Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

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Intranasal midazolam, lorazepam, sufentanil, fentanyl or ketamine for sedation prior to minor procedures - abstracted references:

Abrams, R., J. E. Morrison, et al. (1993). "Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures." Anesth Prog 40(3): 63-6.

            Thirty children presenting to the dental clinic of a pediatric hospital who required brief but urgent dental care, and who could not be satisfactorily examined or treated, were administered one of three medications--ketamine (Ketalar), 3 mg/kg; midazolam (Versed), 0.4 mg/kg; or sufentanil (Sufenta), 1.5 or 1.0 micrograms/kg--intranasally in a randomized, double-blinded protocol. The patients were brought to the day surgery area following appropriate fasting and administered one of the medications diluted in a dose of 0.1 mL/kg normal saline while sitting in a nurse's arms. Cardiorespiratory monitors were applied when tolerated, and the child was placed on the operating room table. Each child was injected locally with up to one dental cartridge of 2% lidocaine with 1:100,000 epinephrine before dental extractions. A sedation score was recorded using a scale where 1 = hysterical/untreatable, 5 = ideal sedation, and 10 = obtunded and desaturated, requiring airway management assistance. Midazolam administration resulted in acceptable sedation (mean score: 4) with no desaturations below 90% as measured by pulse oximetry and a mean recovery room observation time of only 3 +/- 2 min (+/- SD). Ketamine also had a mean sedation score of 4 and a short recovery period (7 +/- 7 min); however, two children experienced brief desaturations. Sufentanil at 1.5 micrograms/kg was noted to produce much more heavily sedated children (mean score 7), with a high incidence of significant oximetry desaturation (80%) and prolonged recovery room duration (58 +/- 40 min). Use of 1.0 microgram/kg sufentanil resulted in no desaturations, less sedation (mean score 4), and a brief recovery time (7 +/- 13 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Acker, A. and M. A. Jamieson (2013). "Use of intranasal midazolam for manual separation of labial adhesions in the office." J Pediatr Adolesc Gynecol 26(3): 196-198.

Use of orally administered flavored midazolam elixir in the office setting has been previously described as an alternative to general anesthetic for manual separation of severe or persistent labial adhesions. We share the technique of using atomized intranasal midazolam for sedation (and amnesia) that has quicker onset, shorter duration, and well described safety and patient tolerance. This technique eliminates the problems associated with a child who refuses to swallow the elixir.

Acworth, J. P., D. Purdie, et al. (2001). "Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation." Emerg Med J 18(1): 39-45.

            OBJECTIVES: This study compared intranasal midazolam (INM) with a combination of intravenous ketamine and intravenous midazolam (IVKM) for sedation of children requiring minor procedures in the emergency department. METHOD: A single blinded randomised clinical trial was conducted in the emergency department of a major urban paediatric hospital. Subjects requiring sedation for minor procedures were randomised to receive either INM (0.4 mg/kg) or intravenous ketamine (1 mg/kg) plus intravenous midazolam (0.1 mg/kg). Physiological variables and two independent measures of sedation (Sedation Score and Visual Analogue Sedation Scale) were recorded before sedation and at regular intervals during the procedure and recovery period. Times to adequate level of sedation and to discharge were compared. RESULTS: Fifty three patients were enrolled over a 10 month period. Sedation was sufficient to complete the procedures in all children receiving IVKM and in 24 of the 26 receiving INM. Onset of sedation was an average of 5.3 minutes quicker with IVKM than with INM (95%CI 3.2, 7.4 minutes, p<0.001). Children given INM were discharged an average of 19 minutes earlier than those given IVKM (95%CI 4, 33 minutes, p=0.02). Mean Sedation Scores and Visual Analogue Sedation Scale scores for the 30 minutes after drug administration were significantly better in children given IVKM compared with INM (2.4 and 1.8 versus 3.5 and 3.8, respectively). Both doctors and parents were more satisfied with sedation by intravenous ketamine and midazolam. CONCLUSIONS: Intravenous ketamine plus midazolam used in an appropriate setting by experienced personnel provides an excellent means of achieving sedation suitable for most non-painful minor procedures for children in the emergency department. This combination is superior to INM in terms of speed of onset and consistency of effect. INM delivered via aerosol spray has a more variable effect but may still be adequate for the completion of many of these procedures.

Aldrete, J. A., J. C. Roman-de Jesus, et al. (1987). "Intranasal Ketamine as induction adjunct in children: Preliminary report." Anesthesiology 67(3): A514.          

Aldrete, J. A., L. J. Russell, et al. (1988). "Intranasal administration of ketamine: possible applications." Acta Anaesthesiol Belg 39(3): 95-96.

Adrian, E. R. (1994). "Intranasal versed: the future of pediatric conscious sedation." Pediatr Nurs 20(3): 287-92.

            Conscious sedation of pediatric patients for procedures is occurring with increasing frequency in hospitals and outpatient settings. Nurses need to be aware of current AAP guidelines for conscious sedation as well as current trends in medication. The pediatric applications and current literature regarding intranasal midazolam and flumazenil are reviewed.

Akin, A., A. Bayram, et al. (2012). "Dexmedetomidine vs midazolam for premedication of pediatric patients undergoing anesthesia." Paediatr Anaesth 22(9): 871-876.

          Background: Dexmedetomidine, an alpha(2) -receptor agonist, provides sedation, analgesia, and anxiolytic effects, and these properties make it a potentially useful anesthetic premedication. In this study, we compared the effects of intranasal dexmedetomidine and midazolam on mask induction and preoperative sedation in pediatric patients. Methods: Ninety children classified as ASA physical status I, aged between 2 and 9, who were scheduled to undergo an elective adenotonsillectomy, were enrolled for a prospective, randomized, and double-blind controlled trial. All of the children received intranasal medication approximately 45-60 min before the induction of anesthesia. Group M (n = 45) received 0.2 mg.kg(-1) of intranasal midazolam, and Group D (n = 45) received 1 mug.kg(-1) of intranasal dexmedetomidine. All of the patients were anesthetized with nitrous oxide, oxygen, and sevoflurane, administered via a face mask. The primary end point was satisfactory mask induction, and the secondary end points included satisfactory sedation upon separation from parents, hemodynamic change, postoperative analgesia, and agitation score at emergence. Results: Satisfactory mask induction was achieved by 82.2% of Group M and 60% of Group D (P = 0.01). There was no evidence of a difference between the groups in either sedation score (P = 0.36) or anxiety score (P = 0.56) upon separation from parents. The number of patients who required postoperative analgesia was higher in the midazolam group (P = 0.045). Conclusion: Intranasal dexmedetomidine and midazolam are equally effective in decreasing anxiety upon separation from parents; however, midazolam is superior in providing satisfactory conditions during mask induction.

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.

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.

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.

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.

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.

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.

Cimen, Z. S., A. Hanci, et al. (2013). "Comparison of buccal and nasal dexmedetomidine premedication for pediatric patients." Paediatr Anaesth 23(2): 134-138.

BACKGROUND: Alpha-2 adrenergic agonists are used to premedicate pediatric patients to reduce separation anxiety and achieve calm induction. The clinical effects of clonidine are similar whether via the oral or nasal route. However, oral dexmedetomidine is not preferred because of its poor bioavailability. The objective of this study was to evaluate the effects of nasal versus buccal dexmedetomidine used for premedication in children. METHODS: Sixty-two patients, aged 2-6 years, undergoing minor elective surgery were randomly assigned to two groups to receive dexmedetomidine, either 1 mug.kg(-1) buccally (group B) or 1 mug.kg(-1) intranasally (group N) for premedication 45 min before the induction of anesthesia. Heart rate, peripheral oxygen saturation, and respiratory rate were measured before and every 10 min after administering dexmedetomidine in all children. Level of sedation was assessed every 10 min until transport to operating room. Drug acceptance, parental separation, and face mask acceptance scores were recorded. RESULTS: There was no significant difference between the two groups in patient characteristics, nor was there any significant difference between the two groups in heart rate, respiratory rate, or SpO(2) values at all times after premedication. Levels of sedation, parental separation, and mask acceptance scores were significantly higher in group N than in group B at the various times. CONCLUSIONS: These results suggest that intranasal administration of 1 mug.kg(-1) dexmedetomidine is more effective than buccal administration of 1 mug.kg(-1) dexmedetomidine for premedication 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.

            Objective To evaluate the safety and efficacy of a sedation protocol based on intranasal lidocaine spray and midazolam (INM) in children who are anxious and uncooperative when undergoing minor painful or diagnostic procedures, such as peripheral line insertion, venipuncture, intramuscular injection, echocardiogram, CT scan, audiometry testing and dental examination and extractions. Patients and design 46 children, aged 5-50 months, received INM (0.5 mg/kg) via a mucosal atomiser device. To avoid any nasal discomfort a puff of lidocaine spray (10 mg/puff) was administered before INM. The child's degree of sedation was scored using a modified Ramsay sedation scale. A questionnaire was designed to evaluate the parents' and doctors' opinions on the efficacy of the sedation. Statistical analysis was used to compare sedation times with children's age and weight. Results The degree of sedation achieved by INM enabled all procedures to be completed without additional drugs. Premedication with lidocaine spray prevented any nasal discomfort related to the INM. The mean duration of sedation was 23.1 min. The depth of sedation was 1 on the modified Ramsay scale. The questionnaire revealed high levels of satisfaction by both doctors and parents. Sedation start and end times were significantly correlated with age only. No side effects were recorded in the cohort of children studied. Conclusions This study has shown that the combined use of lidocaine spray and atomised INM appears to be a safe and effective method to achieve short-term sedation in children to facilitate medical care and procedures.

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.

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.

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.

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.

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.

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. (2016). "Comparison of oral midazolam with intranasal dexmedetomidine premedication for children undergoing CT imaging: a randomized, double-blind, and controlled study." Paediatr Anaesth.

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.

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.

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.

            We describe a 3-year-old child who became over-sedated after receiving intranasal (IN) midazolam (0.53 mg.kg(-1)) and IN sufentanil (1 mcg.kg(-1)) for dental restorations in the dental office. Desaturation was attributed to laryngospasm, which was managed with positive pressure ventilation and oxygen. The sedation was reversed with a combination of IN flumazenil and naloxone.

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.

            OBJECTIVE: To determine whether flumazenil, a drug used to reverse benzodiazepine-induced respiratory depression and approved only for i.v. use, is effective by alternative routes. METHODS: A randomized, controlled, nonblinded, crossover canine trial was performed to evaluate reversal of midazolam-induced respiratory depression by flumazenil when administered by alternative routes. Mongrel dogs were sedated with thiopental 19 mg/kg i.v., then tracheally intubated. With the dogs spontaneously breathing, tidal volume, end-tidal CO2, and O2 saturation were observed until a stable baseline was achieved. Incremental doses of midazolam were administered until respiratory depression (30% decline in tidal volume, 10% decrease in O2 saturation, and 15% increase in end-tidal CO2) occurred. Flumazenil was administered by a randomly selected route [0.2 mg followed 1 minute later by 0.3 mg i.v., sublingual (s.l.) or intramuscular (i.m.); or 1 mg followed 1 minute later by 1.5 mg per rectum (PR)]. Time to return to baseline respiratory functions was recorded ("time to reversal"). Each of 10 dogs was studied using all 4 routes of flumazenil administration with a washout period of at least 7 days. An additional dog served as a control (no flumazenil). RESULTS: The control time to reversal was 1,620 seconds. The i.v. route was significantly faster (mean 120 +/- 24.5 sec) than the other 3 routes (p < 0.005). The SL route was the second fastest (mean 262 +/- 94.5 sec), the IM route was the third fastest (mean 310 +/- 133.7 sec) and the PR route was the s;owest (mean 342 +/- 84.4 sec). The SL, IM, and PR routes did not differ significantly from one another. CONCLUSIONS: Flumazenil administered by all 4 routes reversed midazolam-induced respiratory depression in a dog model. For the selected dosages used, the i.v. route was significantly faster than all 3 other routes, and SL was the second fastest.

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.

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.

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.

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.

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

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.

            BACKGROUND: Anxiety and movement in children during transthoracic echocardiography (TTE) can compromise study quality and reliability. Minimal sedation is often required. Intranasal midazolam (INM), used in various procedures, is an excellent sedative. Optimal INM dosing strategies for uncooperative children undergoing TTE are largely unknown, including second-dose INM strategies, introduced to maximize the potential for successful sedation and minimize risk. The purpose of this retrospective review was to evaluate the effectiveness of a second-dose INM minimal sedation strategy recently adopted at the Children's Hospital of Pittsburgh. METHODS: The strategy incorporates a second dose of INM if needed (10-15 minutes after the first dose) to obtain the desired level of anxiolysis. The effectiveness of this strategy was assessed in 100 consecutive patients (age range, 1-59 months). RESULTS: There were no reported complications, minimal untoward side reactions, and no delays in discharge. Eighty patients attained satisfactory minimal sedation levels. CONCLUSION: A second-dose INM strategy was effective in achieving satisfactory minimal sedation in children undergoing TTE. The results of this study also suggest that only a small proportion of patients would benefit from a one-dose INM strategy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background: Clonidine is a commonly used premedication in paediatric population to reduce separation anxiety and achieve steal induction. Oral route is usually preferred but has considerable delay in onset. Aim of the present study was to compare the clinical efficacy of clonidine premedication administered by oral and nasal route. Patients & Methods: Sixty patients, aged 1-7 years, scheduled for elective surgical procedures were randomly allocated in four groups to receive clonidine either by oral route 3μg kg-1 (group 3CO), 4μg kg-1 (group 4CO) or nasal route 3μg kg-1 (group 3CN), 4μg kg-1 (group 4CN). Drug acceptance, preoperative sedation, anxiolysis, quality of mask acceptance and recovery profile were evaluated in all four groups. Results: After sixty minutes of premedication, level of anxiolysis and sedation were comparable in all four groups of patients. Onset of sedation was 40.3±6.7 min (group 4CO) and 47.1±7.1 min (group 3CO) in oral group, while 21.6±10.7 min (group 4CN) and 29.8±9.5 min (group 3CN) in nasal group. Similarly onset time for anxiolysis was significantly less in intranasal group compare to oral group. Conclusion: Clinical effects of clonidine were similar with oral and nasal route. However onset of sedation and anxiolysis was faster in intranasal group.

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.

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.

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).

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.

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.

Plum, A. W. and T. M. Harris (2015). "Intranasal midazolam for anxiolysis in closed reduction of nasal fractures in children." Int J Pediatr Otorhinolaryngol 79(7): 1121-1123.

OBJECTIVES: Nasal fractures can result in obstruction of the nasal airflow and cosmetic deformities, and are treated either with observation, closed reduction, or a delayed rhinoplasty. In the pediatric patient, closed reduction is challenging due to anxiety and poor patient cooperation. Here, we describe the unique topical use of intranasal midazolam for anxiolysis in two pediatric patients at the time of closed reduction of nasal fractures, which has not been previously described. METHODS: Retrospective case series. RESULTS: In this case series, intranasal midazolam was used in two pediatric patients with isolated nasal fractures during closed reduction for anxiolysis in the Emergency department at a single academic medical institution between 2012 and 2013. There were no adverse outcomes and anxiolysis was achieved in both patients. CONCLUSIONS: Intranasal midazolam can provide effective anxiolysis for pediatric patients during closed reduction of nasal fractures.

Primosch, R. E. and F. Bender (2001). "Factors associated with administration route when using midazolam for pediatric conscious sedation." ASDC J Dent Child 68(4): 233-8, 228.

            Midazolam conscious sedation records of pediatric dental patients, one to six years of age, were reviewed retrospectively to: 1) examine the factors associated with the use of oral and nasal routes of administration and their effect on displayed behavior during dental treatment and 2) determine whether a child's compliance with oral administration is predictive of the intraoperative behavior displayed during dental treatment. Two hundred and fifty-seven conscious sedation records for 222 pediatric dental patients sedated with orally or nasally administered midazolam for dental treatment at the University of Florida were reviewed. Data collected included the patient's age, gender, route of administration, dose, compliance with oral administration, appointment type (planned vs. emergency), previous sedation experience with midazolam, operator vs. parent administration of the medication, use of papoose board and nitrous oxide/oxygen inhalation, types of procedures performed (restorations only, extractions only, or both), length of treatment rendered, and preoperative and intraoperative behavioral assessments of the child. The collected data were analyzed with Statview software using ANOVA and Chi-square analyses. There was a statistically significant difference (p < 0.001) between oral and nasal administration for the parameters of age, procedure length, appointment type, procedures performed, previous sedation experience and use of the papoose board and nitrous oxide/oxygen inhalation. While there was no statistically significant influence of chronological age on the preoperative Frankl behavior ratings, there was a statistically significant mean age difference with respect to the administrator of the medication (parent vs. operator), papoose board use, N2O/O2 use and previous sedation experience. Forty- five percent of the subjects were willing to accept oral administration of the medication, however, there was no statistically significant difference (p = 0.114) between the child's compliance to accept the medication and the intraoperative Frankl behavioral ratings displayed during dental treatment. In this review of midazolam conscious sedation records of pediatric dental patients. 1) route of administration was significantly influenced by several patient and procedural variables, resulting in different behavioral outcomes and 2) compliance with oral administration was not predictive of behavior displayed during treatment.

Ransford, N. J., M. C. Manley, et al. (2010). "Intranasal/intravenous sedation for the dental care of adults with severe disabilities: a multicentre prospective audit." Br Dent J 208(12): 565-569.

OBJECTIVE: This study was designed to provide an evaluation of the combined intranasal/intravenous midazolam sedation technique. It involved adults with severe disabilities which prevented them from being able to co-operate with dental treatment and intravenous cannulation for sedation. METHOD: Following a previous retrospective audit, additional treatment centres were enrolled and a standardised form used to collect prospective data about the effectiveness of the technique in facilitating cannulation, dental examination and treatment. Data was also collected on safety and patient acceptability. RESULTS: In a total of 316 sedation episodes in primary and secondary care settings, cannulation was achieved in 96.2% (304). Dental examination and treatment was able to be carried out without major interference from the patient in 78.8% (241) episodes. Adverse sedation events occurred in 6.0% (19), the most frequent being desaturation which was easily managed. There were no incidents with serious sequelae. Favourable acceptability ratings were given by carers regarding advantages of ease of administration and speed of onset of the intranasal dose, plus reduction in the stress associated with cannulation and treatment. CONCLUSIONS: This study provides further evidence to support the effectiveness, safety and acceptability of this technique. The authors suggest this provides sufficient basis to justify its use by suitably trained dental practitioners in primary care as part of the spectrum of anxiety and behaviour management for this group.

Reich, D. L. and G. Silvay (1989). "Ketamine: an update on the first twenty-five years of clinical experience." Can J Anaesth 36(2): 186-97.

            In nearly 25 years of clinical experience, the benefits and limitations of ketamine analgesia and anaesthesia have generally been well-defined. The extensive review of White et al. and the cardiovascular review of Reves et al. are broad in their scope and have advanced the understanding of dissociative anaesthesia. Nevertheless, recent research continues to illuminate different aspects of ketamine pharmacology, and suggests new clinical uses for this drug. The identification of the N-methylaspartate receptor gives further support to the concept that ketamine's analgesic and anaesthetic effects are mediated by separate mechanisms. The stereospecific binding of (+)ketamine to opiate receptors in vitro, more rapid emergence from anaesthesia, and the lower incidence of emergence sequelae, make (+)ketamine a promising drug for future research. Clinical applications of ketamine that have emerged recently, and are likely to increase in the future, are the use of oral, rectal, and intranasal preparations for the purposes of analgesia, sedation, and anaesthetic induction. Ketamine is now considered a reasonable option for anaesthetic induction in the hypotensive preterm neonate. The initial experience with epidural and intrathecal ketamine administration has not been very promising but the data are only preliminary in this area. The use of ketamine in military and catastrophic settings is likely to become more common. The clinical availability of midazolam will complement ketamine anaesthesia in several ways. This rapidly metabolized benzodiazepine reduces ketamine's cardiovascular stimulation and emergence phenomena, and does not have active metabolites. It is dispensed in an aqueous medium, which is usually non-irritating on intravenous injection, unlike diazepam. The combination of ketamine and midazolam is expected to achieve high patient acceptance, which never occurred with ketamine as a sole agent. Finally, it is necessary to point out the potential for abuse of ketamine. While ketamine is not a controlled substance (in the United States), the prudent physician should take appropriate precautions against the unauthorized use of this drug.

Reid, C., R. Hatton, et al. (2011). "Case report: prehospital use of intranasal ketamine for paediatric burn injury." Emerg Med J 10.1136/emj.2010.092825.

                In this study, the administration of an intravenous ketamine formulation to the nasal mucosa of a paediatric burn victim is described in the pprehospital environment. Effective analgesia was achieved without the need for vascular or osseous access. Intranasal ketamine has been previously described for chronic pain and anaesthetic premedication. This case highlights its potential as an option for prehospital analgesia.

Reinoso-Barbero, F., M. Gutierrez-Marquez, et al. (1998). "Prevention of halothane-induced bradycardia: is intranasal premedication indicated?" Paediatr Anaesth 8(3): 195-9.

            Eighty ambulatory surgical patients with ASA physical status 1 and 2, aged 1-10 years, were studied. One group received intranasal (IN) midazolam 0.25 mg.kg-1; a second group received IN 0.25 mg.kg-1 of midazolam plus 0.02 mg.kg-1 of atropine; the third group received 0.25 mg.kg-1 of midazolam plus 0.02 mg.kg-1 of atropine administered intramuscularly, and the fourth group received IN saline drops. All patients were anaesthetized with nitrous oxide, oxygen and halothane administered via mask. Heart rate (HR) was recorded every minute up to start of surgery. Children receiving midazolam had better preoperative sedation and anaesthesia induction scores. The IN administration of neither midazolam alone nor midazolam-atropine altered the incidence or degree of halothane-induced bradycardia.

Robertson, S. A. and S. Eberhart (1994). "Efficacy of the intranasal route for administration of anesthetic agents to adult rabbits." Lab Anim Sci 44(2): 159-65.

            Anesthetic agents were administered to adult rabbits by using the intranasal route. Six sedative or anesthetic protocols were studied as follows: group 1 (n = 12), 2.0 mg midazolam/kg body weight (BW); group 2 (n = 8), 25.0 mg ketamine/kg BW; group 3 (n = 8), 10 mg of combination of tiletamine and zolazepam/kg BW; group 4 (n = 10), 3 mg xylazine/kg BW and 10 mg ketamine/kg BW; group 5 (n = 8), 1.0 mg midazolam/kg BW and 25 mg ketamine/kg BW; and group 6 (n = 6), 0.3 ml of a combination of fentanyl and droperidol/kg BW. All drugs were diluted to a final volume of 0.4 ml/kg BW and an equal volume was administered with a catheter-tipped syringe into each nostril. Time to onset and duration of sedation or anesthesia were recorded. Muscle relaxation was graded as poor, fair, or excellent on the basis of flexibility of limbs. Presence or absence of a toe pinch response was recorded. Heart rate, respiratory rate, and hemoglobin saturation were measured before and at 5-min intervals after drug administration. The mean onset times for groups 1, 2, 3, 4, and 5 were 3.0, 1.2, 2.5, 2.0, and 0.8 min, respectively. The mean duration of action was 24.6, 36.7, 44.4, 35.2, and 52.5 min for midazolam, ketamine, tiletamine/zolazepam, xylazine/ketamine, and midazolam/ketamine, respectively. All protocols resulted in a significant decrease in respiratory rate. Hemoglobin saturation decreased in all groups except group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Roelofse, Ja, et al. (2004). "Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison." Anesth Prog 51(4): 114-21.

            This article details a double-blind, randomized study evaluating the efficacy and safety of intranasal sufentanil and intranasal midazolam (S/M) when compared with intranasal ketamine and intranasal midazolam (K/M) for sedation and analgesia in pediatric patients undergoing dental surgery. Fifty healthy ASA status 1 children aged 5-7 years, weighing 15-20 kg, and having 6 or more teeth extracted, were randomly allocated to 2 groups of 25 patients each (n = 50). In the S/M group, 25 children received intranasal sufentanil 20 microg, and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. In the K/M group, 25 children received intranasal ketamine 5 mg/kg and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. Sevoflurane in nitrous oxide and oxygen was used for induction and maintenance of anesthesia. This study demonstrated the safety and efficacy of both methods with ease of administration, combined with a rapid onset of action. Both groups were equally sedated. A smooth mask induction of anesthesia was experienced in the majority of children. Effective postoperative analgesia for multiple dental extractions was provided. The intranasal administration of drugs for sedation and analgesia has some promising features in preschool children undergoing multiple dental extractions.

Rose, E., D. Simon, et al. (1990). "[Premedication with intranasal midazolam in pediatric anesthesia]." Ann Fr Anesth Reanim 9(4): 326-30.

            To evaluate nasally administered midazolam 0.2 mg.kg-1 for preinduction of anaesthesia in paediatric patients the authors studied ASA 1 patients scheduled for elective surgery. Forty-five children, ages 3 to 126 months, were randomized in three groups: group D (n = 16) received diazepam 0.33 mg.kg-1 orally, group P (placebo) (n = 13) 0.04 ml.kg-1 normal saline via the nasal route; in group MDZ (n = 16) the children were given intranasal midazolam 0.3 mg.kg-1. The premedication was assessed on a 5-point sedation scale, modified to include the response to mask placement and the quality of the induction of general anaesthesia. The degree of sedation, heart rate, blood pressure, respiratory rate and oxygen saturation levels were recorded on the arrival in the operating room (0 min) and 3, 6, 9, 12 and 15 min (mask placement) after drug administration. With intranasal midazolam sedation was demonstrable at 6 min and was significant at 9 and 12 min. In this group all the children were calm or drowsy. The induction of anaesthesia was equivalent in group D and MDZ but easier than in those patients receiving normal saline. Vital signs did not change during the study period in any of the three groups. Intranasal midazolam was slightly more effective than oral diazepam. In children, it produces anxiolysis and sedation with rapid onset and is an attractive alternative to other routes for preanaesthetic medication.

Saint-Maurice, C., A. Landais, et al. (1990). "The use of midazolam in diagnostic and short surgical procedures in children." Acta Anaesthesiol Scand Suppl 92(1): 39-41.

            A new technique of sedation for children is described, in which midazolam (0.2 mg.kg-1) was administered topically by the nasal route, followed by ketamine (9.0 mg.kg-1) administered rectally in 32 patients breathing air spontaneously. Sedation was good in 23, seven required further ketamine (1.0 mg.kg-1 i.v.), and in two, halothane was introduced. There was no evidence of severe respiratory depression except during oesophagoscopy. Cardiovascular stability was excellent. Of 21 patients over 5 years old, 19 developed complete and two partial anterograde amnesia for the administration of ketamine and surgery. The major complications were nausea and vomiting (five patients) and salivation (eight patients). The mean recovery time was 40 min (s.d. 33 min). It provided a relatively safe, adaptable, non-invasive method of inducing sedation in children.

Sakurai, Y., T. Obata, et al. (2010). "Buccal administration of dexmedetomidine as a preanesthetic in children." J Anesth 24(1): 49-53.

          PURPOSE: The objective of this study was to evaluate the efficacy and safety of buccal dexmedetomidine as a preanesthetic in children, to compare it with diazepam, and to investigate the optimal dosage for buccal dexmedetomidine administration by measuring its serum concentration. METHODS: We performed a prospective study with 40 children who were assigned to two groups. The patients underwent an operation for inguinal or umbilical hernia. Twenty children received dexmedetomidine buccally at 3-4 microg/kg (Dex Group) and 20 received a diazepam suppository at 0.7 mg/kg (Diazepam Group) as preanesthetics 1 h before the operation. Heart rate, systolic blood pressure, SpO2, and respiratory rate were measured 1 h after premedication in all children. Sedation level was preoperatively evaluated, and compared with the Ramsay score, in the ward, at the entrance to the main operating rooms, and at anesthesia induction between the two groups. To investigate the optimal dosage of buccal dexmedetomidine, we compared the mean serum concentration of dexmedetomidine at induction between patients with a Ramsay score of 5 or greater and those with a Ramsay score less than 5. The Mann-Whitney U test was used for statistical analysis. RESULTS: There was no significant difference between the two groups in age or body weight. Furthermore, there was no significant difference between the two groups in heart rate, systolic blood pressure, SpO2, or respiratory rate after administration of either medication. The Ramsay score of the Dex Group was significantly higher than that of the Diazepam Group at all times. The mean serum dexmedetomidine concentration at induction in patients with a Ramsay score of 5 or greater (75 +/- 50 pg/ml) was significantly higher than in those with a Ramsay score less than 5 (34 +/- 36 pg/ml, P < 0.05). CONCLUSION: These results suggest that the buccal administration of dexmedetomidine (3-4 microg/kg) 1 h before the operation can be safely and effectively applied as a preanesthetic in children.

Savla, J. R., B. Ghai, et al. (2014). "Effect of intranasal dexmedetomidine or oral midazolam premedication on sevoflurane EC50 for successful laryngeal mask airway placement in children: a randomized, double-blind, placebo-controlled trial." Paediatr Anaesth 24(4): 433-439.

INTRODUCTION: This study was conducted to determine the effect of oral midazolam (OM) or intranasal dexmedetomidine (IND) on the EC50 of sevoflurane for successful laryngeal mask airway placement in children. We hypothesize that premedication with either agent might reduce the sevoflurane EC50 for laryngeal mask airway placement in children to a similar extent. METHODS: Fifty-two American Society of Anesthesiologists (ASA) I children (aged 1-6 years) scheduled for general anesthesia with laryngeal mask airway were randomized to one of the three groups: group M received 0.5 mg . kg(-1) OM with honey and intranasal saline, group D received 2 mug . kg(-1) IND along with oral honey, and group P received oral honey and intranasal saline at least 30 min prior to induction of anesthesia. Anesthesia was induced with incremental sevoflurane up to 8% in 100% O2 . A predetermined target endtidal sevoflurane (ETsevo ) concentration (2% in the first child of all three groups) was sustained for 10 min before the attempt of laryngeal mask airway insertion by adjusting dial concentration. No intravenous anesthetic or neuromuscular blockade was used. ETsevo was increased/decreased (step size 0.2%) using Dixon's and Massey's up and down method in next patient depending upon previous patient's response. Placement of the laryngeal mask airway without movement, coughing, biting, or bucking was considered as successful. EC50 of sevoflurane was calculated as the average of the crossover midpoints in each group, which was further confirmed by probit analysis. RESULTS: The EC50 of sevoflurane for laryngeal mask airway placement after OM (1.66 +/- 0.31) and IND (1.57 +/- 0.14) premedications was significantly lower than the placebo group (2.00 +/- 0.17, P < 0.0001). The EC95 (95% CI) derived from probit regression analysis was 2.34% (2.22-2.51%) with OM, 1.88% (1.77-2.04%) with IND, and 2.39% (2.25-2.35%) with placebo group. CONCLUSIONS: Oral midazolam and IND premedications significantly reduce the sevoflurane EC50 for laryngeal mask airway insertion in children by 17% and 21%, respectively.

Scheepers, L. D., C. J. Montgomery, et al. (2000). "Plasma concentration of flumazenil following intranasal administration in children." Can J Anaesth 47(2): 120-4.

            PURPOSE: A pharmacokinetic study in children to determine plasma flumazenil concentrations after the intranasal administration of 40 microg x kg(-1). METHODS: Following institutional approval and informed written consent, 11 ASA physical status I-II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 microg x kg(-1) flumazenil Anexate, Roche, 0.1 mg x mL(-1) (0.4 mL x kg(-1))) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t = 0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the on-site laboratory and then stored at -70 degrees C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.). RESULTS: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean Cmax was 67.8 ng x mL(-1) (SD 41.9), with Tmax at two minutes. The calculated half-life was 122 min (SD 99). CONCLUSION: The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.

Schrier, L., R. Zuiker, et al. (2016). "Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation." Br J Clin Pharmacol.

AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam were characterized and related to outcome variables for sedation (Saccadic Peak Velocity, the Bond and Lader Visual Analogue Scale for sedation, the Simple Reaction Time Task and the Observer's Assessment of Alertness/Sedation). Nasal tolerance was evaluated through subject reporting and ENT examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng/ml (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng/ml (CV, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 +/- 0.7 min after administration of 2.5 mg intravenous midazolam, 7 +/- 4.4 min after 2.5 mg Nazolam, and 4 +/- 1.8 min after 5 mg Nazolam. Sedation duration was 118 +/- 95.6 min for 2.5 mg intravenous midazolam, 76 +/- 80.4 min for 2.5 mg Nazolam, and 145 +/- 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation. This article is protected by copyright. All rights reserved.

Shanmugaavel, A. K., S. Asokan, et al. (2016). "Comparison of Drug Acceptance and Anxiety Between Intranasal and Sublingual Midazolam Sedation." Pediatr Dent 38(2): 106-111.

PURPOSE: The purpose of the study was to assess and compare the changes in anxiety level and drug acceptance after intranasal and sublingual midazolam sedation. METHODS: Forty three- to seven-year-olds were randomly assigned to Group A (N equals 20; 0.2 mg/kg intranasal midazolam sedation) or Group B (N equals 20; 0.2 mg/kg sublingual midazolam sedation) sedation. The anxiety levels at various time periods were assessed from recorded videos using the Venham clinical anxiety scale by two pediatric dentists. The acceptance of the drug administration was assessed using a four-point scale. The Wilcoxon signed rank test and Mann-Whitney U test were used for statistical analysis using SPSS 17.0 software. RESULTS: There was a significant decrease in anxiety level from baseline to 20 minutes after drug administration in Group A (P<0.001) and Group B (P<0.001). However, there was no significant difference in the anxiety level between the two groups. The sublingual route of drug administration was better accepted (P=0.001) than the intranasal route of drug administration. CONCLUSIONS: Both intranasal and sublingual administrations of midazolam were equally effective in reducing the child's anxiety. The sublingual route of drug administration was better accepted than the intranasal route.

Shapira, J., G. Holan, et al. (1996). "The effectiveness of midazolam and hydroxyzine as sedative agents for young pediatric dental patients." ASDC J Dent Child 63(6): 421-5.

            The purpose of the study was to compare hydroxyzine (HYD) and 0.2mg/Kg midazolam (MDZ) as sedative agents for young pediatric dental patients. Twenty-nine healthy two-to-four-year-old children participated in the study. Hydroxyzine was dripped nasally 10 minutes before treatment. The patient's crying, alertness, movement and general behavior were blindly assessed and statistically analyzed. No differences were found between the mean general behavior scores nor between the first and second visits in both groups. A significant difference (p &lt; 0.02) was found in the acceptance of the face and nasal masks by children of the midazolam group between the first and second appointments. None of the children of this group cried nor moved at the first visit. The results of the study indicate that midazolam is somewhat more effective than hydroxyzine as a sedative agent for short procedures in young pediatric dental patients.

Shashikiran, Nd, et al. (2006). "Conscious sedation--an artist's science! An Indian experience with midazolam." J Indian Soc Pedod Prev Dent 24(1): 7-14.

            The present study was undertaken to evaluate Midazolam as a Paediatric conscious sedative agent for a routine Indian dental setup and to compare its efficacy and safety when administered by intranasal and intramuscular routes, at a dosage of 0.2 mg/kg body weight. The present study was accomplished in two phases: Phase 1: Preliminary dose finding pilot study on 10 children. Phase 2: Single dose, randomized parallel clinical trial on 40 children between the ages of 2 and 5 years. These children were randomly assigned to two groups consisting of 20 subjects each. Group M, received Midazolam intramuscularly, while Group N received Midazolam intranasally. Both the intranasal and intramuscular groups showed highly significant decrease in crying levels, motor movements and sensory perception levels, post-sedation (P P < 0.001). Midazolam could be safely and successfully employed by intranasal and intramuscular routes for Paediatric conscious sedation in a routine dental setup with basic facilities at a dosage of 0.2 mg/ kg body weight. Whenever the clinical situation warrants a faster action, peak and recovery, the intranasal route should be the obvious choice.

Shavit, I., L. Feraru, et al. (2013). "Midazolam for urethral catheterisation in female infants with suspected urinary tract infection: a case-control study." Emerg Med J.

OBJECTIVES: Based on the 2010 Israeli Medical Association recommendations, young children with suspected urinary tract infection (UTI) are mildly sedated with oral or intranasal midazolam to reduce the distress associated with urethral catheterisation (UC). The primary objective of this study was to examine the rate of urine culture contamination (UCC) in infants who underwent UC with and without sedation. Other objectives were to evaluate serious adverse events and emergency department (ED) length of stay. METHODS: A retrospective case-control study was conducted in a paediatric ED. RESULTS: Two cohorts of patients who underwent UC were compared, 164 female infants who were sedated with midazolam (case subjects) and 173 who were not (controls). Cases and controls had a mean temperature of 38.3 degrees C and 38.2 degrees C, respectively. One hundred and forty-one patients were treated with oral midazolam and 23 received the drug intranasally. Cases and controls had a UCC rate of 20/164 (12%) and 45/173 (26%), respectively. Compared with controls, cases had lower odds of UCC (OR=0.39, 95% CI 0.21 to 0.73).Serious adverse events related to midazolam were not recorded. Case subjects and controls had a mean ED length of stay of 2.96 h and 2.50 h, respectively. The difference between the groups was statistically significant (p<0.014, 95% CI 0.10 to 0.90 for difference between means). CONCLUSIONS: In this cohort of febrile infants, sedation with oral or intranasal midazolam reduced the risk of culture contamination during UC without causing serious adverse events. However, patients who were treated with sedation had longer length of stay in the ED.

Sidhu, G. K., S. Jindal, et al. (2016). "Comparison of Intranasal Dexmedetomidine with Intranasal Clonidine as a Premedication in Surgery." Indian J Pediatr.

OBJECTIVES: To compare effectiveness of intranasal dexmedetomidine and clonidine as anxiolytics and sedatives in pediatric patients undergoing various surgeries. METHODS: This double blind randomized placebo controlled study was conducted on 105 surgical patients of American Society of Anesthesiologist (ASA) physical status capital I, Ukrainian-capital I, Ukrainiancapital I, Ukrainian, aged between 2 and 9 y in a tertiary-care hospital (February 2014 to September 2015). Participants were randomly allocated to three groups to receive either intranasal dexmedetomidine 2 mug/kg (Group capital I, Ukrainian) or intranasal clonidine 3 mug/kg (Group capital I, Ukrainiancapital I, Ukrainian) or intranasal saline 0.5 ml (Group capital I, Ukrainiancapital I, Ukrainiancapital I, Ukrainian). The primary outcome measure was proportion of patients with satisfactory anxiolysis and sedation at 30 min after drug administration. Secondary outcome measures included time taken to achieve Aldrete score of 9 and number of doses of rescue analgesia required in 12 h after surgery. RESULTS: Satisfactory anxiolysis was achieved by 88.5% in Group capital I, Ukrainian vs. 60% in Group capital I, Ukrainiancapital I, Ukrainian (p = 0.001) and satisfactory sedation by 57.1% in Group capital I, Ukrainian vs. 25.7% in Group capital I, Ukrainiancapital I, Ukrainian (p = 0.001) 30 min after premedication. Rescue analgesia requirement was significantly less in Group capital I, Ukrainian as compared to Group capital I, Ukrainiancapital I, Ukrainian (p = 0.001) while time taken to achieve Aldrete score was comparable between the study groups (p = 0.185). CONCLUSIONS: Intranasal dexmedetomidine is a better anxiolytic and sedative as compared to clonidine. Postoperative analgesic requirement was also significantly decreased after intranasal dexmedetomidine. Thus, it can be preferred as compared to clonidine for premedication in pediatric surgical patients.

Sikchi, S., S. Kulkarni, et al. (2013). "Evaluation of efficacy of intranasal midazolam spray for preanaesthetic medication in paediatric patients." J Evol Med Dend Sci 2(22): 3946-3958.

ABSTRACT:  BACKGROUND: Preoperative  anxiety  and  long-term  behavioural  problems  are inevitable  consequences  in  absence  of  preoperative  sedation  in  paediatric  patients  undergoing surgery. An ideal premedicant removes fear and anxiety in tender minds of children and achieves a calm, sedated child for smooth induction of anaesthesia and rapid recovery in postoperative period. Midazolam is the most commonly used premedicant in children as it satisfies most of the criteria of ideal premedicant but its route of administration is a debatable issue in anaesthesia practice. AIMS:This  study  evaluated  the  efficacy  of  atomized  intranasal  midazolam  spray  as  a  painless,  userfriendly,  needleless  system  of  drug  administration  for  pre-anaesthetic  medication  in  paediatric patients.  SETTINGS AND DESIGN: Tertiary hospital, a prospective, randomized, controlled, clinical study.  METHODS  AND  MATERIAL: 60  ASA  physical  status  I  children  of  2-5  years  age group, weighing  10-18  kg  scheduled  for  routine  surgeries  participated  in  the  study.  Children  were randomly  assigned  to  Group  M:  Received  intranasal  midazolam  spray  in  doses  of  0.2  mg/kg  and Group N: Received normal saline drops (1-2 drops/nostril). Patients were observed in preoperative room for 20 min. Acceptance of drug, response to drug administration, sedation scale, separation score,  acceptance  to  mask,  recovery  score  and  side  effects  of  drug  were  noted.  STATISTICAL ANALYSIS: Student ‘t’ test, standard error of difference between two means and Chi-square test. p value<0.05 was considered as statistically significant.  RESULTS AND CONCLUSION:35% children in group M and 42.10% children in group N cried after drug administration who were not crying before drug administration (p>0.05). 20 min after premedication 76.66% in group M and 10.00% group  N,  children  showed  satisfactory  sedation  (p<0.05).  73.33%  in  group  M  while  26.66%  in group  N,  children  showed  acceptable  parental  separation  and  86.66%  in  group  M  while  23.33% group N, children showed satisfactory acceptance to mask (p<0.05). Transient nasal irritation in the form of rubbing of nose, watering, sneezing and lacrimation was observed in 40% children of group M.    Intranasal  midazolam  by  atomized  spray  is  safe  and effective  premedicant  in  paediatric patients.  It  produces  effective  sedation  and  anxiolysis  in  children. Transient  nasal irritation  is  an undesirable side effect observed with intranasal route.

Sheta, S. A., M. A. Al-Sarheed, et al. (2014). "Intranasal dexmedetomidine vs midazolam for premedication in children undergoing complete dental rehabilitation: a double-blinded randomized controlled trial." Paediatr Anaesth 24(2): 181-189.

BACKGROUND: This prospective, randomized, double-blind study was designed to evaluate the use of intranasally administered dexmedetomidine vs intranasal midazolam as a premedication in children undergoing complete dental rehabilitation. METHODS: Seventy-two children of American Society of Anesthesiology classification (ASA) physical status (I & II), aged 3-6 years, were randomly assigned to one of two equal groups. Group M received intranasal midazolam (0.2 mg.kg(-1)), and group D received intranasal dexmedetomidine (1 mug.kg(-1)). The patients' sedation status, mask acceptance, and hemodynamic parameters were recorded by an observer until anesthesia induction. Recovery conditions, postoperative pain, and postoperative agitation were also recorded. RESULTS: The median onset of sedation was significantly shorter in group M 15 (10-25) min than in group D 25 (20-40) min (P = 0.001). Compared with the children in group M, those in group D were significantly more sedated when they were separated from their parents (77.8% vs 44.4%, respectively) (P = 0.002). Satisfactory compliance with mask application was 58.3% in group M vs 80.6% in group D (P = 0.035). The incidences of postoperative agitation and shivering were significantly lower in Group D compared with group M. Thirteen children (36.1%) in group M, showed signs of nasal irritation with teary eyes, and none of these signs was seen in the children in group D (P = 0.000). There were no incidences of bradycardia, hypotension, in either of the groups during study observation. CONCLUSION: Intranasal dexmedetomidine (1 mug.kg(-1)) is an effective and safe alternative for premedication in children; it resulted in superior sedation in comparison to 0.2 mg.kg(-1) intranasal midazolam. However, it has relatively prolonged onset of action.

Shrestha, G. S., P. Joshi, et al. (2015). "Intranasal midazolam for rapid sedation of an agitated patient." Indian J Crit Care Med 19(6): 356-358.

                Rapidly, establishing a difficult intravenous access in a dangerously agitated patient is a real challenge. Intranasal midazolam has been shown to be effective and safe for rapidly sedating patients before anesthesia, for procedural sedation and for control of seizure. Here, we report a patient in intensive care unit who was on mechanical ventilation and on inotropic support for management of septic shock and who turned out extremely agitated after accidental catheter removal. Intravenous access was successfully established following sedation with intranasal midazolam, using ultrasound guidance.

Smith, D., H. Cheek, et al. (2016). "Lidocaine Pretreatment Reduces the Discomfort of Intranasal Midazolam Administration: A randomized, double-blind, placebo-controlled trial." Acad Emerg Med.

OBJECTIVE: Intranasal (IN) midazolam is a commonly prescribed medication for pediatric sedation and anxiolysis. One of its most frequently-encountered adverse effects is discomfort with administration. While it has been proposed that premedicating with lidocaine reduces this undesirable consequence, this combination has not been thoroughly researched. The objective of our study was to assess whether topical lidocaine lessens the discomfort associated with IN midazolam administration. METHODS: This was a double-blinded, randomized, placebo-controlled trial performed in an urban, academic pediatric emergency department. Children 6-12 years of age who were receiving IN midazolam for procedural sedation received either 4% lidocaine or 0.9% saline (placebo) via mucosal atomizer. Subjects were subsequently given IN midazolam in a similar fashion, and then rated their discomfort using the Wong-Baker FACES Pain Rating Scale (WBS). The primary endpoint of WBS score was analyzed with a two-tailed Mann-Whitney U test, with P < 0.05 considered statistically significant. RESULTS: Seventy-seven patients were enrolled over a consecutive 8-month period. One child was excluded from analysis due to a discrepancy in recording the drug identification number. Study groups were similar in regards to demographic information and indication for sedation. Subjects who received IN lidocaine reported less discomfort with IN midazolam administration (median WBS 3, interquartile range [IQR] 0-6) than those who received placebo (median WBS 8, IQR 2-9) (P=0.006). CONCLUSIONS: Premedication with topical lidocaine reduces the discomfort associated with administration of IN midazolam. (ClinicalTrials. gov, NCT02396537). This article is protected by copyright. All rights reserved.

Singer, A. J. (1995). "Intranasal midazolam in pediatric conscious sedation." Ann Emerg Med 25(6): 851-2.

Stella, M. J. and A. G. Bailey (2008). "Intranasal clonidine as a premedicant: three cases with unique indications." Paediatr Anaesth 18(1): 71-3.

            Clonidine is experiencing increasing use in the pediatric population as a sedative and analgesic because of its central alpha2-adrenergic agonism. We report three cases of preoperative use of intranasal clonidine in pediatric patients, all for different indications. One patient was treated for preoperative agitation and hallucinations associated with oral midazolam. One patient was given clonidine as a premedicant. The third patient was treated for preoperative agitation and hypertension. All three patients had subjective resolution of indicated symptoms and none experienced adverse outcomes.

Sulton, C., P. Kamat, et al. (2014). "The use of intranasal dexmedetomidine for pediatric sedation: A report from the pediatric sedation research consortium.

Background: Dexmedetomidine is a potent and highly selective alpha-2 receptor agonist. It is well established to have both sedative and analgesic effects in children. There are extensive reports in the literature of the efficacy of intravenous dexmedetomidine for procedural sedation in children, particularly for non-invasive imaging.1,2,3 The use of dexmedetomidine delivered intranasally (IN) has been reported in multiple settings and in a broad dose range.4,5,6 This report describes the use IN dexmedetomidine in a prospective collection of patients from the Pediatric Sedation Research Consortium (PSRC). Methods: The Pediatric Sedation Research Consortium is an organization of hospitals and universities dedicated to understanding and improving the process of pediatric sedation and sedation outcomes for all children. The consortium is composed of 40 pediatric institutions across the United States that submit data prospectively on sedation encounters. We searched the 2007 version of the PSRC database for instances in which dexmedetomidine was delivered intranasally as the sedation agent. There were no exclusion criteria. In this report we describe patient demographics, dosage administered, procedures performed, practitioners involved, adjunctive medications used, as well as complications noted and interventions performed. Results: A total of 776 sedations encounters met our inclusion criteria. 56% were male. Median age was 18 months. ASA class was designated 1 or 2 in 77% of cases. Dosages ranged from 0.3 to 8.2 mcg/kg (mean: 2.8). The most frequent study performed was CT (n=385), followed by MRI (n=259), and then BART (n=102). There were 4 instances in which sedation was suboptimal. Most sedations (89%) required no interventions. Of those interventions performed, blow by oxygen (8.5%), repositioning (4.0%), and suction (2.45%) were the most frequently performed. Five patients required oropharyngeal airway placement (0.6%) and 2 required nasopharyngeal airway placement (0.3%). Adjunctive midazolam was used in 93% of cases. Registered Nurses were the monitoring provider in 97% of cases. Conclusions: To date this is the first large scale prospective report of sedation encounters with IN dexmedetomidine. Based on this data, it would appear that it is effective to accomplish a wide range of procedures with a low failure rate. The complication rate was low for this group of patients.

Surendar, M. N., R. K. Pandey, et al. (2014). "A comparative evaluation of intranasal dexmedetomidine, midazolam and ketamine for their sedative and analgesic properties: a triple blind randomized study." J Clin Pediatr Dent 38(3): 255-261.

OBJECTIVES: To evaluate and compare the efficacy and safety of Intranasal (IN) Dexmedetomidine, Midazolam and Ketamine in producing moderate sedation among uncooperative pediatric dental patients. STUDY DESIGN: This randomized triple blind comparative study comprises of eighty four ASA grade I children of both sexes aged 4-14 years, who were uncooperative and could not be managed by conventional behavior management techniques. All the children were randomized to receive one of the four drug groups Dexmedetomidine 1 microg/ kg (D1), 1.5 microg/kg (D2), Midazolam 0.2 mg/kg (M1) and Ketamine 5 mg/kg (K1) through IN route. These drug groups were assessed for efficacy and safety by gauging overall success rate and by monitoring vital signs, respectively. RESULTS: The onset of sedation was significantly rapid with M1 and K1 as compared to D1 and D2 (p = < 0.001). The overall success rate was highest in D2 (85.7%) followed by D1 (81%), K1 (66.7%) and M1 (61.9%), however, the difference among them was not statistically significant (p = > 0.05). Even though all the vital signs were within physiological limits, there was significant reduction in pulse rate (PR) (p = < 0.001) and systolic blood pressure (SBP) (p = < 0.05) among D1 and D2 as compared to M1 and K1. D1, D2 and K1 produced greater intra- and post-operative analgesia as compared to M1. There were no significant adverse effects with any group. CONCLUSION: Dexmedetomidine, Midazolam and Ketamine, all the three drugs evaluated in the present study can be used safely and effectively through IN route in uncooperative pediatric dental patients for producing moderate sedation.

Talon, M. D., L. C. Woodson, et al. (2009). "Intranasal Dexmedetomidine Premedication is Comparable With Midazolam in Burn Children Undergoing Reconstructive Surgery." J Burn Care Res 30(4): 599-605.

            Preoperative anxiety and emergence delirium in children continue to be common even with midazolam premedication. Midazolam is unpleasant tasting even with a flavored vehicle and as a result, patient acceptance is sometimes poor. As an alternative, we evaluated dexmedetomidine administered intranasally. Dexmedetomidine an alpha-2 adrenergic agonist is tasteless, odorless, and painless when administered by this route. Alpha-2 adrenergic agonists produce sedation, facilitate parental separation, and improve conditions for induction of general anesthesia, while preserving airway reflexes. Institutional review board approval was obtained to study 100 pediatric patients randomized to intranasal dexmedetomidine (2 mug/kg) or oral midazolam (0.5 mg/kg) administered 30 to 45 minutes before the surgery. Subjects received general anesthesia with oxygen, nitrous oxide, isoflurane, and analgesics (0.05-0.1 mg/kg morphine or 0.1 mg/kg methadone). Nurses and anesthetists were blinded to the drug administered and evaluated patients for preoperative sedation, conditions for induction of general anesthesia, emergence from anesthesia, and postoperative pain. Responses of 100 patients (50 dexmedetomidine and 50 midazolam) were analyzed. Dexmedetomidine (P = .003) was more effective than midazolam at inducing sleep preoperatively. Dexmedetomidine and midazolam were comparable for conditions at induction (P > 0.05), emergence from anesthesia (P > 0.05), or postoperative pain (P > 0.05). Both drugs were equieffective in these regards. In pediatric patients, dexmedetomidine 2 mug/kg administered intranasally and midazolam 0.5 mg/kg administered orally produced similar conditions during induction and emergence of anesthesia. Intranasal administration of dexmedetomidine is more effective at inducing sleep and in some circumstances offers a useful alternative to oral midazolam in children.

Tang, C., X. Huang, et al. (2015). "Intranasal Dexmedetomidine on Stress Hormones, Inflammatory Markers, and Postoperative Analgesia after Functional Endoscopic Sinus Surgery." Mediators Inflamm 2015: 939431.

                Background. A strong ongoing intraoperative stress response can cause serious adverse reactions and affect the postoperative outcome. This study evaluated the effect of intranasally administered dexmedetomidine (DEX) in combination with local anesthesia (LA) on the relief of stress and the inflammatory response during functional endoscopic sinus surgery (FESS). Methods. Sixty patients undergoing FESS were randomly allocated to receive either intranasal DEX (DEX group) or intranasal saline (Placebo group) 1 h before surgery. Stress hormones, inflammatory markers, postoperative pain relief, hemodynamic variables, blood loss, surgical field quality, body movements, and satisfaction were assessed. Results. Plasma epinephrine, norepinephrine, and blood glucose levels were significantly lower in DEX group as were the plasma IL-6 and TNF-alpha levels (P < 0.05). The weighted areas under the curve (AUCw) of the VAS scores were also significantly lower in DEX group at 2-12 h after surgery (P < 0.001). Furthermore, hemodynamic variables, blood loss, body movements, discomfort with hemostatic stuffing, surgical field quality, and satisfaction scores of patients and surgeons were significantly better (P < 0.05) in DEX group. Conclusions. Patients receiving intranasal DEX with LA for FESS exhibited less perioperative stress and inflammatory response as well as better postoperative comfort with hemostatic stuffing and analgesia.

Theroux, M. C., D. W. West, et al. (1993). "Efficacy of intranasal midazolam in facilitating suturing of lacerations in preschool children in the emergency department." Pediatrics 91(3): 624-7.

            Sedating children safely and effectively for minor laceration repair is a well-recognized clinical problem. A randomized, double-blind, and controlled study was conducted to evaluate the efficacy of intranasal midazolam for reducing stress during the suturing of lacerations in preschool children. Fifty-nine children with simple lacerations that required suturing were randomly assigned to one of three groups. Group 1 received intranasal midazolam, 0.4 mg/kg, prior to suturing. Group 2 received an equivalent volume of normal saline intranasally prior to suturing as a placebo. Group 3 was the control group and received no intervention prior to suturing. Heart rate, respiratory rate, blood pressure, and pulse oximetry were monitored at 5-minute intervals throughout the procedure. Subjective variables were also measured at 5-minute intervals and included a cry score, a motion score, and a struggle score. Parent satisfaction was measured via a short telephone interview the following day. There were no significant differences in outcome between the placebo group and the control group. Their results were pooled and compared with the results for the midazolam group. The midazolam group showed significant reductions for mean heart rate, maximum heart rate, and maximum systolic blood pressure when compared with the placebo/control group. Scores for two of the three subjective variables, cry and struggle, were significantly reduced for the midazolam group. The papoose board was considered unnecessary in retrospect for more than half of patients in the midazolam group compared with only one fifth of patients in the placebo/control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Tolksdorf, W. and C. Eick (1991). "[Rectal, oral and nasal premedication using midazolam in children aged 1-6 years. A comparative clinical study]." Anaesthesist 40(12): 661-7.

            Midazolam is often used for the premedication of children in the pre- school age group. Different noninvasive routes of administration have been described. In a prospective study we compared the effects of oral, rectal, and nasal midazolam in commonly used dosages. PATIENTS AND METHODS. Ninety children undergoing surgery under general anesthesia were assigned to oral (0.4 mg/kg) (MO), rectal (0.5 mg/kg) (MR), or nasal (0.2 mg/kg) midazolam (MN), according to the child's and/or parent's preferred route of administration, after having obtained the parent's informed consent. It was applied on the ward before transport to the operating room. The following parameters were assessed by the observer and the anesthesiologist at different times: sedation, acceptance (child, anesthesiologist), mood, emotion, resistance, pain, nausea and vomiting, blood pressure, and heart and respiratory rates. The Wilcoxon test (P less than 0.05) was used for statistical analysis. RESULTS. All groups were comparable with respect to age, weight, and surgery experience. There was no difference in the anesthesiologist's acceptance of the premedication or the cooperation of the children. The children accepted MO significantly better compared to MN and MR. The fastest onset of sedation was found after MR. Immediately after MN many children became euphoric, and it turned out that the effect of MN was rather euphoric than sedative. The effect of MO was good in many children, but less predictable. This led to a significant delay in transport to the operating room. MO children experienced more nausea and vomiting (P less than 0.05) in the postoperative period. There were no differences in physiological parameters. DISCUSSION AND CONCLUSIONS. The results can be explained by the different characteristics of absorption and patient acceptance. The route of administration according to the child's or parent's choice can be recommended but does not guarantee success. MR had the fastest onset of sedative action due to faster absorption of the drug. MN had a euphoric effect that resulted almost immediately. Oral premedication was best accepted, nasal administration worst. MO produced more side effects than MR and MN in the postoperative period. If the child accepts the rectal route of administration, this should be preferred because of the high success rate and few side effects.

Tschirch, F. T., K. Gopfert, et al. (2007). "Low-dose intranasal versus oral midazolam for routine body MRI of claustrophobic patients." Eur Radiol 17(6): 1403-10.

            The purpose of this study was to assess prospectively the potential of low-dose intranasal midazolam compared to oral midazolam in claustrophobic patients undergoing routine body magnetic resonance imaging (MRI). Seventy-two adult claustrophobic patients referred for body MRI were randomly assigned to one of two treatment groups (TG1 and TG2). The 36 patients of TG1 received 7.5 mg midazolam orally 15 min before MRI, whereas the 36 patients of TG2 received one (or, if necessary, two) pumps of a midazolam nasal spray into each nostril immediately prior to MRI (in total, 1 or 2 mg). Patients' tolerance, anxiety and sedation were assessed using a questionnaire and a visual analogue scale immediately before and after MRI. Image quality was evaluated using a five-point-scale. In TG1, 18/36 MRI examinations (50%) had to be cancelled, the reduction of anxiety was insufficient in 12/18 remaining patients (67%). In TG2, 35/36 MRI examinations (97%) were completed successfully, without relevant adverse effects. MRI image quality was rated higher among patients of TG2 compared to TG1 (p<0.001). Low-dose intranasal midazolam is an effective and patient-friendly solution to overcome anxiety in claustrophobic patients in a broad spectrum of body MRI. Its anxiolytic effect is superior to that of the orally administrated form.

Tsze, D. S., D. W. Steele, et al. (2012). "Intranasal ketamine for procedural sedation in pediatric laceration repair: a preliminary report." Pediatr Emerg Care 28(8): 767-770.

                OBJECTIVE: The objective of this study was to compare the efficacy of 3 doses of intranasal ketamine (INK) for sedation of children from 1 to 7 years old requiring laceration repair. METHODS: This was a randomized, prospective, double-blind trial of children requiring sedation for laceration repair. Patients with simple lacerations were randomized by age to receive 3, 6, or 9 mg/kg INK. Adequacy and efficacy of sedation were measured with the Ramsay sedation score and the Observational Scale of Behavioral Distress-Revised. Serum ketamine and norketamine levels were drawn during the procedure. Sedation duration and adverse events were recorded. RESULTS: Of the 12 patients enrolled, 3 patients achieved adequate sedation, all at the 9-mg/kg dose. The study was suspended at that time as per predetermined criteria. CONCLUSIONS: Nine milligrams of INK per kilogram produced a significantly higher proportion of successful sedations than the 3- and 6-mg/kg doses.

Tug, A., A. Hanci, et al. (2015). "Comparison of Two Different Intranasal Doses of Dexmedetomidine in Children for Magnetic Resonance Imaging Sedation." Paediatr Drugs 17(6): 479-485.

OBJECTIVE: Anaesthetic agents used for magnetic resonance imaging (MRI) in paediatric patients should cause few adverse effects and allow fast anaesthetic induction and recovery. The administration route is also important and should be minimally invasive. In this study, we aimed to compare two different doses of intranasal dexmedetomidine applied to children for MRI sedation. METHODS: Sixty patients between 1 and 10 years of age with American Society of Anesthesiologists Physical Status classification I or II who were scheduled for MRI were recruited into this prospective, randomized, double-blind study. Intranasal dexmedetomidine was administered at doses of 3 microg kg(-1) (Group 1) and 4 microg kg(-1) (Group 2) before imaging. Heart rate (HR), peripheral oxygen saturation, respiratory rate and Ramsay Sedation Scale (RSS) scores were recorded before the anaesthetic induction of sedation and every 10 min until discharge. If intranasal sedation failed, an intravenous cannula was placed and propofol was applied as a rescue anaesthetic. Bispectral Index (BIS) scores were also recorded before and after MRI. We recorded onset time of sedation, mood at separation from parents (defined as parental separation score), imaging quality, MRI duration, rescue anaesthetic requirement, total duration of sedation, recovery duration, parents' satisfaction and adverse effects. RESULTS: The results related to age, weight and adverse effects were not statistically different between the groups. The parental separation score was significantly higher in Group 2 (P = 0.003). Rescue anaesthetic requirement was significantly higher in Group 1 (P = 0.002). The results related to recovery duration, MRI duration, parents' satisfaction, onset time of sedation and total duration of sedation were not statistically different. HR was significantly lower in all time intervals compared with basal values in both groups. In Group 2, RSS scores were significantly higher in the 30th, 40th and 50th min. The BIS scores in Group 2 were lower at the 50th min. Neither bradycardia nor oxygen desaturation were observed. Imaging studies were completed successfully in all patients. CONCLUSIONS: Based on lower rescue anaesthetic requirements, sufficient sedation and parental separation scores in Group 2, intranasal dexmedetomidine 4 microg kg(-1) was more efficient than intranasal dexmedetomidine 3 microg kg(-1). The intranasal route may be an alternative noninvasive route to apply drugs for MRI sedation in paediatric patients. Trial registration ClinicalTrials.gov: NCT02299232.

Uygur-Bayramicli, O., R. Dabak, et al. (2002). "Sedation with intranasal midazolam in adults undergoing upper gastrointestinal endoscopy." J Clin Gastroenterol 35(2): 133-7.

            The use of intranasal (IN) midazolam in adults for sedation in upper gastrointestinal endoscopy has been evaluated in a controlled clinical study. Eighty-one patients with a mean age of 37.02 +/- 12.50 years who underwent upper gastrointestinal endoscopy for various reasons were included in the study. Three groups were formed according to the sedation regimen. In the first group (n = 30), patients received IN midazolam. In the second group (n = 28) intravenous (IV) midazolam was given for sedation, and the third group of patients (n = 23) received placebo before the procedures. Patients were monitored (using a pulse oximeter with an interval of 5 minutes until the 45th minute after the procedure) for arterial oxygen saturation, heart rate, systolic and diastolic arterial blood pressure, and respiratory rate. Efficacy of sedation, amnesia, side effects, and patients' preferences were evaluated. Superior results regarding the efficacy of sedation has been documented with the use of IV midazolam (p < 0.001), and this was the preferred route for drug application according to the patients' answers (p < 0.01). However, regarding amnesia, IN midazolam was found to be almost equally effective as IV midazolam (p < 0.05); moreover, IN route of drug application caused significantly fewer side effects than did the IV form (p < 0.001 ). Intranasal application of midazolam for gastrointestinal endoscopy appeared to be an interesting alternative to the IV route, the usage of which might be limited because of its potentially serious side effects. In contrast to the IV application of midazolam, the IN route may not even necessitate the monitoring of the patient during upper gastrointestinal endoscopy.

Vercauteren, M., E. Boeckx, et al. (1988). "Intranasal sufentanil for pre-operative sedation." Anaesthesia 43(4): 270-3.

            Sufentanil, a short-acting and potent narcotic agent, was studied as a premedicant administered by the nasal route. A total dose of 5 micrograms appeared to be too low, while either 10 or 20 micrograms was very effective in producing sedation. Side effects were minor. There appeared to be no differences between nose drops and spray. In a further study, sufentanil nose drops were compared with saline 0.9% in a double-blind fashion. Sedation of rapid onset but of limited duration was observed in the majority of patients who received sufentanil.

Vesal, Eskandari, et al. (2006). "Sedative effects of midazolam and xylazine with or without ketamine and detomidine alone following intranasal administration in Ring-necked Parakeets." J Am Vet Med Assoc 228(3): 383-8.

            OBJECTIVE: To evaluate the effects of intranasal administration of midazolam and xylazine (with or without ketamine) and detomidine and their specific antagonists in parakeets. DESIGN: Prospective study. ANIMALS: 17 healthy adult Ring-necked Parakeets (Psittacula krameri) of both sexes (mean weight, 128.83+/-10.46 g [0.28+/-0.02 lb]). PROCEDURE: The dose of each drug or ketamine-drug combination administered intranasally that resulted in adequate sedation (ie, unrestrained dorsal recumbency maintained for >or=5 minutes) was determined; the onset of action, duration of dorsal recumbency, and duration of sedation associated with these treatments were evaluated. The efficacy of the reversal agents flumazenil, yohimbine, and atipamezole was also evaluated. RESULTS: In parakeets, intranasal administration of midazolam (7.3 mg/kg [3.32 mg/lb]) or detomidine (12 mg/kg [5.45 mg/lb]) caused adequate sedation within 2.7 and 3.5 minutes, respectively. Combinations of midazolam (3.65 mg/kg [1.66 mg/lb]) and xylazine (10 mg/kg [4.55 mg/lb]) with ketamine (40 to 50 mg/kg [18.2 to 22.7 mg/lb]) also achieved adequate sedation. Compared with detomidine, duration of dorsal recumbency was significantly longer with midazolam. Intranasal administration of flumazenil (0.13 mg/kg [0.06 mg/lb]) significantly decreased midazolam-associated recumbency time. Compared with the xylazineketamine combination, duration of dorsal recumbency was longer after midazolam-ketamine administration. Intranasal administration of flumazenil, yohimbine, or atipamezole significantly decreased the duration of sedation induced by midazolam, xylazine, or detomidine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Intranasal administration of sedative drugs appears to be an acceptable method of drug delivery in Ring-necked Parakeets. Reversal agents are also effective when administered via this route.

Vesal and Zare (2006). "Clinical evaluation of intranasal benzodiazepines, alpha-agonists and their antagonists in canaries." Vet Anaesth Analg 33(3): 143-8.

            OBJECTIVE: To evaluate the effects of intranasal benzodiazepines (midazolam and diazepam), alpha(2)-agonists (xylazine and detomidine) and their antagonists (flumazenil and yohimbine) in canaries. STUDY DESIGN: Prospective randomized study. ANIMALS: Twenty-six healthy adult domesticated canaries of both sexes, weighing 18.3 +/- 1.0 g. METHODS: In Study 1 an attempt was made to determine the dose of each drug that allowed treated canaries to be laid in dorsal recumbency for at least 5 minutes, i.e. its effective dose. This involved the evaluation of various doses, during which equal volumes of the tested drug were administered slowly into each nostril. In study 2 the onset of action, duration and quality of sedation induced by each drug at its effective dose were evaluated. The efficacy of flumazenil and yohimbine in antagonizing the effects of the sedative drugs was also studied. RESULTS: In study 1 administration of 25 microL per nostril diazepam (5 mg mL(-1) solution) or midazolam (5 mg mL(-1) solution) to each bird caused adequate sedation within 1-2 minutes; birds did not move when placed in dorsal recumbency. After administration of 12 microL per nostril of either xylazine (20 mg mL(-1)) or detomidine (10 mg mL(-1)), birds seemed heavily sedated and assumed sternal recumbency but could not be placed in dorsal recumbency. Higher doses of xylazine (0.5 mg per nostril) or detomidine (0.25 mg per nostril) prolonged sedation but did not produce dorsal recumbency. In study 2 in all treatment groups, onset of action was rapid. Duration of dorsal recumbency was significantly longer (p < 0.05) with diazepam (38.4 +/- 10.5 minutes) than midazolam (17.1 +/- 2.2 minutes). Intranasal flumazenil (2.5 microg per nostril) significantly reduced recumbency time. Duration of sedation was longer with alpha(2)-agonists compared with benzodiazepines. Detomidine had the longest duration of effect (257.5 +/- 1.5 minutes) and midazolam the shortest (36.9 +/- 2.4 minutes). Nasally administered flumazenil significantly reduced the duration of sedation with diazepam and midazolam while yohimbine (120 microg per nostril) effectively antagonized the effects of xylazine and detomidine. CONCLUSION: Intranasal benzodiazepines produce rapid and effective sedation in canaries. Intranasal alpha(2) agonists produce sedation but not sustained recumbency. Specific antagonists are also effective when used by this route. Clinical relevance Intranasal sedative drug administration is an acceptable alternative method of drug delivery in canaries.

Vivarelli, R., F. Zanotti, et al. (1998). "[Premedication with intranasal midazolam in children of various ages]." Minerva Anestesiol 64(11): 499-504.

            BACKGROUND AND AIM: To evaluate the efficacy of premedication with midazolam (mdz) administered using a nasal route compared to diazepam (dz) administered by mouth in children of different ages. EXPERIMENTAL DESIGN: A comparative type study was performed in randomly selected pediatric patients undergoing surgery. The study lasted 3 months. SETTING: Recovery room and operating theatre for Pediatric Surgery and ENT. PATIENTS: A total of 248 patients were studied, divided into 3 age groups: group A were aged under 2 years; group B were pre-school age and group C were school-age. OPERATIONS: Two subgroups were formed based on the premedication used: group M = 0.2 mg/kg of mdz using a nasal route on arrival in the operating unit; group D = 0.2 mg/kg of dz per os 45' before induction. PARAMETERS STUDIED: In addition to acceptance of treatment, which was deemed to be good, poor or refused, the authors evaluated the level of sedation (score from 5 to 1: awake-asleep), anxiety on entering SO (score from 1 to 4: none-excessive) and the level of collaboration during the induction of general anesthesia (score 1-4: excellent-nil). RESULTS: The nasal route was well accepted by 59% of patients in group A, 62% of group B and 97% of group C. Statistical analysis using Kruskall Wallis test showed significant differences in groups A and B between the two subgroups M and D for all the parameters studied, whereas there were no significant differences in group C. CONCLUSIONS: Premedication with mdz using a nasal route was safe and efficacious, above all in early and later infancy.

Wang, S. S., M. Z. Zhang, et al. (2014). "The sedative effects and the attenuation of cardiovascular and arousal responses during anesthesia induction and intubation in pediatric patients: a randomized comparison between two different doses of preoperative intranasal dexmedetomidine." Paediatr Anaesth 24(3): 275-281.

OBJECTIVE: Premedication with intranasal dexmedetomidine (DEX) has shown to be an effective sedative in pediatric patients. This prospective, randomized, and controlled investigation was designed to evaluate whether the difference in intranasal DEX dosing would produce different beneficial effects on the attenuation of cardiovascular and arousal responses during anesthesia induction and intubation. METHODS: Forty children, aged from 3 to 6 years, of American Society of Anesthesiologists physical status I or II and scheduled for elective adenotonsillectomy randomly received intranasal DEX 1 mug.kg(-1) (group D1) or 2 mug.kg(-1) (group D2) 30 min before anesthesia induction. Anesthesia was induced with sevoflurane in oxygen flow. Mean arterial pressure (MAP) and heart rate (HR) as measurements of cardiovascular response and bispectral index (BIS) as an index of arousal response were recorded every 5 min after intranasal DEX administration and measured every 1 min for 5 min after intubation. Sedation status, behavior scores, and mask induction scores were also assessed. RESULTS: Mean arterial pressure did not show statistical differences during the anesthesia induction, but did demonstrate significantly milder responses to laryngoscopy and intubation in group D2 compared with group D1. Change in HR was consistent with MAP during laryngoscopy and intubation. Patients who received 2 mug.kg(-1) DEX presented with deeper sedation and less anxiety by the assessments of the alertness scale, behavior score, and BIS scores. Group D2 dosing achieved more favorable scores in children undergoing mask induction. CONCLUSION: Intranasal DEX 2 mug.kg(-1) administered 30 min before anesthesia induction provides considerable effect to attenuate the increase in MAP caused by intubation response. Changes in HR and BIS also demonstrate that this kind of premedication provides effective attenuation of intubation response. And preoperative intranasal DEX 2 mug.kg(-1) produces optimal-sedation, more favorable anesthesia induction course in pediatric patients. Premedication of intranasal DEX is a considerable way to blunt cardiovascular and arousal responses to endotracheal intubation.

Weber, Wulf, et al. (2003). "Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children." Can J Anaesth 50(5): 470-5.

            PURPOSE: To evaluate the efficacy and safety of intranasally administered s-ketamine and midazolam for premedication in pediatric patients. METHODS: Ninety children were randomly allocated to receive intranasally administered s-ketamine 1 mg.kg(-1) and midazolam 0.2 mg.kg(-1) (Group K1, n = 30), s-ketamine 2 mg.kg(-1) and midazolam 0.2 mg.kg(-1) (Group K2, n = 30), or midazolam 0.2 mg.kg(-1) (Group M, n = 30) as premedicants, using a double-blind study design. Sedation and anxiolysis were evaluated using a sedation and cooperation scale and recorded at several time points. RESULTS: Acceptable conditions (K1: 23; K2: 26, M: 19) for parental separation were not different between groups. Induction conditions were acceptable in 26 patients in K2 (P < 0.05 vs M) (K1: 23; M: 19). Compared to baseline values individual conditions significantly improved in groups K1 and K2 from 2.5 min after premedication until induction of anesthesia (P < 0.003), in group M conditions improved only five minutes after premedication (P < 0.05). Adverse effects observed in this series were within an acceptable range and similar for the three groups. CONCLUSION: Intranasal administration of s-ketamine and midazolam is an appropriate premedication in preschool children.

Weber, Wulf, et al. (2004). "S-ketamine and s-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children." Paediatr Anaesth 14(12): 983-8.

            BACKGROUND: It has been suggested that nasal administration of s-ketamine may be used to improve sedation or premedication in combination with nasal midazolam in pediatric patients. In this study we measured and compared plasma concentrations of s-ketamine and its main metabolite s-norketamine after nasal and i.v. administration in preschool children. METHODS: During sevoflurane anaesthesia, 20 children, aged 1-7 years, weight 11-25 kg, received s-ketamine 2 mg x kg(-1) either intranasally (Group IN, n = 10), or i.v. (Group IV, n = 10). Six venous blood samples were obtained up to 60 min after drug administration for measurement of s-ketamine and s-norketamine plasma concentrations. RESULTS: Plasma concentrations [mean +/- sd] of s-ketamine in group IN peaked at 355 +/- 172 ng x ml(-1) within 18 +/- 13 min vs. 1860 +/- 883 ng x ml(-1) within 3 +/- 1 min in group IV (P < 0.01). Plasma concentrations of s-norketamine in group IN peaked at 90 +/- 128 ng x ml(-1) within 50 +/- 11 min vs. 429 +/- 277 ng x ml(-1) within 40 +/- 16 min in group IV (P < 0.01). One child in group IN experienced rapid and high level s-ketamine absorption with a peak plasma concentration of 732 ng x ml(-1) after 2 min, which decreased to 274 ng x ml(-1) after 60 min. Systolic blood pressure and heart rate remained unaltered in both study groups after s-ketamine administration. CONCLUSIONS: Nasal administration of s-ketamine 2 mg x kg(-1) results in a wide spread of plasma concentrations and absorption times. Rapid and high level drug absorption after nasal drug administration is possible. The use of a pulse oximeter and continuous observation after nasal administration of s-ketamine for pediatric premedication is recommended.

Weber, E. R., D. Holida, et al. (1995). "New routes in pediatric sedation: a research-based protocol for intranasal midazolam." J Nurs Care Qual 10(1): 55-60.

            The quality assurance and improvement committee on a general pediatric unit identified a problem with sedation for neuroradiologic studies. Twenty-three percent of children (n = 63) failed to sedate with one dose of chloral hydrate, resulting in delays or cancellations. For children receiving a second dose of chloral hydrate, average time to study completion was 97 minutes, and 70 percent of the children (n = 10) were successfully sedated. A protocol was developed for the use of intranasal midazolam as the follow-up agent. Evaluation on a pilot unit revealed that the average time to test completion decreased to 55 minutes and that the success rate was 82 percent (n = 11). The nursing staff prefer the use of intranasal midazolam as the follow-up agent because of its quicker sedation and decreased duration of action.

Weksler, N., L. Ovadia, et al. (1993). "Nasal ketamine for paediatric premedication." Can J Anaesth 40(2): 119-21.

            Ketamine in a dose of 6 mg.kg-1 was nasally administered in 86 healthy children (ASA I and II), aged from two to five years undergoing elective general, urological or plastic surgery, 20 to 40 min before the scheduled surgery time. These children were compared with 62 others, also aged from two to five years, in whom promethazine and meperidine, 1 mg.kg-1 of each, were injected im. Sedation was started as excellent in 48 and as adequate in 19 children in the ketamine group, compared with nine and 12 respectively in Group 2 (P 0.05), while salivation was similar in both groups. We conclude that nasal ketamine is an alternative to im preanaesthetic sedation administration in children aged from two to five years.

Wilton, N. C., J. Leigh, et al. (1988). "Preanesthetic sedation of preschool children using intranasal midazolam." Anesthesiology 69(6): 972-5.

Wolfe, T. R. and T. Bernstone (2004). "Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases." J Emerg Nurs 30(2): 141-7.

Wood, M. (2010). "The safety and efficacy of intranasal midazolam sedation combined with inhalation sedation with nitrous oxide and oxygen in paediatric dental patients as an alternative to general anaesthesia." SAAD Dig 26: 12-22.

            INTRODUCTION: Conscious Decision' was published in 2000 by the Department of Health, effectively ending the provision of dental general anaesthesia (DGA) outside the hospital environment. Other aspects of dental anxiety and behavioural management and sedation techniques were encouraged before the decision to refer for a DGA was reached. Although some anxious children may be managed with relative analgesia (RA), some may require different sedation techniques for dentists to accomplish dental treatment. Little evidence has been published in the UK to support the use of alternative sedation techniques in children. This paper presents another option using an alternative conscious sedation technique. AIM: to determine whether a combination of intranasal midazolam (IN) and inhalation sedation with nitrous oxide and oxygen is a safe and practical alternative to DGA. STUDY DESIGN: A prospective clinical audit of 100 cases was carried out on children referred to a centre for DGA. METHOD: 100 children between 3 and 13 years of age who were referred for DGA were treated using this technique. Sedation was performed by intranasal midazolam followed by titrating a mixture of nitrous oxide and oxygen. A range of dental procedures was carried out while the children were sedated. Parents were present during the dental treatment. Data related to the patient, dentistry and treatment as well as sedation variables were collected at the treatment visit and a telephonic post-operative assessment from the parents was completed a week later. RESULTS: It was found that 96% of the required dental treatment was completed successfully using this technique, with parents finding this technique acceptable in 93% of cases. 50% of children found the intranasal administration of the midazolam acceptable. There was no clinically relevant oxygen desaturation during the procedure. Patients were haemodynamically stable and verbal contact was maintained throughout the procedure. CONCLUSIONS: In selected cases this technique provides a safe and effective alternative to DGA and could reduce the number of patients referred to hospitals for DGA. It is recommended that this technique should only be used by dentists skilled in sedation with the appropriate staff and equipment at their disposal.

Xu, Y., X. Song, et al. (2014). "[ED50 of dexmedetomidine nasal drip in induction of hypnosis in children during computed tomography]." Zhonghua Yi Xue Za Zhi 94(24): 1886-1888.

OBJECTIVE: To explore the 50% effective dose (ED(5)(0)) of dexmedetomidine nasal drip in the induction of hypnosis in children during computed tomography (CT). METHODS: A total of 34 American Society of Anesthesiologists (ASA)I-IIautistic children scheduled for brain CT examination were studied. The induction was made by dexmedetomidine nasal drip and the ED(5)(0) of dexmedetomidine determined by up-and down sequential experiment.When eyelash reflex became lost or Ramsay score was >/= 4 in 1 hour after dosing, hypnosis was achieved. The study ended after 8 crossovers (successive "accept" and "refuse"). RESULTS: Among them, the ED(5)(0) of dexmedetomidine was 1.76 microg/kg (95% confident interval:1.64-1.88 microg/kg). CONCLUSION: The ED(5)(0) of dexmedetomidine nasal drip is 1.76 microg/kg in the induction of hypnosis in children.

Yanagihara, Ohtani, et al. (2003). "Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers." Biopharm Drug Dispos 24(1): 37-43.

                Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.

Yao, Y., B. Qian, et al. (2014). "Intranasal dexmedetomidine premedication reduces the minimum alveolar concentration of sevoflurane for tracheal intubation in children: a randomized trial." J Clin Anesth 26(4): 309-314.

STUDY OBJECTIVE: To determine the effects of dexmedetomidine premedication on the minimum alveolar concentration of sevoflurane for tracheal intubation (MACTI) in children. DESIGN: Prospective, randomized, clinical comparison study. SETTING: Operating room of an academic hospital. PATIENTS: 90 pediatric, ASA physical status 1 patients, aged 3 to 7 years, scheduled for minor elective surgery. INTERVENTIONS: Patients were randomized to three groups to receive placebo, dexmedetomidine 1 mug/kg, or dexmedetomidine 2 mug/kg approximately 60 minutes before anesthesia. Anesthesia was induced with sevoflurane. Each concentration of sevoflurane for which a tracheal intubation was attempted was predetermined according to modification of the Dixon's up-and-down method, with 0.25% as a step size and held constant for at least 15 minutes before tracheal intubation. All responses ("movement" or "no movement") to tracheal intubation were assessed. MEASUREMENTS AND MAIN RESULTS: The MACTI of sevoflurane was 2.82% +/- 0.17% in the control group, 2.26% +/- 0.18% in the 1 mug/kg dexmedetomidine group, and 1.83% +/- 0.16% in the 2 mug/kg dexmedetomidine group. Dexmedetomidine premedication (1 and 2 mug/kg) decreased the MACTI of sevoflurane by 20% and 35%, respectively. There were no clinically significant episodes of hypotension or bradycardia in any patients. CONCLUSION: Intranasal dexmedetomidine premedication produces a dose-dependent decrease in the concentration of sevoflurane needed for tracheal intubation in children.

Yao, Y., B. Qian, et al. (2015). "Intranasal dexmedetomidine premedication reduces minimum alveolar concentration of sevoflurane for laryngeal mask airway insertion and emergence delirium in children: a prospective, randomized, double-blind, placebo-controlled trial." Paediatr Anaesth 25(5): 492-498.

                BACKGROUND: We conducted a prospective, randomized, double-blind, placebo-controlled study to verify the hypothesis that intranasal dexmedetomidine premedication can reduce the minimum alveolar concentration of sevoflurane for laryngeal mask airway insertion in children. METHODS: Ninety American Society of Anesthesiologists (ASA) physical status I subjects, aged 3-7 years, were randomized to three equal groups to receive saline (Group S), dexmedetomidine 1 mug . kg(-1) (Group D1 ), or dexmedetomidine 2 mug . kg(-1) (Group D2 ) approximately 45 min before anesthesia. The minimum alveolar concentration for laryngeal mask airway insertion of sevoflurane was determined according to the Dixon's up-and-down method. Emergence delirium was evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale in the postanesthesia care unit (PACU). RESULTS: Dexmedetomidine premedication of 1 and 2 mug . kg(-1) was associated with reduction in sevoflurane from 1.92% to 1.53% and 1.23%, corresponding to decrease of 20% and 36%, respectively. The peak PAED scores (median [IQR]) were 9 [8-11.5], 5 [3-5.3], and 3 [2-4] in Group S, Group D1, and Group D2 , respectively. The incidence of emergence delirium (defined as peak PAED score >/= 10) was significantly lower in Groups D1 and D2 than in Group S (P < 0.001). Simultaneously, the induction qualities and the parent's satisfaction scores were significantly higher in Groups D1 and D2 than in Group S (P < 0.001). CONCLUSION: Intranasal dexmedetomidine premedication produces a dose-dependent decrease in the minimum alveolar concentration for laryngeal mask airway insertion of sevoflurane and emergence delirium in the PACU.

Yealy, D. M., J. H. Ellis, et al. (1992). "Intranasal midazolam as a sedative for children during laceration repair." Am J Emerg Med 10(6): 584-7.

            We performed a retrospective chart review to determine the onset, duration, safety, and clinical sedative effects of 0.2 to 0.5 mg/kg intranasal midazolam in young children during laceration repair. Of 408 children treated for lacerations during an 8-month period, 42 (10%) received intranasal midazolam. Documentation was adequate for detailed analysis in 40 cases. Data are reported as mean +/- standard deviation and the frequency with 95% confidence limit (CL) estimates. The mean age of the study population was 32 +/- 9 months (range 12 months to 6 years), and the mean body mass was 14.5 +/- 3 kg. Topical or injected local anesthesia was used in 37 cases. Overall, 73% (CL 56% to 85%) of the children achieved adequate sedation. However, those receiving 0.2 to 0.29 mg/kg had adequate sedation in only 27% (CL 6% to 60%) of the cases compared with 80% (CL 52% to 95%) and 100% (CL 79% to 100%) when 0.3 to 0.39 and 0.4 to 0.5 mg/kg respectively were administered. When achieved, sedation occurred within 12 +/- 4 minutes, recovery occurred at 41 +/- 9 minutes, and discharge occurred at 56 +/- 11 minutes. No vomiting or clinically significant oxygen desaturation (defined as a drop of &gt; 4% or to &lt; 91%) was observed. We conclude that intranasal midazolam is a safe and effective sedative for laceration repair under local anesthesia in preschool-aged children. We recommend a dose of 0.3 to 0.5 mg/kg, with treatment failure less likely after 0.4 to 0.5 mg/kg compared with less than 0.3 mg/kg.

Yoo, H., T. Iirola, et al. (2015). "Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects." Eur J Clin Pharmacol.

                PURPOSE: Dexmedetomidine is an alpha2-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects. METHOD: Single doses of 84 mug of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data (Eur J Clin Pharmacol 67: 825, 2011). RESULTS: Pharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82 %. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects. CONCLUSION: The comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC 50 values) than cardiovascular effects of dexmedetomidine.

 

Yuen, V. M., T. W. Hui, et al. (2008). "A comparison of intranasal dexmedetomidine and oral midazolam for premedication in pediatric anesthesia: a double-blinded randomized controlled trial." Anesth Analg 106(6): 1715-21.

            BACKGROUND: Midazolam is the most commonly used premedication in children. It has been shown to be more effective than parental presence or placebo in reducing anxiety and improving compliance at induction of anesthesia. Clonidine, an alpha(2) agonist, has been suggested as an alternative. Dexmedetomidine is a more alpha(2) selective drug with more favorable pharmacokinetic properties than clonidine. We designed this prospective, randomized, double-blind, controlled trial to evaluate whether intranasal dexmedetomidine is as effective as oral midazolam for premedication in children. METHODS: Ninety-six children of ASA physical status I or II scheduled for elective minor surgery were randomly assigned to one of three groups. Group M received midazolam 0.5 mg/kg in acetaminophen syrup and intranasal placebo. Group D0.5 and Group D1 received intranasal dexmedetomidine 0.5 or 1 microg/kg, respectively, and acetaminophen syrup. Patients' sedation status, behavior scores, blood pressure, heart rate, and oxygen saturation were recorded by an observer until induction of anesthesia. Recovery characteristics were also recorded. RESULTS: There were no significant differences in parental separation acceptance, behavior score at induction and wake-up behavior score. When compared with group M, patients in group D0.5 and D1 were significantly more sedated when they were separated from their parents (P < 0.001). Patients from group D1 were significantly more sedated at induction of anesthesia when compared with group M (P = 0.016). CONCLUSIONS: Intranasal dexmedetomidine produces more sedation than oral midazolam, but with similar and acceptable cooperation.

Yuen, V. M., T. W. Hui, et al. (2010). "Optimal timing for the administration of intranasal dexmedetomidine for premedication in children." Anaesthesia.

Summary Previous studies have shown that 1 mug.kg(-1) intranasal dexmedetomidine produces significant sedation in children aged between 2 and 12 years. This investigation was designed to evaluate the onset time. One hundred children aged 1-12 years of ASA physical status 1-2 undergoing elective surgery were randomly allocated to five groups. Patients in groups A to D received intranasal dexmedetomidine 1 mug.kg(-1). Patients in Group E received intranasal placebo (0.9% saline). Children from groups A, B, C, D and E had intravenous cannulation attempted at 30, 45, 60, 75 and 45 min respectively after intranasal drug or placebo administration. Vital signs, behaviour and sedation status of the children were assessed regularly until induction of anaesthesia. More children from groups A to D achieved satisfactory sedation at the time of cannulation when compared to group E (p < 0.001). The proportion of children who achieved satisfactory sedation was not significantly different among groups A to D. Overall 62% of the children who received intranasal dexmedetomidine had satisfactory sedation at the time of cannulation. The median (95% CI) time for onset of sedation was 25 (25-30) min. The median (95% CI) duration of sedation was 85 (55-100) min.

Zedie, N., D. W. Amory, et al. (1996). "Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients." Clin Pharmacol Ther 59(3): 341-8.

            BACKGROUND: Intranasally administered midazolam was compared with sufentanil as a premedicant for 60 patients, aged 1/2 to 6 years, undergoing outpatient surgery of 2 hours or less. METHODS: Thirty minutes before anesthetic induction (halothane in 50% nitrous oxide/oxygen), patients were randomly assigned to receive either intranasal midazolam (0.2 mg/kg) or sufentanil (2 microg/kg). A &quot;blinded&quot; observer evaluated preoperative emotional state, response to premedication, induction, and emergence from anesthesia and side effects. RESULTS: Children who had not previously cried were more likely to cry when midazolam was administered compared with sufentanil (71% versus 20%, p = 0.0031). Of 31 midazolam patients, 20 experienced nasal irritation. Approximately 15 to 20 minutes after drug administration, most patients in both groups could be comfortably separated from their parents. The sufentanil group appeared to be more sedated and more cooperative during induction of anesthesia. Vital signs and oxygen saturation did not change significantly with either medication before or after surgery, although two sufentanil patients had a moderate reduction in ventilatory compliance after anesthetic induction. Sufentanil was associated with more nausea and vomiting than midazolam (34% versus 6%, p &lt; 0.02). CONCLUSION: Both intranasal midazolam and sufentanil provide rapid, safe, and effective sedation in small children before anesthesia for ambulatory surgery. Sufentanil provided somewhat better conditions for induction and emergence. Midazolam causes more nasal irritation during instillation, and sufentanil causes more postoperative nausea and vomiting. Both drugs enabled patients to be separated from their parents with a minimum of distress. Patients in the midazolam group were discharged approximately 40 minutes earlier (p &lt;0.005).

Zhang, X., X. Bai, et al. (2013). "The safety and efficacy of intranasal dexmedetomidine during electrochemotherapy for facial vascular malformation: a double-blind, randomized clinical trial." J Oral Maxillofac Surg 71(11): 1835-1842.

PURPOSE: Intranasal dexmedetomidine is noninvasive and has been reported as premedication for children undergoing surgery. The aim of this study was to evaluate the safety and efficacy of intranasal dexmedetomidine during electrochemotherapy for facial vascular malformation under local anesthesia. MATERIALS AND METHODS: A placebo-controlled randomized clinical trial was designed. Patients with facial vascular malformation scheduled for electrochemotherapy under local anesthesia were randomly assigned to 1 of 3 groups (group IN, IV, or C). Patients in group IN received dexmedetomidine 1 mug/kg intranasally. Patients in group IV received dexmedetomidine 1 mug/kg intravenously. Patients in group C received 0.9% saline intranasally and intravenously. Sedation status and vital signs were assessed at baseline, 15 and 30 minutes after drug administration, before surgery, and 15 minutes after the start of surgery. Midazolam was used as a rescue. Data were analyzed by 2-way repeated measures analysis of variance. RESULTS: Sixty patients with American Society of Anesthesiologists physical status I or II were enrolled. Patients in groups IN and IV were significantly more sedated than those in group C before the beginning of surgery (P < .001 for the 2 comparisons). After nasal administration, adequate sedation was achieved within 30 to 45 minutes. In group IV, the onset of sedation was 15 to 20 minutes. There were no clinically significant adverse effects. CONCLUSIONS: Intranasal dexmedetomidine has a sedative effect under local anesthesia and offers a noninvasive, better-tolerated alternative to intravenous administration.

Zhang, W., Z. Wang, et al. (2015). "Comparison of rescue techniques for failed chloral hydrate sedation for magnetic resonance imaging scans-additional chloral hydrate vs intranasal dexmedetomidine." Paediatr Anaesth.

          BACKGROUND: Chloral hydrate, a commonly used sedative in children during noninvasive diagnostic procedures, is associated with side effects like prolonged sedation, paradoxical excitement, delirium, and unpleasant taste. Dexmedetomidine, a highly selective alpha-2 agonist, has better pharmacokinetic properties than chloral hydrate. We conducted this prospective, double-blind, randomized controlled trial to evaluate efficacy of intranasal dexmedetomidine with that of a second oral dose of chloral hydrate for rescue sedation during magnetic resonance imaging (MRI) studies in infants. METHODS: One hundred and fifty infants (age group: 1-6 months), who were not adequately sedated after initial oral dose of 50 mg.kg-1 chloral hydrate, were randomly divided into three groups with the following protocol for each group. Group C: second oral dose chloral hydrate 25 mg.kg-1 ; Group L and Group H: intranasal dexmedetomidine in a dosage of 1 and 2 mcg.kg-1 , respectively. Status of sedation, induction time, time to wake up, vital signs, oxygen saturation, and recovery characteristics were recorded. RESULTS: Successful rescue sedation in Groups C, L, and H were achieved in 40 (80%), 47 (94%), and 49 (98%) of infants, respectively, on an intention to treat analysis, and the proportion of infants successfully sedated in Group H was more than that of Group L (P < 0.01). There were no significant differences in sedation induction time; however, the time to wake up was significantly shorter in Group L as compared to that in Group C or H (P < 0.01). No significant adverse hemodynamic or hypoxemic effects were observed in the study. CONCLUSION: Intranasal dexmedetomidine induced satisfactory rescue sedation in 1- to 6-month-old infants during MRI study, and appears to cause sedation in a dose-dependent manner.

Zhang, W., Y. Fan, et al. (2016). "Median Effective Dose of Intranasal Dexmedetomidine for Rescue Sedation in Pediatric Patients Undergoing Magnetic Resonance Imaging." Anesthesiology.

BACKGROUND: The median effective dose (ED50) of intranasal dexmedetomidine after failed chloral hydrate sedation has not been described for children. This study aims to determine the ED50 of intranasal dexmedetomidine for rescue sedation in children aged 1 to 36 months, who were inadequately sedated by chloral hydrate administration during magnetic resonance imaging (MRI). METHODS: This study was performed on 120 children, who were 1 to 36 months old and underwent MRI scanning. Intranasal dexmedetomidine was administered as a rescue sedative to children not adequately sedated after the initial oral dose of chloral hydrate (50 mg/kg). Children were stratified into four age groups. ED50 values were estimated from the up-and-down method of Dixon and Massey and probit regression. Other variables included induction time, time to wake up, vital signs, oxygen saturation, MRI scanning time, and recovery characteristics. RESULTS: ED50 of intranasal dexmedetomidine for rescue sedation was 0.4 mug/kg (95% CI, 0.34 to 0.50) in children aged 1 to 6 months, 0.5 mug/kg (95% CI, 0.48 to 0.56) in children aged 7 to 12 months, 0.9 mug/kg (95% CI, 0.83 to 0.89) in children aged 13 to 24 months, and 1.0 mug/kg (95% CI, 0.94 to 1.07) in children aged 25 to 36 months. There were no significant differences in sedation induction time or time to wake up between the different age groups. Additionally, no significant adverse hemodynamic or hypoxemic effects were noted. CONCLUSIONS: The authors determined the ED50 for rescue sedation using intranasal dexmedetomidine after failed chloral hydrate sedation in children. It was found that ED50 increases with advancing age during the first 3 yr of life.

Zhang, W., Z. Wang, et al. (2016). "Comparison of rescue techniques for failed chloral hydrate sedation for magnetic resonance imaging scans--additional chloral hydrate vs intranasal dexmedetomidine." Paediatr Anaesth 26(3): 273-279.

BACKGROUND: Chloral hydrate, a commonly used sedative in children during noninvasive diagnostic procedures, is associated with side effects like prolonged sedation, paradoxical excitement, delirium, and unpleasant taste. Dexmedetomidine, a highly selective alpha-2 agonist, has better pharmacokinetic properties than chloral hydrate. We conducted this prospective, double-blind, randomized controlled trial to evaluate efficacy of intranasal dexmedetomidine with that of a second oral dose of chloral hydrate for rescue sedation during magnetic resonance imaging (MRI) studies in infants. METHODS: One hundred and fifty infants (age group: 1-6 months), who were not adequately sedated after initial oral dose of 50 mg . kg(-1) chloral hydrate, were randomly divided into three groups with the following protocol for each group. Group C: second oral dose chloral hydrate 25 mg . kg(-1); Group L and Group H: intranasal dexmedetomidine in a dosage of 1 and 2 mcg . kg(-1), respectively. Status of sedation, induction time, time to wake up, vital signs, oxygen saturation, and recovery characteristics were recorded. RESULTS: Successful rescue sedation in Groups C, L, and H were achieved in 40 (80%), 47 (94%), and 49 (98%) of infants, respectively, on an intention to treat analysis, and the proportion of infants successfully sedated in Group H was more than that of Group L (P < 0.01). There were no significant differences in sedation induction time; however, the time to wake up was significantly shorter in Group L as compared to that in Group C or H (P < 0.01). No significant adverse hemodynamic or hypoxemic effects were observed in the study. CONCLUSION: Intranasal dexmedetomidine induced satisfactory rescue sedation in 1- to 6-month-old infants during MRI study, and appears to cause sedation in a dose-dependent manner.