|Year : 2016 | Volume
| Issue : 4 | Page : 478-484
Addition of dexamethasone–chlorpheniramine mixture reduces the incidence of vomiting associated with oral ketamine premedication after pediatric dental procedures
Ayman A Abdellatif1, Manal M Kamal2, Rania A.H. Ishak3
1 Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Anesthesia and Intensive Care Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3 Department of Pharmaceutics and Faculty of Medicine Industrial Pharmacy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||21-Jan-2016|
|Date of Acceptance||25-Apr-2016|
|Date of Web Publication||12-Jan-2017|
Ayman A Abdellatif
9, Postal code 23341 Dr Mohammad Kamel Hussein St., Heliopolis, Cairo
Source of Support: None, Conflict of Interest: None
Oral ketamine has been shown to induce safe and effective sedation in children, but with a high incidence of postoperative vomiting. Vendexine (dexamethasone–chlorpheniramine mixture) is a commercially available syrup used primarily to treat allergic conditions. Each of its components has antiemetic effects. In the present study, we aimed to determine whether the addition of vendexine to oral ketamine premedication affects the incidence of postoperative vomiting.
Patients and methods
Sixty-four children scheduled for elective dental procedures under general anesthesia were enrolled in this prospective, randomized, double-blind study. They received an oral premedication mixture (total volume of 0.42 ml/kg) of either ketamine 6 mg/kg (0.12 ml/kg) mixed with dextrose 50% and apple juice (the K group), or ketamine 6 mg/kg (0.12 ml/kg) mixed with dextrose 50% and vendexine syrup (0.25 ml/kg) (the VK group). Sedation onset was noted. Scores for drug acceptance, sedation, emotional status, and behavior during parents’ separation, on venipuncture, and face mask application were rated. Incidence of postoperative vomiting, emergence agitation score, fentanyl consumption, and recovery time were also recorded.
The two groups were comparable as regards sedation onset, scores for drug acceptance, sedation, emotional status, and behavior during parents’ separation, on venipuncture, and face mask application. However, a significant reduction of postoperative vomiting in the VK group was noticed compared with the K group (9.3 vs. 37.5%). In addition, emergence agitation and fentanyl consumption were significantly reduced in the VK group.
Vendexine added to oral ketamine reduces the incidence of postoperative vomiting associated with ketamine premedication in children.
Keywords: chlorpheniramine, dental, oral ketamine, oral pediatric premedication, vomiting
|How to cite this article:|
Abdellatif AA, Kamal MM, Ishak RA. Addition of dexamethasone–chlorpheniramine mixture reduces the incidence of vomiting associated with oral ketamine premedication after pediatric dental procedures. Ain-Shams J Anaesthesiol 2016;9:478-84
|How to cite this URL:|
Abdellatif AA, Kamal MM, Ishak RA. Addition of dexamethasone–chlorpheniramine mixture reduces the incidence of vomiting associated with oral ketamine premedication after pediatric dental procedures. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2018 Jul 17];9:478-84. Available from: http://www.asja.eg.net/text.asp?2016/9/4/478/198269
| Introduction|| |
Smooth premedication and calm induction of anesthesia in young children is a challenging task in anesthesia practice. Children usually have fear of hospitals, physicians, and nurses . Despite some children behaving cooperatively, most of them are very resistant to forceful intravenous or intramuscular injections and aggressive face mask application even in the presence of their parents. Parents have found that these compelling management techniques are no longer acceptable . This forced anesthesia induction or forced separation from parents during anesthesia induction can result in traumatic experience for the children, which might result in postoperative nightmares and behavior disorders ,,.
A safe and effective oral premedication is considered the best acceptable method for those children ,.
In many reports, ketamine (a phencyclidine derivative) has been shown to be an effective and safe oral premedication agent ,,,,. It leads to a state of dissociative anesthesia, in which the child appears to be awake but is not due to the intense analgesia and amnesia provided by the anesthetic used ,. Orally administered ketamine has many advantages: it is an acceptable route for anesthesia induction in children, has a relatively fast onset (20–30 min) ,, maintains an intact protective airway reflexes, and has a safe cardiorespiratory profile .
Postoperative vomiting is considered one of the most consistent side effects of oral ketamine, with an incidence range between 5 and 50% ,,. Its incidence has been shown to reach 60% in a study by Sullivan et al.  when 10 mg/kg ketamine was used; they reported vomiting to be a regrettable side effect of oral ketamine administration. Other adverse effects include bitter taste, salivation with the possibility of laryngospasm, nausea, and emergence agitation ,.
Vendexine syrup (Eva Pharma, Cairo, Egypt) (http://www.evapharma.com/products/Vendexine-Syrup/), a commercially available yellow mixture with an acceptable taste, contains dexamethasone and chlorpheniramine. Although its primary indication is the treatment of allergic conditions like urticaria, croup, and bronchial asthma, each component of the syrup has an antiemetic effect.
Dexamethasone, a synthetic long-acting glucocorticoid, has been shown to be a clinically effective antiemetic agent for postoperative , chemotherapy-related , and radiation-related vomiting .
Chlorpheniramine is a first-generation potent antihistaminic with antiemetic, anticholinergic, and sedating properties ,.
This study was designed to evaluate the effect of adding vendexine to orally administered ketamine as a sedative pediatric premedication on the incidence of postoperative vomiting. We assumed that vendexine added to oral ketamine may reduce ketamine postoperative vomiting (primary outcome), improve oral acceptance of ketamine, reduce incidence of salivation and laryngospasms, as well as improve the quality of sedation and recovery (secondary outcomes).
As no previous clinical studies were available on mixing chlorpheniramine and dexamethasone [vendexine (Eva Pharma)] with ketamine [(Ketamax-50; Troikaa Pharmaceuticals Ltd, Gujarat, India)] for Gujarat oral administration, we first conducted a pharmaceutical study to ensure safety of the mixture and deny any possible pharmaceutical interactions if any (study 1). Then we evaluated the effect of this mixture on the reduction of ketamine-related adverse effects (study 2).
| Study 1; pharmaceutical study|| |
Preparation of ketamine HCl–vendexine mixture
A ketamax-50 vial contains ketamine HCl (50 mg/ml), while vendexine solution contains dexamethasone 0.1 mg and chlorpheniramine 0.4 mg/ml.
As the dose for oral pediatric premedication that was going to be tested was 6 mg/kg for ketamine HCl , 0.025 mg/kg for dexamethasone, and 0.1 mg/kg for chlorpheniramine (http://www.drugs.com/dosage/dexamethasone.html)  (as recommended by authors 1 and 2), a volume of 0.12 ml/kg ketamine and 0.25 ml/kg vendexine was mixed (0.37 ml/kg mixture volume).
Thus, for an expected average child body weight of 20 kg, the volume to be swallowed would be 2.4 ml of ketamine HCl mixed with 5 ml vendexine solution (7.4 ml mixture volume).
Palatability test of the prepared mixture
The mixture was tested for palatability without any additives and by adding different volumes (0.5 and 1 ml) of dextrose solutions prepared at different concentrations [25 and 50% (w/v)], aiming to increase the mixture palatability.
High-performance liquid chromatography determination of ketamine HCl
Two milliliters of ketamine HCl solution was mixed and adjusted to 10 ml by adding deionized water. The prepared solution was analyzed instrumentally using high-performance liquid chromatography. The chromatographic system consisted of Agilent Technologies’ (Santa Clara, USA) 1200 series LC − G 1311A solvent delivery pump equipped with a 20-µl loop and rheodyne sample injector and a G1315D diode array detector. The column used was Agilent TC-C18 analytical column (5 µm particle size; 250×4.6 mm ID). The mobile phase consisted of a methanol–acetonitrile–phosphate buffer adjusted at pH 4.0 (15 : 20 : 65, v/v/v) and used at a flow rate of 1 ml/m . The eluate was monitored at 254 nm. The sensitivity was set at 0.001 Absorbance unit full scale (AUFS). The data were recorded and calculated using the ChemStation B.04.01 software.
In-vitro interaction study by high-performance liquid chromatography
An in-vitro interaction study was carried out by preparing the ketamine HCl–vendexine mixture in a well-closed glass vial (as described above in the preparation section). The vial was placed in a shaking water bath maintained at constant temperature (37°C) and stirring rate (50 rpm) for 24, 48, and 72 h. At different time intervals, aliquots were withdrawn and filtered through a millipore filter (0.45 µm) and analyzed through high-performance liquid chromatography, by using the proposed method described above. Peak areas of the mixture were recorded and compared with the individual ketamine solution kept under the same condition, from which the degrees of interactions were evaluated .
% recovered after interaction with each other=peak area of ketamine HCl–Vendexine mixture/peak area of ketamine HCl solution×100.
Palatability of ketamine HCl–vendexine mixture
The palatability of the mixture was significantly improved with the highest volume and concentration of dextrose solution − that is, 1 ml of 50% (w/v) dextrose added on to the mixture of 7.4 ml (8.4 ml total volume for a 20 kg child).
In-vitro interaction study by high-performance liquid chromatography
The availability of ketamine HCl in presence of vendexine solution was 105.16±3.2, 102.67±1.3, and 103.21±2.1% for 24, 48, and 72 h incubation periods, respectively. Hence, it could be confirmed that there was no significant interaction between ketamine HCl and vendexine solution.
| Study 2; clinical trial|| |
The study protocol was approved by the local research ethics committee of Ain Shams University Hospitals. After obtaining a written informed consent from parents, 64 children scheduled for elective dental restoration with or without teeth extraction were enrolled in this prospective, randomized, double-blind study. Children included belonged to ASA (American Society of Anesthesiologists) physical status I or II, were between 2 and 6 years of age, between 10 and 25 kg in weight, and with an expected surgery duration time of 1–2 h.
A child was excluded if he or she was hypersensitive to any of the drugs used in the study, had congenital heart disease, mental retardation, developmental problems, autism, organ dysfunction, history of epilepsy or active upper respiratory tract infection, or previous dental or operative experience. All children had their preanesthetic evaluation done at least 1 week before the date of operation. Laboratory investigations requested included complete blood picture, bleeding time, and clotting time. A fasting of 6 h for food and 2 h for clear fluids was ordered.
On the day of operation, the child was first re-evaluated for anesthesia readiness and then moved to the holding area of the surgical unit with his parents. A well-trained anesthesia nurse prepared the premedication mixtures according to a previously prepared computer-generated random numbers. Each child was given a toy appropriate to his/her sex as an incentive to swallow the medication. Each child had equal chance to be in one of the two groups (K and VK).
According to the child’s weight, in group VK we gave 0.25 ml/kg vendexine and 0.12 ml/kg ketamine (6 mg/kg) plus 0.05 ml/kg dextrose 50% (0.42 ml/kg total volume). In group K we gave 0.12 ml/kg ketamine plus 0.05 ml/kg dextrose 50% mixed with 0.25 ml/kg apple juice (to match the yellow color of vendexine) (0.42 ml/kg total volume).
A blinded anesthesia resident, not aware of the child’s group assignment, used a modified pediatric premedication scoring system adopted from previous studies ,, ([Table 1]).
|Table 1: Scoring system for drug acceptance, sedation, emotional status, and behavior during parent separation, on venipuncture, and face mask application|
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He first evaluated drug acceptance and then assessed sedation and emotional status scores every 5 min. When adequate sedation started (score≥3), the child was separated from his/her parents. Time-to-reach adequate sedation and the behavior score during separation were recorded. Any postpremedication adverse effects like salivation, vomiting, or laryngospasm were also noted.
If any child did not completely swallow the premedication, he was excluded and his randomization code was then assigned to the following enrolled case in the study.
After start of sedation, child was moved on a stretcher to the operating room and transferred to the operating room table; monitors were applied (pulse oximetry, ECG, noninvasive blood pressure), while an intravenous line was inserted (22–24 G). Face mask with sevoflurane in 100% O2 was applied to deepen the anesthesia, after which 0.5 mg/kg atracurium was given intravenously. The behavior during intravenous cannula insertion and face mask application was recorded. After 2.5 min of bag mask ventilation, a nasal endotracheal intubation using an appropriate size of RAE nasal tube was performed. Proper tube placement was confirmed by positive capnogram and bilateral chest auscultation. After securing the tube, a small throat pack was inserted. Anesthesia was maintained with sevoflurane 1.5–3% in O2 and atracurium. Minute ventilation was adjusted to maintain end tidal-CO2 between 35 and 40 mmHg. No antiemetics or narcotics were used. As per the surgeon protocol, all children were given local blocks. Intravenous Ringer’s solution was infused at a rate of 6 ml/kg/h. After completion of the dental procedure, sevoflurane was discontinued, and paracetamol suppository 20 mg/kg was inserted. The oropharynx was examined and suctioned under vision; the pack was removed, and neostigmine and atropine were given for reversing the effect of the muscle relaxant. Extubation was performed when the child opens his or her eyes on verbal command. Time from discontinuation of sevoflurane till extubation was recorded as the recovery time. The child was then moved to the postanesthesia care unit (PACU), which the parents were allowed into. Parameters measured in the PACU were as follows:
- Quality of recovery, which was evaluated by using the five-point emergence agitation score  ([Table 2]).
- PACU time, which was measured till a modified Alderete score of at least 9 was recorded.
- Incidence of postoperative vomiting.
- Parents’ satisfaction, which was graded as bad=1, fair=2, good=3, and excellent=4.
A child was considered agitated if he scored more than or equal to 4 despite efforts by parents to calm the child. For those, a 0.5 μg/kg fentanyl intravenously was given, to be repeated after 10 min while they were monitored for any signs of hypoventilation.
For postoperative vomiting, 0.1 mg/kg intravenous metoclopramide was given.
All recordings were completed by the same blinded anesthesia resident to minimize interobserver variability.
On the basis of the data from Alfonzo-Echeverri et al. , the incidence of vomiting after oral ketamine premedication was found to be 40%. Thus, it was calculated that a sample size of 32 per group achieves 80% power to detect a difference of 30% reduction in the incidence of vomiting, with significance level of 0.05.
Statistical analysis was performed using SPSS (version 17). Quantitative parametric variables were analyzed using the unpaired Student t-test and expressed as mean±SD. Nonparametric data were analyzed using the Mann–Whitney test and expressed as median and interquartile range, whereas qualitative variables were analyzed using the χ2-test and expressed as numbers and percentages (%).
| Results|| |
The two groups were matched as regards age, sex, weight, ASA physical status distribution, as well as number of procedures with extractions, duration of anesthesia, time for adequate sedation, recovery time, and PACU time ([Table 3]).
Both premedication regimens resulted in similar scores as regards child’s drug acceptance, sedation, emotional status, and behavior during parental separation, on venipuncture, and face mask application ([Table 4]).
|Table 4: Scores for drug acceptance, sedation, emotional status, and behavior during parents’ separation, on venipuncture, and face mask application|
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In the postpremedication period and before induction of anesthesia, salivation occurred in four children in the K group and three children in the VK group (P > 0.05), with no recorded cases of laryngospasm or vomiting in the two groups.
Postoperative data showed significant reduction in the rate of postoperative vomiting in the VK group [three cases (9.3%)] when compared with the K group [12 cases (37.5%)] (P < 0.05). In addition, emergence agitation was significantly less in the VK group [score: 2 (2–3)] when compared with the K group [score: 3 (2.25–4)], (P < 0.05) ([Table 5]).
|Table 5: Emergence agitation, postoperative vomiting, parents’ satisfaction, and postanesthesia care unit fentanyl consumption|
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Median dose of fentanyl consumption was less in the VK group [0 (0–1)] compared with the K group [3 (3–6.25)] (P < 0.05). In addition, the number of children that needed fentanyl was lower in the VK group (two cases) compared with the K group (10 cases) (P < 0.05). Parents’ satisfaction was found to be similar in the two groups ([Table 5]).
| Discussion|| |
Oral ketamine sedation has been used to premedicate children safely and effectively, but postoperative vomiting remains a prominent side effect associated with its use .
The current study showed that the addition of vendexine (dexamethasone–chlorpheniramine mixture) reduced the incidence of postoperative vomiting associated with oral ketamine premedication in children undergoing dental procedures under general anesthesia from 37.5 to 9.3%.
In pediatric oral ketamine sedation, the reported ketamine doses ranged from 3 to 10 mg/kg with a dose-dependent increase in the success of sedation, as well as an increase in the rate of side effects, especially vomiting ,,,.
Gutstein et al.  compared oral ketamine 3 and 6 mg/kg for pediatric premedication. While 3 mg/kg was associated with unsatisfactory sedation scores, the 6 mg/kg dose provided predictable uniform sedation, allowed calm parental separation, and resulted in good conditions for anesthesia induction.
The 6 mg/kg dose of oral ketamine is a commonly used one, and in many studies has been found to achieve satisfactory sedation ,,. That is why we chose the 6 mg/kg dose in our study. High frequency of postoperative vomiting occurred with the use of the 6 mg/kg oral dose, with reported incidence ranging between 20 and 40% ,,. In the present study, we found comparable results for the quality of sedation and the incidence of postoperative vomiting (37.5%).
The use of first-generation antihistaminics as an adjuvant to ketamine may be beneficial to enhance the sedation properties on the one hand and to counter the common adverse effects of ketamine, like salivation and postoperative vomiting, on the other hand.
The addition of chlorpheniramine to oral ketamine had not been tried in human studies. However, Issabeagloo and colleagues examined its effectiveness in an animal study involving cats. They reported that the addition of chlorpheniramine to oral ketamine (both by sublingual route) accelerated the onset and improved the quality of sedation compared with ketamine alone. However, they did not comment on the incidence of salivation or vomiting .
Similarly, in our study we expected chlorpheniramine to fasten the onset and improve the quality of ketamine sedation and decrease the incidence of salivation, which did not happen. This may be due to the sublingual route of administration used in cats, which might have led to the faster drug absorption. This may make us consider using another earlier dose of vendexine in future trials.
Another antihistaminic, promethazine, was added by Bui and colleagues to oral ketamine (10 mg/kg) for pediatric dental sedation. Although promethazine did not improve the onset or the quality of ketamine sedation, it reduced the incidence of vomiting from 27 to 0% . However, promethazine is not recommended for day-case pediatric premedication because of its long elimination half-life (8–12 h), and because of its reported dystonic adverse effects .
Dexamethasone has been used to decrease postoperative vomiting . Its oral administration via vendexine could have enhanced the antiemetic effect observed in the VK group. Furthermore, in our hospital, dexamethasone is routinely requested by the dental surgeons as intravenous prophylaxis to decrease postoperative facial edema. In the current study, we did not use any intravenous dexamethasone, and neither we nor the dental surgeon observed any increase in facial edema.
Quality of recovery was better in the VK group, evidenced by lower emergence agitation scores and less need for fentanyl administration. This may be attributed to the sedating effect of chlorpheniramine present in vendexine, which started to show its effect late during child recovery.
We chose to study children scheduled for dental procedures as it is easy to recruit a healthy and homogenous group of children to be included in such a comparative study. It is feasible to use a standardized anesthetic technique in such procedures; moreover, use of intraoperative opioids could be avoided as local anesthetic blocks are used as routine practice to minimize the effect of variables during postoperative assessment. On the other hand, we excluded any child with a history of any previous dental or operative experience, which could be unpleasant enough to affect the child’s behavior during the premedication procedure.
No placebo control group was used, as the effectiveness of oral ketamine sedation has been already established over placebo in many previous reports ,,,.
In the K group, we chose to use apple juice to match the yellow color of vendexine to keep a blinded study.
A previous study by Feld et al.  suggested that small volumes of oral fluids (5–10 ml) before induction of general anesthesia in pediatrics did not increase the risk for aspiration of gastric contents. In their study, Turhanoglu et al.  used a volume of 0.4 ml/kg (with a 10 ml maximum limit) to compare different doses of ketamine oral premedication in children: they did not report any case of aspiration. Although in the present study we slightly exceeded the volume by 0.02 ml/kg, no case of aspiration was reported.
| Conclusion|| |
Vendexine (dexamethasone–chlorpheniramine mixture) addition to oral ketamine premedication reduces the incidence of postoperative vomiting in children. It also decreases the emergence agitation during their recovery.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]