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Introduction: Emergence from general anaesthesia can be complicated by the presence of agitation in children and thus presents a challenging situation for postanesthesia care providers. Several factors are associated with emergence agitation (EA). These include pain, preoperative anxiety, young age, poor adaptability, short time to recovery, among others. Objective: This study aimed to determine the effect of oral midazolam in preventing postoperative EA in children. Materials and Methods: This was a case–control study carried out among 80 healthy children aged 1–10 years scheduled for day-case surgery. The children were randomly assigned to receive either a syrup of paracetamol 10 mg/kg with injectable midazolam 0.5 mg/kg added to the syrup (Group A) or a placebo in the form of paracetamol syrup (Group B) at a dose of 10 mg/kg 30 min before induction of anesthesia. Patients' state of agitation was assessed every 5 min for the 1st h by means of an EA scale. Children with an agitation score of 3 or 4 were classified as agitated. Prolonged agitation was defined as a score of ≥3 lasting 15 min after arrival in the recovery room. Data were analyzed using the Statistical Software for Social Sciences version 20. Results: Eighty children aged 1–10 years were enrolled in the study. Majority of the procedures were circumcisions (48.75%), while urethral dilatation, examination under anesthesia, and tongue release were the least (1.25%). There was no statistically significant difference in the agitation state of the two groups (P = 0.60). Conclusion: Premedication with oral midazolam 0.5 mg/kg administered 30 min preoperatively does not prevent EA in all cases.

BACKGROUND: Oral administration of midazolam syrup is one of the most favorable methods of premedication, the optimal dose of midazolam and midazolam with S-ketamine for preschool children has not been determined. This prospective, double-blind, randomized, sequential dose-finding study was designed to estimate the 90% effective doses of oral midazolam with and without intranasal S-ketamine in a grade III child medical center. METHODS: Eighty successive children were recruited and randomly allocated to midazolam group and midazolam with S-ketamine group. The initial oral doses of midazolam were 0.25 mg/kg in both groups, and the dose of midazolam for the next child was based on the response of the preceding child as the biased coin up-and-down designed. The primary outcome was parental separation anxiety score = 1 throughout the period of transferring from premedication center to the operation room 30 min after premedication. Secondary outcomes were the preoperative and post-operative observations. Finally, the 90% effective dose and 95% confidence intervals were estimated by isotonic regression. RESULTS: The 90% effective dose of oral midazolam or oral midazolam with intranasal S-ketamine was 0.461 mg/kg (95% confidence interval: 0.425–0.488) and 0.253 mg/kg (95% confidence interval: 0.242–0.278), respectively. Oral midazolam with intranasal S-ketamine was quicker onset (8.9±3.8 vs. 19.7±7.4 min, P

BACKGROUND Forty children of ASA grade I, aged 1 to 8 years, both males and females undergoing elective surgery under general anaesthesia and regional anaesthesia for procedures such as herniotomy and circumcision were included in the study. MATERIALSAND METHODS Children were allocated randomly into 2 groups. In order to get statistically significant results, a sample size of 20 was allotted to each groups. Group 1 children in this group received oral midazolam 0.5 mg/kg as premedication and group 2 children received oral ketamine 5 mg/kg as premedication. Parenteral formulation of both the drugs was given to the children after mixing with honey. All children were observed and scores allotted by the investigator. Child’s emotional reaction and sedation status were noted on arrival in operation theatre on insertion of IV cannula and on acceptance of facemask. The children were separated from their parents 30 minutes after ingestion of the drug. Any side effect after ingestion of the drug until 4 hours in the postoperative period was looked for. Time of recovery from anaesthesia was noted. It was observed that both the drugs were well accepted by the children. RESULTS Sedation and anxiolysis was better in ketamine group during separation from parents at IV cannulation and facemask application. Both oral midazolam and oral ketamine are excellent agents for premedication in paediatric outpatient surgeries. Considering sedation and emotional scores during arrival in OT, IV cannulation and facemask application, oral ketamine is superior to oral midazolam. No significant adverse effects were found in both the groups. In the recovery room, the 2 groups did not differ significantly with respect to side effects like nausea, vomiting, emergence phenomenon and need for airway support. No haemodynamic instability was recorded. The time of discharge was not delayed in both the groups. CONCLUSION Considering sedation and emotional scores during arrival in OT, IV cannulation and facemask application, oral ketamine is superior to oral midazolam.

The efficacy of midazolam as premedication in children for providing pre-operative sedation and reducing parental separation anxiety has been well established. Many studies have compared the effectiveness and medication acceptance of midazolam via oral and intranasal routes. In this study, we have compared the ease of administration of oral midazolam syrup and intranasal midazolam spray as premedication, administered by parents to children. Ninety children were randomly allocated into one of the two groups: group N received nasal midazolam spray 0.2 mg/kg and group O received oral midazolam syrup 0.5 mg/kg administered by the parent. The parent recorded ease of administration score and facial hedonic score. The observer recorded modified medication acceptance score. Vitals and sedation scores were assessed at specific intervals. Thirty minutes after drug administration the child was separated from the parent, and parental separation anxiety score was recorded. Mask acceptance score was recorded after application of mask upon arrival in the OT. Oral midazolam syrup was found to have better ease of administration than intranasal midazolam spray as felt by the parent. Medication acceptance was better for oral midazolam. Both the groups had similar sedation scores at 15 and 30 min. Children in the oral group had a better reduction in parental separation anxiety at 30 min after drug administration and better mask acceptance than the nasal group. Oral midazolam syrup is easier for parents to administer and has better medication acceptance in children when compared to intranasal midazolam spray.

Background and Aims: Sevoflurane is the most often used inhalational agent in paediatric anaesthesia, but emergence agitation (EA) remains a major concern. Oral midazolam and parenteral dexmedetomidine are known to be effective in controlling EA. We attempted to elucidate whether oral dexmedetomidine is better than midazolam in controlling EA. Methods: Prospective double-blinded study involving ninety patients aged 1–10 years, undergoing elective surgeries of 10; 0 vs. 0). Conclusion: Premedication with oral dexmedetomidine provides smooth induction and recovery, reduces the EA and provides better analgesia and sedation as compared to oral midazolam.

Although midazolam is a frequently used sedative in neonatal intensive care units, its use in preterm neonates has been off-label. Recently, a new dosing advice for midazolam for sedation on intensive care units has been included in the label (0.03 mg/[kg center dot h] for preterm neonates 32 weeks). Concentration-time data of a prospective multicenter study (29 patients, median gestational age 26.7 [range 24.0-31.1 weeks]) were combined with previously published data (26 patients, median gestational age 28.1 [range 26.3-33.6 weeks]), and a population pharmacokinetic model describing the maturation of midazolam pharmacokinetics was developed in NONMEM 7.3. Clearance was 73.7 mL/h for a neonate weighing 1.1 kg and changed nonlinearly with body weight (exponent 1.69). Volume of distribution increased linearly with body weight and was 1.03 L for a neonate weighing 1.1 kg. Simulations of the newly registered dosing show considerable differences in steady-state concentrations in preterm neonates. To reach similar steady-state concentrations of 400 mu g/mL (+/- 100 mu g/mL), a dose of 0.03 mg/(kg center dot h) is adequate for neonates >= 1 kg and 2 kg and

Background and aims Caudal epidural block is widely used in pediatric surgeries to provide intraoperative and postoperative analgesia in infra-umbilical surgeries. The conventional technique involves the risk of multiple punctures and other complications such as dural puncture, vascular puncture, and intraosseous injection. Material and methods Around 106 children aged between 6 months to 10 years belonging to ASA class I-II scheduled for elective infra-umbilical surgeries were included after obtaining written informed consent from parents/guardians. All children were randomized into two groups: ultrasound-guided (Group U) or conventional caudal group (Group C). All were premedicated with oral midazolam and inhalational induction was done with oxygen and 6-8% sevoflurane. Caudal block of 1 mL/kg of 0.125% bupivacaine was administered in both groups. The primary outcome assessed was 1st puncture success rate and the secondary outcomes assessed were number of skin punctures, block performing time, and block success rate. Results Group U had a higher first puncture success rate (P = 0.001) than Group C (90.6% v/s 64.2%) and was statistically significant. The number of punctures were significantly less (P = 0.01) in Group U (1.09 ± 0.295) than Group C (1.45 ± 0.667). Block performing time was significantly higher (P = 0.0005) in Group U (53.19 ± 10.97 s) than Group C (30.34 ± 7.34 s). There was no difference in the overall block success rate between the groups (98.1% v/s 100%). Conclusion Ultrasound-guided caudal injection increases the first puncture success rate and decreases the number of punctures required compared to conventional caudal block in pediatric infra-umbilical surgeries.

Aims We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients. Methods For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4β-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in CYP3A4, CYP3A5 and P450 oxidoreductase, among others. Results MDZ Cl/F/W, 4β-OHC/C/W, EBT and TAC Cl/F/W were all moderately correlated (r = 0.262–0.505). Neither MDZ Cl/F/W nor 4β-OHC/C/W explained variability in TAC Cl/F/W in CYP3A5 expressors (n = 29). For CYP3A5 non-expressors (n = 118), factors explaining variability in TAC Cl/F/W in a MDZ-based model were MDZ Cl/F/W (R2 = 0.201), haematocrit (R2 = 0.139), TAC formulation (R2 = 0.107) and age (R2 = 0.032; total R2 = 0.479). In the 4β-OHC/C/W-based model, predictors were 4β-OHC/C/W (R2 = 0.196), haematocrit (R2 = 0.059) and age (R2 = 0.057; total R2 = 0.312). When genotype information was ignored, predictors of TAC Cl/F/W in the whole cohort were 4β-OHC/C/W (R2 = 0.167), MDZ Cl/F/W (R2 = 0.045); Tac QD formulation (R2 = 0.036), and haematocrit (R2 = 0.032; total R2 = 0.315). 4β-OHC/C/W, but not MDZ Cl/F/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors. Conclusions A MDZ-based model explained more variability in TAC clearance in CYP3A5 non-expressors. However, 4β-OHC/C/W was superior in a model in which no genotype information was available, likely because 4β-OHC/C/W was influenced by the CYP3A4*1b polymorphism.

This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC(0-a)) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P

For fearful and uncooperative children behavioral management techniques are used. In order to control the pain and anxiety in pedodontic patients, pharmacologic sedation, anesthesia and analgesia are commonly used. Midazolam is commonly used as an oral sedation agent in children; it has several features such as safety of use, quick onset and certain degree of amnesia that makes it a desirable sedation agent in children. This review paper discusses various aspects of oral midazolam, ketamine and their combinations in conscious sedation including, advantages of oral route of sedation, pharmacokinetics, range of oral doses, and antagonists for clinical dental treatment procedures.

Context: Oral premedication is widely used in pediatric anesthesia to provide preoperative anxiolysis and ensure smooth induction. Midazolam is currently the most commonly used premedicant, but newer drugs such as the α2-agonists have emerged as alternatives for premedication in children. Aims: The aim of this study was to compare clinical effects of oral midazolam and oral dexmedetomidine on preanesthetic sedation and postoperative recovery profile in children. Settings and Design: Randomized controlled trial. Materials and Methods: We performed a prospective, randomized, controlled study in 60 children, aged 1-7 years undergoing elective, minor, lower abdominal surgeries under general anesthesia. Patients were randomly assigned to receive either oral midazolam 0.75 mg/kg (Group M, n = 30) or oral dexmedetomidine 4 μg/kg (Group D, n = 30) 40 min prior to mask induction. Preoperative sedation and anxiolysis, the response at parental separation, quality of mask acceptance and recovery profile were compared for the two groups. Statistical Analysis Used: Results were analyzed using unpaired Student's t-test and Chi-squared test. P < 0.05 was considered statistically significant. Results: There was no significant difference in the levels of preoperative sedation and anxiolysis between the two groups, but the onset of sedation was significantly faster with midazolam (18.90 ± 3.68 min) than with dexmedetomidine (30.50 ± 4.44 min). Response to parental separation and quality of mask acceptance was comparable between two groups (P > 0.05). The incidence of postoperative agitation was significantly less in the dexmedetomidine group (P < 0.05). Conclusions: In this study, premedication with oral dexmedetomidine produced equally effective preoperative sedation and a better recovery from anesthesia in children in comparison to oral midazolam.

Background: Children’s fear of surgery and preoperative separation from parents can contribute to anxiety and distress in children undergoing surgery. The study addressed the comparable efficacy of oral premedication of midazolam, dexmedetomidine, and melatonin to alleviate preoperative anxiety and easing the children’s separation from parents. Materials and Methods: A double-blinded trial enrolled three equal-sized groups of children (n = 153, aged 2–10 years) undergoing elective surgery who received oral midazolam, melatonin, and dexmedetomidine 30 min before induction. The observation sedation score, and ease of separation, acceptance of drug both preceding and following premedication administration were assessed and recorded every 5min till anesthesia induction. Results: A significant difference was observed in the mean scores of sedation before premedication and after separation from parents, as well as in the degree of the separation when comparing between the midazolam and melatonin groups and the dexmedetomidine and melatonin groups (P < 0.001). The scores were significantly lower in the melatonin group than the other two groups, whereas no significant difference was found in those between the midazolam and dexmedetomidine groups, as well as in the acceptance of anesthesia induction between the midazolam and melatonin groups (P = 0.250). The differences were significant between the midazolam and dexmedetomidine groups (P = 0.002) and melatonin and dexmedetomidine groups (P < 0.001) and anesthesia induction was effective in the dexmedetomidine group than that in the other two groups. Conclusion: Dexmedetomidine is more effective in acceptance of anesthesia induction. Furthermore, the midazolam and dexmedetomidine groups indicated better ease of separation and sedation scores than melatonin.

Objective: We aimed to examine if changes in oxygen saturation and pulse rate of pediatric patients during conscious sedation with midazolam and nitrous oxide are associated with child's behavior, midazolam dose, the type and duration of the treatment and demographic parameters. Study Design: This study was a retrospective chart review of consecutive pediatric patients, aged 2.5–12.5 years, who had undergone conscious sedation for dental treatment with oral midazolam (with or without nitrous oxide) between January 2011 and September 2015 at the Department of Pediatric Dentistry of Tel Aviv University. Oral midazolam was administered according to the patients' weight, either at 0.4 mg/kg, 0.5 mg/kg or at a maximum dose of 10 mg. In all cases pulse rate and oxygen saturation were monitored every 15 minutes during treatment, Results: 147 sedation sessions (82 of females and 65 of males) were included in the study. Sedation was successful in 80% of cases. Children with poor behavior scores had statistically significant different mean saturation levels, albeit within normal range, during the treatment (p

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.

The purpose of this study was to compare effects of tablet-based interactive distraction (TBID; 1 minute preseparation) with oral midazolam (15 to 45 minutes of preseparation) on preoperative anxiety, emergence delirium, and postanesthesia length of stay in children, 4 to 12 years undergoing outpatient surgery.Single-blinded prospective design with randomized assignment to TBID or oral midazolam group was conducted at a large pediatric hospital in southwestern United States.A total of 102 children and caregivers were enrolled. Outcome measures included anxiety scores at baseline, separation, and mask induction; postemergence delirium scores; caregiver ratings of child anxiety and satisfaction; and time from postanesthesia care unit arrival to discharge and posthospital behaviors.The TBID group demonstrated significantly lower anxiety at separation and mask induction (P.001) and emergence delirium at 15 minutes postawakening (P = .001), were extubated earlier (P = .007), arrived to phase II earlier (P = .03), and discharged earlier (P = .0001).TBID was more effective than oral midazolam in reducing preoperative anxiety, emergence delirium, and postanesthesia length of stay.

Gal Neuman,1,* Rana Swed Tobia,2,* Liron Koren,3 Ronit Leiba,4 Itai Shavit5 1Clinical Pharmacology and Toxicology Unit, 2Department of Pediatrics, Ruth Children’s Hospital, Rambam Health Care Campus, 3Rappaport Faculty of Medicine, Technion – Institute of Technology, 4Quality of Care Unit, 5Emergency Department, Ruth Children’s Hospital, Rambam Health Care Campus, Haifa, Israel *These authors contributed equally to this work Background: In the pediatric emergency department, patients are commonly treated with a single dose of oral midazolam for minor procedures. We sought to evaluate the effect of this treatment on procedure completion rates.Methods: We conducted a single-center retrospective cohort study of all patients who were treated with pre-procedure oral midazolam between January 2011 and June 2016. The primary outcome was the procedure completion rate.Results: During the study period, 1,504 patients were treated with oral midazolam as per department protocol; 1,467 received midazolam and 37 declined midazolam. Oral midazolam was used in 14 different types of emergency department procedures. The procedure completion rates in the treatment and non-treatment groups were 1,402/1,467 (95.6%) and 24/37 (64.8%), respectively (difference 30.7%; 95% confidence interval [CI] 17.3%–46.8%); p

Background: Effective and safe pediatric procedural sedation is still a concern especially in areas outside operation theatres. The aim of the study was to compare the efficacy and safety of oral triclofos and oral midazolam in children undergoing computed tomography.Methods: A prospective randomized double blind study was conducted in 100 children aged one to five years. Group-I (n=50) received oral triclofos 100 mg/kg and Group-II (n=50) oral midazolam 0.75 mg/kg. Both groups were given oral atropine 0.03 mg/kg and supplemented with intravenous midazolam upto 0.1 mg/kg in case of inadequate effect. Onset and duration of sedation, success for completion of procedure and time to recovery were noted. Student’s t test and Z test of proportions were used for statistical analysis.Results Majority of children 36(72%) in Group-I achieved Ramsay Sedation Score >4 as compared to 25(50%) in Group-II. Computed tomography scan could be successfully completed at comparable rate (52% vs 56%). Success rate improved to 96% vs 80% after supplementing intravenous midazolam in Group I & II respectively (p< 0.05). Onset (37.91minutes ± 7.96 vs 26 ± 10), duration of sedation ( 117.91minutes ± 72.41 vs 66.2minutes ± 33) were significantly shorter and recovery (98.19minutes ± 72.58 vs 47.4minutes ± 31.42) in Group I & II respectively was faster in children who received oral midazolam (p< 0.05).Conclusion We conclude that both drugs were equally effective and safe for computed tomography scan in children. However better recovery profile of midazolam makes it more suitable for day care procedures.Journal of Society of Anesthesiologists of Nepal 2015; 2(2): 41-45

Not applicable

Our aim was to characterize effectiveness and complications in children receiving oral midazolam alone, nasal midazolam alone, or oral midazolam with other sedatives. Children received oral midazolam alone, nasal midazolam, or oral midazolam in combination with other sedative medications. All subjects received a presedation history and physical examination and were sedated per protocol by any of 28 resident providers under attending supervision. Sedations were rated for success and complications by clinicians. Postoperative complications were assessed by trained staff up to 48 hours postoperatively. Seven hundred and one encounters, completed over 24 months, yielded 650 usable sedations. The majority of children were healthy (469; 68.2%) and 86% (532) weighed between 10 and 25 kg. Sedations were deemed successful in about 80% of cases. Planned treatment was completed in over 85% of encounters. Oral midazolam alone yielded the best behavior. Physical assessment factors of behavior and age were correlated (P = .035) with effectiveness. Hiccups and a positive medical history were significantly related (P = .049). Side effects of either nausea/vomiting, dysphoria, or hiccups occurred in less than 10% of cases. All 3 regimens were effective with minimal postoperative complications.