The preoperative period can be a traumatic time for young children undergoing surgery. Pediatric anesthesiologists strive to minimize distress for children in the operating room (OR) environment and to provide a smooth induction of anesthesia.1 Preoperative anxiety stimulates the sympathetic, parasympathetic, and endocrine systems, leading to an increase in heart rate (HR), blood pressure, and cardiac excitability.2,3 Anxiety and fear associated with dental procedures have been well documented and are thought to represent a model of an acute stressor.4
Various drugs have been advocated as premedication to allay anxiety and facilitate the smooth separation of children from parents. The ideal premedicant in children should be readily acceptable and should have a rapid and reliable onset with minimal side effects.5 Dexmedetomidine is a tasteless, colorless, and odorless drug that acts as a selective α-2 adrenergic agonist with both sedative and analgesic effects via actions in the central nervous system.6,7 Dexmedetomidine may be a suitable adjunct to ketamine because it ameliorates the cardiostimulatory effects of ketamine.8 Ketamine is an N-methyl-D-aspartate receptor antagonist that produces a state of sedation, anesthesia, immobility, analgesia, amnesia, and dissociation from the environment.9
This study was designed to evaluate and compare the efficacy and safety of nebulized dexmedetomidine, nebulized ketamine, and their combination as a premedication prior to general anesthesia (GA) in pediatric outpatient dental surgeries. The primary end point was the degree of sedation when the child was first seen in the OR 30 minutes after sedation, based on the Modified Observer’s Assessment of Alertness/Sedation Scale. The secondary end points were tolerance of mask induction, hemodynamic changes, analgesia, sedation at emergence, and wake-up behavior.
The present study was conducted at the Alexandria Main University Hospital on 60 patients ASA physical status I and II, aged between 3 and 6 years, scheduled for minor outpatient dental procedures under GA after the approval of the Medical Ethics Committee and after obtaining informed, written parental consent from all parents. Children with a history of chronic illness, prematurity, or developmental delay were excluded from the study. Patients were randomly categorized into 3 equal groups (20 each) using a random numbers table. The study was designed as a randomized, double-blinded study (for both patients and researchers). Group K patients were premedicated with nebulized ketamine solution (2 mg/kg), group D patients were premedicated with nebulized dexmedetomidine solution (2 μg/kg), and group DK patients were premedicated with combined dexmedetomidine/ketamine (1 μg/kg + 1 mg/kg) nebulized solution. Drugs were prepared in 3 mL of saline 0.9% before administration by a standard hospital jet nebulizer via a mouthpiece, with a continuous flow of 100% oxygen at 6 L/min for 10 to 15 minutes (30 minutes before GA). Treatment was stopped when the nebulizer began to sputter. All solutions were prepared in identical syringes with matching random codes by an independent investigator not involved in the observation or the administration of the anesthesia. The observers and attending anesthesiologists were blinded to the drug being administered. All children received EMLA cream (Eutectic Mixture of Local Anesthetics; AstraZeneca, London, UK), unless contraindicated.
Patient acceptance of the medication was evaluated by a blinded observer as excellent (accepted medication without complaint), good (complained, was briefly tearful or unhappy, but then accepted medication), fair (complained, initially uncooperative but eventually accepted medication), or poor (refused medication). Reaction to separation from the parents was assessed 30 minutes after sedation by ease of separation and ease of induction score system (Table 1).10 The degree of sedation was recorded at the baseline before sedation, when the child was first seen in the OR 30 minutes after sedation and at the end after reversal of residual neuromuscular block based on the Modified Observer’s Assessment of Alertness/Sedation Scale (Table 2).11 Routine monitoring was performed. Vital signs (HR, mean arterial blood pressure [MAP], arterial oxygen saturation [SpO2%], and respiratory rate [RR]) were recorded before sedation, before induction of GA (30 minutes after sedation), and continuously monitored intraoperatively and postoperative every 30 minutes until discharge.
On arrival to OR, an intravenous cannula was inserted, and the ease of venipuncture was graded as poor (uncooperative without success), fair (uncooperative with success), good (minor resistance), or excellent (no reaction) by an anesthesiologist blinded to the treatment group. Facemask acceptance was graded as poor (terrified, crying, and combative), fair (moderate fear of mask not calmed with reassurance), good (slight fear of mask, easily reassured), or excellent (unafraid, cooperative, and accepts mask readily).
All patients received the same anesthetic. GA was induced with 100% oxygen, sevoflurane was administered via a facemask, endotracheal intubation was facilitated by IV atracurium 0.5 mg/kg, and IV ketorolac 0.5 mg/kg was given for intraoperative analgesia. Anesthesia was maintained by 2% sevoflurane in oxygen and incremental doses of atracurium. Ventilation was controlled to maintain an end-tidal carbon dioxide partial pressure (PaCO2) of 35 to 40 mm Hg. An intraoperative IV infusion of 2.5% glucose with 70 mM sodium was started at a rate of 5 mL/kg/h. At the end of surgery, residual neuromuscular block was antagonized with IV neostigmine 0.05 mg/kg and atropine 0.02 mg/kg. Duration of anesthesia was recorded in minutes.
Recovery was assessed by an anesthesiologist, blinded to the treatment groups, using the Vancouver sedative recovery scale for children.12 Recovery time from discontinuation of anesthesia until regaining baseline sedation score was recorded in minutes. Discharge time from discontinuation of anesthesia until the patient discharge to home, using the Short-Stay Surgery Discharge Score, was recorded in minutes (A score of 10–12 was needed for discharge).13 Children and Infants Postoperative Pain Scale was scored postoperatively (at recovery, 30 minutes, 1 hour, and 2 hours).14 The maximum score is 10, with scores of 4 or greater indicating the need for analgesia; such children were given a diclofenac sodium suppository in doses of 1 mg/kg. The first dose and the total amount of the analgesic were recorded. Emergence agitation was assessed according to a 3-point scale: 1 = calm; 2 = restless but calms to verbal instructions; and 3 = combative and disoriented. Any postoperative adverse effects (vomiting, bradycardia, and hypotension) were recorded.
The raw data were coded, entered, and analyzed using IBM SPSS Software Package version 21 (IBM SPSS Statistics for Windows, Version 21.0., Released 2012, IBM Corp., Armonk, NY). The 0.05 level was used as the cutoff value for statistical significance, and the following statistical measures were used: descriptive statistics, including counts and percentages, arithmetic mean, standard deviation, and median. Using t distribution and standard error of the mean (SEM), a 95% 2-sided confidence interval around the population mean was done. One sample Kolmogorov-Smirnov test was used for testing the distribution of quantitative variables and, accordingly, parametric or nonparametric statistics were selected. As most of the variables showed to be non-normally distributed, nonparametric statistics was used for the analysis. χ2 test was used to test the association between 2 categorical variables or to detect difference between 2 or more proportions, Monte Carlo exact probability was used in case if invalid χ2 (>20% of the expected cells have count <5). Univariate analyses, including the Mann-Whitney U test and the Kruskal-Wallis H test, which are nonparametric tests, were used for comparing 2 (Mann-Whitney U) or more (Kruskal-Wallis) independent quantitative non-normally distributed variables. Post hoc testing was adjusted using the Bonferroni correction.
Power analysis was omitted because it was no longer accurate after a change in the primary outcome during the course of the study.
All studied groups were comparable as regards demographic data (age, weight, sex, and ASA physical status; Table 3). Ease of separation, ease of venipuncture, and facemask acceptance scores for the 3 treatment groups are summarized in Table 4. Level of sedation at 30 minutes was significantly greater in group DK than either group K (P = 0.003) or group D (P = 0.009). Group DK had the briefest recovery times, followed in order by group K and group D, with progressively longer recovery times. Recovery time was significantly briefer in group DK compared with either group K (P = 0.039) or group D (P < 0.0001). Group DK had briefer discharge times compared with group D (P < 0.0001; Table 5). Postoperative analgesia was significantly better in group DK compared with group K (P = 0.008). As regards the recovery profile, children in all 3 groups recovered spontaneous ventilation and could be tracheally extubated within 5 to 10 minutes.
Basal HR, MAP, RR, and SpO2% were comparable between the 3 groups. After premedication, none of the patients in the study had bradycardia (HR < 20% of baseline), hypotension (MAP < 20% of baseline), or desaturation episodes (SpO2< 95%). HR and MAP values at 30 minutes after administration of premedication were significantly lower in group D compared with baseline values and with both group K and group DK values. Group K and group DK showed no significant differences between baseline HR and MAP values and values at 30 minutes after administration of premedication. There were no significant differences in RR and SpO2% values between the 3 groups at 30 minutes after administration of premedication or during the intraoperative and postoperative periods. No significant differences among the 3 groups were recorded as regards intraoperative HR and MAP.
No patients in groups DK and K developed postoperative hypotension and bradycardia, whereas 2 patients in group D developed significant postoperative hypotension and bradycardia. Postoperative agitation (combative and disoriented) was recorded in 1 patient in group D, in 2 patients in group K, and in 1 patient in group DK. Vomiting was recorded in 2 patients in group D, in 2 patients in group K, and in 1 patient in group DK. The Children and Infants Postoperative Pain Scale score was significantly lower in groups DK and K compared with group D at recovery until 1 hour postoperatively (P = 0.008; Fig. 1). The first dose of diclofenac sodium was given at 30 minutes postoperatively in group D and at 2 hours postoperatively in groups K and DK.
Preinduction sedation and analgesia for children remain an elusive goal. Many sedative analgesics and routes of delivery for facilitation of parental separation have been studied, with varying degrees of patient acceptance, efficacy, and safety. In our study, we compared effects of nebulized dexmedetomidine versus nebulized ketamine and their combination on mask induction and satisfactory sedation upon separation from parents in children undergoing dental surgeries. Nebulized combination of low-dose ketamine and dexmedetomidine produced more satisfactory sedation and provided for a smoother induction of GA, than nebulized ketamine or dexmedetomidine alone, with more rapid recovery and no significant side effects.
Nebulized dexmedetomidine administration may allow rapid drug absorption through nasal, respiratory, and buccal mucosa, which allow bioavailability of 65% through nasal mucosa and 82% through buccal mucosa.15,16 Nebulized drug administration may be preferred over intranasal administration, as the primary disadvantage of the intranasal route is transient nasal irritation, with some patients also experiencing cough, vocal cord irritation, or laryngospasm. Oral administration may be even more difficult in uncooperative children. Converting the drug to an atomized spray results in maximizing surface area coverage with a thin layer of drug, less drug loss to the oropharynx, higher cerebrospinal fluid levels, better patient acceptability, and improved clinical effectiveness.17 Unlike conventional GABAergic sedative drugs, such as midazolam, dexmedetomidine’s site of action in the central nervous system is primarily in the locus coeruleus where it induces electroencephalogram activity similar to natural sleep. Patients are also less likely to become disorientated and uncooperative.18
In a randomized trial, Gyanesh and colleagues19 compared intranasal dexmedetomidine (1 μg/kg), ketamine (5 mg/kg), and placebo (saline) in 150 children between 1 and 10 years undergoing IV placement to facilitate propofol administration for a magnetic resonance imaging. There were no significant differences in the children’s response to administration of the drug. Fewer children in the 2 treatment groups withdrew or fought against IV placement than in the control group (P < 0.01), with dexmedetomidine and ketamine premedication being equally efficacious in this regard. The anesthesiologist was satisfied with the cannulating conditions in 90.4% of the dexmedetomidine patients, 82.7% of the ketamine patients, and 21.7% of the control patients. Jia and colleagues20 studied the premedicant effects of various combinations of intranasal dexmedetomidine combined with oral ketamine in children. The authors concluded that the administration of 2 μg/kg intranasal dexmedetomidine and 3 mg/kg oral ketamine was the optimal combination to facilitate separation from parents and IV placement or facemask acceptance. The combination of dexmedetomidine with ketamine makes pharmacologic sense, as the 2 medications have opposing hemodynamic effects, and the faster onset time of ketamine offsets the slow onset time when dexmedetomidine is used as the sole agent.8,21,22
A major limitation of our study was the use of unvalidated 3- and 4-point scales to assess patient cooperation. However, these scales were consistently applied and include assessments of behavior and procedural conditions familiar to pediatric anesthesiologists.
A nebulized combination of low-dose ketamine and dexmedetomidine produced more satisfactory sedation, and provided more smooth induction of GA, than nebulized ketamine or dexmedetomidine alone, with more rapid recovery and no significant side effects.
Name: Ola M. Zanaty, MD, PhD.
Contribution: This author participated in study design, conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Ola M. Zanaty approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
Name: Shahira El Metainy, PhD.
Contribution: This author participated in study design, conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Shahira El Metainy approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: James A. DiNardo, MD.
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