Oral Preanesthetic Medication In Children: A Comparison of Midazolam Syrup Versus Midazolam Syrup Plus Fentanyl Lozenge

Premedication should provide effective anxiolysis and conscious sedation to improve the conditions for parental separation and induction of general anesthesia. Among different premedicants used for children by the oral route, we used in this study midazolam and fentanyl aiming to determine the value of adding fentanyl lozenge (brand name Actiq®, Cephalon, UT) to midazolam syrup for preoperative sedation of children undergoing superficial inguinal surgery. 40 children aged 3-8 years; classified as ASA physical status I or II, were divided into 2 groups (20 children in each). Children in both groups were premedicated with oral midazolam syrup (0.5 mg.kg) 30 min before start of surgery. However, oral transmucosal fentanyl (brand name Actiq®, Cephalon, UT) was also given to those in group II at the same time. Although the Activity Scale showed no significant difference between the two groups as regards the sedation level at each interval time, the Children’s Hospital of Eastern Ontario Pain Score (CHEOPS) showed a significant difference between the two groups as regards child’s sedation level and analgesia which were more in group II at two interval times: at introduction of IV cannula and at introduction of anesthesia mask. We found a higher incidence of O2 desaturation, vomiting and pruritis with the use of Oral Transmucosal Fentanyl Citrate (OTFC). We recommend the use of OTFC (10 μg.kg) with oral midazolam (0.5 mg.kg) for pediatric sedation, but with caution to deal with any of the reported complications. INTRODUCTION The preanesthetic management of children can be a challenge for the anesthesiologist. Premedication should provide effective anxiolysis and conscious sedation to improve the conditions for parental separation and induction of general anesthesia. Midazolam, fentanyl, ketamine and clonidine have been used as premedicants for children by different routes. Oral applications of these premedicants are widely used in this age group. Key features of good premedication are easy application, short onset, rapid duration of action and lack of significant side effects. The reported efficacy of oral midazolam for preoperative sedation is 60% to 76 %. Oral transmucosal fentanyl citrate (OTFC) has also been used successfully for preoperative sedation in the operating room (OR). Although its efficacy as a sedative lies between 69% and 75%, the use of OTFC has been accompanied by an unacceptable level of complications. As many as 45% of children sedated with OTFC in the OR suffer vomiting, and up to 65% suffer facial pruritis. The efficacy of using oral midazolam and OTFC together for preoperative sedation has not been studied. We hypothesized that a combination of oral midazolam and OTFC would provide superior sedation to either drug alone. Furthermore, given the relationship between dose and the development of side effects related to OTFC, we hypothesized that using a lower dose of OTFC than that used in other studies would lead to a decrease in side effects related to this medication. Identification of a sedation regimen with improved efficacy and an acceptable safety profile could positively impact the patient and anesthetist experience for preoperative sedation in children undergoing superficial inguinal surgery . AIM OF THE STUDY Determination of the safety and efficacy of a combination of oral midazolam plus OTFC in comparison to oral midazolam alone for reducing anxiety in children undergoing superficial inguinal surgery. Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 14 PATIENTS AND METHODS After approval from the local ethical committee, forty children aged 3-8 years; classified as ASA physical status I or II, undergoing elective surgery in the inguinal region participated in this study. Children with a history of chronic illness, prematurity, or developmental delay were excluded from the study. All parents signed a written informed consent. Children were randomly classified into 2 groups (20 children in each): Group Ι Children in this group were premedicated with oral midazolam syrup (0.5 mg.kg) alone 30 min before start of surgery. Group II Children in this group were premedicated with oral midazolam syrup (0.5 mg.kg) plus OTFC (almost equal to 10 μg.kg) lozenge (Actiq, Cephalon, UT) 30 min before start of surgery. A standardized anesthetic technique was applied using Atropine (0.02 mg.kg-1) as a premedicant followed by Propofol (2 mg.kg-1) as an IV induction agent. A laryngeal mask airway was then inserted allowing for spontaneous breathing of Halothane (2 % in O2) as a maintenance inhalational agent. Some hemodynamic (heart rate and mean arterial blood pressure) as well as respiratory measures (respiratory rate and oxygen saturation) were recorded every 10 minutes starting from drug administration. Serum cortisol level was done as follows: a 2-ml sample of blood was withdrawn from each subject twice: in the early morning, on the day of surgery; and just after induction of anesthesia. After obtaining the subjects' blood each sample was transferred immediately into a precooled tube containing heparin. Plasma cortisol concentration was determined in duplicate using radio-immunoassay kits from Diagnostic System Laboratories (Webster, TX)(18). Behavioral assessment of children perioperatively were done using two scales: Activity Scale (measuring child’s sedation level) and Children’s Hospital of Eastern Ontario Pain Score (CHEOPS Scale; measuring child’s behavior related to pain and anxiety) at four interval times: baseline (in preoperative holding area), at separation to the OR, at introduction of IV cannula, and at introduction of anesthesia mask. RESULTS There was no difference in age, weight, or sex as well as duration of surgery between the two groups (P >0.05; Table I). Also hemodynamic data (heart rate and mean arterial blood pressure; Figures 1 & 2) showed no significant difference between the two groups at different interval times mentioned before (P >0.05). In both groups, the serum cortisol level decreased significantly after induction of anesthesia compared to the preoperative value with no significant difference between the two groups (P >0.05; Figure 3) As regards the respiratory data, although no significant difference between both groups was noted in the respiratory rate, lower respiratory rate was evident in group II patients (Figure 4). On the other hand, 3 cases in group II showed significant desaturation (SpO2 < 90%) compared to only 1 case in group I. (Figures 5 & 6). As regards the Activity Scale, gradual decrease in sedation level was noted at different interval times and statistically significant from baseline reading in both groups (F< 0.05). However, there is no significant difference between the two groups as regards the sedation level at each interval time (P >0.05; Figure 7; Table II). The CHEOPS Scale showed gradual increase in child’s behavior to anxiety and pain from preoperative holding area (baseline) to introduction of IV cannula followed by a decrease at time of introduction of anesthesia mask. These changes are statistically significant in group I only (F< 0.05), but not the case in group II (F> 0.05). However, there is a significant difference between the two groups as regards child’s sedation level and analgesia which are more in group II at two interval times: at introduction of IV cannula and at introduction of anesthesia mask (P <0.05;Figure 8; Table II). More incidence of complications i.e. oxygen desaturation (15%), vomiting (20%) and pruritis (20%) was found among patients of group II (P <0.05; Figure 6). Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 15 Table I: Comparison between demographic data of the two studied groups. Group I "n=30" Group II "n=30" P Age (years) Range Mean S.D. 3-8 4.25 2.65 3-8 4.65 2.68 0.25 Weight (kg) Range Mean S.D. 9-16 10.25 3.25 9-17 10.31 3.52 0.36 Sex Male Female 17 (56.7%) 13 (43.3%) 18 (60.0%) 12 (40.0%) 0.21 Duration of surgery (min) Mean S.D. 35.86 6.011 32.5 6.98 0.0986 Table II: Comparison between the two studied groups regarding Activity and CHEOPS Scales at different interval times. Baseline At separation to OR At introduction of IV cannula At introduction of anesthesia mask F Activity Scale Group I Mean S.D. 4.3 1.03 5.65 1.13 7.25 1.23 9.25 2.3 6.35 0.021* Group II Mean S.D. 4.25 0.98 4.95 1.089 6.98 1.65 8.65 2.01 5.25 0.036* P >0.05 >0.05 >0.05 >0.05 CHEOPS Scale Group I Mean S.D. 7.35 2.0 8.25 2.06 12.36 2.33 9.65 1.25 15.2 0.021* Group II Mean S.D. 6.25 1.36 7.03 2.22 8.65 1.98 7.42 1.65 2.36 0.11 P 0.09 0.12 0.001* 0.021* DISCUSSION Fentanyl incorporated into a candy matrix and formulated in a lollipop for oral transmucosal absorption is a novel method of administering premedication in children. OTFC has been used in adults and children as a preanesthetic medication, for postoperative pain, and for cancer pain. More recently it has been used in children for sedation and analgesia during painful procedures. (11-13) Although initial studies suggested OTFC might be a good way of delivering premedication to children, ideal dose ranges were unknown and clinical experience in the pediatric sedation did not exist (10) . The present study depicted no statistical difference between the two studied groups as regards the sedation level, measured by the Activity Scale. However, the CHEOPS Scale showed that fentanyl-midazolam combination (group II) provided more analgesia for children at two interval times: at introduction of IV cannula and at introduction of anesthesia mask. Also, fentanyl-midazolam combination (group II) Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 16 Fig 1. Comparison between the two studied groups regarding heart rate at 10-min time interval. Fig 2. Comparison between the two studied groups regarding mean arterial blood pressure at 10-min time interval. Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 17 Ta = in the early morning, on the day of surgery. Tb = just after induction of anesthesia. Fig 3. Comparison between the two studied groups regarding serum cortisol level in μg/ dl. Fig 4. Comparison between the two studied groups regarding respiratory rate at 10-min time interval. Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 18 Fig 5. Comparison between the two studied groups regarding oxygen saturation at 10-min time interval. O2 desaturation Vomiting Pruritis 0 1 2 3 4 5 M ea n Group I Group II Fig. (6): Comparison between the two studied groups regarding complications. Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 19 Fig 7. Comparison between the two studied groups regarding activity scale at different interval times. Fig 8. Comparison between the two studied groups regarding CHEOPS scale at different interval times. Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 2006 20 provided analgesia and sedation which remained potent and more or less the same all over the four recorded interval times. We used OTFC in a dose of 10 μg.kg. In agreement, Klein et al. (14) found no difference in sedation between children receiving a combination of oral midazolam (0.5 mg.kg) and OTFC (10 μg.kg) and those receiving oral midazolam alone used for sedation during laceration repair. Also, Schechter et al. found a significant analgesic effect of OTFC, during lumbar puncture and bone marrow aspiration. On the other hand, Ashburn et al. reported that OTFC (10 μg.kg) provided both sedative and analgesic effects in children undergoing short operations, in the hospital day-stay unit. Our findings can be explained by the fact that plasma fentanyl concentrations rise slowly after OTFC, compared to intravenous administration, they peak after 20 to 30 minutes of administration of OTFC, and only reach 2.5 ng.ml, producing a significant analgesic effect. Neither heart rate nor blood pressure changes were found either throughout the preoperative holding area or intraoperatively. As regards oxygen saturation and respiratory rate values, only 1 patient in group I was desaturated (SpO2 < 90%) in the preoperative period, in comparison to 3 patients in group II. The difference was statistically significant. No significant difference in respiratory rates was found between the two groups, in spite of the lower values in group II. Similarly, Stanley et al. found no hemodynamic changes with a high incidence of oxygen desaturation, when they studied the effects of OTFC on human volunteers, in a similar dose. In contrast, Streisand et al., after comparing the effects of OTFC in four different doses, reported a significant decrease in respiratory rate, with no effect on oxygen saturation or hemodynamics, on using a dose of 10 μg.kg of OTFC. In our study, desaturation was never a real problem. It always ended by asking the patient to take a deep breath, and it was always transient. In this study, in addition to validated behavioral measures (pain, anxiety and sedation), the serum cortisol level (a physiologic measure) measured in the morning of surgery and immediately after induction of anesthesia showed a strong correlation to the behavioral parameters in both groups i.e. increased anxiety was associated with increased serum cortisol level, with no significant difference between the two groups. In conform to our results; many studies have demonstrated the increased serum cortisol with the preoperative anxiety . We found a higher incidence of complications i.e. vomiting, pruritis and oxygen desaturation with the use of OTFC in a dose of 10 μg.kg. In agreement, Schutzman et al. reported that the high incidence of complications may limit the utility of OTFC in outpatient settings. Also, Friesen et al. reported that OTFC usage in children is associated with a frequent incidence of postoperative nausea and vomiting which is not easily antagonized by prophylactic droperidol. Moreover, Streisand et al. (10) reported a very high incidence (up to 100%) of preoperative facial pruritis after OTFC in children, which was dose-independent. On the other hand, Nelson et al. confirmed that clinically significantrespiratory depression or desaturation israre after OTFC given in doses of 20 μg.kg1 or lower.Our study reported a 20% incidence ofpruritis and vomiting; and a 15% ofdesaturation, when OTFC was used incombination with oral midazolam forpediatric sedation.In conclusion, in spite of thecomplications of OTFC, it adds a goodanalgesic effect to the sedation provided byoral midazolam alone. We recommend theuse of OTFC (10μg.kg) with oralmidazolam (0.5mg.kg) for pediatricsedation but with caution to deal with any ofthe reported complications. REFERENCES1. Weber F, Wulf H, el Saeidi G.Premedication with nasal s-ketamineand midazolam provides goodconditions for induction of anesthesia inpreschool children. Can J Anesth 2003;50: 470–5. Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (9) No. 2 June 200621 2. 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