Therapeutic Intranasal Drug Delivery

al-Rakaf, H., L. L. Bello, et al. (2001). "Intra-nasal midazolam in conscious sedation of young paediatric dental patients." Int J Paediatr Dent 11(1): 33-40.

            OBJECTIVES: To compare the effects of 3 different doses of intra-nasal midazolam in the conscious sedation of young paediatric dental patients and to compare the effectiveness of the sedation in the fasting and non-fasting child. DESIGN: Double blind random controlled trial. SAMPLE AND METHODS: Thirty-eight uncooperative young children aged 2-5 years (mean age 4.02 years) were randomly assigned to one of 3 groups. The groups and the doses of midazolam administered intra-nasally were A: 0.3 mg/kg, B: 0.4 mg/kg, and C: 0.5 mg/kg body weight. Each child in each group had two visits for restorative treatment: one without food (fasting) and the other with soft drink and light food (non-fasting) before treatment. Child behaviour and sedative effects were evaluated using the scoring system of Houpt. The vital signs were monitored continuously using a pulse oximeter and Dinamap machine. RESULTS: There was rapid onset of sedation with the maximal effect between 8 and 15 minutes. This sedation lasted for 25-40 minutes in Groups A and B and for 60 minutes in Group C. Conscious sedation and dental treatment were achieved in 79%, 96% and 100% of the children in Groups A, B and C, respectively. Consistently higher Houpt scores were seen in Groups B and C, with statistically significant differences between Groups A and C, and B and C (Tukey's range test, P < 0.05). There were no significant differences in the general behaviour of the child, the onset and the duration of sedation between the fasting and the non-fasting child (nonparametric ANOVA P > 0.05). All the vital signs were within normal physiological limits and there were no significant adverse effects either with or without fasting. CONCLUSIONS: All 3 doses of intranasal midazolam were effective in modifying the behaviour of the uncooperative child patient to accept dental treatment. This was irrespective of fasting.

AlSarheed, M. A. (2016). "Intranasal sedatives in pediatric dentistry." Saudi Med J 37(9): 948-956.

OBJECTIVES: To identify the intranasal (IN) sedatives used to achieve conscious sedation during dental procedures amongst children. METHODS: A literature review was conducted by identifying relevant studies through searches on Medline. Search included IN of midazolam, ketamine, sufentanil, dexmedetomidine, clonidine, haloperidol, and loranzepam. Studies included were conducted amongst individuals below 18 years, published in English, and were not restricted by year. Exclusion criteria were articles that did not focus on pediatric dentistry. RESULTS: Twenty studies were included. The most commonly used sedatives were midazolam, followed by ketamine and sufentanil. Onset of action for IN midazolam was 5-15 minutes (min), however, IN ketamine was faster (mean 5.74 min), while both IN sufentanil (mean 20 min) and IN dexmedetomidine (mean 25 min) were slow in comparison. Midazolam was effective for modifying behavior in mild to moderately anxious children, however, for more invasive or prolonged procedures, stronger sedatives, such as IN ketamine, IN sufentanil were recommended. In addition, ketamine fared better in overall success rate (89%) when compared with IN midazolam (69%). Intranasal dexmedetomidine was only used as pre-medication amongst children. While its' onset of action is longer when compared with IN midazolam, it produced deeper sedation at the time of separation from the parent and at the time of anesthesia induction. CONCLUSION: Intranasal midazolam, ketamine, and sufentanil are effective and safe for conscious sedation, while intranasal midazolam, dexmedetomidine, and sufentanil have proven to be effective premedications.

Azizkhani, R., F. Heydari, et al. (2020). "Comparing Sedative Effect of Dexmedetomidine versus Midazolam for Sedation of Children While Undergoing Computerized Tomography Imaging." J Pediatr Neurosci 15(3): 245-251.

Background: Pediatric anxiety and restlessness may create issues and difficulties in performing accurate diagnostic studies even noninvasive ones, such as radiological imaging. There are some agents that will help to get this goal. This study aimed to compare the intranasal effect of dexmedetomidine (DEX) and midazolam (MID) for sedation parameters of children undergoing computerized tomography (CT) imaging. Materials and Methods: A double-blind clinical trial was conducted on 162 eligible children who underwent CT imaging. These patients were divided into two groups including MID (n = 81) with dose of 0.3 mg.kg and DEX (n = 81) with dose of 3 mug.kg, which was consumed intranasally. The mean blood pressure (MBP), respiratory rate (RR), heart rate (HR), and oxygen saturation (O2Sat) in children were recorded. Then, time of initiation, level of sedation, and duration effect of medication were measured at 0, 10, 20, and 30 min. Parents and clinician satisfaction score was asked. All data were analyzed using the Statistical Package for the Social Sciences (SPSS) software by t test and chi-square test. Results: Decreasing in MBP and HR was higher in DEX group than MID group (P < 0.001), whereas decrease of O2Sat in MID group was higher than DEX group (0.009). Starting time of sedation (22.72 +/- 11.64 vs. 33.38 +/- 10.17, P = 0.001) was lower in DEX group. Parents (P < 0.001) and physician (P < 0.001) satisfaction score was higher in DEX group than the MID group. Conclusion: Using 3 mug/kg intranasal DEX for sedation of 1-6-year-old children was a suitable method to undergo noninvasive studies such as CT imaging. Intranasal DEX is superior to MID due to higher sedation satisfactory, faster starting effect of sedation, and lower side effects and complications. Nevertheless, in children with hemodynamic instability DEX is not an appropriate choice.

Bahetwar, S. K., R. K. Pandey, et al. (2011). "A comparative evaluation of intranasal midazolam, ketamine and their combination for sedation of young uncooperative pediatric dental patients: a triple blind randomized crossover trial." J Clin Pediatr Dent 35(4): 415-420.

                OBJECTIVE: The purpose of this study was to evaluate and compare the efficacy and safety of intranasal (IN) administration of midazolam (M), ketamine (K) and their combination (MK) to produce moderate sedation in young, uncooperative pediatric dental patients. STUDY DESIGN: In this three stage crossover trial forty five uncooperative ASA type-1 children, who required dental treatment, were randomly assigned to receive one of the three drugs/combination by IN route during three subsequent visits. The efficacy and safety of the agents were assessed by overall success rate and by monitoring of vital signs, respectively. RESULTS: The onset of sedation was rapid with K as compared to M and MK. The difference was statistically significant (P < 0.01) between K and M. The overall success rate was 89% with K, MK was 84% and 69% with M. The difference between the overall success rates of K and M was statistically significant (P < 0.01). Vital signs were within physiological limits and there were no significant adverse effects with any medication. CONCLUSIONS: M, K and MK are safe and effective by IN route to produce moderate sedation for providing dental care to pediatric dental patients who have been otherwise indicated for treatment under general anesthesia.

Baier, N. M., S. S. Mendez, et al. (2016). "Intranasal dexmedetomidine: an effective sedative agent for electroencephalogram and auditory brain response testing." Paediatr Anaesth 26(3): 280-285.

OBJECTIVE: Dexmedetomidine is an alpha2 agonist with sedative, anxiolytic, and analgesic properties. The intranasal (IN) route avoids the pain of intravenous (i.v.) catheter placement but limited literature exists on the use of IN dexmedetomidine. This study examines the effectiveness and safety of IN dexmedetomidine for sedation of patients undergoing electroencephalogram (EEG) and auditory brain response (ABR) testing. STUDY DESIGN: This was a review of all outpatients sedated with IN dexmedetomidine for EEG or ABR between October 1, 2012 and October 1, 2014. An initial dose of 2.5-3 mug . kg(-1) IN dexmedetomidine was given with a repeat dose of 1-1.5 mug . kg(-1) IN if needed 30 min later. Prospectively entered patient information was extracted from a quality assurance database and additional information gathered via retrospective chart review. RESULTS: Intranasal dexmedetomidine was used in 169 patients (EEG = 117, ABR = 52). First-dose success rates were 90.4% for ABR and 87.2% for EEG. Total success rates (with one or two doses of IN dexmedetomidine) were 100% for ABR and 99.1% for EEG. The median time to onset of sleep was 25 min (IQR, 20-32 min). The median duration of sedation was 107 min (IQR, 90-131 min). Adverse events included: 18 patients (10.7%) with hypotension which resolved without intervention, six patients with oxygen desaturation <90%, two of whom received supplemental oxygen, and one patient with an underlying upper airway abnormality who was treated with continuous positive airway pressure. CONCLUSIONS: IN dexmedetomidine is an effective and noninvasive method of sedating children for EEG and ABR.

Baleine, J., C. Milesi, et al. (2014). "Intubation in the delivery room: experience with nasal midazolam." Early Hum Dev 90(1): 39-43.

BACKGROUND: Neonates are often intubated in the delivery room (DR) without anesthesia because vascular access is impossible. AIMS: To assess neonatal comfort and adverse events after use of nasal midazolam (nMDZ) for intubation in the DR. STUDY DESIGN: Prospective data collection over 6months on the intubation of neonates with respiratory distress requiring tracheal instillation of surfactant. SUBJECTS: Twenty-seven neonates with median (Q25-75) gestational age and birthweight of, respectively, 29 (27-33)weeks and 1270 (817-1942)g received a 0.1mg/kg dose of nMDZ, and intubation was performed at the onset of tonus resolution or apnea. OUTCOME MEASURES: Comfort was assessed with a scale of hetero-pain assessment and electrical skin conductance monitoring. Continuous pulse oximetry was recorded in the first postnatal hour, with oscillometric blood pressure measurement every 10min. RESULTS: Seventy percent of the patients required a single dose, with intubation performed 4.8 (3-9)min after administration. Combined electro-clinical assessment found adequate comfort during the procedure in 68% of neonates. Mean blood pressure decreased from 39 (34-44)mmHg before to 31 (25-33)mmHg 1h following nMDZ (p=0.011). CONCLUSION: nMDZ provided rapid and effective sedation to intubate neonates in the DR but potentially exposed them to hypotension, thus requiring close hemodynamic monitoring.

Barends, C. R. M., M. K. Driesens, et al. (2020). "Intranasal dexmedetomidine in elderly subjects with or without beta blockade: a randomised double-blind single-ascending-dose cohort study." Br J Anaesth.

BACKGROUND: The aim of this double-blind, placebo-controlled, single-ascending-dose study was to determine the safety and tolerability of intranasal dexmedetomidine in the elderly. METHODS: We randomly assigned 48 surgical patients >/=65 yr of age to receive single intranasal doses of dexmedetomidine or placebo (5:1 ratio) in four sequential dose cohorts: 0.5, 1.0, 1.5, and 2.0 mug kg(-1). Each dose cohort comprised two groups of six subjects: a group of subjects using beta-blockers and a group not taking beta-blockers. Vital signs and sedation depth (Modified Observer's Assessment of Alertness and Sedation [MOAA/S] and bispectral index) were measured for 2 h after administration. Blood samples were taken to determine dexmedetomidine plasma concentrations. RESULTS: One subject (1.0 mug kg(-1)) had acute hypotension requiring ephedrine. Systolic arterial BP decreased >30% in 15 of 40 subjects (37.5%) receiving dexmedetomidine, lasting longer than 5 min in 11 subjects (27.5%). The MAP decreased >30% (>5 min) in 10%, 20%, 50%, and 30% of subjects receiving dexmedetomidine 0.5, 1.0, 1.5, and 2.0 mug kg(-1), respectively, irrespective of beta-blocker use. HR decreased 10-26%. MOAA/S score </=3 occurred in 18 (45%) subjects; eight (20%) subjects receiving dexmedetomidine showed no signs of sedation. Tmax was 70 min. Cmax was between 0.15 ng ml(-1) (0.5 mug kg(-1)) and 0.46 ng ml(-1) (2.0 mug kg(-1)). CONCLUSIONS: Intranasal dexmedetomidine in elderly subjects had a sedative effect, but caused a high incidence of profound and sustained hypotension irrespective of beta-blocker use. The technique is unsuitable for routine clinical use. CLINICAL TRIAL REGISTRATION: NTR5513 (The Netherlands Trial Registry 5513).

Bates, B. A., S. A. Schutzman, et al. (1994). "A comparison of intranasal sufentanil and midazolam to intramuscular meperidine, promethazine, and chlorpromazine for conscious sedation in children." Ann Emerg Med 24(4): 646-51.

            STUDY OBJECTIVE: To compare intranasal sufentanil and midazolam (IN-SM) with intramuscular meperidine, promethazine, and chlorpromazine (IM-MPC) for sedation in children. DESIGN: Single-blind, randomized, controlled study. SETTING: Urban children's emergency department. PARTICIPANTS: A convenience sample of children aged 1 to 4 years requiring suturing. INTERVENTIONS: IN-SM or IM-MPC. RESULTS: Vital signs, O2 saturation, and anxiety and pain scores were recorded. A 6-point scale was used to assess response to medication, and a 12-point recovery score was used to determine readiness for discharge. Both groups were similar in age and sex distribution. There were no significant adverse effects in either group. Patients tolerated the IN regimen better than the IM regimen. Behavioral scores were lower during repair than at baseline within each group; however, they were not different between groups. Time to discharge was longer and recovery scores were lower (worse) among the IM-MPC group. CONCLUSION: IN-SM is as effective as IM-MPC for sedation in children.

Bayrak, F., I. Gunday, et al. (2007). "A comparison of oral midazolam, oral tramadol, and intranasal sufentanil premedication in pediatric patients." J Opioid Manag 3(2): 74-8.

            BACKGROUND: This study was designed to evaluate the efficacy and safety of oral midazolam, tramadol drops, and intranasal sufentanil for premedication of pediatric patients. METHODS: Sixty children, three to 10 years of age, who were designated as American Society of Anesthesiologists physical status 1 and who were undergoing adenotonsillectomy as inpatients were randomized to receive a dosage of 0.5 mg/kg (total of 4 ml) midazolam in cherry juice (n=20, Group M), 3 mg/kg tramadol drops (n=20, Group T), or 2 microg/kg intranasal sufentanil (n=20, Group S). Clinical responses (sedation, anxiolysis, cooperation) and adverse effects (respiratory, hemodynamic, etc.) were recorded. Safety was assessed by continuous oxygen saturation monitoring and observation. Vital signs (blood pressure, pulse, oxygen saturation, respiratory rate) were recorded before drug administration (baseline) and then every 10 minutes until the induction of anesthesia. RESULTS: Mean blood pressure decreased significantly after five minutes of intranasal sufentanil administration relative to Groups M (p < 0.01) and T (p < 0.05), whereas heart rate remained unchanged. Oxygen saturation and respiratory rate decreased significantly after 20 and 30 minutes of intranasal sufentanil administration relative to Groups M and T (p < 0.05). Anxiety scores showed rates of 45 percent in Group M, 5 percent in Group T, and 40 percent in Group S. Anxiety scores in Groups M and S were better than those of Group T (p < 0.01). Cooperation scores for face-mask acceptance showed rates of 85 percent in Group M, 45 percent in Group T, and 85 percent in Group S (p < 0.01). CONCLUSION: Intranasal sufentanil and oral midazolam are more appropriate premedication options than tramadol drops in children.

Behrle, N., E. Birisci, et al. (2017). "Intranasal Dexmedetomidine as a Sedative for Pediatric Procedural Sedation." J Pediatr Pharmacol Ther 22(1): 4-8.

            OBJECTIVE: This study seeks to evaluate the efficacy and safety of intranasal (IN) dexmedetomidine as a sedative medication for non-invasive procedural sedation. METHODS: Subjects 6 months to 18 years of age undergoing non-invasive elective procedures were included. Dexmedetomidine (3 mcg/kg) was administered IN 40 minutes before the scheduled procedure time. The IN dexmedetomidine cohort was matched and compared to a cohort of 690 subjects who underwent sedation for similar procedures without the use of dexmedetomidine to evaluate for observed events/interventions and procedural times. RESULTS: One hundred (92%) of the 109 included subjects were successfully sedated with IN dexmedetomidine. There were no significant differences in the rate of observed events/interventions in comparison to the non-dexmedetomidine cohort. However, the IN dexmedetomidine group had a longer postprocedure sleep time when compared to the non-dexmedetomidine cohort (p < 0.001), which had a significant effect on recovery time (p = 0.024). Also, the dexmedetomidine cohort had longer procedure time and total admit time (p < 0.001 and p = 0.037, respectively). CONCLUSIONS: IN dexmedetomidine may be used for non-invasive pediatric procedural sedation. Subjects receiving IN dexmedetomidine had a similar rate of observed events/interventions as the subjects receiving non-dexmedetomidine sedation, with the exception of sleeping time. Also, patients sedated with IN dexmedetomidine had longer time to discharge, procedure time, and total admit time in comparison to other forms of sedation.

Berner, J. E. (2007). "Intranasal ketamine for intermittent explosive disorder: a case report." J Clin Psychiatry 68(8): 1305.

Bhat, R., M. C. Santhosh, et al. (2016). "Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study." Anesth Essays Res 10(2): 349-355.

BACKGROUND: Goal of premedication in pediatric anesthesia are relieving pre and postoperative anxiety, good parental separation, and smooth induction of anesthesia. Anxiety can produce aggressive reactions, increased distress, increased postoperative pain and postoperative agitation. The benzodiazepine, midazolam, is the most frequently used premedication in pediatric anesthesia. Midazolam has a number of beneficial effects when used as premedication in children: Sedation, fast onset, and limited duration of action. Though midazolam has a number of beneficial effects, it is far from an ideal premedicant having untoward side effects such as paradoxical reaction, respiratory depression, cognitive impairment, amnesia, and restlessness. Dexmedetomidine is a newer alpha-2-agonist, which can be used as premedicant. AIMS: To compare the level of sedation, parental separation, mask acceptance, postoperative recovery of intranasal premedication with dexmedetomidine and dexmedetomidine-ketamine combination in pediatric patients. SETTINGS AND DESIGN: Prospective randomized double-blind study. SUBJECTS AND METHODS: After written informed consent from the patient's parents or legal guardian, 54 children of American Society of Anesthesiologists physical status I or II, aged between 1 and 6 years, scheduled to undergo elective minor surgery were enrolled. In group D patient received 1 mug/kg dexmedetomidine intranasally and in group DK received 1 mug/kg dexmedetomidine and 2 mg/kg ketamine intranasally. Patients were assessed every 10 min for the level of sedation, parenteral separation, heart rate, and oxygen saturation by an independent observer. Mask acceptance and postoperative agitation were noted using an appropriate scale. STATISTICAL ANALYSIS USED: Pearson Chi-square analysis to determine differences between two groups with respect to separation anxiety and acceptance of the anesthesia mask. Percentages used to represent frequencies. The level of significance was set at P< 0.05. RESULTS: Acceptable parenteral separation was achieved in 90% of patients 30 min after premedication. Sedation was acceptable in 80% of patients at induction. Good mask acceptance was seen in 60% of patients. The incidence of emergence agitation (EA) was 2%. None of the above parameters was statistically significant between the two groups. CONCLUSIONS: Dexmedetomidine, as premedicant in children provides acceptable parenteral separation. However, mask acceptance in operation room is poor. Combination of dexmedetomidine and ketamine does not increase the success of premedication. Use of dexmedetomidine is associated with decreased EA.

Bi, Y., Y. Ma, et al. (2019). "Efficacy of premedication with intranasal dexmedetomidine for removal of inhaled foreign bodies in children by flexible fiberoptic bronchoscopy: a randomized, double-blind, placebo-controlled clinical trial." BMC Anesthesiol 19(1): 219.

BACKGROUND: Tracheobronchial foreign body aspiration in children is a life-threatening, emergent situation. Currently, the use of fiberoptic bronchoscopy for removing foreign bodies is attracting increasing attention. Oxygen desaturation, body movement, laryngospasm, bronchospasm, and breath-holding are common adverse events during foreign body removal. Dexmedetomidine, as a highly selective alpha2-adrenergic agonist, produces sedative and analgesic effects, and does not induce respiratory depression. We hypothesized that intranasal dexmedetomidine at 1 mug kg - 1 administered 25 min before anesthesia induction can reduce the incidence of adverse events during fiberoptic bronchoscopy under inhalation general anesthesia with sevoflurane. METHODS: In all, 40 preschool-aged children (6-48 months) with an American Society of Anesthesiologists physical status of I or II were randomly allocated to receive either intranasal dexmedetomidine at 1 mug.kg - 1 or normal saline at 0.01 ml kg(- 1) 25 min before anesthesia induction. The primary outcome was the incidence of perioperative adverse events. Heart rate, respiratory rate, parent-child separation score, tolerance of the anesthetic mask, agitation score, consumption of sevoflurane, and recovery time were also recorded. RESULTS: Following pre-anesthesia treatment with either intranasal dexmedetomidine or saline, the incidences of laryngospasm (15% vs. 50%), breath-holding (10% vs. 40%), and coughing (5% vs. 30%) were significantly lower in patients given dexmedetomidine than those given saline. Patients who received intranasal dexmedetomidine had a lower parent-child separation score (P = 0.017), more satisfactory tolerance of the anesthetic mask (P = 0.027), and less consumption of sevoflurane (38.18 +/- 14.95 vs. 48.03 +/- 14.45 ml, P = 0.041). The frequency of postoperative agitation was significantly lower in patients given intranasal dexmedetomidine (P = 0.004), and the recovery time was similar in the two groups. CONCLUSIONS: Intranasal dexmedetomidine 1 mug.kg(- 1), with its sedative and analgesic effects, reduced the incidences of laryngospasm, breath-holding, and coughing during fiberoptic bronchoscopy for FB removal. Moreover, it reduced postoperative agitation without a prolonged recovery time. TRAIL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800017273) on July 20, 2018.

Borland, M. L., R. Bergesio, et al. (2005). "Intranasal fentanyl is an equivalent analgesic to oral morphine in paediatric burns patients for dressing changes: a randomised double blind crossover study." Burns 31(7): 831-7.

            INTRODUCTION: The ideal analgesic agent for burns wound dressings in paediatric patients would be one that is easy to administer, well tolerated, and produces rapid onset of analgesia with a short duration of action and minimal side-effects to allow rapid resumption of activities and oral intake. We compared our current treatment of oral morphine to intranasal fentanyl in an attempt to find an agent closer to the ideal. METHODS: A randomised double blind two-treatment crossover study comparing intranasal administration of fentanyl (INF) to orally administered morphine (OM). Children with burn injury aged up to 15 years and weighing 10-75 kg were included. Primary end-point was pain scores. Secondary end-points were time to resumption of age-appropriate activities, time to resumption of fluid intake, sedation and cooperation. Routine observations and vital signs were also recorded. RESULTS: Twenty-four patients were studied with a median age of 4.5 years (interquartile range 1.8-9.0 years) and a median weight of 18.4 kg (interquartile range 12.9-33.2kg). Mean pain difference scores (OM-INF) ranged from -0.500 (95% CI=-1.653 to 0.653) at baseline to -0.625 (05% CI=-1.863 to 0.613) for a retrospective rating of worst pain experienced during the dressing procedure. All measurements were within a pre-defined range of equivalent efficacy. The median time to resumption of fluid intake was 108 min (range 44-175 min) with OM and 140 min (range 60-210 min) with INF. These differences were not statistically significant. Fewer patients experienced mild side-effects with INF compared to OM (n=5 versus n=10). No patients experienced depressed respirations or oxygen saturations. SUMMARY: Intranasal fentanyl was shown to be equivalent to oral morphine in the provision of analgesia for burn wound dressing changes in this cohort of paediatric patients. It was concluded that intranasal fentanyl is a suitable analgesic agent for use in paediatric burns dressing changes either by itself or in combination with oral morphine as a top up titratable agent.

Bregstein, J. S., A. M. Wagh, et al. (2019). "Intranasal Lorazepam for Treatment of Severe Agitation in a Pediatric Behavioral Health Patient in the Emergency Department." Ann Emerg Med.

The treatment of severe agitation, aggression, and violent behavior in behavioral health patients who present to the emergency department (ED) often requires the intramuscular administration of a sedative. However, administering an intramuscular sedative to an uncooperative patient is associated with the risk of needlestick injuries to both patients and health care providers, and times to onset of sedation range from 15 to 45 minutes. Intranasal absorption is more rapid than intramuscular, with sedatives such as lorazepam reaching peak serum concentrations up to 6 times faster when administered intranasally. We present the first report of using intranasal lorazepam as a needle-free method of providing rapid and effective sedation to treat severe agitation in a pediatric behavioral health patient presenting to the ED.

Brunvand, L. and A. Bjerre (1997). "[Light sedation in children. Midazole as nasal drops is a good alternative]." Tidsskr Nor Laegeforen 117(27): 3932-4.

            Many of the procedures carried out on paediatric patients are both painful and frightening to the child. To increase the child's comfort and to promote good working conditions, it may be necessary and advisable to sedate the child. In this study, 125 children (63 boys and 62 girls) were sedated with midazolam. For most children (n = 110) the medication was administered as nose drops. The reasons for sedation were echocardiography (n = 51), venous or lumbar punction (n = 53) and computer tomography scan (n = 21). The overall success rate was 78%. Minor complications were registered in four children. Two children vomited and one child developed a facial rash. One child had prolonged sedation, but this did not affect its respiration. We conclude that midazolam given as nose drops is a safe and convenient way of sedating paediatric patients.

Buonsenso, D., G. Barone, et al. (2014). "Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study." BMC Pediatr 14(1): 67.

BACKGROUND: We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis. Primary outcome: evaluation of Modified Objective Pain Score (MOPS) reduction in children undergoing INKM compared to the placebo group. Secondary outcomes: evaluation of safety of INKM protocol, start time sedation effect, duration of sedation and evaluation of parents and doctors' satisfaction about the procedure. METHODS: In the sedation group, 19 children, mean age 41.5 months, received intranasal Midazolam (0.5 mg/kg) and Ketamine (2 mg/kg). In the placebo group, 17 children received normal saline solution twice in each nostril. The child's degree of sedation was scored using the MOPS. A questionnaire was designed to evaluate the parents' and doctors' opinions on the procedures of both groups. RESULTS: Fifty-seven gastric washings were performed in the sedation-group, while in the placebo-group we performed 51 gastric aspirates. The degree of sedation achieved by INMK enabled all procedures to be completed without additional drugs. The mean duration of sedation was 71.5 min. Mean MOPS was 3.5 (range 1-8) in the sedation-group, 7.2 (range 4-9) in the placebo-group (p <0.0001). The questionnaire revealed high levels of satisfaction by both doctors and parents in the sedation-group compared to the placebo-group. The only side effect registered was post-sedation agitation in 6 procedures in the sedation group (10.5%). CONCLUSIONS: Our experience suggests that atomized INKM makes gastric aspirates more acceptable and easy to perform in children. TRIAL REGISTRATION: Unique trial Number: UMIN000010623; Receipt Number: R000012422.

Burstein, A. H., R. Modica, et al. (1997). "Pharmacokinetics and pharmacodynamics of midazolam after intranasal administration." J Clin Pharmacol 37(8): 711-8.

            This study aimed to characterize the pharmacokinetics and pharmacodynamics of midazolam after intranasal administration to healthy volunteers. Eight participants were given 0.25 mg/kg intranasally and 2 mg intravenously in a randomized, crossover fashion. Blood samples for determination of plasma concentrations of midazolam and measures of cognitive function (using the digit symbol substitution test) were obtained at baseline and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after administration of study medications. Plasma samples were analyzed by gas chromatography (% coefficient of variation &lt; 10%). Pharmacokinetic data were fitted using iterative two-stage analysis to a two-compartment model. Pharmacodynamic data were fitted by a baseline subtraction Hill-type model. The mean (SD) for total clearance, distributional clearance, volume of distribution in the central compartment, volume of distribution in the peripheral compartment, absorption rate constant, bioavailability, and half-life were 0.57 (0.26) L/hr/kg, 0.31 (0.29) L/hr/kg, 0.27 (0.14) L/kg, 0.67 (0.11) L/kg, 2.46 (1.72) hr-1, 50% (13%), and 3.1 (0.84) hours, respectively. The mean (SD) for the concentration at which the effect is half maximal (EC50) and the maximal effect or the maximal change in effect measure from baseline (Emax) were 63.1 (21.2) ng/mL and 52.8 (21.1) correct substitutions, respectively. After intranasal administration, midazolam concentrations rapidly achieve values considered sufficient to induce conscious sedation and produce predictable changes in digit symbol substitution score.

Burstein, A. H., R. Modica, et al. (1996). "Intranasal midazolam plasma concentration profile and its effect on anxiety associated with dental procedures." Anesth Prog 43(2): 52-7.

            The objectives of this study were to describe the serum concentration time profile for midazolam following intranasal administration to adult dental surgery patients and to ascertain the effect of midazolam on anxiety. Six female patients received a single 20 mg (0.32 to 0.53 mg/kg) dose of midazolam. Blood samples were collected at 5, 10, 20, 30, 45, and 60 min following dose administration. Midazolam plasma concentrations were determined by gas chromatography. Anxiety was evaluated using a 100-mm visual analogue scale. The maximum concentration of midazolam was reached 25.8 min (range 18 to 35 min) following dose administration. Maximum concentrations were variable. However, there was no relationship between the weight-adjusted dose and maximal concentration. Patients experiencing baseline anxiety exhibited a trend toward reduction in their measured anxiety score (P = 0.06). Plasma concentrations above the hypothesized minimum effective concentration for sedative effects were attained when midazolam was administered intranasally to adult dental patients.

Cao, Q., Y. Lin, et al. (2017). "Comparison of sedation by intranasal dexmedetomidine and oral chloral hydrate for pediatric ophthalmic examination." Paediatr Anaesth 27(6): 629-636.

            BACKGROUND AND AIM: Pediatric ophthalmic examinations can be conducted under sedation either by chloral hydrate or by dexmedetomidine. The objective was to compare the success rates and quality of ophthalmic examination of children sedated by intranasal dexmedetomidine vs oral chloral hydrate. METHODS: One hundred and forty-one children aged from 3 to 36 months (5-15 kg) scheduled to ophthalmic examinations were randomly sedated by either intranasal dexmedetomidine (2 mug.kg-1 , n = 71) or oral chloral hydrate (80 mg.kg-1 , n = 70). The primary endpoint was successful sedation to complete the examinations including slit-lamp photography, tonometry, anterior segment analysis, and refractive error inspection. The secondary endpoints included quality of eye position, intraocular pressure, onset time, duration of examination, recovery time, discharge time, any side effects during examination, and within 48 h after discharge. RESULTS: Sixty-one children were sedated by dexmedetomidine with a success rate of 85.9%, which is significantly higher than that by chloral hydrate (64.3%) [OR 3.39, 95% CI: 1.48-7.76, P = 0.003]. Furthermore, children in the dexmedetomidine group displayed better eye position in anterior segment analysis than in chloral hydrate group median difference. All children displayed stable hemodynamics and none suffered hypoxemia in both groups. Oral chloral hydrate induced higher percentages of vomiting and altered bowel habit after discharge than dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine provides more successful sedation and better quality of ophthalmic examinations than oral chloral hydrate for small children.

Chatrath, V., R. Kumar, et al. (2018). "Intranasal Fentanyl, Midazolam and Dexmedetomidine as Premedication in Pediatric Patients." Anesth Essays Res 12(3): 748-753.

Background: Surgery is a very stressful experience for patients. Children are the most susceptible to fear, anxiety, and stress due to their limited cognitive capabilities and dependency. In children, pharmacologic agents are frequently used as premedication to relieve the fear of surgery, to make child-parental separation easy, and to carry out a smooth induction of anesthesia. We conducted this study to compare the efficacy of intranasal fentanyl, midazolam, and dexmedetomidine as premedication in pediatric patients. Materials and Methods: The present study was conducted prospectively on 75 patients in the age group of 2-6 years of either sex of the American Society of Anesthesiologists physical Class I or II admitted in Guru Nanak Dev Hospital, attached to Government Medical College Amritsar, scheduled to undergo surgery under general anesthesia. The patients were divided into three groups of 25 each. Group F received intranasal fentanyl 1.5 mug/kg body weight, Group M received intranasal midazolam 0.3 mg/kg body weight, and Group D received intranasal dexmedetomidine 1 mug/kg body weight as nasal drops 50 min before surgery. Results: Children who received intranasal fentanyl and intranasal midazolam had early onset of anxiolysis and sedation as compared to dexmedetomidine. In child-parent separation, quality of induction was better with fentanyl and dexmedetomidine as compared to midazolam. Intravenous cannulation score was best achieved with fentanyl as premedicant. Postoperative sedation was better with dexmedetomidine as compared to fentanyl and midazolam. Conclusion: Onset of action of fentanyl and midazolam is early as compared to that of dexmedetomidine. However, fentanyl provided better conditions for induction and emergence than midazolam. With dexmedetomidine onset of action was delayed and duration of action was prolonged which helped child to remain calm and sedated even after the surgery.

Chen, C., M. You, et al. (2019). "Study of Feasibility and Safety of Higher-Dose Dexmedetomidine in Special Outpatient Examination of Pediatric Ophthalmology." J Ophthalmol 2019: 2560453.

Objective: To investigate the feasibility and safety of higher-dose dexmedetomidine in ophthalmological outpatient examination of children with cataract. Methods: 100 cases of children were recruited in the study and randomly equally divided into two groups. One group was given 2 mug/kg intranasal dexmedetomidine anesthesia, while the other group was under 3 mug/kg. The dosage of dexmedetomidine was calculated by the same anesthesiologist according to the weight of patient. After sufficient sedation, the same ophthalmologist performed ocular examinations manually, including intraocular pressure, keratometry, axial length, and corneal thickness and recorded the ocular position score during intraocular pressure measurement and corneal thickness measurement. Other variables were sedation onset time, recovery time, vital signs, and side effects. Results: In intraocular pressure measurement, only one case in the 2 mug/kg group did not complete the examination, while all cases in the 3 mug/kg group completed the examination and the difference of the success rate between the two groups was nonsignificant (P > 0.05). The success rates of the 3 mug/kg group in corneal curvature, axial length, and corneal thickness examination were 96%, 92%, and 86%, respectively, which were significantly higher than those of the 2 mug/kg group (22%, 18%, and 4%). The average onset time of sedation in the 3 mug/kg group was 15.42 +/- 2.09 minutes, which was significantly shorter than that in the 2 mug/kg group (19.52 +/- 2.43 minutes, P < 0.001). The average time of completing all examinations in the 3 mug/kg group was 18.36 +/- 4.01 minutes, which was significantly shorter than that in the 2 mug/kg group (22.62 +/- 4.13 min, P < 0.001). The recovery time of group 3 mug/kg was 90.62 +/- 27.80 min, which was significantly longer than that of group 2 mug/kg (49.20 +/- 15.50 min). Vital signs such as pulse, blood pressure, oxygen saturation, and heart rate kept in normal range throughout the tests, and no obvious side effects were observed. Conclusion: 3 mug/kg intranasal dexmedetomidine had a higher sedation success rate and quality than 2 mug/kg did in pediatric ocular examinations, without any obvious side effects.

Chen, H., F. Yang, et al. (2020). "Intranasal dexmedetomidine is an effective sedative agent for electroencephalography in children." BMC Anesthesiol 20(1): 61.

BACKGROUND: Intranasal dexmedetomidine (DEX), as a novel sedation method, has been used in many clinical examinations of infants and children. However, the safety and efficacy of this method for electroencephalography (EEG) in children is limited. In this study, we performed a large-scale clinical case analysis of patients who received this sedation method. The purpose of this study was to evaluate the safety and efficacy of intranasal DEX for sedation in children during EEG. METHODS: This was a retrospective study. The inclusion criteria were children who underwent EEG from October 2016 to October 2018 at the Children's Hospital affiliated with Chongqing Medical University. All the children received 2.5 mug.kg(- 1) of intranasal DEX for sedation during the procedure. We used the Modified Observer Assessment of Alertness/Sedation Scale (MOAA/S) and the Modified Aldrete score (MAS) to evaluate the effects of the treatment on sedation and resuscitation. The sex, age, weight, American Society of Anesthesiologists physical status (ASAPS), vital signs, sedation onset and recovery times, sedation success rate, and adverse patient events were recorded. RESULTS: A total of 3475 cases were collected and analysed in this study. The success rate of the initial dose was 87.0% (3024/3475 cases), and the success rate of intranasal sedation rescue was 60.8% (274/451 cases). The median sedation onset time was 19 mins (IQR: 17-22 min), and the sedation recovery time was 41 mins (IQR: 36-47 min). The total incidence of adverse events was 0.95% (33/3475 cases), and no serious adverse events occurred. CONCLUSIONS: Intranasal DEX (2.5 mug.kg(- 1)) can be safely and effectively used for EEG sedation in children.

Cheung, C. W., K. F. Ng, et al. (2011). "Analgesic and sedative effects of intranasal dexmedetomidine in third molar surgery under local anaesthesia." Br J Anaesth 107(3): 430-437.

            BACKGROUND: /st> Dexmedetomidine (DEX) is an alpha 2-adrenoreceptor agonist, which induces sedation and analgesia. This study aimed to determine whether intranasal DEX offered perioperative sedation and better postoperative analgesia. METHODS: /st> Patients having unilateral third molar surgery under local anaesthesia were recruited and allocated to receive either intranasal DEX 1 microg kg(-1) (Group D) or same volume of saline (Group P) 45 min before surgery. Patient-controlled sedation with propofol was offered as a rescue sedative. Perioperative sedation, postoperative pain relief and analgesic consumption, vital signs, adverse events, postoperative recovery, and satisfaction in sedation and analgesia were assessed. RESULTS: /st> Thirty patients from each group were studied. Areas under curve (AUC) of postoperative numerical rating scale (NRS) pain scores 1-12 h at rest and during mouth opening were significantly lower in Group D (P=0.003 and 0.009, respectively). AUC BIS values and OAA/S sedation scores were significantly lower before surgery and at the recovery area (all P<0.01) with significantly less intra-operative propofol used in group D (P<0.01). In group D, heart rate was significantly lower at recovery period (P=0.005) while systolic blood pressure in different periods of the study (all P<0.01), but the decreases did not require treatment. More patients from placebo group experienced dizziness (P=0.026) but no serious adverse event was found. No difference was found in postoperative psychomotor recovery and satisfaction in pain relief and sedation. CONCLUSIONS: /st> Patients receiving intranasal DEX for unilateral third molar surgery with local anaesthesia were more sedated perioperatively with better postoperative pain relief. No delay in psychomotor recovery was seen.

Cheung, C. W., Q. Qiu, et al. (2015). "Intranasal dexmedetomidine in combination with patient-controlled sedation during upper gastrointestinal endoscopy: a randomised trial." Acta Anaesthesiol Scand 59(2): 215-223.

BACKGROUND: Sedation using intranasal dexmedetomidine is a convenient and well-tolerated technique. This study evaluated the sedative efficacy of intranasal dexmedetomidine in combination with patient-controlled sedation (PCS) for upper gastrointestinal endoscopy. METHODS: In this double-blind, randomised, controlled trial, 50 patients received either intranasal dexmedetomidine 1.5 mug/kg (dexmedetomidine group) or intranasal saline (placebo group) 1 h before the procedure. PCS with propofol and alfentanil was provided for rescue sedation. Additional sedative consumption, perioperative sedation scores using Observer's Assessment of Alertness/Sedation (OAA/S) scale, recovery, vital signs, adverse events and patient satisfaction were assessed. RESULTS: Total consumption of PCS propofol and alfentanil was significantly less in the dexmedetomidine than placebo group with a mean difference of -13.8 mg propofol (95% confidence interval -27.3 to -0.3) and -34.5 mug alfentanil (95% confidence interval -68.2 to -0.7) at the completion of the procedure (P = 0.044). Weighted areas under the curve (AUCw ) of OAA/S scores were significantly lower in the dexmedetomidine group before, during and after procedures (P < 0.001, P = 0.024 and P = 0.041 respectively). AUCw of heart rate and systolic blood pressure were also significantly lower during the procedure (P = 0.007 and P = 0.022 respectively) with dexmedetomidine. There was no difference in recovery, side effects or satisfaction. CONCLUSION: Intranasal dexmedetomidine with PCS propofol and alfentanil confers deeper perioperative clinical sedation with significantly less use of additional sedatives during upper gastrointestinal endoscopy.

Chiaretti, A., G. Barone, et al. (2010). "Intranasal lidocaine and midazolam for procedural sedation in children." Arch Dis Child.

Chokshi, A. A., V. R. Patel, et al. (2013). "Evaluation of intranasal Midazolam spray as a sedative in pediatric patients for radiological imaging procedures." Anesth Essays Res 7: 189·193.

Context: Preoperative anxiety and uncooperativeness experienced by pediatric patients are commonly associated with postoperative behavioral problems. Aims: We aimed to evalute the efficacy and safety of intranasal Midazolam as a sedative in a pediatric age group for radiological imaging procedures and to note onset of sedation, level of sedation, condition of patient during separation from parents and effect on the cardio-respiratory system. Settings and Design: Randomized double-blinded study. Subjects and Methods: Fifty patients of t e pediatric age group of American Society of Anesthesiologist grade 2 and 3 who came for any radiological imaging procedures were studied. Patients were randomly allocated to receive, intranasally, either Midazolam 0.5 mg/kg (group A NO = 25) or normal saline (group 8 N = 25) in both nostrils (0.25 mg/kg in each) 15 min before the procedure. Time for onset of sedation and satisfactory sedation, sedation score, separation score, hemodynamic changes and side-effects were recorded. Statistical Analysis Used: Student«SQ»s t-test. Results: Intranasal Midazolam group had a significantly shorter time for onset of sedation and satisfactory sedation. Mean sedation score and mean separation score at 10 min and 15 min intervals were significant in intranasal Midazolam as compared with normal saline (P < 0.001). Conclusions: Intranasal Midazolam 0.5 mglkg is safe and effective and provides adequate sedation or easy separation from the parents and reduced requirement of intravenous supplementation during radiological imaging procedures without any untoward side-effects.

Cioaca, R. and I. Canavea (1996). "Oral transmucosal ketamine: an effective premedication in children." Paediatr Anaesth 6(5): 361-5.

            The oral cavity offers a simple, painless way of drug administration. For this reason, we used oral transmucosal ketamine (5-6 mg.kg-1) for premedication in 25 children and compared it with intranasal ketamine (5-6 mg.kg-1), placebo and intramuscular ketamine (5-6 mg.kg-1). Oral transmucosal ketamine (OTK) provided effective sedation, facilitated i.v. line insertion and was accepted with pleasure by the patients (as lollipops). The lollipops produced a slight increase in gastric volumes but did not affect gastric pH. In conclusion OTK has been shown to be an effective, harmless preoperative medication in paediatric patients.

Connors, K. and T. E. Terndrup (1994). "Nasal versus oral midazolam for sedation of anxious children undergoing laceration repair." Ann Emerg Med 24(6): 1074-9.

            STUDY OBJECTIVE: To compare the efficacy and safety of a single dose of midazolam, as an oral solution of 0.5 mg/kg, or nasal drops of 0.25 mg/kg, in children undergoing emergency department laceration repair. DESIGN: Double-blind, double-placebo, randomized trial. Children underwent standard wound care when judged to demonstrate a reduction in anxiety following study medication. PARTICIPANTS: Fifty-eight patients between 1 and 10 years of age with uncomplicated lacerations judged to be anxious by emergency physicians. RESULTS: An anxiety score and vital signs were recorded at routine intervals. Groups were comparable with respect to age, laceration characteristics, initial vital signs, and anxiety scores. Both groups demonstrated reductions (mean +/- SD) in anxiety scores over time (P &lt; .05; maximum at 10 minutes; 1.2 +/- 0.9 mm for nasal and 0.8 +/- 1.3 for oral), with no significant differences between groups (repeat-measures ANOVA). Median observer-rated effectiveness using a visual analog scale (maximum effectiveness, 10 mm) was not significantly different between groups: nasal, 7.6 mm and oral, 6.9 (Mann-Whitney U test: minimum detectable difference, 0.7, with alpha = 0.05 and beta = 0.2). Complications were judged to be minor only, and were more frequent in the nasal group (5 of 28, 4 with nasal burning) versus 1 of 26 in the oral group. Time from midazolam to ED discharge was not significantly different between groups: nasal, 54 +/- 15 minutes and oral, 57 +/- 16 minutes. CONCLUSION: A single dose of oral or nasal midazolam results in reduced anxiety and few complications in selected children undergoing laceration repair in the ED. The oral route was associated with fewer administration problems.

Cozzi, G., S. Lega, et al. (2016). "Intranasal Dexmedetomidine Sedation as Adjuvant Therapy in Acute Asthma Exacerbation With Marked Anxiety and Agitation." Ann Emerg Med.

We describe 2 patients with acute asthma exacerbation who were admitted to the emergency department (ED) with severe agitation and restlessness as a prominent finding, for which bedside asthma treatment sedation with intranasal dexmedetomidine was performed. In both cases, dexmedetomidine allowed the patients to rest and improved tolerance to treatment. Dexmedetomidine is a unique sedative with an excellent safety profile and minimal effect on respiratory function. These properties render it particularly promising for the management of severe agitation in children admitted to the ED with acute asthma exacerbation.

Cozzi, G., S. Norbedo, et al. (2017). "Intranasal Dexmedetomidine for Procedural Sedation in Children, a Suitable Alternative to Chloral Hydrate." Paediatr Drugs 19(2): 107-111.

            Sedation is often required for children undergoing diagnostic procedures. Chloral hydrate has been one of the sedative drugs most used in children over the last 3 decades, with supporting evidence for its efficacy and safety. Recently, chloral hydrate was banned in Italy and France, in consideration of evidence of its carcinogenicity and genotoxicity. Dexmedetomidine is a sedative with unique properties that has been increasingly used for procedural sedation in children. Several studies demonstrated its efficacy and safety for sedation in non-painful diagnostic procedures. Dexmedetomidine's impact on respiratory drive and airway patency and tone is much less when compared to the majority of other sedative agents. Administration via the intranasal route allows satisfactory procedural success rates. Studies that specifically compared intranasal dexmedetomidine and chloral hydrate for children undergoing non-painful procedures showed that dexmedetomidine was as effective as and safer than chloral hydrate. For these reasons, we suggest that intranasal dexmedetomidine could be a suitable alternative to chloral hydrate.

Dallman, J. A., M. A. Ignelzi, Jr., et al. (2001). "Comparing the safety, efficacy and recovery of intranasal midazolam vs. oral chloral hydrate and promethazine." Pediatr Dent 23(5): 424-30.

            PURPOSE: The purpose of this study was to compare the safety, efficacy and recovery time of intranasal midazolam spray administered using an atomizer to orally administered chloral hydrate and promethazine for the sedation of pediatric dental patients. METHODS: A randomized double- blind crossover study design was utilized in which 31 patients (mean age 41.8 months, range 26-58 months) underwent two restorative dental appointments. At one appointment, subjects received 0.2 mg/kg intranasal midazolam; at the other appointment subjects received 62.5 mg/kg chloral hydrate with 12.5 mg promethazine. Administered at each appointment was 25%-50% N(2)0/0(2). Physiologic parameters (heart rate, blood pressure, respiratory rate, oxygen saturation) and behavior assessments (crying, movement, sleep) using the Houpt Sedation Rating Scale were recorded at baseline and every five minutes during treatment. Overall behavior was assessed at baseline and at the end of treatment. Following treatment, a modified Vancouver Recovery Scale was used to determine the length of time it took each subject to meet established discharge criteria. RESULTS: There were no clinically significant differences in physiologic parameters, however a statistically significant decrease in systolic and diastolic blood pressure was observed in patients sedated with chloral hydrate/promethazine. There were no significant differences in behavior between groups. Patients sedated with intranasal midazolam slept less and recovered quicker than patients sedated with oral chloral hydrate/promethazine. CONCLUSIONS: Intranasal midazolam administered using an atomizer is as safe (as assessed by physiologic parameters) and effective (as assessed by behavior ratings) as oral chloral hydrate/promethazine for conscious sedation of pediatric dental patients.

Dhingra, D., B. Ghai, et al. (2020). "Evaluation of Intranasal Dexmedetomidine as a Procedural Sedative for Ophthalmic Examination of Children With Glaucoma." J Glaucoma 29(11): 1043-1049.

PRECIS: This study evaluated 2 doses of intranasal dexmedetomidine (IND) (3.0 and 3.5 microg/kg) as a procedural sedative for postoperative examination of children with glaucoma. A dose of 3.5 microg/kg was more efficacious and obviated the need for repeated general anesthesia. PURPOSE: This study was carried out to determine the safety and effective dose of IND as a procedural sedative for postoperative follow-up examinations after glaucoma surgery in children in place of repeated examination under anesthesia. MATERIALS AND METHODS: In this prospective randomized double-blinded interventional study, consecutive children aged 6 months to 6 years were randomized to receive 3.0 and 3.5 microg/kg IND using a mucosal atomizer device in the preoperative area of the operating room, under continuous monitoring of vital signs. Intranasal midazolam 0.25 mg/kg was used as a rescue agent in case of inadequate sedation, and general anesthesia was administered in case of persistent failure. All infants underwent a complete anterior and posterior segment evaluation including intraocular pressure and corneal diameter measurements. RESULTS: A total of 30 and 31 children aged 23.9+/-15.0 and 19.2+/-10.1 months, respectively, received 3.0 and 3.5 microg/kg IND. Adequate sedation was possible in 18 of 30 (60%) children receiving 3.0 microg/kg and 24 of 31 (77.4%) receiving 3.5 microg/kg IND alone (P=0.17). In combination with midazolam, successful sedations were 86.6% versus 100%, respectively (P=0.052). One patient in the 3.5 microg/kg group had ventricular arrhythmia, reversed with dextrose-saline infusion and injection glycopyrrolate. CONCLUSIONS: IND appears to be a safe and effective procedural sedative for postoperative follow-up examinations of pediatric glaucoma patients at doses of 3 and 3.5 microg/kg. The dose of 3.5 microg/kg was successful in more children.

Diaz, J. H. (1997). "Intranasal ketamine preinduction of paediatric outpatients." Paediatr Anaesth 7(4): 273-278.

                A double-blinded, placebo-controlled study compared the outcomes of intranasal ketamine premedication with placebo in outpatients. Forty paediatric outpatients were assigned randomly in a prospective fashion to one of two separate study groups of equal size (20 patients per group). A placebo group received 2 ml of intranasal saline, 1 ml per naris. The study group received intranasal ketamine, 3 mg.kg-1, diluted to 2 ml with saline, 1 ml per naris. Using a cooperation index, a play therapist scored resistance to nasal instillation, separation of the child from parents at ten min, and acceptance of anaesthesia monitors and face mask at 15 min. Differences in age, weight, episodes of vomiting, recovery and discharge times among the two groups were not significant. Intranasal ketamine, 3 mg.kg-1, was associated with a significantly better (P = 0.013) cooperation index than intranasal placebo. Intranasal ketamine, permitted pleasant and rapid separation of children from their parents, cooperative acceptance of monitoring and of mask inhalation induction, and did not cause prolonged postanaesthetic recovery or delayed discharge home.

El-Hamid, A. M. A. and H. M. Yassin (2017). "Effect of intranasal dexmedetomidine on emergence agitation after sevoflurane anesthesia in children undergoing tonsillectomy and/or adenoidectomy." Saudi J Anaesth 11(2): 137-143.

Eskandarian, T., S. Arabzade Moghadam, et al. (2015). "The effect of nasal midazolam premedication on parents-child separation and recovery time in dental procedures under general anaesthesia." Eur J Paediatr Dent 16(2): 135-138.

                AIM: For many children medical and dental procedures, unfamiliar dental staff and treatment places are disturbing and stressful. Stress in children often makes them uncooperative. General anaesthesia is indicated for anxious uncooperative children or those who are disabled, immature or too young to undergo dental treatment by other means. Moreover parents' separation while entering the operative room is a traumatic experience for children. Thus premedication such as midazolam is recommended to decrease child's stress. In these situations the increased recovery time was considered as one of the midazolam side effects. There is no study that evaluated the effect of midazolam both in parents-child separation and recovery time in long dental procedure. The purpose of this study was to evaluate the effect of nasal midazolam premedication with placebo on parents-child separation and recovery times in uncooperative paediatric patients undergoing long-lasting general anaesthesia for dental procedures. MATERIALS AND METHODS: STUDY DESIGN: This randomised, double-blind study was done on 60 uncooperative patients (ASA physical status I or II) aged 2-4 years who were scheduled for general anaesthesia for dental treatment. Group A received 0.2 mg/kg intranasal midazolam as premedication, and group B received the same volume of intranasal placebo 20 minutes before entering the operating room for general anaesthesia. General anaesthesia was done with the same method for all patients, then parent-child separation and recovery times were compared between the two groups. STATISTICAL ANALYSIS: Statical significance was set at P</=0.05. Statically analysis was performed using SPSS version17.Chi-squared and student t-tests were applied to analyse the data. RESULTS: We found significant differences in parents- child separation assessment between two groups. Nasal midazolam premedication had a positive effect on parents-child separation; but there was no significant difference between the two groups in terms of recovery time. CONCLUSION: Premedication of nasal midazolam before induction of general anaesthesia did not prolong recovery time but made the separation of children from their parents easier by showing a better behaviour.

Everitt, I. J. and P. Barnett (2002). "Comparison of two benzodiazepines used for sedation of children undergoing suturing of a laceration in an emergency department." Pediatr Emerg Care 18(2): 72-4.

            OBJECTIVES: (1) To determine if oral diazepam (POD) is as effective in sedating children less than 6 years of age for laceration repair as oral midazolam (POM) or intranasal midazolam (INM); and (2) To determine if patients stayed longer in the department after sedation when given POD for sedation. DESIGN/METHODS: Block-randomized, single- blind trial. SETTING: Tertiary pediatric emergency department. PARTICIPANTS: Patients 1 to 5 years old with a laceration requiring sutures were enrolled. INTERVENTIONS: All patients had topical anesthetic applied to the wound and were randomly assigned to POD 0.5 mg/kg, POM 1.0 mg/kg, or INM 0.4 mg/kg for sedation. RESULTS: One hundred twenty-nine patients were enrolled, 42 POD, 45 POM, and 42 INM. Each group was similar at baseline for age, heart rate, respiratory rate, blood pressure, oxygen saturation, previous laceration or sedation, anxiety score, and site of laceration. POM and POD were better tolerated than INM (P = 0.05 and 0.034), respectively. Time to sedation was significantly longer in POD (31.0 +/- 9 min) than INM (26.1 +/- 9 min) (P = 0.011) but there was no significant difference when comparing the other groups. However, this difference was not clinically significant. POD was significantly worse at sedating children compared with POM and INM on all four scores (ie, doctor, nurse, parent, and investigator), but INM and POM were equivalent. Total time in the department was no different between POM and INM or POM and POD, but was significantly different for POD (53.9 +/- 16 min) and INM (48 +/- 12 min); however, this difference was minimal. More patients were said to be drowsy at home in the POM group (51%) than the POD group (32%). CONCLUSIONS: The oral route of delivery of POM and POD was better tolerated than INM. POM and INM were more effective at sedation than POD, but there was no clinical difference between any groups for time to sedation or time to discharge. More patients in the POM group had side effects after leaving the department. POD may be an alternative to POM, but a higher dose may be required, possibly with longer recovery times.

Fallahinejad Ghajari, M., G. Ansari, et al. (2015). "Comparison of Oral and Intranasal Midazolam/Ketamine Sedation in 3-6-year-old Uncooperative Dental Patients." J Dent Res Dent Clin Dent Prospects 9(2): 61-65.

                Background and aims. There are several known sedative drugs, with midazolam and ketamine being the most commonly used drugs in children. The aim of this study was to compare the effect of intranasal and oral midazolam plus ketamine in children with high levels of dental anxiety. Materials and methods. A crossover double-blind clinical trial was conducted on 23 uncooperative children aged 3-6 (negative or definitely negative by Frankel scale), who required at least two similar dental treatment visits. Cases were randomly given ketamine (10 mg/kg) and midazolam (0.5 mg/kg) through oral or intranasal routes in each visit. The sedative efficacy of the agents was assessed by an overall success rate judged by two independent pediatric dentists based on Houpt's scale for sedation. Data analysis was carried out using Wilcoxon test and paired t-test. Results. Intranasal administration was more effective in reduction of crying and movement during dental procedures compared to oral sedation (P<0.05). Overall behavior control was scored higher in nasal compared to oral routes at the time of LA injection and after 15 minutes (P<0.05). The difference was found to be statistically significant at the start and during treatment. However, the difference was no longer significant after 30 minutes, with the vital signs remaining within physiological limits. Recovery time was longer in the intranasal group (P<0.001) with a more sleepy face (P=0.004). Conclusion. . Intranasal midazolam/ketamine combination was more satisfactory and effective than the oral route when sedating uncooperative children.

Fantacci, C., G. C. Fabrizio, et al. (2018). "Intranasal drug administration for procedural sedation in children admitted to pediatric Emergency Room." Eur Rev Med Pharmacol Sci 22(1): 217-222.

OBJECTIVE: Pain relief is a very important aspect in Pediatrician's clinical practice. It is often thought that young children, particularly infants, do not perceive as much pain as adults because of their immature nervous system and that untreated pain would not have adverse long-term consequences. Instead, it has been demonstrated that infants and children experience pain in a similar manner to adults. Many factors, particularly emotional factors, can increase the child's pain perception. Children live with anxiety even minor procedures. This suggests the need for an adequate sedation and the way of sedation should be free of pain itself. We believe the route to be followed may be the intranasal (IN) administration of sedative drugs. MATERIALS AND METHODS: We have conducted a brief review of the literature by Pubmed about the most commonly used sedative drugs: sufentanyl, fentanyl, midazolam, ketamine, nitrous oxide and dexmedetomidine. We have investigated in the literature the type of administration of IN drugs: drop instillation or by a mucosal atomizer device (MAD). RESULTS: In our study, it was noted that IN drugs administration is an effective and safe method to reduce anxiety and to deliver analgesia because it is practical and non-invasive. Moreover, therapeutic levels of sedatives are low due to the presence of a rich vascular plexus in the nasal cavity, which communicates with the subarachnoid space via the olfactory nerve and reduce the time of medication delivery, that is, the onset of action. The use of MAD even gives as better bioavailability of drugs. CONCLUSIONS: IN sedation via MAD is effective and safe and should be one of the first choices for procedural sedation in children.

Filho, E. M., W. B. de Carvalho, et al. (2013). "Aerosolized intranasal midazolam for safe and effective sedation for quality computed tomography imaging in infants and children." J Pediatrics 163: 1217-1219.

This pilot study introduces the aerosolized route for midazolam as an option for infant and pediatric sedation for computed tomography imaging. This technique produced predictable and effective sedation for quality computed tomography imaging studies with minimal artifact and no significant adverse events.

Fishbein, M., R. A. Lugo, et al. (1997). "Evaluation of intranasal midazolam in children undergoing esophagogastroduodenoscopy." J Pediatr Gastroenterol Nutr 25(3): 261-6.

            BACKGROUND: Intravenous midazolam and opioids are used to produce conscious sedation in children undergoing esophagogastroduodenoscopy (EGD). However, children may experience significant fear and anxiety before receiving these medications, especially during separation from parents and during venipuncture. Intranasal administration of midazolam represents a noninvasive method of sedating children before anxiety-producing events. The objective of this study was to determine whether premedication with intranasal midazolam reduces stress and anxiety of separation from parents and of undergoing venipuncture, while maintaining adequate sedation during EGD. METHODS: This was a prospective, randomized, double-blind study in 40 children, aged 2 to 12 years, who were undergoing EGD. Patients in group I were premedicated with intranasal placebo (0.9% NaCl) followed 10 minutes later by intravenous midazolam (0.05 mg/kg) and intravenous meperidine (1 mg/ kg). Patients in group II were premedicated with intranasal midazolam (0.2 mg/kg) followed by intravenous placebo (0.9% NaCl) and intravenous meperidine (1 mg/kg). Anxiolysis and sedation were scored by a blinded observer, who identified minor and major negative behaviors during four observation periods: intranasal drug administration, separation from parents, venipuncture, and EGD. RESULTS: Premedication with intranasal midazolam significantly reduced negative behaviors during separation from parents (p &lt; 0.05); however, no difference between regimens was noted during venipuncture or EGD. Negative behaviors appeared to increase during administration of intranasal midazolam or placebo. CONCLUSIONS: Premedication with intranasal midazolam is effective in reducing negative behaviors during separation from parents, while it maintains sedation during the endoscopic procedure. The benefits of intranasal administration may be negated, however, by irritation, and discomfort caused by intranasal drug delivery.

Fuks, A. B., E. Kaufman, et al. (1994). "Assessment of two doses of intranasal midazolam for sedation of young pediatric dental patients." Pediatr Dent 16(4): 301-5.

            The purpose of this study was to assess the effectiveness of two doses of intranasal midazolam on sedation of young children for dental treatment. Thirty uncooperative children, mean age of 32 months, who needed at least two restorative visits, participated in this study. The patients were assigned randomly to receive either 0.2 mg/kg or 0.3 mg/kg of midazolam intranasally, with the alternate regimen administered at the second appointment. All the children received 50% nitrous oxide, and were restrained in a Papoose Board (Olympic Medical Group, Seattle, WA) with a head holder. Degree of alertness, crying, and movement were evaluated at baseline and at 5-min intervals throughout the procedure. Evaluation of overall behavior at each session was performed by one investigator, blind to the dose, using a separate rating scale. The reliability of ratings was assessed by two investigators from videotapes of the procedures. Statistical analysis showed no differences (P &gt; 0.05) in the behavior of the children receiving the two doses. Successful sedation, as assessed by lack of or minimal crying and/or movement that interrupted treatment, was observed in all the treatment visits with both doses (mean score 4.66 +/- 1.09 for 0.3 mg and 4.40 +/- 1.04 for 0.2 mg). No adverse effects were observed, and all the treatments were completed successfully.

Fukuta, O., R. L. Braham, et al. (1993). "The sedative effect of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 1. The effect of a 0.2 mg/kg dose." J Clin Pediatr Dent 17(4): 231-7.

            The purpose of this study was to determine the sedative effect of a 0.2 mg/kg dose of midazolam, administered intranasally, prior to performing various restorative dental procedures on a group of mentally disabled patients under local anesthesia and nitrous oxide/oxygen analgesia. Twenty-one patients, aged 4 to 21 years, all of whom had previously exhibited highly combative and resistant behavior toward dental treatment under local anesthesia, were sedated with 0.2 mg/kg midazolam. Only patients assessed as ASA anesthesia status I or II were admitted to the study. After administering the midazolam, each patient was allowed to rest before initiating the dental procedures. Behavioral patterns during the various procedures were rated on a behavioral rating scale of 1-7. Each patient served as his or her own control, comparing behavior with or without intranasal midazolam. The results showed a marked improvement in behavioral patterns after administration of intranasal midazolam. Ratings on a scale of 1-7 were noted as &quot;markedly effective&quot; and &quot;effective&quot; for 69.2% of those patients who received infiltration injection anesthesia, 93.8% under rubber dam, 76.2% during cavity preparation, 84.2% for restoration placement and 87.5% during pulpotomy procedures. The majority of patients were discharged within 150 minutes of intranasal instillation. Further studies are indicated to ascertain the most appropriate dose of intranasally administered midazolam.

Fukuta, O., R. L. Braham, et al. (1994). "The sedative effects of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 2: optimal concentration of intranasal midazolam." J Clin Pediatr Dent 18(4): 259-65.

            In a previous paper, we reported on the effect of a 0.2 mg/kg dose of midazolam, administered intranasally, prior to performing various restorative dental procedures on a group of mentally disabled patients under local anesthesia and nitrous oxide/oxygen analgesia. The purpose of this study was to compare the clinical and possible adverse effect of doses of 0.2 mg/kg and 0.3 mg/kg midazolam, administered intranasally, and to determine the most appropriate concentration for the drug when administered by this route. Patients were assessed by a behavioral test which consisted of a scale from 1-7 with 3 ranges: markedly effective (1-3), effective (4-5) or ineffective (6-7). Forty- three mentally handicapped patients, aged 5 to 20 years, all of whom had previously exhibited highly combative and resistant behavior toward dental treatment under local anesthesia, were stratified by age and randomly assigned in a double blind manner to two groups, receiving either 0.2 mg/kg or 0.3 mg/kg midazolam administered intranasally. Group 1, consisting of 22 patients, average age 11 years 8 months, received 0.2 mg/kg. Group 2 consisted of 21 patients, average age 13 years 8 months, each of whom was administered 0.3 mg/kg intranasal midazolam. Only patients assessed as ASA anesthesia status I or II were admitted to the study. Subsequent to intranasal administration of midazolam, no patient rejected the nasal mask nor refused to inhale nitrous oxide/oxygen. The induction of nitrous oxide/oxygen sedation and oral examination were effected smoothly in every case in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Fukuta, O., R. L. Braham, et al. (1997). "Intranasal administration of midazolam: pharmacokinetic and pharmacodynamic properties and sedative potential." ASDC J Dent Child 64(2): 89-98.

            This study investigated the pharmacodynamic effects and sedative potential of midazolam administered by the intranasal route to adult volunteers. A double-blind, randomized, controlled study was carried out on seventeen healthy, male volunteers to study plasma level changes, sedative effects and variations in vital signs following intranasal administration of 0.2 mg/kg and 0.3 mg/kg doses of midazolam. Eight subjects received 0.2 mg/kg midazolam, seven received 0.3 mg/kg. Each subject rested for 15-20 minutes after placement of vital sign monitors and venipuncture needles before administration of midazolam. Behavior during the rest period was designated as the control so that each subject acted as his own control. Each subject's behavior was assessed on a scale of 1 (asleep) to 8 (excited). Plasma concentrations of midazolam were analyzed using venous blood samples from each of three randomly selected subjects for each of the two doses. Vital signs, monitored continuously, included electrocardiogram, heart rate, blood pressure, respiratory rate and oxygen saturation (SPO2). Plasma concentration of midazolam in both groups maintained adequate sedation levels with each group sustaining favorable sedation conditions from 15-20 minutes to 55-60 minutes. Individual variations of midazolam plasma concentration within the 0.3 mg/kg group were greater than those of the 0.2 mg/kg group. Normal vital sign variations due to the nasal instillation of midazolam were observed in both groups. Some minor respiratory depression was observed in the 0.2 mg/kg group. One instance of severe respiratory depression was observed in the higher dose group. Although both doses of midazolam were effective, no benefit was observed using a dose of 0.3 mg/kg. Indeed, a 0.3 mg/kg intranasal dose of midazolam may actually produce severe respiratory depression.

Gan, X., H. Lin, et al. (2016). "Rescue Sedation With Intranasal Dexmedetomidine for Pediatric Ophthalmic Examination After Chloral Hydrate Failure: A Randomized, Controlled Trial." Clin Ther 38(6): 1522-1529.

PURPOSE: It is a challenge to rescue ophthalmology examinations performed in children in the sedation room after initial chloral hydrate failure. Intranasal dexmedetomidine can be used in rescue sedation in children undergoing computed tomography. The present study aimed to assess the efficacy and tolerability of intranasal dexmedetomidine use in children undergoing ophthalmic examination after chloral hydrate failure. METHODS: Sixty uncooperative pediatric patients with cataract (aged 5-36 months; weight, 7-15 kg) presented for follow-up ophthalmic examination. Patients who experienced chloral hydrate failure were randomized to 1 of 2 groups to receive intranasal dexmedetomidine 1 or 2 mug/kg for rescue sedation. Each group contained 30 patients. The primary outcome was the rate of a successful ophthalmic examination. Secondary outcomes included sedation onset time, recovery time, duration of examination, discharge time, and adverse events, including percentage of heart rate reduction, respiratory depression, vomiting, and postsedative agitation. FINDINGS: A successful ophthalmic examination was achieved in 93.3% (28/30) of patients in the 2-mug/kg dose group and in 66.7% (20/30) of patients in the 1-mug/kg dose group (P = 0.021). The onset time, recovery time, and discharge time did not significantly differ between the 2 groups. None of the patients required clinical intervention due to heart rate reduction, and none of the patients in either group experienced vomiting, respiratory depression, or agitation after the administration of dexmedetomidine. IMPLICATIONS: In children undergoing ophthalmic examination, intranasal dexmedetomidine can be administered in the sedation room for rescue sedation after chloral hydrate failure, with the 2-mug/kg dose being more efficacious than the 1-mug/kg dose, as measured by success rate. ClinicalTrials.gov identifier: NCT02077712.

Gao, L., Y. Liu, et al. (2018). "[Effects of intranasal dexmedetomidine for children undergoing dental rehabilitation under general anesthesia: a double-blinded randomized controlled trial]." Beijing Da Xue Xue Bao Yi Xue Ban 50(6): 1078-1082.

OBJECTIVE: To observe the preoperative sedation, the status of separation from parents, compliance with the mask, hemodynamic parameters and postoperative agitation of intranasal dexmedetomidine (DEX) premedication on children undergoing dental rehabilitation under general anesthesia. METHODS: In the study, 60 children of American Society of Anesthesiology classification (ASA I-II), aged 2-9 years, were randomly assigned to one of two equal groups. Thirty minutes before operation, control group received intranasal placebo (0.9% saline) 0.02 mL/kg, and DEX group received intranasal DEX 2 mug/kg. The preoperative sedation score, the status of separation from parents, compliance with the mask and hemodynamic parameters were recorded by an anesthesiologists until anesthesia induction. Recovery conditions, postoperative agitation were also recorded. RESULTS: There was no significant difference between the two groups in patient characteristics, operation time, extubation time and recovery time. Compared with the children in control group, those in DEX group were significantly more sedated when they were separated from their parents (56.7% vs. 26.7%, P<0.05). Satisfactory compliance with mask application was 40% in control group vs. 73.3% in DEX group (P<0.05). There was no significant difference between the two groups regarding the incidences of postoperative agitation and oxygen saturation (SpO2). Compared with control group, the heart rate (HR) of DEX group was decreased after 20 minutes of drug administration [(97.13+/-12.93) beats/min vs.(104.53+/-11.97) beats/min, P<0.05]. The changes of the HR and SpO2 in the two groups were within the normal range. There were no incidences of bradycardia and hypoxemia in either of the groups during study observation. CONCLUSION: Premedication with intranasal DEX 2 mug/kg for children undergoing dental rehabilitation under general anesthesia produces good preoperative sedation. The levels of sedation, scores of parental separation and compliance with the mask were satisfied. The children have good recovery conditions, and no obvious postoperative agitation and respiratory depression after DEX administration. Intranasal DEX 2 mug/kg is an effective and safe alternative for premedication in children.

Gautam, S. N., S. Bhatta, et al. (2007). "Intranasal midazolam Vs ketamine as premedication in paediatric surgical procedure for child separation and induction." Nepal Med Coll J 9(3): 179-181.

                In children pre-anaesthetic medications are frequently administered as pharmacological adjunctions to help alleviate the stress and fear of surgery as well as to ease child parental separation and promote a smooth induction. Oral, rectal, intravenous and intramuscular route has been used; however each route has its disadvantage. Pre-anaesthetic medication administered intranasal for avoidance of painful injection have made it a convenient way to pre-medication. To evaluate the efficacy of intranasal administered Midazolam 0.2 mg/kg and Ketamine 5 mg/kg respectively. Total 50 patients of ASA I and II of age group 1- 7 years, mean age 3.88 +/- 1.26 and 4.56 +/- 1.21 were included in group I and group II respectively, and Scheduled for elective surgery. Mean time of separation was 17.12 +/- 1.21 in-group I and 15.68+11.62 in group II with P value < 0.001 and 0.322, shows significant difference during time of separation from parents and no significant difference for i.v. line insertion in both groups.

Ghai, B., K. Jain, et al. (2017). "Comparison of oral midazolam with intranasal dexmedetomidine premedication for children undergoing CT imaging: a randomized, double-blind, and controlled study." Paediatr Anaesth 27(1): 37-44.

BACKGROUND: Children undergoing computerized tomography (CT) frequently require sedation to allay their anxiety, and prevent motion artifacts and stress of intravenous (IV) cannulation. AIMS: The aim of this trial was to compare the effectiveness of oral midazolam and intranasal dexmedetomidine as sole premedicants in children for carrying out both IV cannulation as well as CT scanning, without the need for additional IV sedatives. METHODS: Fifty-nine children, aged 1-6 years, scheduled to undergo CT imaging under sedation were randomized to receive either 0.5 mg.kg-1 oral midazolam (group M) or 2.5 mcg.kg-1 intranasal dexmedetomidine (group D). After 20-30 min, intravenous cannulation was performed and response to its placement was graded using the Groningen Distress Rating Scale (GDRS). After cannulation, children were transferred on the CT table, and assessed using the Ramsay sedation score (RSS). CT imaging was performed without any further sedative if the RSS was >/=4. If there was movement or decrease in sedation depth (RSS </= 3), ketamine 1 mg.kg-1 IV was given as an initial dose, followed by subsequent doses of 0.5 mg.kg-1 IV if required. RESULTS: A Significantly higher proportion of children in group D (67%) achieved RSS >/= 4 as compared to group M (24%) (P-0.002). The risk ratio (95% CI) was 2.76 (1.38-5.52). Significantly lower GDRS scores were noted in group D (1(1-2)) as compared to group M (2(1-2)) at the time of venipuncture (P = 0.04). CONCLUSION: In the doses and time intervals used in our study, intranasal dexmedetomidine (2.5 mug.kg-1 ) was found to be superior to oral midazolam (0.5 mg.kg-1 ) for producing satisfactory sedation for CT imaging.

Gharde, P., S. Chauhan, et al. (2006). "Evaluation of efficacy of intranasal midazolam, ketamine and their mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair." Ann Card Anaesth 9(1): 25-30.

                We compared the efficacy of intranasal midazolam, ketamine and their mixture as premedication in children with tetralogy of Fallot (TOF) using bispectral index (BIS), sedation score and separation score at the time of separation from parent. Sedation score at the time of intravenous cannulation was also measured. Children with TOF physiology were randomly divided into three equal groups of 20 each. Group-A received intranasal ketamine (10 mg/Kg), Group-B received intranasal midazolam (0.2 mg/Kg), while Group-C received a mixture of ketamine (7.5 mg/Kg) and midazolam (0.1 mg/Kg) intranasally. After 30 minutes of premedication, sedation and separation score were noted. BIS values were recorded at 5 minutes intervals. A 4-point scale for sedation, separation and acceptance of intravenous cannulation was used. Sedation was good in midazolam group (group B-3.25 +/- 0.44), but the separation and acceptance of intravenous catheter was poor (2.9 +/- 0.31 and 2.85 +/- 0.37 respectively). Sedation scores in group A and C were excellent (3.75 +/- 0.44 and 3.80 +/- 0.41 respectively). Separation from parent was excellent in group A (ketamine) and group C (mixture) (group A- 3.90 +/- 0.28 and group C- 3.83 +/- 0.35 respectively). Children of both these groups allowed easy placement of intravenous cannula. At BIS values < 90, the sedation achieved was good. BIS values decreased with increase in sedation scores in groups who received intranasal midazolam and mixture containing ketamine and midazolam (group B and C respectively), while it remained high in children who received ketamine. We conclude that intranasal ketamine is better than intranasal midazolam. The combination of two is better than midazolam alone but provides no benefit as compared with ketamine alone.

Gilchrist, F., A. M. Cairns, et al. (2007). "The use of intranasal midazolam in the treatment of paediatric dental patients." Anaesthesia 62(12): 1262-5.

            The aim of this study was to assess the use of intranasal midazolam in paediatric dental patients requiring extractions or simple surgical procedures who may otherwise have required a general anaesthetic. Twenty children aged between 2-9 years who required simple surgical procedures were given 0.25 mg.kg(-1) midazolam, administered using a MAD (Mucosal Atomization Device; Wolfe Tory Medical Inc., Salt Lake City, UT, USA). Compliance with the full dose was achieved in 14 patients, 13 of whom completed the treatment. One of two patients who allowed only partial administration completed the treatment and three patients did not comply. The mean time to starting treatment was 13 min (range 6-25 min) and patients were discharged after a mean of 46 min (range 25-67 min). Physiological parameters remained stable throughout with no clinically significant episodes of desaturation. One patient vomited at home postoperatively. Midazolam in a dose of 0.25 mg.kg(-1) administered intranasally provided adequate anxiolysis for the majority of children, allowing them to complete their treatment.

Gobeaux, D., F. Sardnal, et al. (1991). "[Intranasal midazolam in pediatric ophthalmology]." Cah Anesthesiol 39(1): 34-6.

            Intranasal midazolam was tested in pediatric patients undergoing ophthalmological examination. 15 children aged 3.5 months to 10 years received 0.35-0.5 mg.kg-1 intranasal midazolam in association with a corneal anesthesia. The onset of sedation was rapid and permitted adequate ocular examination in all cases. In 8 of 15 cases where surgery followed immediately, the induction of inhalational anesthesia was easier. No local or general adverse reaction was noted. This non-invasive method of anesthesia may be compared to the intrarectal administration of midazolam, but the rapid onset of sedation and a cleaner route seem more suitable in surgical environment.

Greaves, A. (2016). "The use of Midazolam as an Intranasal Sedative in Dentistry." SAAD Dig 32: 46-49.

The administration of midazolam intranasally exploits the unique structure of the nasopharynx thus ensuring rapid delivery to the systemic circulation (The Nose - Brain Pathway). The absorption of midazolam nasally is influenced by the volume and concentration of midazolam, its physicochemical properties and the characteristics of the nasal mucosa. Delivering midazolam intranasally is non-titratable. The level of conscious sedation may be equivalent to that achieved by intravenous routes but is approached in a less controlled manner. Randomised Control trials using intranasal sedation in children have shown the technique to be safe and effective in secondary care for dental procedures at concentrations varying from 0.2 mg/kg to 0.5 mg/kg. A combined technique of intranasal midazolam (to facilitate cannulation) and intravenous midazolam is used for adults with moderate to severe learning disabilities. This has revolutionised dental treatment for this group of patients as treatment under General Anaesthesia (GA) may be avoided. Intranasal delivery of midazolam is emerging as a significant tool in our dental armamentarium for the treatment of anxious children, phobic adult patients and patients with learning disabilities.

Gu, H. B., Y. A. Song, et al. (2019). "Median Effective Dose of Intranasal Dexmedetomidine for Transthoracic Echocardiography in Children with Kawasaki Disease Who Have a History of Repeated Sedation." Med Sci Monit 25: 381-388.

BACKGROUND The aim of this study was to investigate the median effective dose (ED50) of intranasal dexmedetomidine for echocardiography in children with Kawasaki disease who had a history of repeated sedation. MATERIAL AND METHODS There were 73 pediatric Kawasaki disease patients aged 1 to 36 months enrolled in this study who had American Society of Anesthesiologists (ASA) I-II, were scheduled to undergo echocardiography under sedation. They were assigned to 2 groups (group A: age 1-18 months, and group B: age 19-36 months). Intranasal dexmedetomidine was administered before echocardiography. The dose of intranasal dexmedetomidine was determined with the up-down sequential allocation, and the initial dose was 2 mug/kg with an increment/decrement of 0.2 mug/kg. The ED50 of intranasal dexmedetomidine for sedation was determined with the up-and-down method of Dixon and Massey and probit regression. The time to effective sedation, time to regaining consciousness, vital signs, oxygen saturation, echocardiographic examination time, clinical side-effects, and characteristics of regaining consciousness were recorded and compared. RESULTS The ED50 of intranasal dexmedetomidine for sedation was 2.184 mug/kg (95% CI, 1.587-2.785) in group A and 2.313 mug/kg (95% CI, 1.799-3.426) in group B. There were no significant differences in the time to sedation and time to regaining consciousness between groups. Additionally, change in hemodynamic and hypoxemia were not noted in both groups. CONCLUSIONS The ED50 of intranasal dexmedetomidine was determined in children with Kawasaki disease who had a history of repeated sedation to be appropriate for repeated-routine sedation of echocardiographic examination in pediatric patients. The ED50 of intranasal dexmedetomidine for echocardiography in this circumstance is similar to that in children receiving initial sedation.

Gudmundsdottir, H., J. F. Sigurjonsdottir, et al. (2001). "Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans." Pharmazie 56(12): 963-6.

            Intranasal administration of midazolam has been of particular interest because of the rapid and reliable onset of action, predictable effects, and avoidance of injections. The available intravenous formulation (Dormicum i.v. solution from Hoffmann-La Roche) is however less than optimal for intranasal administration due to low midazolam concentration and acidity of the formulation (pH 3.0-3.3). In this study midazolam was formulated in aqueous sulfobutylether-beta- cyclodextrin buffer solution. The nasal spray was tested in 12 healthy volunteers and compared to intravenous midazolam in an open crossover trial. Clinical sedation effects, irritation, and serum drug levels were monitored. The absolute bioavailability of midazolam in the nasal formulation was determined to be 64 +/- 19% (mean +/- standard deviation). The peak serum concentration from nasal application, 42 +/- 11 ng ml-1, was reached within 10-15 min following administration and clinical sedative effects were observed within 5 to 10 min and lasted for about 40 min. Intravenous administration gave clinical sedative effects within 3 to 4 min, which lasted for about 35 minutes. Mild to moderate, transient irritation of nasal and pharyngeal mucosa was reported. The nasal formulation approaches the intravenous form in speed of absorption, serum concentration and clinical sedation effect. No serious side effects were observed.

Gupta, A., N. P. Dalvi, et al. (2017). "Comparison between intranasal dexmedetomidine and intranasal midazolam as premedication for brain magnetic resonance imaging in pediatric patients: A prospective randomized double blind trial." J Anaesthesiol Clin Pharmacol 33(2): 236-240.

            BACKGROUND AND AIMS: Preprocedural preparation of children scheduled for magnetic resonance imaging (MRI) is challenging. This prospective, randomized trial compared intranasal midazolam with intranasal dexmedetomidine as premedication for children scheduled for brain MRI. MATERIAL AND METHODS: In total, 60 children, aged 1-8 years, scheduled for elective brain MRI, were randomly assigned to the intranasal dexmedetomidine (1 mug/kg; Group D) or intranasal midazolam (0.2 mg/kg; Group M) group. We compared hemodynamic and respiratory parameters, onset, level, sedation quality, and successful parental separation. All patients received intravenous propofol as an induction and maintenance agent for MRI. RESULTS: No significant differences were observed in demographic, hemodynamic, and respiratory parameters. Group D (14.3 +/- 3.4 min [10-20 min]) had a longer time of sedation onset than Group M (8.7 +/- 3.7 min [5-15 min]; P < 0.001). The median and mean sedation scores were lower in Group D (3 and 3.7 +/- 0.8, respectively) than Group M (4 and 4.3 +/- 1.2, respectively; P = 0.055). Group D (80%) had a higher percentage of children achieving satisfactory sedation at the time of induction than did Group M (53.3%; P = 0.0285). Parental separation was successful in 73.3% of patients in Group D compared with 46.7% of patients in Group M (P = 0.035). CONCLUSION: Intranasal dexmedetomidine results in more successful parental separation and yields a higher sedation level at the time of induction of anesthesia than intranasal midazolam as premedication, with negligible side effects. However, its onset of action is relatively prolonged.

Guthrie, A. M., R. A. Baum, et al. (2019). "Use of Intranasal Ketamine in Pediatric Patients in the Emergency Department." Pediatr Emerg Care.

OBJECTIVES: Ketamine is a safe and widely used sedative and analgesic in the pediatric emergency department (ED). The use of intranasal (IN) ketamine in exchange for the administration of intravenous sedatives or analgesics for procedural sedation in pediatric patients is not commonplace. The goal of this study was to evaluate provider perceptions and patient outcomes at varying doses of IN ketamine for anxiolysis, agitation, or analgesia. METHODS: From January 2018 to May 2018, we performed a prospective survey and chart review of pediatric patients receiving IN ketamine. The primary outcome was to determine provider satisfaction with using IN ketamine. Secondary objectives included comparing outcomes stratified by dose, adverse events, assessing for treatment failure, and ED length of stay (LOS). As a secondary comparison, patients receiving IN ketamine whom otherwise would have required procedural sedation with intravenous sedatives or analgesics were placed into a subgroup. This subgroup of patients was compared with a cohort who received intravenous sedatives or analgesics for procedural sedation during a similar period the preceding year (January 2017 to June 2017). RESULTS: Of the 196 cases, 100% of the providers were comfortable using IN ketamine. The median overall provider satisfaction was 90 out of 100, the perception of patient comfort was 75 out of 100, and perceived patient comfort was maximized when using doses between 3 and 5 mg/kg. There were 15 (7.7%) patients who experienced ketamine treatment failure. Overall, the rate of adverse events was 6%, but were considered minor [nausea (n = 3; 1.5%), dizziness (n = 2; 1%), and drowsiness (n = 2; 1%)]. No patients required respiratory support or intubation. The mean LOS was 237.9 minutes, compared with those who underwent procedural sedation with an LOS of 332.4 minutes (P < 0.001). CONCLUSIONS: This study demonstrates that IN ketamine was able to provide safe and successful analgesia and anxiolysis in pediatric patients in an ED setting. In addition, providers expressed a high degree of satisfaction with using IN ketamine (90 out of 100) in addition to a high degree of patient comfort during the procedure (75 out of 100). Intranasal ketamine provides an alternative to intravenous medication normally requiring more resource-intensive monitoring. Procedural sedations are resource and time intensive activities that increase ED LOS. Intranasal ketamine used for anxiolysis and analgesia offers the benefits of freeing up resources of staff and monitoring while enhancing overall throughput through a pediatric ED.

Gyanesh, P., R. Haldar, et al. (2014). "Comparison between intranasal dexmedetomidine and intranasal ketamine as premedication for procedural sedation in children undergoing MRI: a double-blind, randomized, placebo-controlled trial." J Anesth 28(1): 12-18.

INTRODUCTION: Providing anesthesia to children undergoing MRI is challenging. Adequate premedication, administered noninvasively, would make the process smoother. In this study, we compare the efficacy of intranasal dexmedetomidine (DXM) with the intranasal administration of ketamine for procedural sedation in children undergoing MRI. METHODS: We studied 150 children, between 1 and 10 years of age, divided randomly into three groups (DXM, K, and S). For blinding, every child received the intranasal drugs twice; syringe S1, 60 min before, and syringe S2, 30 min before intravenous (IV) cannulation. For children in group DXM, S1 contained DXM (1 mug/kg) and S2 was plain saline. Children in group K received saline in S1 and ketamine (5 mg/kg) in S2 whereas children in group S received saline in both S1 and S2. The child's response to drug administration, ease of IV cannulation, the satisfaction of the anesthesiologist and child's parents with the premedication, and the total propofol dose required for the satisfactory conduct of the procedure were compared. We also compared the time to awakening and discharge of the child as well as the occurrence of any side effects with these drugs. RESULTS: Both DXM and ketamine were equally effective as premedication in these patients. Most of the children accepted the intranasal drugs with minimal discomfort; 90.4 % of the anesthesiologists in the DXM group and 82.7 % in the ketamine group were satisfied with the conditions for IV cannulation whereas only 21.3 % were satisfied in the saline group. The total dose of propofol used was less in the study groups. Furthermore, children in group DXM and group K had earlier awakening and discharge than those in group S. CONCLUSION: DXM and ketamine were equally effective, by the intranasal route, as premedication in children undergoing MRI.

Hallett, A., F. O'Higgins, et al. (2000). "Patient-controlled intranasal diamorphine for postoperative pain: an acceptability study." Anaesthesia 55(6): 532-9.

            A patient acceptability study was conducted using patient-controlled intranasal diamorphine. Patients undergoing nonemergency orthopaedic or gynaecological surgery self-administered intranasal diamorphine for 24 h postoperatively. Pain, pain relief, sedation, respiratory rate, nausea and vomiting were assessed regularly. After 24 h, patients and their attending nurses completed a questionnaire assessing satisfaction and practical aspects of the technique. Satisfaction was reported as good or complete by 69% of patients and 69% of nurses. Pain relief was assessed as better than expected by 45% of patients and better than normal by 50% of nurses. Seventy-nine per cent of patients would be pleased to use patient-controlled intranasal diamorphine again and 89% of nurses would be happy for their patients to use it again. Sedation was uncommon and mild and there were no episodes of significant respiratory depression. Fifty-three per cent of patients reported no nausea and 74% did not vomit at any stage. There were seven withdrawals, four due to problems with the device and three due to therapeutic problems. The nasal spray may need modification to improve reliability. However, we found patient-controlled intranasal analgesia an effective technique, which was well tolerated by patients and nurses and was without unpleasant side-effects. Further work to determine how it performs compared with intramuscular or intravenous analgesia is now needed.

Han, G., W. W. Yu, et al. (2014). "A randomized study of intranasal vs. intravenous infusion of dexmedetomidine in gastroscopy." Int J Clin Pharmacol Ther 52(9): 756-761.

OBJECTIVE: To compare the respiratory and circulatory parameters between intranasal and intravenous dexmedetomidine in gastroscopy. METHODS: 60 patients undergoing elective gastroscopy were randomly divided into group D1 and D2. Dexmedetomidine (0.5 microg/kg, 1 mL) and normal saline (NS, 1 mL) were given by intranasal route 40 minutes before induction, and then NS (20 mL) and dexmedetomidine (0.5 microg/kg, 20 mL) were given intravenously 10 minutes before induction, respectively, in groups D1 and D2. Propofol (1.5 - 2 mg/kg) was used for induction. Heart rate (HR), mean arterial pressure (MAP), pulse oxygen saturation(SpO(2)), and respiratory rate (RR) were monitored. The latent period of falling asleep, the duration of gastroscopy, the time of awakening, and the total dose of propofol consumption were also recorded. Postoperative sedation scale and adverse reactions were observed. RESULTS: One patient in group D1 was excluded from the study due to atrioventricular block. The HR and SpO(2) were significantly lower, but RR was significantly higher in group D2 than in group D1(all p < 0.05). The time of awakening was significantly longer and the rates of respiratory depression were significantly higher in group D2 than in group D1 (all p < 0.05) There were no significant differences in other parameters between both groups. CONCLUSION: Intranasal dexmedetomidine is a new, safe, and effective approach for gastroscopy because it has more stable respiratory and circulatory parameters and less adverse reactions than intravenous dexmedetomidine.

Harcke, H. T., L. E. Grissom, et al. (1995). "Sedation in pediatric imaging using intranasal midazolam." Pediatr Radiol 25(5): 341-3.

            Intranasal midazolam offers an attractive alternative for use as a sedative agent for medical imaging studies in children. Its convenient administration and rapid onset are significant advantages over intravenous and oral agents. Because of its short duration, it is effective only for short procedures and as an adjunct to other sedative agents. When younger children present with such requirements, a dose of 0.2 mg/kg has been safe and effective in our experience. We advocate its use with adherence to guidelines for sedation published by the American Academy of Pediatrics.

Hartgraves, P. M. and R. E. Primosch (1994). "An evaluation of oral and nasal midazolam for pediatric dental sedation." ASDC J Dent Child 61(3): 175-81.

            Midazolam is a new short-acting benzodiazepine which is more potent than diazepam. Reports on its use in young pediatric dental patients is lacking in the literature. The purpose of this study was to evaluate the sedative qualities of midazolam via the oral and nasal routes in 100 recalcitrant pediatric dental patients between 1.5 and 6 years of age. One half of the patients received oral midazolam at a dose of 0.5 mg/kg administered with 25 mg hydroxyzine pamoate suspension as a vehicle. The other half received nasal midazolam at a dose of 0.2 mg/kg. Nitrous oxide-oxygen inhalation and local anesthesia were used in all cases. The results indicated that a satisfactory level of sedation was achieved in approximately two thirds of the cases. Complications were rare, and not of clinical significance. There was no significant difference in the frequency of success or complications reported between the oral and nasal routes. The results of the present study support the need for future investigations to determine optimal pediatric dosages and regimens for each route.

Heard, C., P. Creighton, et al. (2009). "Intranasal flumazenil and naloxone to reverse over-sedation in a child undergoing dental restorations." Paediatr Anaesth 19(8): 795-7.

Helmers, J. H., H. Noorduin, et al. (1989). "Comparison of intravenous and intranasal sufentanil absorption and sedation." Can J Anaesth 36(5): 494-7.

            The absorption and sedation following an intranasal dose of sufentanil were evaluated and compared with those of the same dose given intravenously. Sixteen adult patients scheduled for elective surgery were randomly allocated to receive as premedication 15 micrograms sufentanil either intravenously or intranasally. Before administration and at fixed time intervals thereafter, the degree of sedation was assessed, vital signs were recorded and venous blood samples were taken for the determination of sufentanil plasma concentrations. Peroperative sedation of rapid onset and limited duration was seen in both groups. However, the onset of sedation was more rapid after intravenous injection. At 10 min, all patients in the IV group were sedated versus only two in the intranasal group (P less than 0.01). No significant intergroup differences in sedation were seen at 20 to 60 min. This clinical effect is in agreement with the measured plasma levels, which were significantly lower after intranasal application at 5 and 10 min, being 36 and 56 per cent of those after IV dosing, respectively. From 30 min, plasma concentrations were virtually identical for the two routes of administration. The AUC0-120 min after intranasal dosing was 78 per cent of that after intravenous injection. Intranasal dosing induced no clinically significant changes in vital signs, whereas after IV sufentanil, a clinically significant decrease in PaO2 was seen at 5 min. The results of this study show that sufentanil, when administered intranasally, is rapidly and effectively absorbed from the human nasal mucosa, so that this route may be an attractive alternative for a premedicant, avoiding the discomfort of an intravenous or intramuscular injection.

Heniff, M. S., G. P. Moore, et al. (1997). "Comparison of routes of flumazenil administration to reverse midazolam-induced respiratory depression in a canine model." Acad Emerg Med 4(12): 1115-8.

Hitt, J. M., T. Corcoran, et al. (2014). "An evaluation of intranasal sufentanil and dexmedetomidine for pediatric dental sedation." Pharmaceutics 6(1): 175-184.

Conscious or moderate sedation is routinely used to facilitate the dental care of the pre- or un-cooperative child. Dexmedetomidine (DEX) has little respiratory depressant effect, possibly making it a safer option when used as an adjunct to either opioids or benzodiazepines. Unlike intranasal (IN) midazolam, IN application of DEX and sufentanil (SUF) does not appear to cause much discomfort. Further, although DEX lacks respiratory depressive effects, it is an alpha2-agonist that can cause hypotension and bradycardia when given in high doses or during prolonged periods of administration. The aim of this feasibility study was to prospectively assess IN DEX/SUF as a potential sedation regimen for pediatric dental procedures. After IRB approval and informed consent, children (aged 3-7 years; n = 20) from our dental clinic were recruited. All patients received 2 mug/kg (max 40 mug) of IN DEX 45 min before the procedure, followed 30 min later by 1 mug/kg (max 20 mug) of IN SUF. An independent observer rated the effects of sedation using the Ohio State University Behavior Rating Scale (OSUBRS) and University of Michigan Sedation Scale (UMSS). The dentist and the parent also assessed the efficacy of sedation. Dental procedures were well tolerated and none were aborted. The mean OSUBRS procedure score was 2.1, the UMSS procedure score was 1.6, and all scores returned to baseline after the procedure. The average dentist rated quality of sedation was 7.6 across the 20 subjects. After discharge, parents reported one child with prolonged drowsiness and one child who vomited at home. The use of IN DEX supplemented with IN SUF provided both an effective and tolerable form of moderate sedation. Although onset and recovery are slower than with oral (PO) midazolam and transmucosal fentanyl, the quality of the sedation may be better with less risk of respiratory depression. Results from this preliminary study showed no major complications from IN delivery of these agents.

Hiwarkar, S., R. Kshirsagar, et al. (2018). "Comparative Evaluation of the Intranasal Spray Formulation of Midazolam and Dexmedetomidine in Patients Undergoing Surgical Removal of Impacted Mandibular Third Molars: A Split Mouth Prospective Study." J Maxillofac Oral Surg 17(1): 44-51.

Purpose: The purpose of this prospective randomized single blinded split mouth study was to conduct a comparative evaluation of the efficacy of intranasal atomised spray formulation of Dexmedetomidine with Midazolam in patients undergoing surgical removal of bilaterally impacted mandibular third molars. Methods: This prospective study was conducted in twenty volunteers. Each volunteer underwent the surgical removal of an impacted mandibular third molar at two separate appointments at an interval of two weeks. The first third molar surgery was conducted using either intranasal Midazolam (Group M) or intranasal Dexmedetomidine (Group D). At the second appointment the surgical procedure was performed using the sedative agent not used at the first appointment. The primary testing outcome variables were Plasma oxygen saturation (SpO2), pulse and blood pressure and Modified Observer's Assessment of Alertness/Sedation (OAA/S) scale. These were recorded at predetermined intervals starting 10 min before the administration of local anaesthesia and continued up to 10 min after completion of the procedure. In addition surgeon's opinion regarding the patient cooperation, event amnesia, post operative nausea & vomiting were obtained. Results: The sample composed of twenty patients (M = 9 and F = 11). There was statistically no significant difference between Group M and Group D with respect to mean SpO2. Minor differences were however noted at 20 and 30 min after sedation. There was no significant difference between the groups with respect to mean pulse rate, blood pressure, OAA/S, event amnesia, post operative nausea and vomiting and patient cooperation. Conclusion: We conclude that Midazolam and Dexmedetomidine are equivalent and can be used in minor oral surgery with minimal complications. These drugs can be used intranasally using nasal atomization device in routine outpatient basis in otherwise normal healthy but anxious patients. All procedures must however be performed in the presence of an anaesthesiologist and with ready availability of emergency drugs and equipment.

Hobbs, G. D., D. M. Yealy, et al. (1997). "Intranasal midazolam for the sedation of young children undergoing laceration repair (abstract)." Acad Emerg Med 4(5): 383-384.

Hogberg, L., M. Nordvall, et al. (1995). "Intranasal versus intravenous administration of midazolam to children undergoing small bowel biopsy." Acta Paediatr 84(12): 1429-31.

            Sixty-three children under the age of 9 years were randomized to receive intravenous (group A, n = 33) or intranasal (group B, n = 30) midazolam as sedation for small bowel biopsy. Mean doses of midazolam given to produce adequate sedation were 0.31 mg (kg body weight)-1 in group A and 0.34 mg (kg body weight)-1 in group B (NS). Four children in group A and 10 children in group B required additional doses to maintain adequate sedation throughout the biopsy procedure (p &lt; 0.05). There was no significant difference between the groups regarding the median procedure time (7 min in group A, 8.5 min in group B) or median fluoroscopy time (5 s in group A, 4 s in group B). All children in group B showed signs of discomfort from the nose when given midazolam intranasally. In conclusion, this study indicates that intravenous administration of midazolam is preferable to the intranasal route.

Hogberg, L., M. Nordwall, et al. (2001). "Small bowel capsule biopsy in children: parents' opinions on children's discomfort." Acta Paediatr 90(8): 876-8.

            This questionnaire study asked the parents of 62 children undergoing small bowel capsule biopsy for their reactions to the discomfort experienced by their children. The children were randomized to receive sedation with midazolam either intravenously or intranasally. With regard to the biopsy procedure the parents of 94% of the children had no objections. The parents of 3% of the children found the biopsy very unpleasant and another 3% suggested that the biopsy should be performed under general anaesthesia. The proportion of parents with negative reactions to the biopsy procedure did not differ significantly between the intravenously and intranasally sedated children. With regard to the sedation given, the parents of 79% of the children did not think that their children were in any discomfort at all. Ten percent of the children had obvious signs of nasal discomfort using the intranasal administration. In the remaining 11% of the children the parents reported various symptoms. CONCLUSION: The vast majority of parents of children undergoing small bowel capsule biopsy found the procedure satisfactory providing that the sedative medication was given intravenously rather than intranasally.

Hollenhorst, J., S. Munte, et al. (2001). "Using intranasal midazolam spray to prevent claustrophobia induced by MR imaging." AJR Am J Roentgenol 176(4): 865-8.

            OBJECTIVE: Up to 37% of patients undergoing MR imaging examinations experience moderate to severe levels of anxiety that necessitate the termination of the procedure in 5-10% of patients. Although the clinical use of MR imaging has increased, effective procedures to handle claustrophobia are lacking. We evaluated the effectiveness of intranasally administered midazolam spray in preventing claustrophobic responses of patients undergoing MR imaging. SUBJECTS AND METHODS: Fifty-four patients scheduled for MR imaging were included in this prospective study. Anxiety and sedation of patients were evaluated before drug administration, immediately before MR imaging, and at the end of the procedure. The Spielberger State-Trait Anxiety Inventory, the visual analogue scale of anxiety, and a five-point sedation scale were used. Half the patients received intranasal spray applications of 4 mg midazolam, whereas the other patients received a placebo, in a randomized, double-blind study design (six sprayings of 0.5% midazolam solution or NaCl 0.9%, respectively). The intensity of the sensation of burning of the nasal mucosa was rated by patients using a three-point scale (no, slight, or strong burning). The quality of scan images was evaluated by a radiologist using a five-point scale (0 = extremely poor, 5 = excellent). RESULTS: No cancellations occurred with patients who received midazolam, whereas four of 27 patients receiving placebo panicked and terminated the scanning procedure. The initial anxiety and sedation scores did not differ between the groups. Patients who received midazolam spray were more sedated and less anxious immediately before entering the MR scanner and reported a more intense slight transient burning of the nasal mucosa than those in the placebo group. The quality of the MR image was higher in the midazolam group. CONCLUSION: A sizeable reduction in MR imaging-related anxiety and improved MR image quality were seen with patients who received intranasal midazolam spray. With the exception of transient burning of the nasal mucosa, no adverse effects were reported. This simple and safe method is useful in sedating patients for MR imaging and other minor procedures.

Huebinger, R. M., H. Q. Zaidi, et al. (2020). "Retrospective Study of Midazolam Protocol for Prehospital Behavioral Emergencies." West J Emerg Med 21(3): 677-683.

INTRODUCTION: Agitated patients in the prehospital setting pose challenges for both patient care and emergency medical services (EMS) provider safety. Midazolam is frequently used to control agitation in the emergency department setting; however, limited data exist in the prehospital setting. We describe our experience treating patients with midazolam for behavioral emergencies in a large urban EMS system. We hypothesized that using midazolam for acute agitation leads to improved clinical conditions without causing significant clinical deterioration. METHODS: We performed a retrospective review of EMS patient care reports following implementation of a behavioral emergencies protocol in a large urban EMS system from February 2014-June 2016. For acute agitation, paramedics administered midazolam 1 milligram (mg) intravenous (IV), 5 mg intramuscular (IM), or 5 mg intranasal (IN). Results were analyzed using descriptive statistics, Levene's test for assessing variance among study groups, and t-test to evaluate effectiveness based on route. RESULTS: In total, midazolam was administered 294 times to 257 patients. Median age was 30 (interquartile range 24-42) years, and 66.5% were male. Doses administered were 1 mg (7.1%) and 5 mg (92.9%). Routes were IM (52.0%), IN (40.8%), and IV (7.1%). A second dose was administered to 37 patients. In the majority of administrations, midazolam improved the patient's condition (73.5%) with infrequent adverse events (3.4%). There was no significant difference between the effectiveness of IM and IN midazolam (71.0% vs 75.4%; p = 0.24). CONCLUSION: A midazolam protocol for prehospital agitation was associated with reduced agitation and a low rate of adverse events.

Iirola, T., S. Vilo, et al. (2011). "Bioavailability of dexmedetomidine after intranasal administration." Eur J Clin Pharmacol 67(8): 825-831.

            PURPOSE: The aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers. METHODS: Single doses of 84 mug of dexmedetomidine were given once intravenously and once intranasally to seven healthy men. Plasma dexmedetomidine concentrations were measured for 10 h, and pharmacokinetic variables were calculated with standard noncompartmental methods. Heart rate, blood pressure, concentrations of adrenaline and noradrenaline in plasma, and central nervous system drug effects (with the Maddox wing, Bispectral Index, and three visual analog scales) were monitored to assess the pharmacological effects of dexmedetomidine. RESULTS: Six individuals were included in the analyses. Following intranasal administration, peak plasma concentrations of dexmedetomidine were reached in 38 (15-60) min and its absolute bioavailability was 65% (35-93%) (medians and ranges). Pharmacological effects were similar with both routes of administration, but their onset was more rapid after intravenous administration. CONCLUSIONS: Dexmedetomidine is rather rapidly and efficiently absorbed after intranasal administration. Compared with intravenous administration, intranasal administration may be a feasible alternative in patients requiring light sedation.

Inokuchi, R., N. Ohashi-Fukuda, et al. (2015). "Comparison of intranasal and intravenous diazepam on status epilepticus in stroke patients: a retrospective cohort study." Medicine (Baltimore) 94(7): e555.

                Administering diazepam intravenously or rectally in an adult with status epilepticus can be difficult and time consuming. The aim of this study was to examine whether intranasal diazepam is an effective alternative to intravenous diazepam when treating status epilepticus. We undertook a retrospective cohort study based on the medical records of 19 stroke patients presenting with status epilepticus to our institution. We measured the time between arrival at the hospital, the intravenous or intranasal administration of diazepam, and the seizure termination. Intranasal diazepam was administered about 9 times faster than intravenous diazepam (1 vs 9.5 minutes, P = 0.001), resulting in about 3-fold reduction in the time to termination of seizure activity after arrival at the hospital (3 minutes compared with 9.5 minutes in the intravenous group, P = 0.030). No adverse effects of intranasal diazepam were evident from the medical records. Intranasal diazepam administration is safer, easier, and quicker than intravenous administration.

Jayaraman, L., A. Sinha, et al. (2013). "A comparative study to evaluate the effect of intranasal dexmedetomidine versus oral alprazolam as a premedication agent in morbidly obese patients undergoing bariatric surgery." J Anaesthesiol Clin Pharmacol 29(2): 179-182.

BACKGROUND: Morbidly obese patients with obstructive sleep apnea are extremely sensitive to sedative premedication. Intranasal dexmedetomidine is painless and quick acting. Intranasal dexmedetomidine can be used for premedication as it produces adequate sedation and also obtund hemodynamic response to laryngoscopy and tracheal intubation. MATERIALS AND METHODS: Forty morbidly obese patients with BMI > 35 were chosen and divided into two groups. Group DEX received intranasal dexmedetomidine 1 mcg/kg (ideal body weight) while other group (AZ) received oral alprazolam 0.5 mg. Sedation scale, heart rate and the mean arterial pressure was assessed in both the groups at 0 hour, 45 minutes, during laryngoscopy and tracheal intubation. RESULTS: The demographic profile, baseline heart rate, means arterial pressure, oxygen saturation and sedation scale was comparable between the two groups. The sedation scores, after 45 min, were statistically significant between the two groups i.e., 2.40 +/- 1.09 in the AZ group as compared to 3.20 +/- 1.79 in DEX group P value 0.034. The heart rate, mean arterial pressure and oxygen saturation were statistically similar between the two groups, after 45 min. The heart rate was significantly lower in the DEX group as compared to the AZ group. There was no statistical difference in the mean arterial pressure between the two groups either during laryngoscopy or tracheal intubation. CONCLUSION: Intranasal dexmedetomidine is a better premedication agent in morbidly obese patients than oral alprazolam.

Karl, H. W., A. T. Keifer, et al. (1992). "Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients." Anesthesiology 76(2): 209-15.

            Nasal administration of sufentanil or midazolam is effective for preinduction of pediatric patients, but there are no data on which to base a choice between them. This blinded randomized study compares behavioral and physiologic responses to sedation with one of these medications followed by inhalation or intravenous induction. Ninety-five patients aged 0.5-10 yr scheduled for elective surgery were stratified by age: 30 infants 0.5-2 yr, 38 preschoolers 2.1-5 yr, and 27 school-age children 5.1-10 yr. They were randomized to receive 0.04 ml/kg of midazolam (0.2 mg/kg) or sufentanil (2 micrograms/kg). Hemoglobin oxygen saturation by pulse oximetry (SpO2) and sedation score were recorded prior to drug administration, at 2.5-min intervals for 10 min, at separation, and during induction with graded halothane in oxygen. Intubation was performed under deep halothane or 3 mg/kg of thiopental and 0.1 mg/kg of pancuronium. Chest wall compliance was assessed qualitatively in all patients prior to intubation. To assess the effects of a mild standardized stress on unpremedicated patients, 75 of the children with parents present were scored before and after oximeter probe placement: of these, in 63% the sedation score did not change; 33% appeared more anxious; and only 4% seemed reassured. Children of all ages reacted negatively to physicians, and 23% were crying prior to administration of drugs. Sufentanil appeared less unpleasant to receive than midazolam: children cried 46 +/- 100 versus 76 +/- 73 s (P less than 0.05), respectively, but by 7.5 min, no child was crying. Median behavior scores at maximum anxiolysis were not different, but response to sufentanil was more variable.(ABSTRACT TRUNCATED AT 250 WORDS)

Karl, H. W., J. L. Rosenberger, et al. (1993). "Transmucosal administration of midazolam for premedication of pediatric patients. Comparison of the nasal and sublingual routes." Anesthesiology 78(5): 885-91.

            BACKGROUND: Nasal transmucosal midazolam is effective for premedication of pediatric patients; however, 61-74% of these patients cry at nasal drug administration. Sublingual benzodiazepines, including midazolam, are effective in adults. The current blinded randomized study compared acceptance of and behavioral responses to transmucosal midazolam administered via the intranasal and sublingual routes. METHODS: Ninety-three patients aged 0.5-10 yr were stratified by age: 30 infants and toddlers, 0.5-2 yr; 39 preschoolers, 2.1-5 yr; and 24 school age, 5.1-10 yr. They were randomized to receive 0.2 mg/kg of midazolam in the nose or under the tongue without or with additional flavoring. For the group receiving sublingual flavored midazolam, the syringe tip was dipped in candy flavor and sugar. Duration of crying and compliance with instructions for sublingual drug administration were recorded. Hemoglobin oxygen saturation by pulse oximetry and sedation score were recorded by three observers before drug administration, at 2.5-min intervals for 10 min, at separation from parents, and during induction with halothane in O2. RESULTS: Children accepted midazolam administered via the sublingual route better than that given intranasally. In children not crying before drug administration, the frequency and duration of crying was greater following intranasal compared with sublingual administration (71% vs. 18% (P &lt; 0.0001) and 48 +/- 56 vs. 25 +/- 49 s (P = 0.004), respectively). Lack of total compliance with instructions for sublingual administration did not alter drug effect, and there were no differences between the three study groups in maximum sedation, response to separation from parents, and behavior at induction of anesthesia; 80% displayed adequate or excellent behavior. Finally, the addition of candy flavor did not improve acceptance of or compliance with sublingual midazolam administration. CONCLUSIONS: Sublingual administration of midazolam is as effective as, and better accepted than, intranasal midazolam as a preanesthetic sedative in children.

Kaufman, E., E. Davidson, et al. (1994). "Comparison between intranasal and intravenous midazolam sedation (with or without patient control) in a dental phobia clinic." J Oral Maxillofac Surg 52(8): 840-3; discussion 844.

            Two new modes of sedation; patient-controlled sedation (PCS) and intranasal sedation (INS) were compared with the traditional bolus intravenous sedation (BIVS) while delivering dental care to apprehensive patients in a specialized dental fear clinic. Effective sedation was evaluated in a randomized, prospective study in 42 ASA 1 and 2 patients, in a factorial design. Eighteen patients were sedated with .5% midazolam INS. Ten patients received intravenous PCS via a patient-controlled analgesia pump containing midazolam, and 14 patients received intermittent intravenous boluses of 1 mg midazolam given as needed (BIVS). Appropriate local anesthetic nerve blocks with 2% lidocaine with 1:100,000 epinephrine, and supplementary inhalation of nitrous oxide and oxygen via a nasal mask, were also given to all patients in the study. The dosage requirement with PCS was higher than that found with INS or BIVS. However, PCS produced some anxiety reduction when compared with INS and BIVS. It also reduced interfering movements during treatment more effectively than the other sedation modes. No complications were detected in any of the patients and they were able to leave the clinic within 1 hour after completion of treatment.

Kawanda, L., et al., Sedation with intranasal midazolam of Angolan children undergoing invasive procedures. Acta Paediatr, 2012. 101(7): p. e296-8.

                AIM: Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures. METHODS: Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty). RESULTS: Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001). CONCLUSION: These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier.

Kazemi, A. P., H. Kamalipour, et al. (2005). "Comparison of intranasal midazolam versus ketamine as premedication in 2-5 years old paeditric surgery patients." Pak J Med Sci 21(4): 460-464.

                Background and Aim: Surgery and anesthesia can cause considerable distress and psychological consequences for children. In children, preanesthetic medications are frequently administered as pharmacologic adjuncts to help alleviate the stress and fear of surgery as well as to ease childparental separation and promote a smooth induction of anesthesia. Oral, rectal, intravenous and intramuscular preanesthetic medication administration have been used. However, each route has disadvantages. Pre anaesthetic medication administered nasaly, due to its rapid and reliable onset of action, avoidance of painful injections and ease of administration have made it a convenient way to premedicate children. The aim of the present study is to compare the sedative effect of ketamine and midazolam administered nasaly as premedication. Patients and Methods: 130 children aged 2-5 years and with ASA class I-II randomly allocated in three groups and 20 minutes before operation time received either 0.2mg/kg midazolam or 5mg/kg ketamine or 2ml normal saline, intranasally. After administration of intranasal premedication the children were under direct observation of anesthesiology resident near their parents. At the time of separation and at the time of IV line insertion, on the basis of Sury and Cole sedation score they received a sedation score. Results: According to statistical analysis, at the time of separation from parents in midazolam group, 90% of patients were sedated (60% had mild sedation, 30% had good sedation), in ketamine group, 89% were sedated (32.5% had mild sedation, 59.5% had good sedation) while in placebo group, 47.5% showed sedation (40% mild, 7.5% good). At the time of intra venous line insertion, in midazolam group, 86% of patients were sedated (56% had mild sedation, 30% had good sedation), in ketamine group, 80% were sedated (57.5% had mild sedation, 22.5% had good sedation) while in placebo group 22.5% (20% had mild sedation, 2.5% had good sedation) showed sedation. Conclusion: On the basis of results midazolam and ketamine administered intra nasaly are effective in inducing sedation. Comparing these drugs with placebo, they are effective adjunctive premedicant.

Kendall, J. M. and V. S. Latter (2003). "Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects." Clin Pharmacokinet 42(6): 501-13.

            Diamorphine is a semisynthetic derivative of morphine that is currently licensed for use in the treatment of moderate to severe acute pain, administered by the intramuscular, intravenous or subcutaneous routes. It is highly water-soluble and has a number of properties that render it suitable for administration via the nasal route. Administration via the intranasal route is well described for other drugs, but has only recently been evaluated in a clinical setting for diamorphine. A well-tolerated and rapidly effective analgesic agent has proven elusive in the paediatric setting. The pharmacokinetic profile of intranasal diamorphine in adults has been systematically studied. It is rapidly and dose-dependently absorbed as a dry powder, with peak plasma concentrations occurring within 5 minutes, and has a similar pharmacokinetic profile to that of intramuscular diamorphine. It is rapidly converted to 6-acetylmorphine (peak concentrations within 5-10 minutes) and thence to morphine (peak concentrations within 1 hour). The pharmacodynamic properties of intranasal diamorphine have also been studied in comparison with intramuscular diamorphine. Intranasal and intramuscular administration of diamorphine resulted in similar physiological responses (including pupil diameter, respiration rate and temperature). Changes in behavioural measures (including euphoria, sedation and dysphoria) were also similar. Intranasal administration of diamorphine, therefore, produces the expected drug effects on the same timescale and of the same magnitude as intramuscular injection. Intranasal diamorphine has been clinically evaluated in a randomised controlled trial versus intramuscular morphine in the setting of acute orthopaedic pain in children with fractures. Intranasal diamorphine provided the same overall degree of pain relief as intramuscular morphine, but with a quicker onset of action. It was found to be well tolerated with an acceptable safety profile. It has also been studied in the setting of patient-controlled analgesia for postoperative pain in adults, with encouraging results. The pharmacokinetic and pharmacodynamic properties of intranasal diamorphine, and particularly the ability to administer it without a needle (and therefore reduce the incidence of transmissible infection), have made this a popular route for abuse amongst opioid addicts. In this setting, however, the intranasal route is not free from adverse events, including deaths. The primary clinical need in the paediatric population is for a well tolerated, effective and expedient analgesic agent that is safe to use; intranasal diamorphine has pharmacokinetic properties that would make it suitable for such a clinical indication and, in clinical evaluations to date, appears to be promising.

Khalil, W. and N. Raslan (2019). "The effectiveness of topical lidocaine in relieving pain related to intranasal midazolam sedation: a randomized, placebo-controlled clinical trial." Quintessence Int: 2-7.

OBJECTIVE: Intranasal midazolam (INM) is an increasingly popular agent for sedation in the emergency department and outside the hospital in physician, imaging, and dental offices, to facilitate diagnostic and minor surgical procedures and avoid the need for an operating room and general anesthesia. The use of INM has been commonly associated with a burning sensation of the nasal mucosa. Despite its significance, this subject has received little adequate research focus. The objective of the current study was to evaluate the effectiveness of topical lidocaine in relieving pain related to INM administration. METHOD AND MATERIALS: This was a blinded, randomized placebo-controlled trial. Sixty-three uncooperative children undergoing dental treatment, aged 4 to 11 years, were randomly assigned to one of three groups to receive the drug nasally via a precalibrated spray as per the following assignments: group A received 0.5 mg/kg midazolam, group B received lidocaine 2% prior to 0.5 mg/kg midazolam, and group C received saline 0.9% (placebo), 0.5 mg/kg. Children were asked to record the degree of pain using the Wong-Baker faces scale. Parental acceptance was also rated. RESULTS: Topical lidocaine prior to INM administration reduced the burning sensation in the nasal mucosa and improved the drug acceptance. The median score of pain was 8, 1, and 4 in groups A, B, and C, respectively. The differences among the three groups were statistically significant (P > .05). The children's acceptance and parents' future acceptance regarding the intranasal drug administration was significantly higher in group B. CONCLUSION: INM administration results in burning sensation in the nasal mucosa with high levels of pain. Using topical lidocaine 2% counteracted the burning sensation and achieved a higher acceptance rate and lower pain scores.

Khazin, V., S. Ezra, et al. (1995). "Comparison of rectal to intranasal administration of midazolam for premedication of children." Mil Med 160(11): 579-81.

            Sixty children aged 3 to 9, undergoing minor surgical procedures, were studied to compare 0.5 mg/kg intranasal with 0.5 mg/kg rectal midazolam as a premedication. The children were evaluated for their ability to tolerate the medication, preanesthetic sedation, and alertness after anesthesia. Both premedication routes were equally effective in sedating the children. In both groups, a significant loss of effectiveness was noted if induction of the anesthesia began more than 30 minutes after administration of the medication (p &lt; 0.0003). Rectal midazolam was much better tolerated by the children than the intranasal route (30 versus 3, p &lt; 0.0001). We advocate the rectal over the intranasal route for premedication with midazolam in children, and anesthetic induction should occur no more than 30 minutes after administration of premedication.

Klein, E. J., J. C. Brown, et al. (2011). "A Randomized Clinical Trial Comparing Oral, Aerosolized Intranasal, and Aerosolized Buccal Midazolam." Ann Emerg Med.

            STUDY OBJECTIVE: We determine whether aerosolized intranasal or buccal midazolam reduces the distress of pediatric laceration repair compared with oral midazolam. METHODS: Children aged 0.5 to 7 years and needing nonparenteral sedation for laceration repair were randomized to receive oral, aerosolized intranasal, or aerosolized buccal midazolam. Patient distress was rated by blinded review of videotapes, using the Children's Hospital of Eastern Ontario Pain Score. Secondary outcomes included activity scores, sedation adequacy, sedation onset, satisfaction, and adverse events. RESULTS: For the 169 subjects (median age 3.1 years) evaluated for the primary outcome, we found significantly less distress in the buccal midazolam group compared with the oral route group (P=.04; difference -2; 95% confidence interval -4 to 0) and a corresponding nonsignificant trend for the intranasal route (P=.08; difference -1; 95% confidence interval -3 to 1). Secondary outcomes (177 subjects) favored the intranasal group, including a greater proportion of patients with an optimal activity score (74%), a greater proportion of parents wanting this sedation in the future, and faster sedation onset. Intranasal was the route least tolerated at administration. Adverse events were similar between groups. CONCLUSION: When comparing the administration of midazolam by 3 routes to facilitate pediatric laceration repair, we observed slightly less distress in the aerosolized buccal group. The intranasal route demonstrated a greater proportion of patients with optimal activity scores, greater proportions of parents wanting similar sedation in the future, and faster onset but was also the most poorly tolerated at administration. Aerosolized buccal or intranasal midazolam represents an effective and useful alternative to oral midazolam for sedation for laceration repair.

Kogan, A., J. Katz, et al. (2002). "Premedication with midazolam in young children: a comparison of four routes of administration." Paediatr Anaesth 12(8): 685-9.

            Background: We undertook a study to determine the effects of four routes of administation on the efficacy of midazolam for premedication. Methods: In a randomized double-blind study, 119 unmedicated children, ASA I-II, aged 1.5-5 years, who were scheduled for minor elective surgery and who had been planned to received midazolam as a premedicant drug, were randomly assigned to one of four groups. Group I received intranasal midazolam 0.3 mg.kg-1; group II, oral midazolam 0.5 mg.kg-1; group III, rectal midazolam 0.5 mg.kg-1; and group IV, sublingual midazolam 0.3 mg.kg-1. A blinded observer assessed the children for sedation and anxiolysis every 5 min prior to surgery. Quality of mask acceptance for induction, postanaesthesia care unit behaviour and parents' satisfaction were evaluated. Thirty patients were enrolled in each of groups I, III and IV. Twenty-nine patients were enrolled in group II. Results: There were no significant differences in sedation and anxiety levels among the four groups. Average sedation and anxiolysis increased with time, achieving a maximum at 20 min in group I and at 30 min in groups II-IV. Patient mask acceptance was good for more than 75% of the children. Although the intranasal route provides a faster effect, it causes significant nasal irritation. Seventy-seven percent of the children from this group cried after drug administration. Most parents in all groups (67-73%) were satisfied with the premedication. Conclusions: Intranasal, oral, rectal and sublingual midazolam produces good levels of sedation and anxiolysis. Mask acceptance for inhalation induction was easy in the majority of children, irrespective of the route of drug administration.

Kronenberg and Rh (2002). "Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration." J Pain Palliat Care Pharmacother 16(3): 27-35.

                Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain. Ketamine also has been reported to produce opioid dose sparing and good patient acceptance. A transdermal formulation is currently under patent review in Brazil and an intranasal formulation is currently undergoing phase I/II clinical trials.

Ku, L. C., C. Simmons, et al. (2019). "Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit." J Neonatal Perinatal Med 12(2): 143-148

BACKGROUND: The intranasal route is a minimally invasive method for rapidly delivering midazolam and fentanyl to provide short-term analgesia and sedation in infants. However, intranasal use of midazolam and fentanyl is not labeled for infants and safety data are sparse. The objective of this study is to evaluate the safety of intranasal midazolam and intranasal fentanyl in infants admitted to the Neonatal Intensive Care Unit (NICU). METHODS: We retrospectively identified all infants receiving intranasal midazolam or fentanyl in the NICU from 2009 to 2015. We recorded indication for use and vital signs and determined the proportion of infants experiencing the following adverse events: death within 24 hours, hypotension, bradycardia, worsening respiratory status, and chest wall rigidity. Vital signs 4 hours before and after each dose were compared using the Wilcoxon signed-rank test. RESULTS: We identified 17 infants (gestational ages 23- 41 weeks) receiving 25 intranasal doses. None of the infants died or developed hypotension, bradycardia, or chest wall rigidity. Intranasal delivery was most commonly used for sedation during magnetic resonance imaging studies. Other indications include analgesia or sedation for retinopathy of prematurity surgery, intubation, and peripherally inserted central catheter placement. One infant receiving intranasal midazolam experienced worsening respiratory status. Vital signs before and after dosing were not significantly different. CONCLUSIONS: Intranasal midazolam and fentanyl use in term and preterm infants appeared safe and well-tolerated in this small cohort of infants. Larger, prospective studies evaluating the safety and efficacy of intranasal midazolam and fentanyl use in infants are warranted.

Kulbe, J. (1998). "The use of ketamine nasal spray for short-term analgesia." Home Healthc Nurse 16(6): 367-70.

Kumar, L., A. Kumar, et al. (2017). "Efficacy of intranasal dexmedetomidine versus oral midazolam for paediatric premedication." Indian J Anaesth 61(2): 125-130.

            BACKGROUND AND AIMS: Premedication is an integral component of paediatric anaesthesia which, when optimal, allows comfortable separation of the child from the parent for induction and conduct of anaesthesia. Midazolam has been accepted as a safe and effective oral premedicant. Dexmedetomidine is a selective alpha-2 agonist with sedative and analgesic effects, which is effective through the transmucosal route. We compared the efficacy and safety of standard premedication with oral midazolam versus intranasal dexmedetomidine as premedication in children undergoing elective lower abdominal surgery. METHODS: This was a prospective randomised double-blinded trial comparing the effects of premedication with 0.5 mg/kg oral midazolam versus 1 mug/kg intranasal dexmedetomidine in children between 2 and 12 years undergoing abdominal surgery. Sedation scores at separation and induction were the primary outcome measures. Behaviour scores and haemodynamic changes were secondary outcomes. Student's t-test and Chi-square were used for analysis of the variables. RESULTS: Sedation scores were superior in Group B (dexmedetomidine) than Group A (midazolam) at separation and induction (P < 0.001). The behaviour scores at separation, induction and wake up scores at extubation were similar between the two groups. The heart rate and blood pressure showed significant differences at 15, 30 and 45 min in Group B but did not require pharmacological intervention for correction. CONCLUSION: Intranasal dexmedetomidine at a dose of 1 mug/kg produced superior sedation scores at separation and induction but normal behavioural scores in comparison to oral midazolam in paediatric patients.

Kunusoth, R., G. Tej, et al. (2019). "Comparative Analysis of Intravenous Midazolam with Nasal Spray for Conscious Sedation in Minor Oral and Maxillofacial Surgeries." J Pharm Bioallied Sci 11(Suppl 1): S42-S50.

Aim: The aim of the current study was to evaluate the efficacy of nasal spray midazolam by collating it with conventional intravenous midazolam for conscious sedation in minor oral surgeries. Materials and Methods: Sixty patients were selected randomly and divided into two groups: group A for intranasal midazolam atomized spray (n = 30) and group B for intravenous midazolam (n = 30). Physiological parameters, anxiety score, sedation rating, patient's cooperation score, and retrograde and anterograde amnesia were recorded for each patient during preoperative, intraoperative, and postoperative period. Final evaluation of safety and efficacy in the nasal and intravenous routes of midazolam drug during minor oral surgery was compared. Results: In this study, both intranasal and intravenous groups showed decrease in systolic blood pressure and diastolic blood pressure intraoperatively but within physiological limits and increase in the average pulse rates in both the groups. The average oxygen saturation levels were maintained to normal range in both the groups. The average respiratory rate decreased in both intranasal and intravenous groups during surgical procedure. The preoperative to postoperative anxiety scores were decreased significantly in the both groups and there was no significant difference in pre- to postoperative anxiety scores between the groups. Conclusion: Both intravenous and intranasal administration of midazolam showed better patient cooperation, satisfaction, and clinical effectiveness. Intranasal midazolam spray is effective in the reduction of subjective stress, reliable anxiolysis while preserving protective reflexes.

Kupietzky, A., G. Holan, et al. (1996). "Intranasal midazolam better at effecting amnesia after sedation than oral hydroxyzine: a pilot study." Pediatr Dent 18(1): 32-4.

            Providing amnesia about a surgery is a desired side effect of a medication. This study compares anterograde amnesic effects of midazolam with hydroxyzine in children undergoing dental treatment with those drugs plus nitrous oxide, using a recall test. Thirty ASAI children 24-28 months, were shown a Standard-Binet intelligence scale-memory for objects subtest before entering treatment room. Twenty-lone randomly determined children received 3.7 mg/kg hydroxyzine 45 min before treatment or 0.2 mg/kg intranasal midazolam in two succeeding appointments, alternatively. Recall in the 30-subject treatment group was 90%. Recall in the 21-subject treatment group was 71% for hydroxyzine and 29% for midazolam. Midazolam was more effective in creating amnesia than hydroxyzine in this study.

Lacoste, L., S. Bouquet, et al. (2000). "Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and pharmacokinetics (0.4 mg/kg) with bioavailability determination." Lab Anim 34(1): 29-35.

            Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18 +/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of 0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally (i.n.) in a cross-over protocol with a one-week wash-out period between each. In series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min, without a significant difference between 0.2 and 0.4 mg/kg doses for any of the studied parameters. In series 2, after intranasal midazolam administration of 0.4 mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5 min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and reliable sedation, adapted to laboratory piglets.

Lawrence, L. M. and S. W. Wright (1998). "Sedation of pediatric patients for minor laceration repair: effect on length of emergency department stay and patient charges." Pediatr Emerg Care 14(6): 393-5.

            INTRODUCTION: Sedating children can facilitate minor laceration repair by minimizing physical and psychic discomfort. However, some clinicians are reluctant to use sedation, in part because of concern about increased patient charges and fear that the emergency department (ED) stay will be prolonged. The purpose of this study was to determine the extent to which sedative use during the repair of simple facial lacerations in children increased the length of ED stay and patient charges. METHODS: This was a retrospective cohort study of 152 children with small, simple, facial lacerations. Patients with complex lacerations and those requiring specialty consultation were excluded. Patients, at the discretion of the treating physician, received either intramuscular ketamine (n = 14), intranasal or rectal midazolam (n = 38), or no sedation (n = 100). Length of ED stay and the total patient charges were analyzed. RESULTS: Groups were equal with respect to age, sex, and length of the wound. The mean patient time in the ED, from placement in examination room to discharge, was significantly longer for those given ketamine (149+/-37 minutes) and midazolam (98+/-31 minutes) compared with those given no sedation (82+/-28 minutes). Patient charges were also higher in those given ketamine ($695+/-172) or midazolam ($498+/-153) compared with those receiving no sedation ($390+/-86). CONCLUSIONS: The results of this study demonstrate that sedation with ketamine or midazolam increases the length of ED stay compared with using no sedation. However, the increased lengths of stay were modest, particularly for midazolam. Fear of prolonged recovery time should not dissuade clinicians from using either sedative for minor procedures. The patient charges are considerably higher with both midazolam and ketamine, but they may not reflect the actual cost of patient care.

Lazol, J. P. and C. G. DeGroff (2009). "Minimal sedation second dose strategy with intranasal midazolam in an outpatient pediatric echocardiographic setting." J Am Soc Echocardiogr 22(4): 383-7.

Lee-Kim, S. J., S. Fadavi, et al. (2004). "Nasal versus oral midazolam sedation for pediatric dental patients." J Dent Child (Chic) 71(2): 126-30.

            PURPOSE: The purpose of this study was to evaluate and compare intranasal (IN) and oral (PO) midazolam for effect on behavior, time of onset, maximum working time, efficacy, and safety for patients requiring dental care. METHODS: Forty anxious subjects (20 IN, 20 PO, Frankl Scale 3 and 4, ages 2-6 years, ASA I and II) were sedated randomly with either IN (0.3 mg/kg) or PO (0.7 mg/kg) midazolam. The dental procedure under sedation was videotaped and rated by a blinded and calibrated evaluator using Houpt's behavior rating scale. RESULTS: There was no statistical difference for overall behavior (F3,27 = 0.407; P = .749). The planned contrasts showed significant interactions between time and route (IN vs PO) between 25 and 30 minutes after starting sedation. The time of onset (P = .000) and the working time (P = .007) were significantly different between IN and PO midazolam. There were no statistically significant differences in vital signs (O2 sat, HR, RR, BP) between PO and IN (P = .595). IN subjects showed more movement and less sleep toward the end of the dental procedures, and faster onset time but shorter working time than PO. Vital signs were stable throughout the procedures with no significant differences. CONCLUSIONS: Mean onset time was approximately 3 times faster with IN administration compared to PO administration. Mean working time was approximately 10 minutes longer with PO administration than it was with IN administration. Overall behavior under PO and IN was similar. However, more movement and less sleep were shown in subjects under IN than those under PO toward the end of the dental session. All vital signs were stable throughout the procedures and showed no significant differences between PO and IN administration.

Lei, H., L. Chao, et al. (2020). "Incidence and risk factors of bradycardia in pediatric patients undergoing intranasal dexmedetomidine sedation." Acta Anaesthesiol Scand 64(4): 464-471.

BACKGROUND: Dexmedetomidine is widely used for non-invasive pediatric procedural sedation. However, the hemodynamic effects of intravenous dexmedetomidine are a concern. There has been a growing interest in the application of intranasal dexmedetomidine as a sedative in children. OBJECTIVE: To investigate the incidence of bradycardia in children undergoing intranasal dexmedetomidine sedation and to identify the associated risk factors. METHODS: Data pertaining to pediatric patients who underwent intranasal dexmedetomidine sedation for non-invasive investigations at the Kunming Children's Hospital between October 2017 and August 2018 were retrospectively analyzed. RESULTS: Out of 9984 children who qualified for inclusion, 228 children (2.3%) developed bradycardia. The incidence of bradycardia in the group that received additional dose of dexmedetomidine was higher than that in the group that did not receive additional dose (9.2% vs 16.7%; P = .003). The incidence of bradycardia in males was higher than that in females (2.6% vs 1.8%; P = .007). On multivariate logistic regression, only male gender showed an independent association with the occurrence of bradycardia (odds ratio 1.48; 95% confidence interval 1.11-1.97; P = .008). CONCLUSIONS: The overall incidence of bradycardia in children after sole use of intranasal dexmedetomidine sedation was 2.3%. Male children showed a 1.48-fold higher risk of bradycardia. However, the blood pressure of the children who developed bradycardia was within the normal range. Simple wake-up can effectively manage bradycardia induced by intranasal dexmedetomidine sedation.

Lejus, C., M. Renaudin, et al. (1997). "Midazolam for premedication in children: nasal vs. rectal administration." Eur J Anaesthesiol 14(3): 244-9.

            The authors compared the acceptance and efficacy of rectal and nasal administration of midazolam (MDZ) for premedication. Ninety-five ASA I and II paediatric patients (8 months to 12 years) scheduled for elective surgery were randomly allocated to two groups. Group R received 0.3 mg kg-1 of rectal midazolam (in 5 mL saline). Group N received 0.2 mg kg-1 of nasal midazolam (5 mg ml-1). Both groups were divided in two subgroups according to age (group RA (&lt; or = 6 years, n = 33), group RB (&gt; 6 years, n = 18), group NA (&lt; or = 6 years, n = 28), group NB (&gt; 6 years, n = 16)). At the time of premedication, tolerance to the administration was confirmed. Twenty min after rectal or 10 min after nasal administration the quality of sedation was recorded. The nasal midazolam, in commonly used dosages, induced a sedation similar to that following rectal administration with a shorter delay of onset. Nasal administration was more often painful than rectal administration. Swallowing (nasal midazolam) and concerns about modesty (rectal midazolam) were more frequent in older children. Because of its poor tolerance, nasal premedication should be reversed for cases where there is no alternative. Rectal premedication should be avoided in older children.

Lei, H., L. Chao, et al. (2019). "Incidence and risk factors of bradycardia in pediatric patients undergoing intranasal dexmedetomidine sedation." Acta Anaesthesiol Scand.

BACKGROUND: Dexmedetomidine is widely used for non-invasive pediatric procedural sedation. However, the hemodynamic effects of intravenous dexmedetomidine are a concern. There has been a growing interest in the application of intranasal dexmedetomidine as a sedative in children. OBJECTIVE: To investigate the incidence of bradycardia in children undergoing intranasal dexmedetomidine sedation and to identify the associated risk factors. METHODS: Data pertaining to pediatric patients who underwent intranasal dexmedetomidine sedation for non-invasive investigations at the Kunming Children's Hospital between October 2017 and August 2018 were retrospectively analyzed. RESULTS: Out of 9984 children who qualified for inclusion, 228 children (2.3%) developed bradycardia. The incidence of bradycardia in the group that received additional dose of dexmedetomidine was higher than that in the group that did not receive additional dose (9.2% vs 16.7%; P = .003). The incidence of bradycardia in males was higher than that in females (2.6% vs 1.8%; P = .007). On multivariate logistic regression, only male gender showed an independent association with the occurrence of bradycardia (odds ratio 1.48; 95% confidence interval 1.11-1.97; P = .008). CONCLUSIONS: The overall incidence of bradycardia in children after sole use of intranasal dexmedetomidine sedation was 2.3%. Male children showed a 1.48-fold higher risk of bradycardia. However, the blood pressure of the children who developed bradycardia was within the normal range. Simple wake-up can effectively manage bradycardia induced by intranasal dexmedetomidine sedation.

Lewis, J. and C. R. Bailey (2019). "Intranasal dexmedetomidine for sedation in children; a review." J Perioper Pract: 1750458919854885.

Li, B. L., V. M. Yuen, et al. (2014). "Intranasal dexmedetomidine following failed chloral hydrate sedation in children." Anaesthesia 69(3): 240-244.

Chloral hydrate is the most commonly used sedative for paediatric diagnostic procedures in China with a success rate of around 80%. Intranasal dexmedetomidine is used for rescue sedation in our centre. This prospective investigation evaluated 213 children aged one month to 10 years who were not adequately sedated following administration of chloral hydrate. Children were randomly assigned to receive rescue intranasal dexmedetomidine at 1 mug.kg(-1) (group 1), 1.5 mug.kg(-1) (group 2) or 2 mug.kg(-1) (group 3). The sedation level was assessed every 10 min using a modified observer's assessment of alertness/sedation scale. Successful rescue sedation in groups 1, 2 and 3 were 56 (83.6%), 66 (89.2%) and 51 (96.2%), respectively. Increasing the rescue dose was associated with an increased success rate with an odds ratio of 4.12 (95% CI 1.13-14.98), p = 0.032. We conclude that intranasal dexmedetomidine is effective for sedation in children who do not respond to chloral hydrate.

Li, B. L., J. Ni, et al. (2015). "Intranasal dexmedetomidine for sedation in children undergoing transthoracic echocardiography study-a prospective observational study." Paediatr Anaesth 25(9): 891-896.

                BACKGROUND: Intranasal dexmedetomidine has been used for sedation in children undergoing nonpainful procedures. OBJECTIVE: The aim of this study was to determine the success rate of intranasal dexmedetomidine sedation for children undergoing transthoracic echocardiography examination. METHODS: This was a prospective observational study of 115 children under the age of 3 years undergoing echocardiography examination under sedation with intranasal dexmedetomidine at 3 mcg.kg(-1) . RESULTS: Of the 115 children, 100 (87%) had satisfactory sedation with intranasal dexmedetomidine. The mean onset time was 16.7 +/- 7 min (range 5-50 min). The mean wake up time was 44.3 +/- 15.1 min (range 12-123 min). The wake up time was significantly correlated with duration of procedure with R = 0.540 (P < 0.001). Aside from one patient who required oxygen supplementation, all children in this investigation had an acceptable heart rate and blood pressure and required no medical intervention. CONCLUSION: Sedation by intranasal dexmedetomidine at 3 mcg.kg(-1) is associated with acceptable success rate in children undergoing echocardiography with no adverse events in this cohort.

Li, B. L., V. M. Yuen, et al. (2018). "A randomized controlled trial of oral chloral hydrate vs intranasal dexmedetomidine plus buccal midazolam for auditory brainstem response testing in children." Paediatr Anaesth 28(11): 1022-1028.

           BACKGROUND: Moderate to deep sedation is required for an auditory brainstem response test when high-intensity stimulation is used. Chloral hydrate is the most commonly used sedative, whereas intranasal dexmedetomidine is increasingly used in pediatric non-painful procedural sedations. OBJECTIVE: The aim of this study was to compare the sedation success rate after oral chloral hydrate at 50 mg kg(-1) and intranasal dexmedetomidine at 3 mug kg(-1) plus buccal midazolam at 0.1 mg kg(-1) for an auditory brainstem response test. METHODS: Children who required an auditory brainstem response test were recruited and randomly assigned to receive oral chloral hydrate at 50 mg kg(-1) and intranasal placebo, or intranasal dexmedetomidine at 3 mug kg(-1) with buccal midazolam 0.1 mg kg(-1) . The primary outcome was the rate of successful sedation for auditory brainstem response tests. RESULTS: Fifty-seven out of 82 (69.5%) were successfully sedated after chloral hydrate, while 70 out of 78 (89.7%) children were successfully sedated with dexmedetomidine plus midazolam combination, with the odd ratio (95% CI) for successful sedation between dexmedetomidine plus midazolam combination and chloral hydrate estimated to be 3.84 (1.61-9.16), P = 0.002. Dexmedetomidine plus midazolam was associated with quicker onset with median onset time 15 (IQR 11.0-19.8) for dexmedetomidine plus midazolam and 20 (IQR 15.0-27.0) for chloral hydrate respectively, with difference between median (95% CI) of 5 [3-8], P < 0.0001). The behavior observed during drug administration of intranasal dexmedetomidine and buccal midazolam was better that of the children who had oral chloral hydrate. No children required oxygen therapy or medical intervention for hemodynamic disturbances in this study and the incidence of hypotension and bradycardia was similar. CONCLUSION: Intranasal dexmedetomidine plus buccal midazolam was associated with higher sedation success with deeper level of sedation, with similar discharge time and adverse event rate when compared to chloral hydrate.

Li, L. Q., C. Wang, et al. (2018). "Effects of different doses of intranasal dexmedetomidine on preoperative sedation and postoperative agitation in pediatric with total intravenous anesthesia undergoing adenoidectomy with or without tonsillectomy." Medicine (Baltimore) 97(39): e12140.

Dexmedetomidine is a highly selective alpha2 receptor agonist, this study aimed to investigate the effects of different doses of intranasal dexmedetomidine on the preoperative sedation and postoperative agitation in pediatric with total intravenous anesthesia (TIVA) for adenoidectomy with or without tonsillectomy.This is a double-blind placebo-controlled randomized trial. Pediatric were randomly divided into the D1, D2, and S groups, each group contained 30 patients. Twenty-five to 40 minutes before surgery, the D1 and D2 groups received intranasally dexmedetomidine 1 mug kg or 2 mug kg, respectively, while the S group received saline of the same volume. A unified protocol of TIVA induction and maintenance was used for the three groups. The preoperative sedation, behavior of separation from parents, postoperative agitation, and postoperative pain of the children were evaluated.The proportions of satisfactory sedation in the D1, D2, and S groups were 63.3%, 76.7%, and 0%, respectively. There was a statistically significant difference between D1 and S groups (P = .000) and D2 versus S groups (P = .000), while there was no statistically significant difference between D1 and D2 groups (P = .399). As for scale on the behavior of separation from parents, there was a statistically significant difference between D1 and S groups (P = .009) and D2 versus S groups (P = .009), whereas there was no significant difference between D1 and D2 groups (P = 1). The incidence of postoperative agitation in the D1, D2, and S groups was 43.3%, 30.0%, and 63.3%, respectively, and there was a statistical difference between D2 and S groups (P = .010). There was a significant difference in the Pediatric Anesthesia Emergence Delirium (PAED) scale between D2 and S groups (P = .029). The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) in the D2 group was significantly lower than the S group (P = .013).The intranasal dexmedetomidine of 1 or 2 mug kg 25 to 40 minute before induction of anesthesia both could deliver effective preoperative sedation, reducing the children's distress of separation from parents. Moreover, intranasal dexmedetomidine of 2 mug kg could deliver more effective postoperative analgesia and reduce postoperative agitation, without prolonging postoperative recovery or causing severe adverse events.

Li, B. L., V. M. Yuen, et al. (2019). "A Comparison of Intranasal Dexmedetomidine and Dexmedetomidine Plus Buccal Midazolam for Non-painful Procedural Sedation in Children with Autism." J Autism Dev Disord 49(9): 3798-3806.

Children with autism often need sedation for diagnostic procedures and they are often difficult to sedate. This prospective randomized double-blind control trial evaluates the efficacy and safety using intranasal dexmedetomidine with and without buccal midazolam for sedation in children with autism undergoing computerized tomography and/or auditory brainstem response test. The primary outcome is the proportion of children attaining satisfactory sedation. One hundred and thirty-six children received intranasal dexmedetomidine and 139 received intranasal dexmedetomidine with buccal midazolam for sedation. Combination of intranasal dexmedetomidine and buccal midazolam was associated with higher sedation success when compared to intranasal dexmedetomidine. Since intranasal and buccal sedatives required little cooperation this could be especially useful technique for children with autism or other behavioral conditions.

Li, L., J. Zhou, et al. (2020). "Intranasal dexmedetomidine versus oral chloral hydrate for diagnostic procedures sedation in infants and toddlers: A systematic review and meta-analysis." Medicine (Baltimore) 99(9): e19001.

BACKGROUND: Intranasal dexmedetomidine is a relatively new way to sedate young children undergoing nonpainful diagnostic procedures. We performed a meta-analysis to compare the efficacy and safety of intranasal dexmedetomidine in young children with those of oral chloral hydrate, which has been a commonly used method for decades. METHODS: We searched PubMed, Embase, and the Cochrane Library for all randomized controlled trials that compared intranasal dexmedetomidine with oral chloral hydrate in children undergoing diagnostic procedures. Data on success rate of sedation, onset time, recovery time, and adverse effects were extracted and respectively analyzed. RESULTS: Five studies with a total of 720 patients met the inclusion criteria. Intranasal dexmedetomidine provided significant higher success rate of sedation (relative risk [RR], 1.12; 95% confidence interval [CI], 1.02 to 1.24; P = .02; I = 74%) than oral chloral hydrate. Furthermore, it experienced significantly shorter onset time (weight mean difference [WMD], -1.79; 95% CI, -3.23 to -0.34; P = .02; I = 69%). Nevertheless, there were no statistically differences in recovery time (WMD, -10.53; 95% CI, -24.17 to 3.11; P = .13; I = 92%) and the proportion of patients back to normal activities (RR, 1.11; 95% CI, 0.77-1.60; P = .57; I = 0%). Intranasal dexmedetomidine was associated with a significantly lower incidence of nausea and vomiting (RR, 0.05; 95% CI, 0.01-0.22; P < .0001; I = 0%) than oral chloral hydrate. Although adverse events such as bradycardia, hypotension and hypoxia were not synthetized due to lack of data, no clinical interventions except oxygen supplementation were required in any patients. CONCLUSION: Our meta-analysis revealed that intranasal dexmedetomidine is possibly a more effective and acceptable sedation method for infants and toddlers undergoing diagnostic procedures than oral chloral hydrate. Additionally, it shows similar safety profile and could be a potential alternative to oral chloral hydrate.

Lin, S. M., K. Liu, et al. (1990). "Rectal ketamine versus intranasal ketamine as premedicant in children." Ma Tsui Hsueh Tsa Chi 28(2): 177-183.

                The effects of ketamine administered per nasus (PN) or per rectum (PR) as pre-anesthetic medication for day surgery was studied in 70 ASA class I children with age ranging from 6 months to 6 years. Before study they were divided into 3 groups. Group A (n = 25) received no premedicant, while group B (n = 25) and group C (n = 20) received ketamine 6 mg/kg PR and 3 mg/kg PN as premedicant respectively. It was demonstrated that patients in group B and group C accepted the facemask during induction of anesthesia more willingly and peacefully than those in group A. In group B and group C there was accompaniment of analgesic effect seen postoperatively. The incidence of adverse reactions (nausea, vomiting, laryngospasm, salivation, respiratory depression) was low following the use of PR or PN ketamine although the children in these two groups emerged more belatedly from anesthesia and stayed in the post-anesthetic recovery room (PARR) for a longer time than in group A.

Linares Segovia, B., M. A. Garcia Cuevas, et al. (2014). "[Pre-anesthetic medication with intranasal dexmedetomidine and oral midazolam as an anxiolytic. A clinical trial.]." An Pediatr (Barc).

INTRODUCTION: Dexmedetomidine is a pharmacological option for sedation in children. In this study, the efficacy of intranasal dexmedetomidine to reduce preoperative anxiety in pediatric patients is compared with that of oral midazolam. MATERIAL AND METHODS: A prospective, randomized, double-blind, controlled trial was conducted on children 2-12 years of age, randomly assigned to one of the following two groups: group A received premedication with oral midazolam and intranasal placebo, group B received intranasal dexmedetomidine and oral placebo. Anxiety was assessed with the modified Yale scale, and a risk analysis and number needed to treat was performed. RESULTS: A total of 108 patients were included, 52 (48.1%) treated with dexmedetomidine, and 56 (51.9%) with midazolam. Anxiety was less frequent in the dexmedetomidine group at 60minutes (P=.001), induction (p=.04), and recovery (P=.0001). Risk analysis showed that dexmedetomidine reduced the risk of anxiety by 28% (RAR=0.28, 95% CI; 0.12 to 0.43) and to prevent one case of anxiety, four patients need to be treated with intranasal dexmedetomidine (NNT=4, 95% CI: 3-9).Changes in heart rate, mean arterial pressure, and oxygen saturation, were statistically significant in the dexmedetomidine group, with no clinical consequences. There were no cases of bradycardia, hypotension or oxygen desaturation. CONCLUSIONS: Intranasal dexmedetomidine premedication is more effective than oral midazolam to reduce preoperative anxiety in pediatric patients.

Liu, J., M. Du, et al. (2019). "Sedation effects of intranasal dexmedetomidine combined with ketamine and risk factors for sedation failure in young children during transthoracic echocardiography." Paediatr Anaesth 29(1): 77-84.

BACKGROUND: Sedation is often required for young children during transthoracic echocardiography. Dexmedetomidine and ketamine are two sedatives that are commonly used in children for procedural sedation, but they have some disadvantages when they are used alone. AIMS: The aim of this retrospective study was to analyze the effects and safety of intranasal sedation with a combination of dexmedetomidine and ketamine during transthoracic echocardiography in young children and to analyze risk factors for sedation failure. METHODS: After IRB approval, we retrospectively evaluated data on patients who underwent echocardiography between May 2016 and August 2017 utilizing a combination of dexmedetomidine 2 mug/kg and ketamine 1 mg/kg. We collected information including heart rate, pulse oxygen saturation, sedation onset time, exam time, recovery time, and adverse reactions. Stepwise logistic regression analyses were performed to analyze the risk factors for sedation failure. RESULTS: Sedation was successful in 2212 patients (96%) and took effect in 15.7 (IQR: 10-23) min, while sedation failed in 92 patients. Cyanotic heart disease, history of sedation failure, history of congenital heart disease surgery, and fever were independent risk factors for sedation failure. Most of the patients in this study had an American Society of Anesthesiologists (ASA) grade of II to III, but no severe adverse reactions were observed. CONCLUSION: Intranasal sedation with a combination of dexmedetomidine and ketamine is effective and appears to have an acceptable safety profile for young children during transthoracic echocardiography.

Liu, H., M. Sun, et al. (2019). "Determination of the 90% effective dose of intranasal dexmedetomidine for sedation during electroencephalography in children." Acta Anaesthesiol Scand 63(7): 847-852.

BACKGROUND: The intranasal route of dexmedetomidine (DEX) administration is becoming increasingly popular for providing adequate sedation during short examinations in infants and children. However, data on the 90% effective dose (ED90) of intranasal DEX are rare in children under 3 years old. METHODS: This is a double-blind trial using a biased coin design up-and-down sequential method (BCD-UDM). Fifty-three children aged under 3 years old requiring DEX for EEG were included in our study. The first patient received 2.5 mug kg(-1) DEX, and the dose of DEX administered to the subsequent patient was determined by the response of the previous patient. The patient responses were recorded and analysed to calculate the ED90 by isotonic regression. The 95% confidence interval (CI) was estimated using a bootstrapping method. RESULTS: Fifty-three patients were included in our study, of which 45 patients were successfully sedated, and the 8 instances of failed sedation were rescued using sevoflurane inhalation, allowing the completion of the procedure. The 90% effective dose of DEX was calculated to be 3.28 microg kg(-1) , and the 95% CI was 2.74 ~ 3.39 microg kg(-1) . No significant adverse events occurred in any of the patients. CONCLUSION: The 90% effective dose of intranasal DEX sedation for EEG was 3.28 mug kg(-1) in children under 3 years old.

Liu, S., Y. Wang, et al. (2019). "Safety and sedative effect of intranasal dexmedetomidine in mandibular third molar surgery: a systematic review and meta-analysis." Drug Des Devel Ther 13: 1301-1310.

Objective: The focus of this meta-analysis was to assess the sedative effect and safety of intranasal dexmedetomidine (Dex) in mandibular third molar surgery. Methods: The PubMed/Medline, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases were searched for studies published until May 1, 2018. Eligible studies were restricted to randomized controlled trials (RCTs) and controlled clinical trials. The evaluation indicators mainly included the bispectral index, observer assessment of alertness/sedation scale, systolic blood pressure, and heart rate. Data for each period in the Dex and control groups were pooled to evaluate its sedative effect and safety. Results: Five RCTs met the inclusion criteria. This study included 363 patients: 158 patients received intranasal inhalation of Dex before surgery, and 158 patients were negative controls. The pooled results showed a good sedative effect during tooth extraction when intranasal inhalation of Dex was performed 30 minutes before third molar extraction (assessment of alertness/sedation, Dex vs control SMD -1.20, 95% CI -1.73 to -0.67, I (2)=0, P=0.95; bispectral index, Dex vs control SMD -11.68, 95% CI -19.49 to -3.87, I (2)=89%; P=0.0001), and parameters returned to normal within 90 minutes after inhalation. During the operation, blood pressure and heart rate decreased to some extent, but the decreases did not exceed 20% of the baseline, and all patients returned to normal conditions within 90 minutes after inhalation. Conclusion: Intranasal inhalation of Dex 30 minutes before third molar extraction can provide a good sedative effect, and large-sample multicenter RCTs are needed to evaluate the analgesic effect of Dex.

Ljungman, G., A. Kreuger, et al. (2000). "Midazolam nasal spray reduces procedural anxiety in children." Pediatrics 105(1 Pt 1): 73-8.

            OBJECTIVE: Anxiety and pain even in minor procedures are still great problems in pediatrics, not least in pediatric oncology. Conscious sedation is indicated when other means to overcome a child's fear fail. The aim of this study was to investigate whether intranasal administration of midazolam given before insertion of a needle in a subcutaneously implanted central venous port could reduce anxiety, discomfort, pain, and procedure problems. METHOD: Forty-three children with cancer participated in this randomized, double-blind, placebo- controlled, crossover study in which nasal administration of midazolam spray,.2 mg/kg body weight, was compared with placebo. Children, parents, and nurses completed a visual analog scale questionnaire to evaluate efficacy. RESULTS: Parents and nurses reported reduced anxiety, discomfort, and procedure problems for children in the midazolam group and would prefer the same medication at next procedure. They also reported pain reduction. Children reported reduced anxiety and procedure problems but reduction of pain and discomfort was not significant. No serious or unexpected side effects occurred. Nasal discomfort was the most common side effect (17/38 approximately 45%) and the primary reason for dropouts (8/43 approximately 19%). Anxiety varied with age but not with gender. When anxiety increased, the differences between midazolam and placebo increased. CONCLUSION: Nasal midazolam spray offers relief to children anxious about procedures, such as insertion of a needle in a subcutaneously implanted intravenous port, venous blood sampling, venous cannulation, etc. Its use, however, may be limited by nasal discomfort in some patients for whom rectal and oral routes might be alternatives.

Lloyd, C. J., T. Alredy, et al. (2000). "Intranasal midazolam as an alternative to general anaesthesia in the management of children with oral and maxillofacial trauma." Br J Oral Maxillofac Surg 38(6): 593-595.

            The study assessed the dosage, clinical sedative effect, and safety of intranasal midazolam in 32 children. Data were complete for 29 patients (21 with lacerations and 8 cases of dental trauma). Sedation was adequate to ensure successful completion of treatment under local with or without topical anaesthetic in 22 of the 29 cases (76%). They became sedated at a mean (SD) of 14 (5) minutes, with completion of treatment at 20 (13) minutes. Sedation was achieved with a mean (SD) of 5 (2)mg of midazolam. There were no signs of respiratory depression or of oxygen desaturation below 94% on pulse oximetry. No supplemental oxygen was required and there were no other complications. We conclude that intranasal midazolam is a safe and effective alternative to general anaesthesia in the definitive treatment of children with oral and maxillofacial injuries. Copyright 2000 The British Association of Oral and Maxillofacial Surgeons.

Louon, A., J. Lithander, et al. (1993). "Sedation with nasal ketamine and midazolam for cryotherapy in retinopathy of prematurity." Br J Ophthalmol 77(8): 529-30.

Louon, A. and V. G. Reddy (1994). "Nasal midazolam and ketamine for paediatric sedation during computerised tomography." Acta Anaesthesiol Scand 38(3): 259-61.

            We have studied the sedation achieved with a mixture of midazolam (0.56 mg/kg-1) and ketamine (5 mg/kg-1) administered nasally in 30 children weighing less than 16 kg undergoing computerised tomography. Assessment was two fold using a visual analogue scale; the radiologist/radiographer rated the exam from "failed examination" to "perfect working conditions" while the anesthetist's assessment ranged from "poor sedation" to "perfect sedation with clinical well being". This new method proved to be effective alone in 83% of the cases and there were no complications. The rapid onset obtained after intranasal midazolam and ketamine offers advantages over orally or rectally administered drugs. The absence of respiratory depression and oxygen desaturation suggests that this technique is safe and efficient in the CT room with its particular working conditions.

Liu, Y., Q. Yu, et al. (2017). "Median effective dose of intranasal dexmedetomidine sedation for transthoracic echocardiography examination in postcardiac surgery and normal children: An up-and-down sequential allocation trial." Eur J Anaesthesiol.

            BACKGROUND: Dexmedetomidine (DEX) has been used for sedation in young infants and children undergoing transthoracic echocardiography (TTE). The median effective dose of intranasal DEX has not been described for postcardiac surgery children. Postcardiac surgery children could require more DEX to achieve satisfactory sedation for TTE examination than children suspected of congenital heart disease. OBJECTIVES: To study whether postcardiac surgery children need a larger dose of DEX for TTE than normal children. DESIGN: A double-blind sequential allocation trial with doses determined by the Dixon and Massey up-and-down method. SETTING: A tertiary care teaching hospital from 25 October to 30 November 2016. PATIENTS: Children under the age of 3 years requiring intranasal DEX for TTE. INTERVENTIONS: Children were allocated to a postcardiac surgery group (n = 20) or a normal group (n = 19). The first patient in both groups received intranasal DEX (2 mug kg): using the up-and-down method of Dixon and Massey, the next dose was dependent on the previous patient's response. MAIN OUTCOME MEASURES: Median effective dose was estimated from the up-and-down method of Dixon and Massey and probit regression. A second objective was to study haemodynamic stability and adverse events with these doses. RESULTS: The median effective dose (95% confidence interval) of intranasal DEX was higher in postcardiac surgery children than in normal children, 3.3 (2.72 to 3.78) mug kg versus 1.8 (1.71 to 2.04) (mug kg), respectively (P < 0.05). There were no significant differences in time to sedation, time to wake-up or TTE examination time between the two groups for successful sedation. Additionally, there were no significant adverse events. CONCLUSION: The median effective dose of intranasal DEX for TTE sedation in postcardiac surgery children was higher than in normal children. TRIAL REGISTRATION: chictr.org.cn identifier: ChiCTR-OOC-16009846.

Mahdavi, A., M. Fallahinejad Ghajari, et al. (2018). "Intranasal Premedication Effect of Dexmedetomidine Versus Midazolam on the Behavior of 2-6-Year-Old Uncooperative Children in Dental Clinic." J Dent (Tehran) 15(2): 79-85.

Objectives: The aim of this study was to compare the intranasal premedication effect of newly introduced dexmedetomidine (DEX) versus midazolam on the behavior of uncooperative children in the dental clinic. Materials and Methods: This crossover double-blind clinical trial was conducted on 20 uncooperative children aged 2-6 years who required at least two similar dental treatment visits. The subjects were randomly given 1 mug/kg of DEX and 0.5 mg/kg of midazolam via the intranasal route. For the sedation protocol in the two groups, 0.25 mg/kg of atropine in combination with 0.5 mg/kg of midazolam added to 1-2 mg/kg of ketamine were used 30 minutes after premedication and transferring the patient to the operating room. Dental treatments were carried out by a pediatric dentist blinded to the type of the administered premedication. The sedative efficacy (overall success rate) of the agents was assessed by two independent pediatric dentists based on the Houpt scale. Data analyses were carried out according to Wilcoxon signed-rank test and paired t-test. Results: There were no significant differences in the premedication efficacy of intranasal DEX and midazolam according to the Houpt scale (P>0.05). Conclusions: Intranasal midazolam and DEX are satisfactory and effective premedication regimens for uncooperative children.

Malhotra, P. U., S. Thakur, et al. (2016). "Comparative evaluation of dexmedetomidine and midazolam-ketamine combination as sedative agents in pediatric dentistry: A double-blinded randomized controlled trial." Contemp Clin Dent 7(2): 186-192.

BACKGROUND: Pharmacological methods have been used as an adjunct to enhance child cooperativeness and facilitate dental treatment. OBJECTIVE: Purpose of this study was to evaluate and compare the effect of sedation by intranasal dexmedetomidine and oral combination drug midazolam-ketamine in a group of children with uncooperative behavior requiring dental treatment. MATERIALS AND METHODS: This was a prospective, randomized, double-blind study that included patients 3-9 years old with American Society of Anesthesiologists-I status. About 36 children presenting early childhood caries were randomly assigned to one of three groups studied: Group MK received intranasal saline and oral midazolam (0.5 mg/kg) with ketamine (5 mg/kg) mixed in mango juice; Group DX received intranasal dexmedetomidine (1 mug/kg) and oral mango juice; and Group C received intranasal saline and oral mango juice. Patients' heart rate, blood pressure, and oxygen saturation were recorded before, during, and at the end of the procedure. Patients' behavior, sedation status, and wake up behavior were evaluated with modified observer assessment of alertness and sedation scale. Ease of treatment completion was evaluated according to Houpt scale. RESULTS: Hemodynamic changes were statistically insignificant in Group MK and Group DX. About 75% patients in Group MK were successfully sedated as compared to 53.9% Group DX and none of the patients in Group C. Ease of treatment completion was better with Group MK as compared to Group DX and least with Group C. Around 50% patients in Group MK had postoperative complications. CONCLUSION: Oral midazolam-ketamine combination and intranasal dexmedetomidine evaluated in the present study can be used safely and effectively in uncooperative pediatric dental patients for producing conscious sedation.

Malia, L., V. M. Laurich, et al. (2019). "Adverse events and satisfaction with use of intranasal midazolam for emergency department procedures in children." Am J Emerg Med 37(1): 85-88.

PURPOSE: Procedural sedation is commonly performed in the emergency department (ED). Having safe and fast means of providing sedation and anxiolysis to children is important for the child's tolerance of the procedure, parent satisfaction and efficient patient flow in the ED. OBJECTIVE: To evaluate fasting times associated with the administration of intranasal midazolam (INM) and associated complications. Secondary objectives included assessing provider and caregiver satisfaction scores. METHODS: A prospective observational study was conducted in children presenting to an urban pediatric emergency department who received INM for anxiolysis for a procedure or imaging. Data collected included last solid and liquid intake, procedure performed, sedation depth, adverse events and parent and provider satisfaction. RESULTS: 112 patients were enrolled. The mean age was 3.8years. There were no adverse events experienced by any patients. Laceration repair was the most common reason for INM use. The median depth of sedation was 2.0 (cooperative/tranquil). The median liquid NPO time was 172.5min and the median NPO time for solids was 194.0min. 29.8% were NPO for liquids </=2h and 62.5% were NPO for solids </=2h. Parent and provider satisfaction was high: 90.4% of parents' and 88.4% of providers' satisfaction scores were a 4 or 5 on a 5 point Likert scale. CONCLUSION: Our data suggest that short NPO of both solids and liquids are safe for the use of INM. Additionally, parent and provider satisfaction scores were high with the use of INM.

Malinovsky, J. M., C. Lejus, et al. (1993). "Plasma concentrations of midazolam after i.v., nasal or rectal administration in children." Br J Anaesth 70(6): 617-20.

            Midazolam is used frequently for premedication in children, preferably by non-parenteral administration. We have compared plasma concentrations of midazolam after nasal, rectal and i.v. administration in 45 children (aged 2-9 yr; weight 10-30 kg) undergoing minor urological surgery. General anaesthesia consisted of spontaneous respiration of halothane and nitrous oxide in oxygen via a face mask. After administration of atropine and fentanyl i.v., children were allocated randomly to receive midazolam 0.2 mg kg-1 by the nasal, rectal or i.v. route. In the nasal group, children received 50% of the dose of midazolam in each nostril. In the rectal group, midazolam was given rectally via a cannula. Venous blood samples were obtained before and up to 360 min after administration of the drug. Plasma concentrations of midazolam were measured by gas chromatography and electron capture detection. After nasal and rectal administration, midazolam Cmax was 182 (SD 57) ng ml-1 within 12.6 (5.9) min, and 48 (16) ng ml-1 within 12.1 (6.4) min, respectively. Rectal administration resulted in smaller plasma concentrations. In the nasal group, a plasma concentration of midazolam 100 ng ml-1 occurred at about 6 min. After 45 min, the concentration curves after i.v. and nasal midazolam were similar.

Malinovsky, J. M., C. Populaire, et al. (1995). "Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations." Anaesthesia 50(4): 351-4.

            We report a study performed to compare the time and plasma drug concentrations necessary to achieve a similar state of sedation after midazolam premedication given by various routes in children of 2-5 years old. Children were randomly allocated to one of three groups to receive midazolam 0.2 mg.kg-1 given intranasally, 0.5 mg.kg-1 given orally or 0.3 mg.kg-1 given rectally. Sedation was measured regularly until venepuncture was possible in a cooperative child. At this time, a first blood sample was taken to measure plasma concentration, followed by another 10 min later. Anaesthesia consisted of intravenous propofol supplemented with regional analgesia. At recovery from anaesthesia, a third blood sample was taken. Adequate sedation occurred sooner (7.7, SD 2.4 min) with intranasal than oral (12.5, SD 4.9 min) or rectal (16.3, SD 4.2 min) midazolam. The initial blood levels were lower when the drug was given by the alimentary routes despite higher doses (146, SD 51 ng.ml-1 in 11.5, SD 3.9 min; 104, SD 34 ng.ml-1 in 21 +/- 6 min; and 93, SD 63 ng.ml-1 in 23.1, SD 3.5 min for the intra nasal, rectal and oral routes respectively). Duration of surgical procedures, and of propofol infusion, and recovery from anaesthesia was similar for the three groups. The only problem arose in a 30-month-old boy in the intranasal group who developed respiratory depression with a plasma midazolam concentration of 169 ng.ml-1. Intranasal midazolam is an excellent alternative for rapid premedication provided that respiratory monitoring is used.

Malinovsky, J. M., F. Servin, et al. (1996). "Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children." Br J Anaesth 77(2): 203-7.

            It has been suggested that nasal administration of ketamine may be used to induce anaesthesia in paediatric patients. We have examined the pharmacokinetics of ketamine and norketamine after nasal administration compared with rectal and i.v. administration in young children. During halothane anaesthesia, 32 children, aged 2-9 yr, weight 10-30 kg, were allocated randomly to receive ketamine 3 mg kg-1 nasally (group IN3) or ketamine 9 mg kg-1 nasally (group IN9); ketamine 9 mg kg-1 rectally (group IR9); or ketamine 3 mg kg-1 i.v. (group IV3). Venous blood samples were obtained before and up to 360 min after administration of ketamine. Plasma concentrations of ketamine and norketamine were measured by gas liquid chromatography. Statistical comparisons were performed using ANOVA and the Kruskall-Wallis test, with P 0.05 as significant. Mean plasma concentrations of ketamine peaked at 496 ng ml- 1 in group IN3 within 20 min, 2104 ng ml-1 in group IN9 within 21 min, and 632 ng ml-1 in group IR9 within 42 min. Plasma concentrations of norketamine peaked at approximately 120 min after nasal ketamine, but appeared more rapidly after rectal administration of ketamine and were always higher than ketamine concentrations in the same situation. Calculated bioavailability was 0.50 in groups IN3 and IN9 and 0.25 in group IR9. We conclude that nasal administration of low doses of ketamine produced plasma concentrations associated with analgesia, but using high doses via the nasal route produced high plasma concentrations of ketamine similar to those that induce anaesthesia. However, the large volume of ketamine required was partly swallowed and led to an unacceptable variability of effect that precludes this route for induction of anaesthesia.

Manley, M. C., N. J. Ransford, et al. (2008). "Retrospective audit of the efficacy and safety of the combined intranasal/intravenous midazolam sedation technique for the dental treatment of adults with learning disability." Br Dent J, 205; 1-5.

Introduction: The provision of dental care for adults with severe learning disability presents problems. The approach to treatment has often been provided under general anaesthesia tending to result in exodontia rather than restorative care. This paper presents an alternative to this option using conscious sedation. Methods: A multi-centred retrospective audit was reported on using data from Canterbury, Warwick, Dorset and Cardiff. Patients included adults with varying degrees of disability for whom treatment using local anaesthesia, inhalation sedation, and the acceptance of intravenous cannulation was not possible. Sedation was provided by midazolam first administered by the intranasal followed by the intravenous route. Results: From a total of 222 episodes of sedation 128 (57.65%) accepted treatment well and 75 (33.78%) presented slight problems which did not compromise treatment. In 19 cases (8.55%) treatment with sedation was not possible and a referral was made for general anaesthesia. Conclusions: Results showed that a range of different treatments were carried out including advanced restorative care. This paper proposes that the technique described is safe and effective in providing a good standard of dental care for adults with severe learning disability.

Mathieu, Cnudde, et al. (2006). "Intranasal sufentanil is effective for postoperative analgesia in adults." Can J Anaesth 53(1): 60-6.

            PURPOSES: The aim of this prospective, randomized, double-blind study was to compare two doses of intranasal sufentanil for postoperative analgesia, titrated according to individual requirements based upon a numeric rating scale (NRS) from 0 to 10 for pain. METHODS: Forty patients, American Society of Anesthesiologists physical status I-II, scheduled for herniorrhaphy or hemorrhoidectomy under general anesthesia, were included when postoperative NRS was > 3. Nurses used a nasal puff device delivering a constant volume. Patients were randomized into two groups: Group A patients received a dose of 0.025 microg x kg(-1) /puff, Group B patients a dose of 0.05 microg x kg(-1) /puff. Puffs were administered as often as needed to obtain NRS < or = 3, with an interval time of five minutes. Hemodynamic, respiratory measures and sedation were recorded every five minutes.Results: The probability of persistence of pain in Group B was consistently lower than in Group A. After 20 min, 20% of the patients had a NRS score > 3 in Group B, as opposed to 60% in Group A. At 60 min, no patient had a NRS > 3 in Group B, whereas there was a probability of 20% to record a NRS > 3 for Group A. Hemodynamic, respiratory parameters and sedation remained stable with no intergroup differences. CONCLUSIONS: Nasal administration of 0.050 microg x kg(-1) /puff sufentanil allowed a NRS < 4 to be attained within one hour in all patients, with efficacy achieved after 20 min. These findings suggest that the intranasal route is an effective mode of sufentanil administration for immediate postoperative analgesia in adult patients.

Mayel, M., M. A. Nejad, et al. (2020). "Intranasal midazolam sedation as an effective sedation route in pediatric patients for radiologic imaging in the emergency ward: A single-blind randomized trial." Turk J Emerg Med 20(4): 168-174.

OBJECTIVES: Prevention and reduction of pain, anxiety, and fear during medical procedures is one of the most important factors that should be considered in pediatric emergencies. The aim of this study was to compare the efficacy of oral versus intranasal midazolam in sedation during radiologic imaging in the largest province of Iran, Kerman. MATERIALS AND METHODS: Eighty children were enrolled in this single-blind clinical trial based on convenience sampling and were divided into two groups receiving 0.5 mg/kg midazolam in oral route administration and 0.2 mg/kg midazolam in intranasal route administration. Finally, 75 patients remained for evaluating medication acceptability, sedation level, onset time of sedation, additional sedative dose, adverse effects of sedation, and provider satisfaction. RESULTS: Children in the intranasal group accepted medication more easily (89.8% vs. 36.9%; P </= 0.001), while these children received a lower sedation dose, but the sedation level in both methods was similar (P = 0.72). Our findings showed that children in the intranasal sedation group had a faster onset of sedation compared to the oral group (17.94 +/- 8.99 vs. 34.50 +/- 11.45; P </= 0.001). The frequency of midazolam side effects had no difference between the groups (29.7% vs. 15.8%; P = 0.15). CONCLUSION: Intranasal midazolam with a lower sedation dose induces a faster onset and better acceptance. Intranasal midazolam can be used as an effective sedative method for pediatric patients, especially in emergency wards.

McCormick, A. S., V. L. Thomas, et al. (2008). "Plasma concentrations and sedation scores after nebulized and intranasal midazolam in healthy volunteers." Br J Anaesth 100(5): 631-6.

BACKGROUND: An efficacious, reliable, and non-invasive route of administration for midazolam, a drug used for sedation and pre-anaesthetic medication, would have obvious advantages. This study compares two potential methods of administering midazolam by the nasal and nebulized routes. METHODS: Midazolam (0.2 mg kg(-1)) was given by both nebulizer and nasally by liquid instillation to 10 healthy volunteers in a randomized, double-blind crossover study. Plasma concentrations of midazolam, Ramsay sedation scores, visual analogue scores, critical flicker fusion frequency, and parameters of cardiovascular and respiratory function were measured over 60 min and summarized using 'area under the curve'. RESULTS: Nasal instillation caused more sedation than nebulized administration. This was demonstrated by higher Ramsay sedation scores (P=0.005), lower visual analogue scores (P<0.001), and lower critical flicker fusion frequency (P<0.02). Nasal instillation was associated with higher plasma concentrations of midazolam (P<0.001). Unpleasant symptoms were recorded by six volunteers in the intranasal and one in the nebulized group (P=0.06). CONCLUSIONS: There was some evidence that midazolam caused less discomfort when given by nebulizer compared with intranasally. Comparative bioavailability of midazolam, estimated by the ratio (nebulized:nasal) of area under the 60 min plasma concentration curve, was 1:2.9. A higher dose may need to be administered for adequate pre-anaesthetic medication when midazolam is given by nebulizer.

McDonald, A. J. and M. G. Cooper (2001). "Patient-controlled analgesia: an appropriate method of pain control in children." Paediatr Drugs 3(4): 273-84.

            Patient-controlled analgesia (PCA) is an analgesic technique originally used in adults but now with an established role in paediatric practice. It is well tolerated in children as young as 5 years and has uses in postoperative pain as well as burns, oncology and palliative care. The use of background infusions is more frequent in children and improves efficacy; however, it may increase the occurrence of adverse effects such as nausea and respiratory depression. Monitoring involves measurement of respiratory rate, level of sedation and oxygen saturation. Efficacy is assessed by self-reporting, visual analogue scales, faces pain scales and usage patterns. This is optimally performed both at rest and on movement. The selection of opioid used in PCA is perhaps less critical than the appropriate selection of parameters such as bolus dose, lockout and background infusion rate. Moreover, opioid choice may be based on adverse effect profile rather than efficacy.The concept of PCA continues to be developed in children, with patient-controlled epidural analgesia, subcutaneous PCA and intranasal PCA being recent extensions of the method. There may also be a role for patient-controlled sedation. PCA, when used with adequate monitoring, is a well tolerated technique with high patient and staff acceptance. It can now be regarded as a standard for the delivery of postoperative analgesia in children aged &gt;5 years.

McGlone, R. G., S. Ranasinghe, et al. (1998). "An alternative to &quot;brutacaine&quot;: a comparison of low dose intramuscular ketamine with intranasal midazolam in children before suturing." J Accid Emerg Med 15(4): 231-6.

            OBJECTIVE: To compare the use of low dose intramuscular ketamine with high dose intranasal midazolam in children before suturing. METHODS: Altogether 102 children with simple wounds between 1 and 7 years old were allocated to the two study groups. RESULTS: Two children were excluded from the study because of deviation from the agreed protocol. The 50 children in the ketamine group were less likely to cry or need to be restrained during the procedure than those in the midazolam group (p &lt; 0.01). The median oxygen saturation was 97% in both groups. There was no difference in the recovery behaviour and the range of time at which children were ready for discharge, although the median time for the latter was shorter in the midazolam group (75 v 82 minutes). Vomiting occurred in nine of the ketamine and four of the midazolam group. After discharge both groups had an unsteady gait (73% v 71%) which usually resolved within two hours. CONCLUSION: Intranasal midazolam (0.5 mg/kg) effectively sedated the children in that none could remember the suturing. However a significant number still had to be restrained (86% v 14%). Intramuscular ketamine (2.5 mg/kg) produced dissociative anaesthesia in the majority of cases and was the preferred drug of nurse, doctor, and parent.

McIlwain, M., R. Primosch, et al. (2004). "Allergic reaction to intranasal midazolam HCl: a case report." Pediatr Dent 26(4): 359-61.

            An acute allergic reaction in a 5-year-old healthy male, after receiving midazolam by intranasal atomizer for sedation purposes in the dental clinic, was reported. Shortly after the midazolam was provided, the child developed urticaria in both ankles, which rapidly progressed to the lower extremities, stomach, back, arms, neck, and face. The periorbital skin also became edematous. In the emergency room, the diagnosis of an urticaria allergic reaction was confirmed. The child was treated with intramuscular diphenylhydramine, discharged from the emergency room after 5 hours, and prescribed oral diphenylhydramine (Benadryl) and prednisolone (Orapred). Children who receive sedatives such as midazolam in the dental clinic should be carefully monitored from the moment they receive the sedative, in order to disclose and treat undesirable side effects of the sedative agents as early as possible. The implications of allergic reactions to sedative agents in the dental clinic are reviewed.

Mekitarian Filho, E., F. Robinson, et al. (2015). "Intranasal Dexmedetomidine for Sedation for Pediatric Computed Tomography Imaging." J Pediatr.

This prospective observational pilot study evaluated the aerosolized intranasal route for dexmedetomidine as a safe, effective, and efficient option for infant and pediatric sedation for computed tomography imaging. The mean time to sedation was 13.4 minutes, with excellent image quality, no failed sedations, or significant adverse events.

Mellion, S. A., D. Bourne, et al. (2017). "Evaluating Clinical Effectiveness and Pharmacokinetic Profile of Atomized Intranasal Midazolam in Children Undergoing Laceration Repair." J Emerg Med 53(3): 397-404.

            BACKGROUND: Atomized intranasal midazolam is a common adjunct in pediatrics for procedural anxiolysis. There are no previous studies of validated anxiety scores with pharmacokinetic data to support optimal procedure timing. OBJECTIVES: We describe the clinical and pharmacokinetic profile of atomized intranasal midazolam in children presenting for laceration repair. METHODS: Children 11 months to 7 years of age and weighing <26 kg received 0.4 mg/kg of atomized intranasal midazolam for simple laceration repair. Blood samples were obtained at 3 time points in each patient, and the data were fit with a 1-compartment model. Patient anxiety was rated with the Observational Scale of Behavioral Distress. Secondary outcomes included use of adjunctive medications, successful completion of procedure, and adverse events. RESULTS: Sixty-two subjects were enrolled, with a mean age of 3.3 years. The median time to peak midazolam concentration was 10.1 min (interquartile range 9.7-10.8 min), and the median time to the procedure was 26 min (interquartile range 21-34 min). There was a trend in higher Observational Scale of Behavioral Distress scores during the procedure. We observed a total of 2 adverse events, 1 episode of vomiting (1.6%) and 1 paradoxical reaction (1.6%). Procedural completion was successful in 97% of patients. CONCLUSIONS: Atomized intranasal midazolam is a safe and effective anxiolytic to facilitate laceration repair. The plasma concentration was >90% of the maximum from 5 to 17 min, suggesting this as an ideal procedural timeframe after intranasal midazolam administration.

Messeha, M. M. and G. Z. El-Morsy (2018). "Comparison of Intranasal Dexmedetomidine Compared to Midazolam as a Premedication in Pediatrics with Congenital Heart Disease Undergoing Cardiac Catheterization." Anesth Essays Res 12(1): 170-175.

Background: The intranasal route is a reliable way to administer preanesthetics and sedatives to children. The aim of this study was to compare the anxiolytic and sedative effect of intranasal dexmedetomidine and midazolam as a premedication in pediatrics with simple congenital heart disease undergoing cardiac catheterization. Patients and Methods: Sixty children 3-6 years old of either sex with simple congenital heart disease undergoing cardiac catheterization were randomly allocated into two groups: Dexmedetomidine group who received intranasal dexmedetomidine (0.1 mug/kg) and midazolam group who received intranasal midazolam (0.2 mg/kg) 30 min before induction. Heart rate, mean arterial blood pressure, and oxygen saturation were monitored up to 30 min after drug administration. The sedation score, anxiety score, and child-parent separation score were recorded until the child taken to the operating room. The postoperative agitation score was also observed. Results and Conclusion: The premedication of children with intranasal dexmedetomidine attained satisfactory and significant sedation and lower anxiety level with better parental separation than those who received intranasal midazolam.

Miguez, M. C., C. Ferrero, et al. (2019). "Retrospective Comparison of Intranasal Fentanyl and Inhaled Nitrous Oxide to Intravenous Ketamine and Midazolam for Painful Orthopedic Procedures in a Pediatric Emergency Department." Pediatr Emerg Care.

OBJECTIVES: To compare the efficacy and adverse events of 2 pharmacological strategies: intranasal fentanyl and nitrous oxide (FN) inhaled against intravenous ketamine and midazolam (KM) as procedural sedation and analgesia (PSA) in painful orthopedic procedures in the pediatric emergency department (ED). METHODS: This is an observational retrospective cohort study. Patients were included that submitted to PSA for carrying out a painful orthopedic procedure in the ED of a tertiary hospital over a period of 2 years. The main outcome variable was efficacy and adverse events of the PSA procedure. RESULTS: Eighty-three patients were included. Fifty-two patients received FN and 31 KM. The PSA strategy was considered efficacious in 82.7% of the patients in the KM group and 80.6% in the FN cohort. No differences between both strategies were found (P = 0.815). Seventeen children showed early adverse events, 2 in the FN cohort and 15 in the KM group (relative risk of the KM strategy, 23.48; 95% confidence interval (CI), 3.24-169.99). The average of satisfaction obtained by the families was of 10 (CI, 10-10) in the KM cohort and of 9 (CI, 8-9.5) in the FN group (P = 0.152). The length of stay in the ED was longer in the KM cohort (P < 0.001). Hospital admission rate differences were not statistically different (9.6% vs 22.6%, P = 0.144) in the KM versus FN cohort. CONCLUSIONS: Both PSA strategies presented similar efficacy. The FN strategy was associated with a lower risk of adverse events and shorter ED length of stay than KM in this ED setting.

Milesi, C., J. Baleine, et al. (2018). "Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial." Arch Dis Child Fetal Neonatal Ed.

            OBJECTIVE: To compare the effectiveness of sedation by intranasal administration of midazolam (nMDZ) or ketamine (nKTM) for neonatal intubation. DESIGN: A multicentre, prospective, randomised, double-blind study. SETTING: Delivery rooms at four tertiary perinatal centres in France. PATIENTS: Preterm neonates with respiratory distress requiring non-emergent endotracheal intubation for surfactant instillation. INTERVENTIONS: Treatment was randomly allocated, with each neonate receiving a bolus of 0.1 mL/kg in each nostril, corresponding to 0.2 mg/kg for nMDZ and 2 mg/kg for nKTM. The drug was repeated once 7 min later at the same dose if adequate sedation was not obtained. MAIN OUTCOME MEASURES: Success was defined by adequate sedation before intubation and adequate comfort during the procedure. Intubation features, respiratory and cardiovascular events were recorded. RESULTS: Sixty newborns, with mean (SD) gestational age and birth weight of 28 (3) weeks and 1100 (350) g, were included within the first 20 min of life. nMDZ was associated with a higher success rate (89% vs 58%; RR: 1.54, 95% CI 1.12 to 2.12, p<0.01) and shorter delays between the first dose and intubation (10 (6) vs 16 (8) min, p<0.01).Number of attempts, time to intubation, mean arterial blood pressure measures over the first 12 hours after birth and length of invasive ventilation were not different. CONCLUSIONS: nMDZ was more efficient than nKTM to adequately sedate neonates requiring intubation in the delivery room. The haemodynamic and respiratory effects of both drugs were comparable. CLINICAL TRIAL: This clinical trial was recorded on the National Library of Medicine registry (NCT01517828).

Miller, J., B. Xue, et al. (2015). "Comparison of dexmedetomidine and chloral hydrate sedation for transthoracic echocardiography in infants and toddlers: a randomized clinical trial." Paediatr Anaesth.

BACKGROUND: Procedural sedation using chloral hydrate is used in many institutions to improve the quality of transthoracic echocardiograms (TTE) in infants and young children. Chloral hydrate has limited availability in some countries, creating the need for alternative effective sedatives. OBJECTIVE: The aim of our study was to compare the effectiveness of two doses of intranasal dexmedetomidine vs oral chloral hydrate sedation for transthoracic echocardiography. METHODS: This is a randomized, prospective study of 150 children under the age of 3 years with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation. Group CH received oral chloral hydrate 70 mg.kg-1 , group DEX2 received 2 mug.kg-1 intranasal dexmedetomidine, and group DEX3 received 3 mug.kg-1 intranasal dexmedetomidine. Acceptance of drug administration, sedation onset and duration, heart rate, and oxygen saturation, sonographer and parent satisfaction were recorded. RESULTS: All patients were successfully sedated for TTE. A second sedative dose (rescue) for failed single-dose sedation was required for 4% of patients after CH, none of the patients after DEX2, and 4% of patients after DEX3. Patients in group CH had an average heart rate decline of 22% during sedation, while group DEX2 decreased 27%, and group DEX3 23% (P = 0.2180). Mean time from administration of the sedative to final patient discharge was 96 min after CH, 83 min after DEX2, and 94 min after DEX3 (P = 0.1826). CONCLUSION: Intranasal dexmedetomidine 2 and 3 mug.kg-1 were found to be as effective for TTE sedation as oral chloral hydrate with similar sedation onset and recovery time and heart rate changes in this study population.

Miller, J. W., A. A. Divanovic, et al. (2016). "Dosing and efficacy of intranasal dexmedetomidine sedation for pediatric transthoracic echocardiography: a retrospective study." Can J Anaesth 63(7): 834-841.

            PURPOSE: We designed this retrospective observational study on the use of alpha2-agonist dexmedetomidine to determine the optimum intranasal dose to achieve sedation for pediatric transthoracic echocardiography and to identify any dose-related adverse effects. METHODS: Outpatient children aged three months to three years with diverse diagnoses of congenital heart disease, including cyanotic cardiac defects, underwent transthoracic echocardiography under dexmedetomidine sedation. Aerosolized intranasal dexmedetomidine was administered with initial doses ranging from 1-3 microg.kg(-1). A rescue dose of 1 microg.kg(-1) was administered if adequate sedation was not achieved within 45 min following the first dose. The primary study outcome was the achievement of adequate sedation to allow transthoracic echocardiography (TTE) scanning, including subxiphoid and suprasternal probe manipulation. RESULTS: Sedation with intranasal dexmedetomidine for transthoracic echocardiography was successful in 62 of the 63 (98%) patients studied, with an intranasal rescue dose required in 13 (21%) patients. Intranasal doses of dexmedetomidine 2.5-3.0 microg.kg(-1) were required for tolerating TTE probe placement, including subxiphoid and suprasternal manipulation, with minimal response and a 90% success rate. Excluding patients who required a second dose of dexmedetomidine, the mean (standard deviation) time from administration to achieving such sedation (onset time) was 26 (8) min for low-dose (1-2 microg.kg(-1)) dexmedetomidine and 28 (8) min for moderate-dose (2.5-3.0 microg.kg(-1)) dexmedetomidine (P = 0.33). Time from administration of low-dose dexmedetomidine to discharge, including TTE scan time, was 80 (14) min, and it increased with moderate-dose dexmedetomidine to 91 (22) min (P = 0.05). Mild to moderate bradycardia and hypotension were observed, but no interventions were required. CONCLUSION: We found that aerosolized intranasal dexmedetomidine offers satisfactory conditions for TTE in children three months to three years of age with an optimal dose of 2.5-3.0 microg.kg(-1)administered under the supervision of a pediatric cardiac anesthesiologist.

Miller, J., L. Ding, et al. (2017). "Sedation methods for transthoracic echocardiography in children with Trisomy 21-a retrospective study." Paediatr Anaesth 27(5): 531-539.

            BACKGROUND: Many children with Trisomy 21 have neurologic or behavioral problems that make it difficult for them to remain still during noninvasive imaging studies, such as transthoracic echocardiograms (TTEcho). Recently, intranasal dexmedetomidine sedation has been introduced for this purpose. However, dexmedetomidine has been associated with bradycardia. Children with Trisomy 21 have been reported to have a higher risk of bradycardia and airway obstruction with sedation or anesthesia compared to children without Trisomy 21. OBJECTIVE: Our aim was to quantify the incidence of age-defined bradycardia and other adverse effects in patients with Trisomy 21 under sedation for TTEcho using a variety of sedation and anesthesia techniques available and utilized at our institution in this challenging patient population, including intranasal dexmedetomidine, oral pentobarbital, general anesthesia with propofol, and general anesthesia with sevoflurane. Our primary hypothesis was that intranasal dexmedetomidine sedation would result in a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens. METHODS: This is a retrospective, observational study of 147 consecutive patients with Trisomy 21 who were sedated or anesthetized for transthoracic echocardiography. Efficacy of sedation was defined as no need for rescue sedation or conversion to an alternate technique. Lowest and highest heart rate, systolic blood pressure, oxygen saturation, and PR interval from formal electrocardiograms were extracted from the electronic medical record. These data were compared to age-defined normal values to determine adverse events. RESULTS: Four methods of sedation or anesthesia were utilized to perform sedated transthoracic echocardiography: general anesthesia with sevoflurane by mask, general anesthesia with sevoflurane induction followed by intravenous propofol maintenance, oral pentobarbital, and intranasal dexmedetomidine. Intranasal dexmedetomidine 2.5 mcg.kg-1 was an effective sedative as a single dose for TTEcho in 37 of 41 (90%) cases. Oral pentobarbital 5 mg.kg-1 as a single dose for young children with Trisomy 21 was effective in 55 of 75 (73%) cases. Intranasal dexmedetomidine sedation was not associated with a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens, when compared to oral pentobarbital for patients under 2 years of age and general anesthesia for children 3 years and older. The two general anesthesia groups showed lowest heart rates of 66.9 +/- 15.9 min-1 for sevoflurane and 69.0 +/- 11.5 min-1 for sevoflurane-propofol. Hypotension was present in all groups ranging between an incidence of 56% in the sevoflurane group to 11% in the oral pentobarbital group. Oxygen saturation and clinically significant desaturation occurred in 14% of the oral pentobarbital group. CONCLUSION: Intranasal dexmedetomidine sedation was not associated with a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens.

Miller, J. W., R. Balyan, et al. (2018). "Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study." Br J Anaesth 120(5): 1056-1065.

BACKGROUND: Atomised intranasal dexmedetomidine administration is an attractive option when sedation is required for paediatric diagnostic procedures, as vascular access is not required. The risk of haemodynamic instability caused by dexmedetomidine necessitates better understanding of its pharmacokinetics in young children. To date, intranasal dexmedetomidine pharmacokinetics has only been studied in adults. METHODS: Eighteen paediatric patients received dexmedetomidine 1 or 2 mug kg(-1) intranasally or 1 mug kg(-1) i.v. Plasma concentrations were determined by liquid chromatography/mass spectrometry. Non-compartmental analysis provided estimates of Cmax and Tmax. Volume of distribution, clearance, and bioavailability were estimated by simultaneous population PK analysis of data after intranasal and i.v. administration. Dexmedetomidine plasma concentration-time profiles were evaluated by simulation for intranasal and i.v. administration. RESULTS: An average peak plasma concentration of 199 pg ml(-1) was achieved 46 min after 1 mug kg(-1) dosing and 355 pg ml(-1) was achieved 47 min after 2 mug kg(-1) dosing. A two-compartment pharmacokinetic model, with allometrically scaled parameters, adequately described the data. Typical bioavailability was 83.8% (95% confidence interval 69.5-98.1%). CONCLUSION: Mean arterial plasma concentrations of dexmedetomidine in infants and toddlers approached 100 pg ml(-1), the low end reported for sedative efficacy, within 20 min of an atomised intranasal administration of 1 mug kg(-1). Doubling the dose to 2 mug kg(-1) reached this plasma concentration within 10 min and achieved almost twice the peak concentration. Peak plasma concentrations with both doses were reached within 47 min of intranasal administration, with an overall bioavailability of 84%.

Miller, J. W., L. Ding, et al. (2018). "Comparison of Intranasal Dexmedetomidine and Oral Pentobarbital Sedation for Transthoracic Echocardiography in Infants and Toddlers: A Prospective, Randomized, Double-Blind Trial." Anesth Analg 126(6): 2009-2016.

            BACKGROUND: Acquisition of transthoracic echocardiographic (TTEcho) images in children often requires sedation. The optimal sedative for TTEcho has not been determined. Children with congenital heart disease are repeatedly exposed to sedatives and anesthetics that may affect brain development. Dexmedetomidine, which in animals alters brain structure to a lesser degree, may offer advantages in this vulnerable population. METHODS: A prospective, randomized, double-blind trial enrolled 280 children 3-24 months of age undergoing outpatient TTEcho, comparing 2.5 microg.kg intranasal dexmedetomidine to 5 mg.kg oral pentobarbital. Rescue sedation, for both groups, was intranasal dexmedetomidine 1 microg.kg. The primary outcome was adequate sedation within 30 minutes without rescue sedation, assessed by blinded personnel. Secondary outcomes included number of sonographer pauses, image quality in relation to motion artifacts, and parental satisfaction. RESULTS: Success rates with a single dose were not different between sedation techniques; 85% in the pentobarbital group and 84% in the dexmedetomidine group (P = .8697). Median onset of adequate sedation was marginally faster with pentobarbital (16.5 [interquartile range, 13-21] vs 18 [16-23] minutes for dexmedetomidine [P = .0095]). Time from drug administration to discharge was not different (P = .8238) at 70.5 (64-83) minutes with pentobarbital and 70 (63-82) minutes with dexmedetomidine. Ninety-five percent of sedation failures with pentobarbital and 100% of dexmedetomidine failures had successful rescue sedation with intranasal dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine was comparable to oral pentobarbital sedation for TTEcho sedation in infants and did not increase the risk of clinically important adverse events. Intranasal dexmedetomidine appears to be an effective "rescue" sedative for both failed pentobarbital and dexmedetomidine sedation. Dexmedetomidine could be a safer option for repeated sedation in children, but further studies are needed to assess long-term consequence of repeated sedation in this high-risk population.

Mitra, S., S. Kazal, et al. (2013). "Intranasal clonidine vs midazolam as premedication in children: A randomized controlled trial." Indian Pediatr (In press) (click for free article)

Objectives: To compare anxiolysis produced by intranasal clonidine with intranasal midazolam as premedication in children undergoing surgery. Design: Double-blind randomized controlled study. Setting: Tertiary-care hospital, July 2009 to June 2010. Patients: 60 American Society of Anesthesiologists physical status I-II surgical patients 1-10y old. Intervention: The participants were randomly allocated to two groups to receive either intranasal clonidine 4mcg/kg (Group I) or intranasal midazolam 0.3mg/kg (Group II). Outcome measures: The primary outcome measure was proportions of patients with satisfactory anxiolysis at 30 min after drug administration. Secondary outcome measures included satisfactory mask acceptance, times of onset of sedation and anxiolysis, drug acceptance, level of sedation, wake-up score and side effects. Results: All children achieved satisfactory anxiolysis at 30 min. Group I fared significantly better than Group-II on mask acceptance (100% in Group I vs. 80% in Group II; P=0.024), drug acceptance (93% vs. 13%; P<0.001) and proportion of patients with satisfactory wake-up scores (100% vs. 53%; P<0.001). Group II patients had significantly faster onset of sedation (median 10 min vs. 15 min; P<0.05) but not that of anxiolysis compared to Group-I (median 10 min for both groups; P>0.05). Side effects were significantly more frequent in Group II. Conclusions: Though intranasal midazolam produced faster sedation, both the drugs produced satisfactory anxiolysis at 30 min. Mask acceptance and several other secondary outcomes were significantly better with intranasal clonidine.

Moksnes, K., O. M. Fredheim, et al. (2008). "Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference?" Eur J Clin Pharmacol.

            OBJECTIVE: We have investigated the arterio-venous difference in the pharmacokinetics of 50 mug fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naive middle-aged to elderly patients. METHODS: Twelve male patients (range in age 47-84 years) scheduled for transurethral resection of the prostate gland received a 100-mul dose of 50 mug fentanyl base as a fentanyl citrate formulation in one nostril. Simultaneous arterial and venous blood samples for analyses of fentanyl were drawn at baseline and at 1, 3, 5, 7, 9, 13, 15, 20, 25, 35, 45 and 60 min after drug administration. Vital signs, sedation and symptoms of local irritation were recorded. RESULTS: The arterial C(max) (maximum serum concentration) of 0.83 ng/ml was nearly twofold higher than the venous C(max) of 0.47 ng/ml, and the arterial T(max) (time to maximum serum concentration) of 7.0 min was about 5 min shorter than the venous T(max) of 11.6 min. The arterial AUC(0-60) (area under the curve from 0 to 60 min after administration) of 21 min*ng/ml was approximately 30% larger than the venous AUC(0-60) of 15 min*ng/ml (all p values </= 0.005). Venous T(max) and C(max) did not predict the corresponding arterial values. No significant adverse events were observed. CONCLUSION: A significant arterio-venous difference was present after intranasal administration of fentanyl. The short arterial T(max) complies with its rapid onset of action. The use of venous concentrations for the prediction of onset time of analgesia should be discouraged. A 50-mug dose of nasal fentanyl was well tolerated by opioid-naive middle-aged to elderly male patients.

Mondardini, M. C., A. Amigoni, et al. (2019). "Intranasal dexmedetomidine in pediatrics: update of current knowledge." Minerva Anestesiol 85(12): 1334-1345.

Intranasal dexmedetomidine, although still off-label, recently boasted an increasing consensus for different uses, namely, in diagnostic non-painful procedures, in painful procedures and in surgical premedication. However, at present, there is no consensus regarding indications, dosage and timing for administration. This article aims to provide a comprehensive literature analysis and summarize the more recent evidence of research on pediatric intranasal dexmedetomidine, in the effort to better delineate usefulness and limits for each specific indication. In summary, available pediatric evidence confirms efficacy and safety of dexmedetomidine for intranasal administration. Pharmacological profile for the various pediatric ages and procedures still needs quality studies and pharmacokinetic in-depth analysis.

Montero, J. V., E. M. Nieto, et al. (2015). "Intranasal midazolam for the emergency management of hypercyanotic spells in tetralogy of fallot." Pediatr Emerg Care 31(4): 269-271.

                The case of a 2-month-old boy with previously diagnosed tetralogy of Fallot who was brought to the emergency department with a hypercyanotic spell is described.Because partly of the difficulty of intravenous placement, especially in an infant crying with marked hypernea and deeply cyanotic, intranasal midazolam was administered.Before 3 minutes of hypernea terminated increasing the oxygen saturation successfully and intravenous line was easily placed with the baby remaining in calm.Sedation is an important step in the management of patients with cyanotic spells. Intranasal midazolam offers an alternative use as an initial method of calming the child that was effective in a patient with a severe cyanotic spell because of tetralogy of Fallot in the emergency department.

Moss, M. L., P. A. Buongiorno, et al. (1993). "Intranasal midazolam for claustrophobia in MRI." J Comput Assist Tomogr 17(6): 991-2.

            The authors present their preliminary results using intranasal midazolam for claustrophobic MRI patients. This route of administration reduced the necessity for intravenous sedation from 67 to 17% in this select group of patients. The only side effect encountered was a burning sensation of the nasal mucosa. Further investigation is necessary to determine the efficacy of intranasal midazolam in claustrophobic patients scheduled for MR examinations.

Mukherjee, S., R. Manjushree, et al. (2010). "Clonidine Premedication for Paediatric Patients: A comparison of the oral & nasal route." J Anaesth Clin Pharmacol 26(3): 319-322.

Mukherjee, A., A. Das, et al. (2015). "Emergence agitation prevention in paediatric ambulatory surgery: A comparison between intranasal Dexmedetomidine and Clonidine." J Res Pharm Pract 4(1): 24-30.

OBJECTIVE: Emergence agitation (EA), a short-lived, self-limiting phenomenon, arises frequently after the use of inhalational agents and hampers the implementation of pediatric ambulatory surgery in spite of using so many drugs with variable efficacy. METHODS: In this prospective, double-blinded, parallel group study (2008-2009), 80 children of both sex aged 3-7 years, with American Society of Anesthesiologists (ASA) physical status grade I-II, undergoing sevoflurane-based general anesthesia for elective day care surgery were randomly assigned into groups C or D. Group C received 4 mug/kg intranasal clonidine, whereas group D received 1 mug/kg intranasal dexmedetomidine, 45 min before induction of anesthesia. In postanesthesia care unit (PACU), the incidence of EA was assessed with Aonos four-point scale and the severity of EA was assessed with pediatric anesthesia emergence delirium scale upon admission (T0), after 5 min (T5), 15 min (T15), and 25 min (T25). Extubation time, emergence time, duration of PACU stay, dose and incidence of fentanyl use for pain control were noted. FINDINGS: Based on comparable demographic profiles, the incidence and severity of EA were significantly lower in group D as compared to group C at T0, T5, T15, and T25. But time of regular breathing, awakening, extubation, and emergence were significantly delayed in group D than C. The number and dose of fentanyl used in group C were significantly higher than group D. PACU and hospital stay were quite comparable between groups. CONCLUSION: Intranasal dexmedetomidine 1 mug/kg was more effective than clonidine 4 mug/kg in decreasing the incidence and severity of EA, when administered 45 min before the induction of anesthesia with sevoflurane for pediatric day care surgery. Dexmedetomidine also significantly reduced fentanyl consumption in PACU.

Musani, I. E. and N. V. Chandan (2015). "A comparison of the sedative effect of oral versus nasal midazolam combined with nitrous oxide in uncooperative children." Eur Arch Paediatr Dent.

                AIM: To compare a combination of oral midazolam (0.2 mg/kg body weight) and nitrous oxide-oxygen sedation with a combination of intranasal midazolam (0.1 mg/kg body weight) and nitrous oxide-oxygen sedation for effectiveness, patient acceptability and safety profile in controlling the behaviour of uncooperative children. METHODS: Thirty children, 4-10 years of age, referred for dental treatment were included in the study with a crossover design. Each patient was sedated with a combination of either oral midazolam and nitrous oxide-oxygen sedation or intranasal midazolam and nitrous oxide-oxygen sedation at subsequent dental treatment visits. During the treatment procedure, the study recorded scales for drug acceptability, onset of sedation, acceptance of nasal mask, sedation, behavioural, safety, overall behaviour and alertness. RESULTS: The grade of acceptability of midazolam in both groups was consistently good. There was a significant difference (p < 0.001) in the time of onset of sedation, which was significantly quicker with the intranasal administration of midazolam. The mean time of onset for oral midazolam was 20.1 (17-25) min and for intranasal midazolam 12.1 (8-18) min. The efficacy profile of the present study included: acceptance of nasal mask, sedation score, crying levels, motor movements and overall behaviour scores. The results did not show any statistically significant differences. All the parameters were highly satisfactory. The difference in alertness was statistically significant (p value <0.05), being higher in the intranasal group than the oral group and suggestive of faster recovery using intranasal midazolam. CONCLUSION: The intranasal route of midazolam administration has a quick onset of action and a quick recovery of the patient from sedation as compared to the oral route of midazolam administration. Midazolam administered through the intranasal route is as effective as the oral route at a lower dosage. Therefore, it is an effective alternative to oral route for a paediatric dental situation.

Narendra, P. L., R. W. Naphade, et al. (2015). "A comparison of intranasal ketamine and intranasal midazolam for pediatric premedication." Anesth Essays Res 9(2): 213-218.

AIMS AND OBJECTIVES: The aim of our study is to compare the efficacy and side-effects of Ketamine and Midazolam administered nasally for the pediatric premedication. MATERIALS AND METHODS: We studied 100 American Society of Anesthesiology I and II children aged from 1 to 10 years undergoing various surgical procedures. Totally, 50 children were evaluated for nasal ketamine (using 50 mg/ml vials) at the dose of 5 mg/kg and the other 50 received nasal midazolam 0.2 mg/kg, before induction in operation theater each patient was observed for onset of sedation, degree of sedation, emotional status being recorded with a five point sedation scale, response to venipuncture and acceptance of mask, whether readily, with persuasion or refuse. RESULTS: The two groups were homogenous. Midazolam showed a statistically significant early onset of sedation (10.76 +/- 2.0352 vs. 16.42 +/- 2.0696 min). There were no significant differences in venipuncture score, sedation scale at 20 min, acceptance of mask and oxygen saturation throughout the study. Significant tachycardia and 'secretions were observed in the ketamine group intra operatively. Postoperatively emergence (8% vs. 0%) and secretions (28% vs. 4%) were significant in the ketamine group. Nausea and vomiting occurred in l6% versus 10% for midazolam and ketamine group. CONCLUSIONS: Both midazolam and ketamine nasally are an effective pediatric premedication. Midazolam has an early onset of sedation and is associated with fewer side-effects.

Neff, C., S. M. Joyce, et al. (2006). "Efficacy and safety of intranasal midazolam administration by EMS personnel for seizures and sedation." NAEMSP Winter abstracts.

Nemeth, M., N. Jacobsen, et al. (2017). "Intranasal Analgesia and Sedation in Pediatric Emergency Care-A Prospective Observational Study on the Implementation of an Institutional Protocol in a Tertiary Children's Hospital." Pediatr Emerg Care.

            OBJECTIVES: Children presenting with acute traumatic pain or in need of therapeutic or diagnostic procedures require rapid and effective analgesia and/or sedation. Intranasal administration (INA) promises to be a reliable, minimally invasive delivery route. However, INA is still underused in Germany. We hence developed a protocol for acute pain therapy (APT) and urgent analgesia and/or sedation (UAS). Our aim was to evaluate the effectiveness and safety of our protocol. METHODS: We performed a prospective observational study in a tertiary children's hospital in Germany. Pediatric patients aged 0 to 17 years requiring APT or UAS were included. Fentanyl, s-ketamine, midazolam, or combinations were delivered according to protocol. Primary outcome variables included quality of analgesia and/or sedation as measured on age-appropriate scales and time to onset of drug action. Secondary outcomes were adverse events and serious adverse events. RESULTS: One hundred pediatric patients aged 0.3 to 16 years were enrolled, 34 for APT and 66 for UAS. The median time onset of drug action was 5 minutes (ranging from 2 to 15 minutes). Fentanyl was most frequently used for APT (n = 19). Pain scores decreased by a median of 4 points (range, 0-10; P < 0.0001). For UAS, s-ketamine/midazolam was most frequently used (n = 25). Sedation score indicated minimal sedation in most cases. Overall success rate after the first attempt was 82%. Adverse events consisted of nasal burning (n = 2) and vomiting (n = 2). No serious adverse events were recorded. CONCLUSIONS: A fentanyl-, s-ketamine-, and midazolam-based INA protocol was effective and safe for APT and UAS. It should then be considered where intravenous access is impossible or inappropriate.

Neville, D. N., K. R. Hayes, et al. (2016). "Double-blind Randomized Controlled Trial of Intranasal Dexmedetomidine Versus Intranasal Midazolam as Anxiolysis Prior to Pediatric Laceration Repair in the Emergency Department." Acad Emerg Med 23(8): 910-917.

OBJECTIVE: The objective of this study was to compare anxiolysis with intranasal dexmedetomidine, an alpha-2 agonist, versus intranasal midazolam for pediatric laceration repairs. METHODS: We performed a double-blind, randomized controlled trial of 40 patients 1-5 years with lacerations requiring suture repair in an academic pediatric emergency department (ED). Patients were randomized to receive either intranasal dexmedetomidine or intranasal midazolam. Our primary outcome measure was the anxiety score at the time of patient positioning for the laceration repair. We chose this time point to isolate the anxiolysis from the medications prior to intervention. Patient encounters were videotaped and scored for anxiety at multiple time points using the modified Yale Preoperative Anxiety Scale. The scale is 23.3-100 with higher scores indicating higher anxiety. We also evaluated these scores as a secondary outcome by dichotomizing them into anxious versus not anxious with a previously validated score cutoff. RESULTS: Of the 40 patients enrolled, 20 in the dexmedetomidine group and 18 in the midazolam group completed the study and were included in the analysis. The median age was 3.3 years (range = 1.0-5.4 years). The median baseline anxiety score was 48.3. The anxiety score at position for procedure for patients receiving dexmedetomidine was 9.2 points lower than those receiving midazolam (median difference = 9.2, 95% confidence interval = 5 to 13.3; median score for dexmedetomidine = 23.3, median score for midazolam = 36.3). The proportion of patients who were classified as not anxious at the position for procedure was significantly higher in the dexmedetomidine group (70%) versus the midazolam group (11%). The number needed to treat with dexmedetomidine instead of midazolam to obtain the result of a not anxious patient at this time point was 1.7 patients. There were also significantly more patients who were classified as not anxious at the time of wound washout in the dexmedetomidine group compared to the midazolam group (35% vs. 6%). Dexmedetomidine and midazolam performed similarly with respect to all other measures including anxiety at other time points, parental perceived anxiety, parent and proceduralist satisfaction, procedural success, complications, and time in the ED. There were no serious adverse events seen in either group. CONCLUSIONS: Intranasal dexmedetomidine is an alternative anxiolytic medication to intranasal midazolam for pediatric laceration repairs, performing similarly in our study, except that patients who received dexmedetomidine had less anxiety at the time of positioning for procedure.

Nielsen, B. N., S. M. Friis, et al. (2014). "Intranasal sufentanil/ketamine analgesia in children." Paediatr Anaesth 24(2): 170-180.

BACKGROUND: The management of procedural pain in children ranges from physical restraint to pharmacological interventions. Pediatric formulations that permit accurate dosing, are accepted by children and a have a rapid onset of analgesia are lacking. OBJECTIVES: To investigate a pediatric formulation of intranasal sufentanil 0.5 mcg.kg(-1) and ketamine 0.5 mg.kg(-1) for procedural pain and to characterize the pharmacokinetic (PK) profile. METHODS: Fifty children (>/=10 kg) scheduled for a painful procedure were included in this prospective nonrandomized open-label clinical trial. Thirteen of these children had central venous access for drug assay sampling; enabling a compartmental PK analysis using nonlinear mixed-effects models. Pain intensity before and during the procedure was measured using age-appropriate pain scales. Heart rate, oxygen saturation and sedation were recorded. RESULTS: Children had a mean age of 8.8 (sd 4.9) years and weight 35.2 (sd 20.1) kg. Sufentanil/ketamine nasal spray was effective (procedural pain intensity scores </=5 (0-10)) in 78% of the painful procedures. The spray was well accepted by 94% of the children. Oxygen saturation and heart rate remained stable, and sedation was minimal. The bioavailability of sufentanil and ketamine was 24.6% and 35.8%, respectively. Maximum plasma concentration (Cmax) of sufentanil was 0.042 mcg.l(-1) (coefficient of variation (CV) 12.9%) at 13.8 min (CV 12.4%) (Tmax). Cmax for ketamine was 0.102 mg.l(-1) (CV 10.8%), and Tmax was 8.5 min (CV 17.3%). CONCLUSION: Sufentanil/ketamine nasal spray provided rapid onset of analgesia for a variety of painful procedures with few adverse effects and has promising features for use in pediatric procedural pain management.

Nooh, N., S. A. Sheta, et al. (2013). "Intranasal atomized dexmedetomidine for sedation during third molar extraction." Int J Oral Maxillofac Surg 42(7): 857-862.

The purpose of this study was to evaluate the intranasal use of 1.5mug/kg atomized dexmedetomidine for sedation in patients undergoing mandibular third molar removal. Eighteen patients underwent third molar removal in two surgical sessions. Patients were randomly assigned to receive intranasal water (placebo group) or 1.5mug/kg atomized dexmedetomidine (group D) at the first session. The alternate regimen was used during the second session. Local anaesthesia was injected 30min after placebo/sedative administration. Pain from local anaesthesia infiltration was rated on a scale from zero (no pain) to 10 (worst pain imaginable). Sedation status was measured every 10min by a blinded observer with a modified Observer's Assessment of Alertness/Sedation (OAA/S) scale and the bispectral index (BIS). Adverse reactions and analgesic consumption were recorded. Sedation values in group D were significantly different from placebo at 20-30min, peaked at 40-50min, and returned to placebo levels at 70-80min after intranasal drug administration. Group D displayed decreased heart rate and systolic blood pressure, but the decreases did not exceed 20% of the baseline values. Intranasal administration of 1.5mug/kg atomized dexmedetomidine is effective, convenient, and safe as a sedative for patients undergoing third molar extraction.

Nordt, S. P. and R. F. Clark (1997). "Midazolam: a review of therapeutic uses and toxicity." J Emerg Med 15(3): 357-65.

            Midazolam is a familiar agent commonly used in the emergency department to provide sedation prior to procedures such as laceration repair and reduction of dislocations. Midazolam is also effective in the treatment of generalized seizures, status epilepticus, and behavioral emergencies, particularly when intravenous access is not available. Midazolam is often employed as an induction agent for rapid sequence endotracheal intubation. Midazolam has a rapid onset of action following intravenous, intramuscular, oral, nasal, and rectal administration. Only 50% of an orally administered dose reaches the systemic circulation due to extensive first-pass metabolism. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites including an active metabolite, alpha-hydroxymidazolam. Cytochrome P450 inhibitors such as cimetidine can profoundly reduce the metabolism of midazolam. Midazolam has a half-life of approximately 1 h, but this half-life may be prolonged in patients with renal or hepatic dysfunction. Midazolam has been associated with respiratory depression and cardiac arrest when used in combination with an opioid, particularly in the elderly, although all ages are at risk for respiratory depression. Midazolam is relatively free of side effects when used alone and offers several advantages over traditional pharmacological agents such as chloral hydrate and the combination of meperidine, chlorpromazine, and promethazine. Hiccups, cough, nausea, and vomiting are the most commonly reported adverse effects. Many of the adverse effects associated with midazolam can be reversed rapidly by the administration of flumazenil, a competitive benzodiazepine receptor antagonist. Midazolam is a safe and effective agent for providing sedation in the emergency department.

Olgun, G. and M. H. Ali (2018). "Use of Intranasal Dexmedetomidine as a Solo Sedative for MRI of Infants." Hosp Pediatr.

BACKGROUND: Dexmedetomidine, a selective alpha-2 receptor agonist, can be delivered via the intranasal (IN) route and be used for procedural sedation. The drug's favorable hemodynamic profile and relative ease of application make it a promising agent for sedation during radiologic procedures, although there are few studies on its efficacy for MRI studies. METHODS: A retrospective chart review was performed between June 2014 and December 2016. Outpatients between 1 and 12 months of age who received 4 mug/kg of IN dexmedetomidine for MRI were included in the analysis. Our aim with this study was to determine the rate of successful completion of the sedation procedure without the need for a rescue drug (other than repeat IN dexmedetomidine). RESULTS: A total of 52 subjects were included in our study. Median (interquartile range) patient age was 7 (5-8) months. Median (interquartile range) procedure length was 40 (35-50) minutes. Overall success rate (including first dose and any rescue dose IN) of dexmedetomidine was 96.2%. None of the patients had significant adverse effects related to dexmedetomidine. CONCLUSIONS: IN dexmedetomidine is an effective solo sedative agent for MRI in infants.

Oliver, F. M., T. W. Sweatman, et al. (2000). "Comparative pharmacokinetics of submucosal vs. intravenous flumazenil (Romazicon) in an animal model." Pediatr Dent 22(6): 489-93.

            PURPOSE: This study was performed to determine the bioavailability and local tissue toxicological safety of flumazenil (Romazicon) when administered by oral submucosal (SM) as opposed to intravenous (i.v.) injection. METHODS: Six dogs each received SM flumazenil (0.2 mg), and their serum was collected at predetermined time intervals (0-2 h) and frozen (-70 degrees C). Seven days later, the dogs received an identical dose of i.v. flumazenil, and serum samples were again collected, as above. Comparative quantitation of flumazenil levels (i.v. vs. SM) was made using a sensitive HPLC assay (UV detection). Direct/local drug toxicity was visually scored by unbiased raters of color photographs (test and control mucosa) taken at 1, 2, and 7 days following SM flumazenil injection. An oral pathologist examined slides processed from control and treatment tissues (hematoxylin and eosin staining) taken (punch biopsy) 1 week following SM injection to compare with direct clinical scores. RESULTS: Serum flumazenil levels reached a plateau (8.5 +/- 1.5 ng/mL, mean +/- SD) within 4 min of SM drug injection and declined thereafter to -2 ng/mL by 2 h. Bioavailability of SM flumazenil was 101 +/- 14%, based upon measuring the area under the serum concentration-time curves over 1.5 h (AUC 0-1.5 h, SM vs. i.v. drug). Thus, serum drug levels following SM drug administration were broadly comparable to those obtained during the elimination phase of corresponding i.v. drug delivery. Regarding drug tissue toxicity, no evidence of direct drug toxicity was observed by unbiased raters of color photographs (test and control mucosa) taken at 1, 2, and 7 days following SM flumazenil injection. Following pathologic review, no difference was seen in the degree of inflammation between treatment and control tissue. CONCLUSION: At the quantity and concentration used, SM drug flumazenil administration appears to be both a safe and a viable alternative to bolus i.v. drug delivery and worthy of further investigation.

Olivier, J. C., M. Djilani, et al. (2001). "In situ nasal absorption of midazolam in rats." Int J Pharm 213(1-2): 187-92.

            Intranasal (i.n.) midazolam (MDZ) administrations may be used successfully for preoperative sedation, especially in young patients. However, clinicians have to use the commercial parenteral formulation, the low pH of which (3.3), necessary to solubilize MDZ (pK(a) 6.1), is probably responsible for the signs of local irritation frequently reported. As a starting point to design a formulation suitable for the nasal route, MDZ nasal absorption was investigated in rats. The effects of the MDZ solution concentration (10--100 microg/ml), osmolality (from less than 10 mOsm/kg up to 450 mOsm/kg) and pH (3.3--7.4) were studied using an in situ perfusion technique. MDZ was determined by reversed-phase HPLC in the circulating solution and results were expressed in clearance terms. MDZ absorption was independent of its concentration. The pH of the solutions was the key-parameter and only a pH above 4 allowed significant absorption. These results were consistent with a passive diffusion absorption of MDZ and partly followed the pH partition theory. In conclusion, satisfactory MDZ absorption should be expected with a formulation at a pH suitable for the nasal route in human (5.5--6.5).

Oriby, M. E. (2019). "Comparison of Intranasal Dexmedetomidine and Oral Ketamine Versus Intranasal Midazolam Premedication for Children Undergoing Dental Rehabilitation." Anesth Pain Med 9(1): e85227.

Background: Dental rehabilitation surgery is associated with significant fear and anxiety with subsequent psychological disturbances. Midazolam has been used frequently as a premedication. However, it may be associated with side effects. Dexmedetomidine and ketamine combination has been suggested as an effective premedication in improving preoperative sedation and analgesia. Objectives: This study compared the effects of combined intranasal dexmedetomidine and oral ketamine versus intranasal midazolam on anxiolysis and postoperative analgesia. Methods: Seventy-six children (aged two to six years) undergoing dental rehabilitation under general anesthesia were assigned randomly to one of the two groups (n = 38 each) receiving either intranasal dexmedetomidine at 2 microg/kg and oral ketamine at 3 mg/kg (Group DK) or intranasal midazolam at 0.2 mg/kg (group M) 30 minutes prior to the anesthesia induction. The sedation levels and parental separation state were evaluated. Time to recovery, postoperative rescue analgesia, and postoperative adverse effects were assessed. Results: Seventy-six children completed the study. Patients in group DK had significantly lower sedation scores than those in group M after 20 and 30 min (P < 0.05). The rate of satisfactory separation showed no statistically significant difference between the two groups 30 minutes after the administration of premedication (P = 0.926). A significantly higher number of patients in group M required rescue analgesic (42%) compared to those in group DK (16%) (P = 0.012). Conclusions: Premedication with intranasal dexmedetomidine 2 microg/kg and oral ketamine 3 mg/kg is a rapid and effective alternative in children undergoing dental rehabilitation when compared to intranasal midazolam 0.2 mg/kg.

Otsuka, Y., T. Yusa, et al. (1994). "[Intranasal midazolam for sedation before anesthesia in pediatric patients]." Masui 43(1): 106-10.

            To evaluate the efficacy of nasally administered midazolam for sedation before anesthesia in pediatric patients, the authors studied 45 ASA PS 1 or 2 patients (aged 9 months-6 years) scheduled for elective surgery. The sedative effect of intranasal midazolam (0.2 mg.kg-1 or 0.3 mg.kg-1) was compared with that of our standard premedication by score. Significant sedative effect was obtained 4 min (in the 0.2 mg.kg-1 group) and 3 min (in the 0.3 mg.kg-1 group) after nasal administration. Most patients (93%) in the midazolam group became either free from anxiety or calm allowing easy separation from the parents and a smooth induction of anesthesia 10 min after nasal administration. There was no respiratory depression or anesthetic complication during induction of anesthesia, and no delayed recovery was observed. These results indicate that intranasal midazolam 0.2 mg.kg-1 is an effective and useful method for rapid sedation of children just prior to the induction of anesthesia.

Ozen, B., S. F. Malamed, et al. (2012). "Outcomes of moderate sedation in paediatric dental patients." Aust Dent J 57(2): 144-150.

          BACKGROUND: The aim of this study was to evaluate the outcomes of moderate sedation with nitrous oxide/oxygen (N(2) O/O(2)) alone or combined with different dosages and administration routes of midazolam in uncooperative paediatric dental patients using the Bispectral Index System (BIS). METHODS: This one-year clinical study examined first-visit moderate sedation performed in 240 healthy children aged 4-6 years. Subjects were randomly divided into four groups according to drug, route and dosage, as follows: Group 1 - 0.20 mg/kg midazolam (40 mg/ml) delivered intranasally; Group 2 - 0.75 mg/kg midazolam (15 mg/3 ml) delivered orally; Group 3 - 0.50 mg/kg midazolam (15 mg/3 ml) delivered orally. All children in these three groups also received inhalation sedation with 50%-50% N(2) O/O(2), whereas children in Group 4 received inhalation sedation with 50%-50% N(2) O/O(2) only. The outcome of sedation was evaluated as either 'successful', 'failed' or 'not accepted'. RESULTS: The highest success rate was found in Group 1 (0.20 mg/kg intranasally, 87%), followed by Group 2 (0.75 mg/kg orally, 79%). The overall mean success rate for all groups was 73%. CONCLUSIONS: Moderate sedation can be successfully used in the clinical management of paediatric dental patients, with both intranasal and oral sedation using midazolam in conjunction with nitrous oxide found to be effective methods.

Pandey, R. K., S. K. Bahetwar, et al. (2011). "A comparative evaluation of drops versus atomized administration of intranasal ketamine for the procedural sedation of young uncooperative pediatric dental patients: a prospective crossover trial." J Clin Pediatr Dent 36(1): 79-84.

                OBJECTIVE: The objective of this study was to compare and evaluate the efficacy and safety of drops and atomized administration of intranasal ketamine (INK) in terms of behavioral response for agent acceptance during administration and for agent efficacy and safety for the sedation of young uncooperative pediatric dental patients. STUDY DESIGN: Thirty-four uncooperative ASA grade-1 children, requiring dental treatment were randomly assigned to receive INK as drops and atomized spray in one of the subsequent visit. This was a two stage cross-over trial and each child received INK by both modes of administration. The vital signs were monitored continuously during each visit. RESULTS: A statistically significant difference in patients acceptance (P < 0.0001) was observed in the atomized administration when compared to drops administration for the procedural event of drug administration. Moreover there were also significant differences (P < 0.05) between onset of sedation and recovery time between two groups. All the vital signs were within normal physiological limits and there were no significant adverse effects in either group. CONCLUSIONS: INK is safe and effective by either mode of intranasal (IN) drug administration for moderate sedation in facilitating dental care for anxious and uncooperative pediatric dental patients. Moreover, INK when administered with the mucosal atomization device, the acceptance of the drug was associated with less aversive reaction, rapid onset and recovery of sedation, as compared to the drop administration of the same agent.

Papolos, D. F., M. H. Teicher, et al. (2013). "Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype." J Affect Disord 147(1-3): 431-436.

OBJECTIVES: Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to exert a rapid antidepressant effect in adults with treatment resistant depression. Children with bipolar disorder (BD) often respond poorly to pharmacotherapy, including polypharmacy. A pediatric-onset Fear of Harm (FOH) phenotype has been described, and is characterized by severe clinical features and resistance to accepted treatments for BD. The potential efficacy and safety of intranasal ketamine in children with BD with FOH-phenotype were assessed by a systematic retrospective chart review of a case series from the private practice of one of the authors, including cases with clear refractoriness to mood stabilizers, antipsychotics and benzodiazepines. METHODS: A comparison was made between routinely collected symptom measures 1-2 weeks prior to and after the administration of ketamine, in 12 treatment-refractory youth, 10 males 2 females ages 6-19years. RESULTS: Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated. CONCLUSIONS: Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted.

Patel, V. J., S. S. Ahmed, et al. (2014). "Vasovagal syncope and severe bradycardia following intranasal dexmedetomidine for pediatric procedural sedation." Paediatr Anaesth 24(4): 446-448.

We report syncope and bradycardia in an 11-year-old girl following administration of intranasal dexmedetomidine for sedation for a voiding cystourethrogram. Following successful completion of VCUG and a 60-min recovery period, the patient's level of consciousness and vital signs returned to presedation levels. Upon leaving the sedation area, the patient collapsed, with no apparent inciting event. The patient quickly regained consciousness and no injury occurred. The primary abnormality found was persistent bradycardia, and she was admitted to the hospital for telemetric observation. The bradycardia lasted ~2 h, and further cardiac workup revealed no underlying abnormality. Unanticipated and previously unreported outcomes may be witnessed as we expand the use of certain sedatives to alternative routes of administration.

Patel, V., N. Singh, et al. (2018). "A comparative assessment of intranasal and oral dexmedetomidine for procedural sedation in pediatric dental patients." J Indian Soc Pedod Prev Dent 36(4): 370-375.

Objectives: The objective of this study was to assess the safety and efficacy of intranasal and oral dexmedetomidine for procedural sedation in pediatric dental patients. Materials and Methods: Forty-four uncooperative American Society of Anesthesiologists Grade-I children, requiring dental treatment were randomly divided into four groups who received different doses of dexmedetomidine through intranasal and oral routes. The vital signs were monitored continuously during each visit. Results: In this study, significant (P < 0.05) differences were found in the onset of sedation, duration, and recovery time between intranasal and oral groups. All vital signs were within normal physiological limits with no significant adverse effects in either of the groups. Conclusion: Dexmedetomidine is a safe and effective agent for procedural sedation in pediatric dental patients with intranasal route having distinct advantages over oral route.

Peerbhay, F. and A. M. Elsheikhomer (2016). "Intranasal Midazolam Sedation in a Pediatric Emergency Dental Clinic." Anesth Prog 63(3): 122-130.

The purpose of this study was to compare the effectiveness and recovery times of 0.3 and 0.5 mg/kg intranasal midazolam (INM) administered with a mucosal atomizer device (MAD) in a pediatric emergency dental hospital clinic. One hundred eighteen children aged from 4 to 6 years were randomly administered either 0.3 or 0.5 mg/kg INM via an MAD in a triple-blinded randomized controlled trial. Sedation was achieved to some degree in 100% of the sample. The pulse rate and oxygen saturation were within the normal range in 99% of the patients. A burning sensation was reported in 9% of children. The recovery time of the 0.5 mg/kg group was statistically longer than that of the 0.3 mg/kg group (16.5 vs 18.8 minutes) but the difference was not clinically significant. The findings of this study show that 0.3 or 0.5 mg/kg doses of INM resulted in safe and effective sedation. The 0.5 mg/kg dose was more effective than the 0.3 mg/kg dose in reducing anxiety.