Therapeutic Intranasal Drug Delivery

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

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

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

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.