Supplementary Low-Dose Oral Ketamine Provides Better Parental Separation and Face Mask Acceptance

C l i n M e d International Library Citation: Seify ZAE, Khattab AM (2014) Supplementary Low Dose Oral Ketamine Provides Better Parental Separation and Face Mask Acceptance. Int J Anesthetic Anesthesiol 1:012. doi.org/10.23937/2377-4630/1/3/1012 Received: August 23, 2014: Accepted: Ocober 28, 2014: Published: November 01, 2014 Copyright: © 2014 Seify ZAE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Seify and Khattab, Int J Anesthetic Anesthesiol 2014, 1:012

than the choice of premedication [1].Unfortunately, a small percent of fearful and uncooperative children cannot be managed solely with these techniques [2].Parents' anxiety may be transferred to the child, so any practice that reduces anxiety in parents may also reduce anxiety in children [3].
When behavioral management strategies fail, some form of pharmacologic sedation or anesthesia becomes a valuable and necessary alternative.The role of an anesthesiologist in preparing children for surgery is to minimize potentially adverse psychological and physiological effects of anesthetic techniques.Premedication is best given by an oral rout in children as they often exhibit an exaggerated psychological response to a needle, and it is easier to distribute a medication orally than to use nasal or rectal routes [4,5].Midazolam, with its rapid onset and relatively short duration of action, has proven to be a useful premedication to decrease preoperative anxiety and facilitate separation from parents with fewer unwanted side effects [5].Several studies suggested that different doses of oral ketamine is a better than oral Midazolam 0.5mg/kg in providing sedation and anxiolysis in children with minimal side effects [6,7] children receiving high dose of Ketamine may experience nystagmus or vomiting [8].Therefore, a relatively low dose ketamine was selected in the current study to overcome its side effects if given in high doses.
The primary aim of this study was to investigate the efficacy of adding a low oral dose of ketamine to midazolam premedication in preschool children undergoing elective surgeries on pleasant childparent separation.Secondary aims include its effectiveness on face mask acceptance and parent satisfaction.

Patients and Method
After obtaining approval from the Hospital Ethics Committee and written informed consent from parents, eighty healthy preschool children (ASA 1 & 11), aged between 2-5 years and scheduled for elective pediatric surgeries under general anesthesia were enrolled into the study (Table 1).Different types of surgeries include; ENT surgeries, Circumcision, hernia repair, and dental rehabilitation (Table 1).Sample size calculation based on a previous study of Kain ZN et al. who calculated that the sample size of 30 participants per group provided 80% power to detect a clinically meaningful, medium effect size in child anxiety [9].This sample size calculation was based on anxiety levels of the child as the primary outcome and anxiety levels of the one-parent group from his previous investigations [10].We calculated that 40 patients per group will provide approximately 90% power of analysis.Because of the frequent cancelation and postponing in pediatric patients, we increased the number of enrolled children to hundred patients.
Flow chart of patients through the trial is shown in Figure 1.
Children were randomly allowed to participate in this double blind randomized study.Exclusion criteria included children with neurological problems, inborn errors of metabolism, morbid obese children, and patients with known allergy to any of the medications used.Patients were randomly assigned via computer-generated random numbers to receive either midazolam (Control group «group C ») or ketamine-midazolam (study group «group S ») as an oral premedication.
During the preoperative visit, the anesthetist explained to the child and family what is going to occur in the morning of surgery.The child was blind to the used drug and was asked to choose a sealed envelope with his/her code number inside.The name, file number and body weight were recorded on the sealed envelope after been chosen.The anesthetist who saw the patient preoperatively and anaesthetized him was blind to the premedication.
Parents were not aware of the premedication components, but oriented and agreed with our protocol.In the morning of operation, the study medications were prepared by a trained nurse (who was not involved in any other part of the study) into identical 10ml syringes that were sequentially numbered.Each labeled syringe was mixed with apple juice to be given to the children.Premedication was given by one of the parents under supervision of another nurse.
(Group C) patients received oral midazolam (Dormicum 5mg/ml; F. Hoffmann, La Roche Ltd, Switzerland) in a dose of 0.5mg/kg mixed with apple juice to fill the syringe up to 10ml, and (group S) patients received the same dose of Dormicumin addition to Ketamine (50mg/ ml, Ketalar; Pfizer, La Jolla, California, USA) in a dose of 2mg/kg.All children were monitored by pulse oximetry to detect hypoxia (due to respiratory depression) if any.Child behavior scores [10] (Acceptance of the drug, Parent separation score and mask acceptance score) and sedation score are shown in (Table 2).
The attending ward nurse reported the onset of premedication action (Table 1) and level of sedation (Table 3) and the occurrence of vomiting was also monitored; children who vomited were excluded from the study.30 min after premedication, Parents accompanied their children till the operating room, but their presence in the induction room was not permitted according to the policy of the hospital.
Child reaction to parents separation was rated according to separation score (Table 3).Induction of anesthesia was carried out  ISSN: 2377-4630 DOI: 10.23937/2377-4630/1/3/1012 using Sevoflurane (Abbott, Abbott Park, Illinois, USA) 6vol% in 100% oxygen (6L/min) through a face mask.The anesthetist asked the child to blow the balloon.Acceptance and tolerance of face mask (Cooperation Score at induction) was recorded according to Cooperation Score at induction (Table 3).Peripherali.v.cannulation was allowed 60 seconds from initiation of mask induction.Atropine 0.02mg/kg, Fentanyl 1-2µg/kg and cisatracurium 0.15mg/kg were given.
Three minutes after starting manual ventilation, intubation was carried out with a suitable sized, lubricated airway device according to the type of surgery.Anesthesia was maintained using Sevoflurane 1.5-2 vol% in (35: 65%) oxygen and air ratio.All patients were monitored using routine non invasive monitoring.At the end of surgery, anesthetic agents were discontinued and replaced with O2 100% (6L/min).Residual neuromuscular blockade was reversed by neostigmine and atropine.Children were extubated.
All scores and observations were recorded by the anesthesia technician or nurse who was unaware of the type of premedication.
Before discharge from the hospital the parents were asked to fill a short questionnaire regarding their satisfaction of the premedication of their child on a 3 point scale, and parent satisfaction score was rated (Table 4,5).

Statistical Methodology
Analysis of data was done by IBM computer using SPSS (Statistical Program for Social Science, version 12; SPSS, Chicago, Illinois, USA) as follows: (1) Quantitative variables were described as mean, SD and range.
(2) Qualitative variables were described as number and percentage.
(3) Chi-square test was used to compare qualitative variables between groups.
(4) Fisher exact test was used instead of chi-square when one expected cell or more less than or equal to 5.
(5) Unpaired t-test was used to compare two groups as regards to quantitative variable in parametric data (SD <50% mean).

Results
Eighty patients {40 of them were premedicated using midazolam only «group C» and 40 with midazolam and ketamine «group S», were included in this study.Demographic and operative data are presented in table 1, and showed no evidence of differences between groups.Children of both groups nicely accepted the premedication mixture according to the *Acceptance Score*, as shown in table 3 (P=0.54).No recorded evidence of respiratory depression (no hypoxia) but vomiting was recorded in one patient within group S, and this patient was excluded from the study.The onset of action of premedication was shorter in group S (16.12 ± 2.5 min) than in group C (19.72 ± 3.25 min) (P=0.000)Table 1.Meanwhile, a reliable degree of sedation was noticed in both groups with no reported cases of deep sedation or crying but the results was more satisfactory with group S as 82.5% of children were drowsy with eye opening versus 60% of group C and 15% versus 40% were awake and calm in both groups respectively (P=0.008).Reaction to parent separation was better in group S compared to group C, (P=0.000).Group S children were more cooperative regarding acceptance and tolerance of the face mask than those of group C, showing significant statistical difference (p=0.02), as shown in Table 3. Parent of groups show greater satisfaction with good evidence for difference between both groups (P=0.03),Table 4.

Discussion
In the present study, adding oral ketamine 2mg/kg to Midazolambased premedication 0.5mg/kg facilitates child-parent separation and induction of anesthesia in comparison to Midazolam alone, without affecting drug palatability and provides shorter onset of action [11,12].Degree of Sedation was similar to the results of Ghai B et al. [13] who proved that the combination of 0.25mg/Kg midazolam with 2.5mg/Kg ketamine provided more children in an awake, calm and quiet state who could be separated easily from parents than 0.5mg/ Kg oral midazolam alone, they found that both Midazolam and a combination provided equally effective anxiolysis and separation characteristics but the combination doses in the current study gave better results.Warner DL et al. and Funk et al. found that the mixture of ketamine 4mg/Kg and midazolam 0.4mg/kg & Ketamine 3mg/Kg and Midazolam 0.5mg/kg respectively proved to be more effective premedication than either drug alone [14,15].These findings suggested the same results of the current study with different doses as we used a smaller dose of ketamine to overcome any of its adverse effects.However they did not investigate the effect of premedication on parents' satisfaction as proved by the current study.Ketamine Dormicum combination offers the advantage of decreasing the psychological side effects of ketamine by Midazolam sedation.Also, any respiratory and cardiovascular depression of midazolam [16] is counteracted by the ketamine.
In contrast to Lin et al. who reported no difference in behavior at separation or induction after administration of midazolam (0.75mg/ kg) or ketamine (6mg/kg) or a combination of ketamine (3mg/ kg) with midazolam (0.5mg/kg) [17].Their success rate using the combination was 80% at separation and 70% at induction.However, they found few advantages in the combination group, i.e. faster onset time (versus both group), fewer secretions and nystagmus (versus ketamine) and faster recovery (versus midazolam).Non-drug methods offer alternatives, but a new review of studies finds that no single method shows a clear advantage in keeping the child calm and cooperative [18].
The ideal premedication in children should be readily accepted by children, with rapid and reliable onset, provide anxiolysis with sedative effect, and have minimal side effects with, rapid elimination to facilitate rapid recovery for early discharge.Earlier studies have indicated that both oral Midazolam and oral Ketamine fulfill many of these characteristics, and both may be useful premedicants in pediatric anesthesia [6].
An effective premedication may facilitate a smoother induction of GA (general anesthesia) with minimal hemodynamic alterations and minimize the emotional trauma in children undergoing surgery.Premedication is best given by an oral route in children as children often exhibit an exaggerated psychological response to a needle, and it is easier to distribute a medication orally than to use nasal or rectal routes [19,20].
We conclude that adding low dose oral ketamine to midazolambased premedication provided better pre-induction situation and pleasant child-parent separation with higher parent satisfaction.

Figure 1 :
Figure 1: Flow chart of patients through the trial.
D)Level of sedation on five point scale.

Table 3 :
Comparison between both groups as regard child behavior and sedation after premedication.

Table 5 :
Comparison between both groups as regard parents satisfaction.

Table 4 :
Parents satisfaction score.Excellent (Accept to give the same premedication to his child if he requires anesthesia next time)