but it was statistically insignificant (P>0.05).
Figure 2 Preoperative heart rate (HR) changes among the studied groups (error bars represent standard error) (n=13) for each group. F=fentanyl group, M=midazolam group, D=dexmedetomidine group.

Click here to view


[Figure 3] shows that the SBP when compared with other groups was comparable at baseline reading in groups F, M, and D and immediately after nebulization. SBP decreased at 10, 20, and 30 min from the baseline (0 min), but a statistically significant fall was seen in group M, only at 10 and 20 min, when compared with other groups (P<0.05). At 30 min, group D showed statistically significant decrease in SBP when compared with groups F and M (P<0.05).
Figure 3 Preoperative changes in the systolic blood pressure (SBP) among the studied groups (error bars represent standard error) (n=13) for each group. F=fentanyl group, M=midazolam group, D=dexmedetomidine group.

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[Figure 4] shows that the DBP was comparable at baseline reading in groups F, M, and D and immediately after nebulization. DBP decreased at 10, 20, and 30 min from the baseline (0 min), with no significant difference among the three groups (P>0.05).
Figure 4 Preoperative changes in the diastolic blood pressure (DBP) among the studied groups (error bars represent standard error) (n=13) for each group. F=fentanyl group, M=midazolam group, D=dexmedetomidine group.

Click here to view


[Figure 5] shows that the RR was comparable at baseline reading in groups F, M, and D and immediately after nebulization. RR decreased at 10, 20, and 30 min from the baseline (0 min), but a statistically significant fall was seen in group F at 10, 20, and 30 min, when compared with other groups (P<0.05). At 20 min group M showed a statistically significant decrease in RR when compared with group D (P<0.05).
Figure 5 Preoperative changes in the respiratory rate (RR) among the studied groups (error bars represent standard error) (n=13) for each group. F=fentanyl group, M=midazolam group, D=dexmedetomidine group.

Click here to view


[
Table 2 Time of onset of sedation among the studied groups (n=13) for each group

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Time of onset of sedation among the studied groups (n=13) for each group


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] shows that there was a highly statistically significant difference between groups F and M when compared with group D regarding onset of sedation (P<0.001), with no significant difference between group F and group M (P>0.05).{Table 2}

[
Table 3 Level of sedation at 30 min after administration of the studied drugs, among the studied groups (n=13) for each group

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Level of sedation at 30 min after administration of the studied drugs, among the studied groups (n=13) for each group


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] shows more sedation in group F, with a highly statistical significant when compared with group M and group D (P<0.001), with no statistically significant difference on comparing group M with group D (P≥0.05).{Table 3}

[
Table 4 Parentral separation,quality of induction and reaction to IV canulation

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Parentral separation,quality of induction and reaction to IV canulation


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] shows that there was a statistically significant difference between group M and groups F and D regarding both parental separation score, quality of induction, and mask acceptance (P<0.05).{Table 4}

In group F, more than half of the group showed easy parental separation (53.8%).

On comparing the reaction to IV cannulation, there was a significant difference among the three groups (F, M, and D). There was a statistically significant difference between group F and group M (P<0.05). However, no statistically significant difference was found on comparing group M with group D and on comparing groups F and D (P>0.05).

Regarding perioperative adverse effects, vomiting occurred in none, one, and three patients in groups F, M, and D, respectively. Two patients had increased salivation in group D. Three patients had bradycardia in group D but did not need intervention.


  Discussion Top


We found that children premedicated with nebulized fentanyl (2 μg/kg) had earlier onset of action, deeper level of sedation, easier in child–parent separation, and rapid recovery time than those who received nebulized midazolam (0.2 mg/kg) and nebulized dexmedetomidine (2 μg/kg). Moreover, nebulized fentanyl was associated with lower hemodynamic complications, particularly bradycardia, hypotension, and lower incidence vomiting.

The inhalation route used in this study is an alternative mode of preoperative sedation, which is relatively easy to set up, and does not require an i.v. cannulation or injection, but on the contrary, it is still associated with high bioavailability [19],[20],[21] McCormick et al. [20] compared inhalation of nebulized midazolam with intranasal midazolam administration. They concluded that nebulized midazolam administration causes less discomfort than intranasal administration. Kaabachi et al [21] compared oral versus inhalation via nebulizer of midazolam for sedative premedication in children and also concluded that mask nebulization with midazolam is an effective, rapid, and safe route for premedication in children. We similarly found that the nebulization technique was simple and very satisfactory.

Intranasal administration generates a spray of drug that increases surface area coverage with a thin layer of drug that enables rapid absorption of the drug through the nasal, buccal, and respiratory mucosa, which can help to achieve higher CSF concentrations and improved clinical effectiveness [19],[20],[21]. Data on pharmacokinetics for the nebulized route are limited [22], and so in our study, we selected the doses of fentanyl, midazolamand, dexmedetomidine based on previous clinical studies that proved the clinical effectiveness of these doses [23],[24].

Opiods action is an agonist to specific opioid receptors at both presynaptic and postsynaptic sites in the CNS (especially the brainstem and spinal cord) as well as at the peripheral sites [25],[26]. The bioavailability of nebulized fentanyl is similar to that of IV delivery [27]. Beside that IV placement is a painful and anxiety-provoking event for a child, and avoiding it or delaying it until sedation has been occurred should have a great benefit to the children. Single dose of fentanyl has short duration of action, the cause of which is its rapid redistribution to other tissue sites like fat and skeletal muscles, which leads to decrease in fentanyl plasma concentration [28].

Benzodiazepines affect by facilitating the actions of gamma-aminobutyric acid [29]. Midazolam is a water-soluble 1,4-benzodiazepine derivative with rapid action and high lipophilicity, leading to rapid redistribution from the brain to inactive tissue sites with rapid hepatic clearance [30].

Dexmedetomidine is a selective agonist to α2-adrenergic receptor. Unlike other sedatives, it can achieve its effects without causing respiratory depression. It causes sedation by decreasing activity of noradrenergic neurons in the locus coeruleus in the brain stem, thereby increasing the activity of inhibitory gamma-aminobutyric acid neurons in the ventrolateral preoptic nucleus [31].

In our study, the mean onset of sedation was 22.03±0.08, 22.01±0.03, and 29.42±0.04 min in groups F, M, and D, respectively.

In agreement with our results, Sheta et al. [32] showed that the 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 10–25 min, with a median of 15 min. In Group D, it was 20–40 min, with a median of 25 min (P=0.001).

The results of our study also correspond with the results of a study conducted by Chatrath et al. [21], who reported that the mean onset of sedation was significantly earlier in group M (intranasal midazolam 0.3 mg/kg) and group F (intranasal fentanyl 1.5 μg/kg) than in group D (intranasal dexmedetomidine 1 μg/kg).

In our study, there was a statistically significant difference between midazolam group and fentanyl and dexmedetomidine groups regarding parental separation score, quality of induction, and mask acceptance (P<0.05).The results of our study also are similar to the results of a study conducted by Chatrath and colleagues, who reported that [21] quality of induction of anesthesia and mask acceptance were significantly better in fentanyl (intranasal fentanyl 1.5 μg/kg) and dexmedetomidine (intranasal dexmedetomidine 1 μg/kg) as compared with midazolam (intranasal midazolam 0.3 mg/kg).

In our study, reaction to intravenous cannulation was better in the fentanyl group.

Ghali et al. [33] found a significant difference (P0.05<) in parental separation between patients who received intranasal dexmedetomidine 1 μg/kg (group D) and oral midazolam 0.5 mg/kg (group M) at 60 and 30 min, respectively before anesthetic induction. Parental separation was easier in patients who received intranasal dexmedetomidine than in others who received oral midazolam.

Our results are also in agreement with the study by Tawfik [34] who compared midazolam syrup versus midazolam syrup plus fentanyl lozenge and concluded that midazolam plus fentanyl lozenge is superior in reducing reaction to IV cannulation.

In our study, statistically significant bradycardia was seen in group D, and this is explained by central sympathetic suppression of dexmedetomidine [35].

Our results showed a significant fall in RR in group F, and this is may be attributed to activation of μ-opioid receptors [36].

In accordance with our study, Plambech and Afshari [37] showed that hypotension and bradycardia are the most common adverse events associated with dexmedetomidine and that respiration is only slightly affected. However, these hemodynamic changes were not clinically significant and did not require any intervention.

However, there are certain limitations of this study. First, the number of patients included in the study was small, and there is a need for increasing the sample size. Second, the present study included only patients who underwent dental surgery under general anesthesia.


  Conclusion Top


Using nebulized fentanyl in a dose of 2 μg/kg in outpatient dental surgeries is better than nebulized midazolam at 0.2 mg/kg and nebulized dexmedetomidine at 2 μg/kg as far as premedication is concerned because of its early onset of action, deeper levels of sedation, easy child–parent separation, and shorter duration of action (rapid recovery time), as well as to avoid dexmedetomidine’s possible adverse effects and hemodynamic complications (particularly bradycardia and hypotension) and vomiting.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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



 

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