|Year : 2016 | Volume
| Issue : 2 | Page : 349-355
Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study
Ravi Bhat1, M.C.B. Santhosh1, Venkatesh M Annigeri2, Raghavendra P Rao1
1 Department of Anaesthesiology, SDM College of Medical Sciences, Dharwad, Karnataka, India
2 Department of Paediatric Surgery, SDM College of Medical Sciences, Dharwad, Karnataka, India
|Date of Web Publication||26-Apr-2016|
Department of Anaesthesiology, SDM College of Medical Sciences, Dharwad - 580 009, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Goal of premedication in pediatric anesthesia are relieving pre and postoperative anxiety, good parental separation, and smooth induction of anesthesia. Anxiety can produce aggressive reactions, increased distress, increased postoperative pain and postoperative agitation. The benzodiazepine, midazolam, is the most frequently used premedication in pediatric anesthesia. Midazolam has a number of beneficial effects when used as premedication in children: Sedation, fast onset, and limited duration of action. Though midazolam has a number of beneficial effects, it is far from an ideal premedicant having untoward side effects such as paradoxical reaction, respiratory depression, cognitive impairment, amnesia, and restlessness. Dexmedetomidine is a newer α-2-agonist, which can be used as premedicant.
Aims: To compare the level of sedation, parental separation, mask acceptance, postoperative recovery of intranasal premedication with dexmedetomidine and dexmedetomidine-ketamine combination in pediatric patients.
Settings and Design: Prospective randomized double-blind study.
Subjects and Methods: After written informed consent from the patient's parents or legal guardian, 54 children of American Society of Anesthesiologists physical status I or II, aged between 1 and 6 years, scheduled to undergo elective minor surgery were enrolled. In group D patient received 1
μ g/kg dexmedetomidine intranasally and in group DK received 1
μ g/kg dexmedetomidine and 2 mg/kg ketamine intranasally. Patients were assessed every 10 min for the level of sedation, parenteral separation, heart rate, and oxygen saturation by an independent observer. Mask acceptance and postoperative agitation were noted using an appropriate scale.
Statistical Analysis Used: Pearson Chi-square analysis to determine differences between two groups with respect to separation anxiety and acceptance of the anesthesia mask. Percentages used to represent frequencies. The level of significance was set at P< 0.05.
Results: Acceptable parenteral separation was achieved in 90% of patients 30 min after premedication. Sedation was acceptable in 80% of patients at induction. Good mask acceptance was seen in 60% of patients. The incidence of emergence agitation (EA) was 2%. None of the above parameters was statistically significant between the two groups.
Conclusions: Dexmedetomidine, as premedicant in children provides acceptable parenteral separation. However, mask acceptance in operation room is poor. Combination of dexmedetomidine and ketamine does not increase the success of premedication. Use of dexmedetomidine is associated with decreased EA.
Keywords: Dexmedetomidine, intranasal premedication, ketamine, sedation
|How to cite this article:|
Bhat R, Santhosh M, Annigeri VM, Rao RP. Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study. Anesth Essays Res 2016;10:349-55
|How to cite this URL:|
Bhat R, Santhosh M, Annigeri VM, Rao RP. Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study. Anesth Essays Res [serial online] 2016 [cited 2020 Jun 1];10:349-55. Available from: http://www.aeronline.org/text.asp?2016/10/2/349/172340
| Introduction|| |
Smooth induction of anesthesia in children needs good premedication. Goal of premedication in pediatric anesthesia are relieving pre and postoperative anxiety, good parental separation, and smooth induction of anesthesia. Anxiety during perioperative period in children can produce aggressive reactions, increased distress, may prolong induction of anesthesia, increased postoperative pain, postoperative behavioral changes, and postoperative agitation. The benzodiazepine, midazolam, is the most frequently used premedication in pediatric anesthesia., Midazolam has a number of beneficial effects when used as premedication in children such as good sedation, fast onset, and limited duration of action., Though midazolam has a number of beneficial effects, it is far from an ideal premedicant having untoward side effects such as paradoxical reaction, respiratory depression, cognitive impairment, amnesia, and restlessness.
Dexmedetomidine is a newer α-2-agonist with a more selective action on the α-2-adrenergic and a shorter half-life. It has been used in pediatric patients for procedural sedation and premedication. Previous studies have shown that combination of midazolam and ketamine results in better sedation and smooth induction of anesthesia than midazolam or ketamine used alone as Premedication. However combining dexmedetomidine with ketamine intranasally was not studied previously.
Aim of the study
We hypothesized combining ketamine with dexmedetomidine will result in better parenteral separation and smooth induction of anesthesia.
To compare the level of sedation, parental separation, mask acceptance, postoperative recovery of intranasal dexmedetomidine and dexmedetomidine-ketamine combination in pediatric patients. Furthermore to study the incidence of emergence agitation (EA) (secondary objective).
| Subjects and Methods|| |
This study was conducted at SDM College of Medical Sciences and Hospital, Dharwad, India between January 2014 and January 2015. After obtaining ethical clearance from Institutional Ethical Committee (Department of Medical Education, SDM College of Medical Sciences, Dharwad), 54 children of either sex, American Society of Anesthesiologists physical status I or II, aged between 1 and 6 years, scheduled to undergo elective minor surgery, were enrolled in this prospective, randomized, double-blind, controlled trial. Written informed consent was obtained from the patient′s parents or legal guardian. Exclusion criteria include known allergy or hypersensitive reaction to dexmedetomidine or ketamine, cardiac arrhythmia or congenital heart disease, raised intracranial tension, raised intraocular pressure and mental retardation, chronic illness, developmental delay and running nose. Patients were randomized into two equal groups (group D and group DK) using computer-generated table of random numbers. Patien′s in group D received 1 µg.kg −1 dexmedetomidine intranasally and group DK received 1 µg.kg −1 dexmedetomidine and 2 mg.kg −1 ketamine intranasally. Study drug was prepared and administered by the investigator not involved in data collection and assessment. In both groups, the drug was given 30 min before surgery using one ml tuberculin syringe and the drug was deposited into both nostril equally. Patients were assessed every 5 min for the level of sedation and parental separation. Continuous monitoring of heart rate and SpO2 was done in the preoperative period by the independent observer and was recorded at 5 min interval.
The parental separation anxiety scale (PSAS) is a four-point scale as follows:
- 1 = Easy separation
- 2 = Whimpers, but is easily reassured, not clinging
- 3 = Cries and cannot be easily reassured, but not clinging to parents
- 4 = Crying and clinging to parents.
A PSAS score of 1 or 2 was classified as an acceptable separation, whereas scores of 3 or 4 was considered difficult separations from the parents.
Level of sedation was assessed using five-point scale as follows (sedation score)
1 = Agitated
2 = Alert
3 = Calm
4 = Drowsy
5 = Asleep.
A score of three and above was acceptable sedation. Once the patient was adequately sedated, the patient was transferred to operation room (OR). Patients in both groups received the same anesthetic. Anesthesia was induced with sevoflurane in oxygen and nitrous oxide mixture. In the operation room, patient′s ability to accept the anesthesia mask was assessed using the mask acceptance scale (MAS).
The MAS scale (four-point Likert scale)
- 1 = Excellent (unafraid, cooperative, accepts mask readily)
- 2 = Good (slight fear of mask, easily reassured)
- 3 = Fair (moderate fear of mask, not calmed with reassurance)
- 4 = Poor (terrified, crying, or combative).
Patient's who had MAS of 1 or 2 was considered “satisfactory” acceptance of the anesthesia mask; scores of 3 or 4 was considered “unsatisfactory.”
Once the patient was induced, intravenous (i.v) access was secured. Fentanyl 2 µg.kg −1 was given. Appropriate sized laryngeal mask airway was inserted for airway control. Anesthesia was maintained with sevoflurane. Electrocardiogram, SpO2, heart rate, end-tidal carbon dioxide was monitored continuously and documented at 5 min intervals. Noninvasive blood pressure was recorded at 5 min intervals. Any episode of bradycardia or hypotension (defined as 30% decrease from baseline value) was noted. For postoperative analgesia whenever possible caudal block was given. In other cases, paracetamol rectal suppositories were inserted at the beginning of the procedure. In the postanesthesia care unit (PACU), the patients were monitored according to PACU protocol. Patients were observed by the research team member during the entire PACU stay. In the postoperative period agitation, repeat, bradycardia, sedation if any was noted. In the PACU, emergence agitation (EA) was assessed using the Watcha scale [Table 1]. Score more than 2 indicates the presence of EA. Patients with agitation score more than 2 received i.v midazolam (0.01–0.02 mg.kg −1). Children who fail to achieve acceptable parenteral separation even after 1 h of premedication were excluded from the study.
A Pearson Chi-square analysis was performed to determine differences between the two groups with respect to separation anxiety and acceptance of the anesthesia mask. An independent sample t- test was used to determine differences between the occurrence and severity of ED in the two groups. The level of significance was set at P < 0.05.
| Results|| |
Both groups were comparable with respect to demographic data [Table 2]. Mean age was 3.38 ± 2.11 years, and mean weight was 12.93 ± 4.63 kg. Even though, surgical and anesthesia duration was statistically significant between the groups, clinically the difference is minute. Heart rate and oxygen saturation were maintained in the normal range in both the groups. No episodes of oxygen desaturation, hypotension, and bradycardia were noted in both the groups. Mean parenteral separation score, sedation score, mask acceptance, and postoperative agitation in both the groups were comparable [Table 3]. Parenteral separation was acceptable in 25 patients (92.6%) in group DK and 24 (88.9%) patients in group D [Table 4]. Mask acceptance was acceptable in 18 (66.6%) patients in DK and 14 (52%) in group D [Figure 1]. Acceptable sedation score was seen in 92% of patients in our study. In group D, 40% of patients were asleep at the time of induction whereas in group DK 55% of patients. Eight (32%) children in group DK and 10 (41%) in group DK were disturbed while transferring from preoperative area to OR. Postoperative agitation was noted in one (3.7%) patient in both the groups [Figure 2]. [Consort flow diagram] shows the distribution of samples in both groups.
|Table 3: Comparison of parenteral separation, sedation and mask acceptance (mean±SD)|
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|Table 4: No of patients with acceptable sedation and parenteral separation|
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|Figure 1: No of patients with various mask acceptance scale (MAS) in both the groups|
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| Discussion|| |
A fearful, anxious, fighting child in the perioperative period is stressful both for anesthesiologist, care givers and parents. The manifestation of anxiety may differ in different children and may convey their preoperative anxiety verbally, behaviorally, subtly, or explicitly which make the induction of anesthesia difficult. Anxiety and fear prior to surgery may also lead to maladaptive postoperative changes in behavior such as sleep and eating disturbances, and new onset nocturnal enuresis that interfere with the daily functioning of the child. Children between 1 and 5 years of age appear to be at highest risk for developing anxiety because children under the age of 1 year rarely experience separation anxiety. Perioperative anxiety in children can be reduced by pharmacological or behavioral interventions. No technique or pharmacological agent of premedication has been completely satisfactory in children. All routes of premedication have been tried including injections, pills, and oral or rectal administration of drugs with each route having some drawbacks.
Intranasal drugs have been used principally in pediatrics patients as a method of evading the necessity of injections or bitter tasting oral drugs. An undiluted solution of the drug should be employed intranasally to circumvent large volumes of liquid being instilled into the nose and possibly entering the pharynx and producing coughing and sneezing, resulting in the expulsion of the drug. Intranasal administration is a noninvasive route with no potential side effects and complications such as nerve injury, inadvertent i.v or arterial injection, and infection that are associated with intramuscular drug administration. Absorption of intranasal drugs occurs directly into the central circulation, bypassing the enterohepatic circulation.
In our study, we used intranasal dexmedetomidine and dexmedetomidine-ketamine combination in pediatric patients as premedicants. Dexmedetomidine is a newer α-2-agonist with a more selective action on the α-2-adrenoceptor and a shorter half-life. Its bioavailability is 81.8% (72.6–92.1%) when administered via the buccal mucosa. Yuen et al. in a randomized, crossover evaluation of healthy adult volunteers demonstrated that intranasal one and 1.5 μg.kg −1 dexmedetomidine produces sedation in 45–60 min and peaks in 90–105 min. Ketamine is a racemic nonbarbiturate cyclohexamine derivative that produces dissociation of the cortex from the limbic system. It is highly lipid soluble and rapidly absorbed after i.v, intramuscular and intranasal administration. After oral administration, ketamine absorption is incomplete and delayed, plasma concentrations are lower compared with parenteral administration and the drug undergoes significant first pass metabolism. When given as premedicant by oral route there is said to be no incidence of dysphoric reactions. Ketamine is an excellent analgesic and amnesic agent.
A study by Karl et al. showed that intranasal midazolam is associated with burning sensation and crying. In our study, none of the patients had a burning sensation and crying. All our patients accepted premedication without any untoward effects.
Previous studies have shown that combination of midazolam and ketamine is better for premedication in children than both the drugs used individually., The combination of midazolam and ketamine are synergistic. Our study results show that combining dexmedetomidine with ketamine does not give the same result as a combination of midazolam and ketamine. Sedation score, parenteral separation, and compliance with mask induction were statistically not significant between the groups. No serious adverse effects such as bradycardia, hypotension, respiratory depression, and excessive salivation, EA were noted in our study.
In a study  comparing intranasal dexmedetomidine and midazolam for premedication in children undergoing complete dental rehabilitation, median onset time of sedation with dexmedetomidine was 25 min (20–40), which is comparable with our results. In our study, 90% children had acceptable parenteral separation at 30 min. The success rate of premedication with midazolam as reported by studies varies between 60% and 80%. Satisfactory mask acceptance was noted in 80% patients premedicated with dexmedetomidine and 58% with midazolam in that study. They concluded that dexmedetomidine is safe and effective alternative and resulted in superior sedation than intranasal midazolam. In another study  used combination of dexmedetomidine 2 μg.kg −1 and sufentanil 1 μg.kg −1 for dental sedation and shown that dental extraction can be done with dexmedetomidine. All patients accepted intranasal drugs without any discomfort. Their study sample was small (20) and in their study sedation score deteriorated at the beginning of procedure compared to preprocedure sedation level. In our study also sedation score deteriorated during transfer to OR and at mask induction.
In a study  to evaluate optimal timing of administration of dexmedetomidine the median onset time of sedation with intranasal dexmedetomidine 1 μg.kg −1 was 25 min and mean duration of sedation was 85 min. They concluded that dose of 1 μg.kg −1 is chosen, the onset time will range from 25 to 45 min with a median duration of sedative effect of 55–100 min. In their study, only 57% patients were sedated at the time of transfer to OR, which is comparable with our results (55%).
In a randomized trail Zanaty and El Metainy. compared nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication. There were no significant difference in ease of parenteral separation and face mask acceptance. Level of sedation was significantly greater in dexmedetomidine-ketamine combination group but heart rate and mean arterial pressure was significantly lower in dexmedetomidine group. They conclude that combination of low dose ketamine and dexmedetomidine produced more satisfactory sedation, smooth induction, and more rapid recovery. In our study, sedation and mask acceptance was comparable in both groups and mask acceptance was 66% compared to their result of 85%.
In a study, Gyanesh et al., compared intranasal dexmedetomidine 1 μg.kg −1, ketamine 5 mg/kg and placebo in 150 children between 1 and 10 years for IV placement for magnetic resonance imaging (MRI) scanning. They conclude that both premedication drugs are equally efficacious in this regard. In another study Jia et al. studied combinations of dexmedetomidine and ketamine in 160 patients. Satisfactory parenteral separation was seen in 84% of patients in their study which is comparable to our result of 92%. Their conclusion was intranasal dexmedetomidine in a dose of 2 μg.kg −1 combined with oral ketamine in a dose of 3 mg.kg −1 when administered as a premedication in children, appears to be the optimal combination. It achieved satisfactory preoperative sedation, allowed calm separation of the patient from their parent, resulted in the acceptance of i.v cannulation and did not cause excessive postoperative nausea, vomiting, or psychological disturbance. In a study  comparing the efficacy of dexmedetomidine, ketamine, and a mixture of both for pediatric MRI sedation the combination of dexmedetomidine-ketamine was superior to either dexmedetomidine or ketamine given individually with regard to the onset of sedation, the sedation failure rate, and hemodynamic stability.
Dexmedetomidine acts on locus coeruleus (central nervous system action) and produces electroencephalogram changes identical to natural sleep., This suggests that patient's sedated with dexmededtomidine can be easily arousable. In our study, 30–40% patients became awake while transferring to operation room from preoperative area even though 90% patients were well sedated at the time of separation from parents. This may be the reason why only 60% of our patients accepted anesthesia induction with a face mask. Another reason could be dexmedetomidine ' peak onset of action is about 45 min, and we assessed patients at 30 min, which may result in awakening at the time of transfer to OR. In a study by Sheta et al. the median time for onset of sedation with intranasal dexmedetomidine was 25 min (20–40) and mask induction compliance was noted in 80% of patients. With intranasal midazolam as premedication compliance with inhalational induction was 58% and they concluded intranasal dexmedetomidine is superior to nasal midazolam but had relatively prolonged onset of action.
Emergence agitation (EA) (postoperative agitation) with sevoflurane has been found in 18–80% patients in previous studies. The reason for EA after inhalational anesthesia can be due to inadequate pain relief, preoperative anxiety, gender, type of surgery, and postoperative environment. In our study, EA was noted in 3.7% patients which are significantly less when compared with data from previous studies. In a study by Kim et al. found that low-dose infusion of dexmedetomidine reduces EA after desflurane anesthesia. They used 0.2 μg.kg −1.h −1 dexmedetomidine infusion and incidence of EA in the study group was 12.8% and in the control group 74%. Furthermore, need for rescue analgesia was less in dexmedetomidine group. For postoperative analgesia majority of our patients received caudal block.
Few limitations of our study are small sample size and transfer of patients to OR 30-40 minutes after administering premedication drug. Some previous studies have shown that peak onset time for dexmedetomidine is about 45 min. This might lead to arousal of sedated children at the time of mask induction in our study.
| Conclusion|| |
Combination of dexmedetomidine and ketamine does not increase the success of premedication. Even though parenteral separation and sedation were acceptable, there was a change in behavior at the time of induction. Use of dexmedetomidine is associated with less incidence of postoperative agitation. Further studies with higher intranasal dose may be considered for assessing the effectiveness of dexmedetomidine-ketamine combination as premedicant.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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