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1.  Midazolam Premedication in Children: A Pilot Study Comparing Intramuscular and Intranasal Administration 
Anesthesia Progress  2005;52(2):56-61.
The purpose of this study was to compare the effectiveness of intramuscular and intranasal midazolam used as a premedication before intravenous conscious sedation. Twenty-three children who were scheduled to receive dental treatment under intravenous sedation participated. The patients ranged in age from 2 to 9 years (mean age, 5.13 years) and were randomly assigned to receive a dose of 0.2 mg/kg of midazolam premedication via either intramuscular or intranasal administration. All patients received 50% nitrous oxide and 50% oxygen inhalation sedation and local anesthetic (0.2 mL of 4% prilocaine hydrochloride) before venipuncture. The sedation level, movement, and crying were evaluated at the following time points: 10 minutes after drug administration and at the times of parental separation, passive papoose board restraint, nitrous oxide nasal hood placement, local anesthetic administration, and initial venipuncture attempt. Mean ratings for the behavioral parameters of sedation level, degree of movement, and degree of crying were consistently higher but not significant in the intramuscular midazolam group at all 6 assessment points. Intramuscular midazolam was found to be statistically more effective in providing a better sedation level and less movement at the time of venipuncture than intranasal administration. Our findings indicate a tendency for intramuscular midazolam to be more effective as a premedication before intravenous sedation.
PMCID: PMC2527044  PMID: 16048152
Midazolam; Dentistry; Sedation; Pediatrics; Intramuscular; Intranasal
2.  Sedative Effect of Oral Midazolam/Hydroxyzine versus Chloral Hydrate/Hydroxyzine on 2–6 Year-Old Uncooperative Dental Patients: A Randomized Clinical Trial 
Different drugs are used for conscious sedation in pediatric dentistry either single or in combination. This study assessed the comparative effect of midazolam/hydroxyzine and chloral hydrate/hydroxyzine on 2–6 year-old uncooperative children needing dental treatment.
Materials and Methods:
A double blind cross-over randomized clinical trial was designed and 16 children aged 2–6 years with ASA1 status who were judged with negative to definitely negative behavior (according to Frankl) were chosen. Cases were divided randomly into two groups. The first group received midazolam/hydroxyzine (MH) at the first visit while the second group received chloral hydrate/hydroxyzine (CHH) as the first medication. Both groups received the other regimen at the second visit. Midazolam 0.5mg/kg and chloral hydrate 50mg/kg with 1mg/kg hydroxyzine were administered. Cases were subsequently assessed for sedation and then dental treatment was performed. Blood oxygen saturation (SpO2) and pulse rate (PR) were measured before and after drug administration, as well as during and after dental treatment. The Houpt scale was also used for the level of sedation before, during and after treatment. Data were analyzed using Wilcox-on signed rank test and the paired t-test.
Sedative success rate was 64.3% in cases of MH and 33.3% in CHH. The difference between groups was significant (P=0.046). The success rate was significantly different between groups at different measurement stages as well (P<0.05). No difference was found on the child’s behavior scale based on the type of drugs used first; this indicates no carry-over effect. Comparing the PR and SpO2 values at different readings showed no significant differences.
Midazolam/hydroxyzine showed a significantly higher sedative effect than chloral hydrate/hydroxyzine in this study.
PMCID: PMC4037271  PMID: 24910681
Conscious sedation; Uncooperative child; Dental treatment; Midazolam, Chloral Hydrate; Hydroxyzine
3.  Efficacy of Chloral Hydrate and Promethazine for Sedation during Electroencephalography in Children; a Randomised Clinical Trial 
Iranian Journal of Pediatrics  2013;23(1):27-31.
The purpose of this study was to compare efficacy and safety of oral chloral hydrate (CH) and promethazine (PZ) for sedation during electroencephalography (EEG) in children.
In a parallel single-blinded randomized clinical trial, sixty 1-10 year old children referred to EEG Unit of Shahid Sadoughi Hospital from January 2010 to February 2011 in Yazd, Iran, were evaluated. They were randomized to receive orally 70 mg/kg chloral hydrate or promethazine 1 mg/kg. The primary outcome was efficacy in adequate sedation and successful recording of EEG. Secondary outcome included clinical side effects, time from administration of the drug to adequate sedation, caregiver's satisfaction on a Likert scale, and total stay time in EEG Unit.
Twenty four cases with mean age 2.9±1.9 years were evaluated. Adequate sedation (Ramsay sedation score of four) was obtained in 43.3% of PZ and 100% of CH group (P=0.00001). Also in 70% of PZ and 96.7% of CH group, EEG was successfully recorded (P=0.006). So, CH was a more effective drug. In CH group, EEG was performed in shorter time after taking the drug (32.82±9.6 vs 52.14±22.88 minutes, P<0.001) and the parents waited less in the EEG unit (1.29±0.54 vs 2.6±0.59 hours, P<0.001). They were also more satisfied (4.6±0.6 scores vs 3.1±1.4 scores, P=0.001). Mild side effects such as vomiting in 20% of CH (n = 6) and agitation in 6.6% of PZ group (n = 2) were seen. No significant difference was seen from viewpoint of side effects frequency between the two drugs.
The results of the present study showed that chloral hydrate can be considered as a safe and more effective drug in sedation induction for sleep EEG in children.
PMCID: PMC3574988  PMID: 23550099
Chloral hydrate; Promethazine; EEG; Sedation
4.  Efficacy of Chloral Hydrate-Hydroxyzine and Chloral Hydrate-Midazolam in Pediatric Magnetic Resonance Imaging Sedation 
Magnetic resonance imaging (MRI) is a useful diagnostic tool for the evaluation of congenital or acquired brain lesions. But, in all of less than 8-year-old children, pharmacological agents and procedural sedation should be used to induce motionless conditions for imaging studies. The purpose of this study was to compare the efficacy and safety of combination of chloral hydrate-hydroxyzine (CH+H) and chloral hydrate-midazolam (CH+M) in pediatric MRI sedation.
Materials & Methods
In a parallel single-blinded randomized clinical trial, sixty 1-7-year-old children who underwent brain MRI, were randomly assigned to receive chloral hydrate in a minimum dosage of 40 mg/kg in combination with either 2 mg/kg of hydroxyzine or 0.5 mg/kg of midazolam. The primary outcomes were efficacy of adequate sedation (Ramsay sedation score of five) and completion of MRI examination. The secondary outcome was clinical side-effects.
Twenty-eight girls (46.7%) and 32 boys (53.3%) with the mean age of 2.72±1.58 years were studied. Adequate sedation and completion of MRI were achieved in 76.7% of CH+H group. Mild and transient clinical side-effects, such as vomiting of one child in each group and agitation in 2 (6.6 %) children of CH+M group, were also seen. The adverse events were more frequent in CH+M group.
Combinations of chloral hydrate-hydroxyzine and chloral hydrate-midazolam were effective in pediatric MRI sedation; however, chloral hydrate-hydroxyzine was safer.
PMCID: PMC4058059  PMID: 24949045
Sedation; Children; MRI; Hydroxyzine; chloral hydrate; Midazolam.
5.  Nitrous Oxide Sedation and Bispectral Index 
European journal of dentistry  2007;1(4):240-245.
To determine whether bispectral analysis (BIS) changes during nitrous oxide (N2O) sedation in anxious children undergoing extraction of primary teeth.
In this prospective study 45, ASA physical status I children, aged between 7 to 12 years and scheduled for primary teeth extraction under N2O/O2 sedation are included. At baseline (T0) and during the sedation procedure (T1-6); BIS levels, Ramsay Sedation Scores (RSS), oxygen saturation (Sp02), and heart rate (HR) were recorded at one-minute intervals. Forty percent N2O in O2 was given by a nasal hood, and N2O concentration was enhanced to 60% in a two-minute period. Paired measurements of BIS levels with Observer’s Assessment of Alertness and Sedation (OAA/S) scores were obtained during sedation procedure.
Since 5 patients refused application of the nasal hood, a total 40 of the original 45 subjects completed the study. Mean age and weight of the children were 9.5 ± 1.4 years and 23.7 ± 9.7 kg, respectively. Nitrous oxide inhalation produced no changes in BIS levels despite a sedation level in OAA/S scores were observed at 40–60% N2O concentrations.
BIS values do not change during N2O/O2 sedation and the BIS monitor is not appropriate to evaluate the depth of sedation provided by N2O/O2 during primary teeth extraction in children.
PMCID: PMC2609910  PMID: 19212474
Nitrous oxide sedation; Bispectral index; Anxiety; Ramsay sedation scale
6.  Combination Effects of Chloral Hydrate and Nitrous Oxide/Oxygen in the Mouse Staircase Test 
Anesthesia Progress  1988;35(3):116-120.
The effects of chloral hydrate and/or nitrous oxide were assessed in the mouse staircase test. In this paradigm, the number of steps ascended is thought to reflect locomotor activity, whereas the number of rears is an index of anxiety. Chloral hydrate alone produced a dose-dependent decrease in the number of rears but no change in the number of steps ascended except at the highest dose. Nitrous oxide alone produced a concentration-related increase in the number of steps ascended but no change in rearing. When the two drugs were combined, nitrous oxide appeared to potentiate the rearing suppressant activity of chloral hydrate. Analysis of our experimental findings suggests that chloral hydrate exerts a specific anxiolytic drug effect that can be potentiated by concurrent treatment with nitrous oxide.
PMCID: PMC2168025  PMID: 3166349
7.  Clinical recovery time from conscious sedation for dental outpatients. 
Anesthesia Progress  2002;49(4):124-127.
For dental outpatients undergoing conscious sedation, recovery from sedation must be sufficient to allow safe discharge home, and many researchers have defined "recovery time" as the time until the patient was permitted to return home after the end of dental treatment. But it is frequently observed that patients remain in the clinic after receiving permission to go home. The present study investigated "clinical recovery time," which is defined as the time until discharge from the clinic after a dental procedure. We analyzed data from 61 outpatients who had received dental treatment under conscious sedation at the Hiroshima University Dental Hospital between January 1998 and December 2000 (nitrous oxide-oxygen inhalation sedation [n = 35], intravenous sedation with midazolam [n = 10], intravenous sedation with propofol [n = 16]). We found that the median clinical recovery time was 40 minutes after nitrous oxide-oxygen sedation, 80 minutes after midazolam sedation, and 52 minutes after propofol sedation. The clinical recovery time was about twice as long as the recovery time described in previous studies. In a comparison of the sedation methods, clinical recovery time differed (P = .0008), being longer in the midazolam sedation group than in the nitrous oxide-oxygen sedation group (P = .018). These results suggest the need for changes in treatment planning for dental outpatients undergoing conscious sedation.
PMCID: PMC2007416  PMID: 12779113
8.  Sleep Inducing for EEG Recording in Children: A Comparison between Oral Midazolam and Chloral Hydrate 
Electroencephalography (EEG) recording is a long duration procedure that needs patient’s cooperation for device setup and performing the procedure. Many children lose their cooperation during this procedure.
Therefore, sedation and sleep are frequently induced using a few agents as pre procedure medication in children before EEG recording. We aimed to compare the sedative effects of oral midazolam versus chloral hydrate before the procedure along with their impacts on EEG recording in children.
Materials & Methods
A randomized trial was carried out to compare the sedative effects of oral midazolam versus chloral hydrate and their impacts on EEG recording in children. A total of 198 children (100 in the midazolam group and 98 in the chloral hydrate group) were enrolled in the study and randomly allocated to receive either oral moidazolam or chloral hydrate.
Oral midazolam had superiority neither in sleep onset latency nor in sleep duration when compared to chloral hydrate. Moreover, the yield of epileptiform discharges in the chloral hydrate group was more than the midazolam group.
The results of this study showed that both chloral hydrate 5% (one ml/kg) and oral midazolam (0.5 mg/kg) could be administered as a pre medication agent for EEG recording in children. However, oral midazolam at this dose had no advantage compared with chloral hydrate.
PMCID: PMC3943082  PMID: 24665284
Chloral hydrate; Oral midazolam; Sleep; Sedation; Electroencephalography; Children
9.  The Effect of Nitrous Oxide Anesthesia on Early Postoperative Opioid Consumption and Pain 
Background and Objectives
Many patients experience moderate to severe postoperative pain. Nitrous oxide exerts analgesia by inhibition of N-Methyl-D-aspartate (NMDA) receptors. Ketamine, another NMDA receptor-antagonist, reduces postoperative opioid consumption and pain. A similar effect of nitrous oxide is plausible, yet understudied. The goal of this study was to determine the effects of nitrous oxide anesthesia on early postsurgical opioid consumption and pain.
This was a retrospective, secondary analysis of the Vitamins In Nitrous Oxide trial, where 500 patients undergoing general anesthesia for noncardiac surgery received 60% nitrous oxide and 125 received no nitrous oxide (otherwise, inclusion/exclusion criteria were identical). Exclusion criteria for this study were regional anesthesia; not extubated after surgery; transfer to ICU; no available PACU record; postsurgical sedation; or treated with naloxone. Primary outcomes were cumulative opioid consumption measured in morphine equivalents and pain scores during the immediate recovery phase.
Four hundred forty-two patients met inclusion criteria. No difference in intraoperative and postoperative opioid consumption was observed between patients who received nitrous oxide (n=353) and patients who did not (n=89). The median [interquartile range] postoperative morphine equivalent dose was 6.7 mg [1.7–14.1] for patients who received nitrous oxide and 6.7 mg [2.1–15.4] for patients who did not (P = 0.73). The maximum pain score was 6 [4–8] for patients who received nitrous oxide versus 6 [3–8] for patients who received nitrous oxide-free anesthesia (P = 0.52). The prevalence of moderate to severe pain was 69% for patients who received nitrous oxide and 68% for patients who did not (P = 0.90).
Nitrous oxide anesthesia was not associated with decreased opioid administration, pain, or incidence of moderate to severe pain in the early postoperative phase.
PMCID: PMC3919543  PMID: 24310050
Analgesia; Nitrous Oxide; Pain; Postoperative; Anesthesia; General
10.  Assessment of recovery from nitrous oxide-oxygen sedation using neuropsychometry. 
Anesthesia Progress  1989;36(1):15-20.
This study measured changes in adult performance following prolonged exposure (90 minutes) to nitrous oxide at psychosedative levels. Using a repeated-measures randomized blind design, experimenters exposed 12 subjects to four treatment combinations. These included: room air for 90 minutes (baseline); 100% oxygen for 90 minutes; nitrous oxide-oxygen sedation for 90 minutes followed by 100% oxygen for 2 minutes; and 90 minutes of nitrous oxide-oxygen sedation followed by 10 minutes of 100% oxygen. Following each treatment, participants were asked to perform six standard neuropsychological tests together with a rating scale measurement where subjects self-evaluated their respective levels of alertness. The tests were: digit span; digit symbol; paced auditory serial addition; controlled word association; letter cancellation; and grooved pegboard. Two-way analysis of variance revealed significant differences between mean scores for treatments on only two tests, grooved pegboard (P less than 0.05) and controlled word association (P less than 0.05). There was also a significant difference in mean scores obtained for the rating scale (P less than 0.001). These findings indicate that psychomotor performance and verbal fluency were affected by prolonged exposure to nitrous oxide even after recovery periods. No impairment of vigilance, immediate memory, or mental tracking could be detected as measured by the other tests. Subjective reports by the subjects accurately reflected their underlying impaired status.
PMCID: PMC2148644  PMID: 2604052
11.  A pilot study of the efficacy of oral midazolam for sedation in pediatric dental patients. 
Anesthesia Progress  1996;43(1):1-8.
Oral midazolam is being used for conscious sedation in dentistry with little documentation assessing its efficacy. In order to accumulate preliminary data, a randomized, double-blind, controlled, crossover, multi-site pilot study was conducted. The objective was to determine if 0.6 mg/kg of oral midazolam was an equally effective or superior means of achieving conscious sedation in the uncooperative pediatric dental patient, compared with a commonly used agent, 50 mg/kg of oral chloral hydrate. Twenty-three children in three clinics who required dentistry with local anesthetic and were determined to exhibit behavior rated as "negative" or "definitely negative" based on the Frankl scale were assessed. They were evaluated with respect to acceptance of medication; initial level of anxiety at each appointment; level of sedation prior to and acceptance of local anesthetic; movement and crying during the procedure; and overall behavior. The results showed that the group randomly assigned to receive midazolam had a significantly greater initial level of anxiety for that appointment (P < 0.02), a finding that could clearly confound further determination of the efficacy of these drugs. Patients given oral midazolam had an increased level of sedation prior to the administration of local anesthetic compared with those given chloral hydrate (P < 0.015). No statistically significant differences were noted in any of the other parameters. The age of the patient was found to have no correlation with the difference in overall behavior (r = -0.09). These preliminary data warrant further clinical trials.
PMCID: PMC2153450  PMID: 10323118
12.  Electromyography: Its Potential as an Adjunct to Other Monitored Parameters During Conscious Sedation in Children Receiving Dental Treatment 
Anesthesia Progress  1990;37(1):11-15.
The purpose of this study was to evaluate the effect of a combination of a low dose of chloral hydrate and hydroxyzine on the frontalis muscle electromyogram in addition to other physiologic parameters in pediatric dental patients. A double blind, two-appointment cross-over design was used. Either a placebo or a combination of chloral hydrate and hydroxyzine was given to children during the first visit with the sequence of placebo/drug conditions being randomly determined. During the second visit, the children received that agent not given during the first visit. Baseline physiologic data was obtained at the beginning of each visit and the physiologic measures were again recorded during topical and local anesthesia administration, high-speed tooth preparation, and at the end of the dental appointment. The results indicated that the frontalis muscle activity and cardiovascular parameters were significantly affected by the drug and dental procedures. Oxygen saturation was least affected. The frontalis muscle appears to be a sensitive physiologic parameter to monitor during conscious sedation as an index of the amount of patient relaxation.
PMCID: PMC2163533  PMID: 2077979
13.  Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures 
Archives of Disease in Childhood  2001;84(6):492-495.
AIMS—To evaluate the efficacy and safety of nitrous oxide for children undergoing painful procedures.
METHODS—Ninety children requiring repeated painful procedures (lumbar puncture, bone marrow aspirate, venous cannulation, or dressing changes) were given nitrous oxide at a variable concentration of 50-70%. Procedure related distress was evaluated using the Observational Scale of Behavioral Distress-Revised (OSBD-R). OSBD-R scores were obtained for each of the following phases of the procedure: phase 1a, waiting period; phase lb, during induction with nitrous oxide; phase 2, during positioning and cleaning of the skin; phase 3, during the painful procedure; and phase 4, immediately following the procedure and withdrawal of nitrous oxide. Side effects were monitored and recorded by a second observer.
RESULTS—OSBD scores reached a maximum during the induction phase with lower scores during subsequent phases. Children over the age of 6 showed a lower level of distress during nitrous oxide administration and the painful procedure. Eighty six per cent of patients had no side effects. The incidence of vomiting, excitement, and dysphoria was 7.8%, 4.4%, and 2% respectively. Eight patients developed oxygen desaturation (SaO2 < 95%), but none developed hypoxia, airway obstruction, or aspiration. Ninety three per cent of patients fulfilled the criteria for conscious sedation, and 65% had no recollection of the procedure. Mean recovery time was three minutes.
CONCLUSIONS—Inhalation of nitrous oxide is effective in alleviating distress during painful procedures, with minimal side effects and short recovery time.

PMCID: PMC1718795  PMID: 11369566
14.  Nitrous Oxide Anesthesia and Plasma Homocysteine in Adolescents 
Anesthesia and analgesia  2011;113(4):843-848.
Nitrous oxide inactivates vitamin B12, inhibits methionine synthase and consequently increases plasma total homocysteine (tHcy). Prolonged exposure to nitrous oxide can lead to neuropathy, spinal cord degeneration and even death in children. We tested the hypothesis that nitrous oxide anesthesia causes a significant increase in plasma tHcy in children.
Twenty-seven children (age 10-18 years) undergoing elective major spine surgery were enrolled and serial plasma samples from 0 – 96 hours after induction were obtained. The anesthetic regimen, including the use of nitrous oxide, was at the discretion of the anesthesiologist. Plasma tHcy was measured using standard enzymatic assays.
The median baseline plasma tHcy concentration was 5.1 μmol/L (3.9 – 8.0 μmol/L, interquartile range) and increased in all patients exposed to nitrous oxide (n=26) by an average of +9.4 μmol/L (geometric mean; 95% CI 7.1 – 12.5 μmol/L) or +228% (mean; 95% CI 178% - 279%). Plasma tHcy peaked between 6-8 hours after induction of anesthesia. One patient who did not receive nitrous oxide had no increase in plasma tHcy. Several patients experienced a several-fold increase in plasma tHcy (max. +567%). The increase in plasma tHcy was strongly correlated with the duration and average concentration of nitrous oxide anesthesia (r= 0.80; p<0.001).
Pediatric patients undergoing nitrous oxide anesthesia develop significantly increased plasma tHcy concentrations. The magnitude of this effect appears to be greater compared to adults; however, the clinical relevance is unknown.
PMCID: PMC3183370  PMID: 21680854
15.  Optimal Initial Dose of Chloral Hydrate in Management of Pediatric Facial Laceration 
Archives of Plastic Surgery  2014;41(1):40-44.
Chloral hydrate (CH) is the primary agent most commonly used for pediatric sedation prior to diagnostic, therapeutic procedures. In the management of pediatric facial laceration, the initial dose of CH has to balance the need for adequate sedation against the need to minimize sedative complications.
A retrospective review of medical records of 834 children who visited our emergency room for facial lacerations from August 2010 to September 2012 was conducted. They were divided into six groups on the basis of the initial dose of CH administered. Further, each group was compared with the standard group (70 to ≤80 mg/kg) with respect to sedation success, augmentation dose, failed sedation, time to procedure, and time of stay.
With respect to the complication rate, only group 1 (range, 40 to ≤50 mg/kg) showed a significantly lower complication rate. In the case of all the other variables considered, there were no significant differences among any of the groups.
An initial CH dose of 48±2 mg/kg does not negatively affect the success rate of sedation or the need for additional sedative during the primary closure of facial lacerations in pediatric patients. Further, lower doses reduce the incidences of adverse effects and do not delay procedure readiness. Therefore, 48±2 mg/kg of CH can be considered the optimal initial dose for pediatric sedation.
PMCID: PMC3915155  PMID: 24511493
Chloral hydrate; Conscious sedation; Infant; Child; Sutures
16.  Success rate of IR midazolam sedation in combination with C-CLAD in pediatric dental patients—a prospective observational study 
PeerJ  2014;2:e254.
Objective. To evaluate the success rate of intra-rectal (IR) midazolam in combination with nitrous oxide/oxygen (N2O) sedation in young uncooperative dental patients when the local anesthesia is delivered by a computerized controlled local anesthetic delivery (C-CLAD).
Study Design. This observational study consisted of 219 uncooperative children (age: 4.3 ± 1.69 y) who received IR midazolam (0.4 mg/kg) and N2O to complete their dental treatment. Measured variables included: child’s pain disruptive behavior during delivery of anesthesia by C-CLAD (CHEOP Scale), child behavior during treatment (Houpt scale), dental procedure performed, and side effects that appeared during treatment.
Results. There was a high level of cooperation (mean score: 6.69 ± 2.1) during administration of local anesthesia. Good-to-excellent behavior was shown by 87% of the children during treatment. Planned treatment was completed by 184 (92%) patients. No statistically significant changes were noticed in the oxygen saturation levels before and after treatment. Children with side effects included 3 (1.3%) with nistagmus, 5 (2.3%) with diplopia, and 18 (8.2%) with hiccups. Three consecutive sedations decreased the overall behavior score by 5.7% compared to the first appointment (p < .05).
Conclusions. IR midazolam-N2O sedation in combination with C-CLAD is very effective for delivery of dental treatment to young uncooperative children.
PMCID: PMC3961156  PMID: 24688838
Apprehensive; Local anesthesia; Dental; Children; Uncooperative
17.  Breath Pentane as a Potential Biomarker for Survival in Hepatic Ischemia and Reperfusion Injury—A Pilot Study 
PLoS ONE  2012;7(9):e44940.
Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation.
Methodology/Principal Findings
Twenty male swine were assigned to two groups: propofol (n = 10) and chloral hydrate groups (n = 10). Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150–360 min) in the chloral hydrate group. All of the swine were alive in the propofol group.
Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation.
PMCID: PMC3439410  PMID: 22984587
18.  Functional Magnetic Resonance Imaging of Hearing-Impaired Children Under Sedation Before Cochlear Implantation 
To investigate functional magnetic resonance imaging (fMRI) in pediatric cochlear implantation candidates with residual hearing who are under sedation for evaluation of auditory function.
During fMRI, subjects heard a random sequence of tones (250−4000 Hz) presented 10 dB above hearing thresholds. Tones were interleaved with silence in a block-periodic fMRI design with 30-second on-off intervals. Twenty-four axial sections (5 mm thick) covering most of the brain were obtained every 3 seconds for a total acquisition time of 5.5 minutes.
Single tertiary academic medical institution.
Severely to profoundly hearing-impaired children (n = 10; mean age, 49.1 months). During fMRI, subjects were awake (n=2) or sedated with pentobarbital sodium if their weight was 10 kg or greater (n=4) or chloral hydrate if their weight was less than 10 kg (n=4).
Main Outcome Measures
Detection of brain activation by fMRI in the primary auditory cortex (A1) in hearing-impaired patients under sedation, and correlation of A1 activation with hearing levels measured after cochlear implantation.
In most subjects, fMRI detected significant levels of activation in the A1 region before cochlear implantation. The improvement in hearing threshold after cochlear implantation correlated strongly (linear regression coefficient, R=0.88) with the amount of activation in the A1 region detected by fMRI before cochlear implantation.
Functional MRI can be considered a means of assessing residual function in the A1 region in sedated hearing-impaired toddlers. With improvements in acquisition, processing, and sedation methods, fMRI may be translated into a prognostic indicator for outcome after cochlear implantation in infants.
PMCID: PMC2763405  PMID: 17638781
19.  A comparison study between ketamine and ketamine-promethazine combination for oral sedation in pediatric dental patients. 
Anesthesia Progress  2002;49(1):14-18.
This study compared the incidence of vomiting and the sedative effectiveness of ketamine to a ketamine-prornethazine combination in pediatric dental patients. Twenty-two patients with American Society of Anesthesiologists' classification I physical status who were between the ages of 21 and 43 months were randomly divided into 2 groups. The control group received 10 mg/kg of ketamine orally, whereas the experimental group received 10 mg/kg of ketamine and 1.1 mg/kg of promethazine orally. Nitrous oxide in oxygen was supplemented between 35 and 50%. Each patient received 1 or 2 quadrants of restoration by one operator. Heart rate, blood pressure, and oxygen saturation were monitored and recorded during the treatment. Crying, alertness, movement, and overall general behavior were rated using the scale by Houpt et al. A dentist-anesthesiologist conducted the vital sign monitoring and behavioral assessment. Ketamine combined with promethazine eliminated the incidence of vomiting. A 2 x 2 chi-square contingency table showed a statistical difference between the 2 groups at P < .05 (control group, 27%; experimental group, 0%). Ketamine alone yielded better sedations than the combined agents as shown by the Mann-Whitney U statistical analysis (P < .05). Ketamine and a ketamine-promethazine combination are effective in the sedation of pediatric dental patients.
PMCID: PMC2007405  PMID: 12779109
20.  Nitrous Oxide Analgesia in Selected Dental Patients 
Anesthesia Progress  1982;29(3):78-80.
Nitrous oxide analgesia is presented as the analgesic method of choice in medically compromised patients. The resemblance between the action of nitrous oxide and that of morphine is emphasized. The combination of the opiate-like action of nitrous oxide with the advantages of an inhalation technique makes it preferable and superior to parenteral opiate administration. It may thus be termed as an inhalation “opiate”.
Since its introduction into clinical use by Wells in 1844 (1), nitrous oxide (N20) has been applied as an anesthetic and analgesic agent in various medical situations, including dentistry (2). The development of equipment affording safe administration of accurate concentrations of either pre-mixed or adjustable N20 and oxygen enabled the application of “relative analgesia” as an important technique in the relief of pain. The pharmacological action and analgesic properties of N20 received renewed interest after Berkowitz et al (3) showed the resemblance between its mode of action and that of opiates. Recent human and animal studies indicated that N20 activates the endogenous opiate system(s) in a manner similar to that of morphine (4). The availability of an analgesic gas which, on the one hand, mimics opiate action whilst on the other hand its administration is continuously adjustable, as opposed to other modes of sedation, makes it into an ideal adjunct in dental procedures. Owing to its minimal side effects, the use of N20 is especially recommended in the management of anxious children and medically compromised patients.
This report presents three illustrative patients in whom nitrous oxide proved to be the drug of choice during dental procedures.
PMCID: PMC2515463  PMID: 6214199
21.  The impacts of nitrous oxide gas on sleep quality during alcohol withdrawal 
BMC Research Notes  2011;4:108.
Poor quality of sleep among alcoholics and persons undergoing alcohol withdrawal has been described as a possible cause of alcohol relapse. It has been suggested earlier that nitrous oxide gas has a significant effect on the signs of alcohol withdrawal syndrome (AWS) and thus might be expected to reduce sleep disturbance during withdrawal. The aim of the present study was to investigate sleep quality during alcohol withdrawal, to evaluate the correlation between sleep quality and the severity of AWS and alcohol craving, and to determine if nitrous oxide treatment does counteract withdrawal's effects on the quality of sleep. Voluntary patients (n = 105) admitted to the A-Clinic detoxification center with AWS were included in the study. The AWS patients were randomly assigned to one of the following 45-minute gas treatments: (1) nitrous oxide/oxygen; (2) normal air/O2; and (3) medical (normal) air. The study was single-blind by design. Sleep quality was assessed after these treatments during the inpatient period; sleep time, sleep efficiency and the fragmentation of sleep were recorded by wrist-worn actigraphs. Severity of AWS was evaluated by the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) and that of alcohol dependence and craving by the Obsessive Compulsive Drinking Scale [OCDS] and the Severity of Alcohol Dependence Data (SADD) questionnaire.
The fragmentation index and the time awake while in bed were both much above the reference values for the Finnish population. These values reflect the restless and disturbed night sleep of the subjects. The only statistically significant effects between the treatment groups were found in the correlations of CIWA-Ar (severity of AWS) scores, OCDS-scores (alcohol craving) and coffee consumption, all of which were positively associated with movement time and negatively with total sleep time and sleep efficiency. The sleep quality of patients treated with nitrous oxide gas did not differ from the sleep quality of those treated with normal air.
The severity of AWS and coffee consumption had the most significant negative impact on sleep quality. According to our results, nitrous oxide gas does not differ from placebo in its effect on sleep quality during alcohol withdrawal.
PMCID: PMC3079658  PMID: 21470436
22.  The effects of idazoxan combined with 30% nitrous oxide on the jaw-opening reflex in the rat. 
Anesthesia Progress  1997;44(3):96-100.
In rats, the jaw-opening reflex is elicited by activation of a nociceptive receptor by the electric stimulation of the tooth pulp. This study was undertaken to assess the effects of 30% nitrous oxide and 30% nitrous oxide with idazoxan, an alpha 2-adrenergic antagonist, on this reflex. Each rat received electric stimulation for the jaw-opening reflex at 3, 5, 7, 10, 15, and 20 min after both the start of inhalation and the withdrawal of 100% oxygen or 30% nitrous oxide in oxygen. Idazoxan, 400 micrograms/ kg, was administered intravenously at the start of the inhalation period. Amplitudes significantly decreased during inhalation of nitrous oxide, but they returned gradually to control levels after cessation of nitrous oxide inhalation. In the cases of 100% oxygen, 100% oxygen with idazoxan, and 30% nitrous oxide in oxygen with idazoxan, amplitudes did not change from controls during and after 30% nitrous oxide inhalation. The latency remained unchanged irrespective of the treatment. Since in rats the degree of inhibition by 30% nitrous oxide in oxygen is partially diminished by administration of idazoxan, we conclude that nitrous oxide affects an alpha 2-adrenergic receptor in the central nervous system.
PMCID: PMC2148931  PMID: 9481969
23.  Choice of Nitrous Oxide and Its Subjective Effects In Light and Moderate Drinkers 
Drug and alcohol dependence  2008;98(1-2):163-168.
Alcohol-drinking status has been shown to modulate the reinforcing and subjective effects of a number of drugs. We have previously published two studies on the modulating effects of alcohol-drinking status on choice for, and subjective effects of, nitrous oxide, but the results were equivocal. Using a methodology different from our previous studies, we sought to determine in a more definitive fashion the degree to which the choice of nitrous oxide and its subjective effects were modulated by drinking status.
Four concentrations of nitrous oxide (0, 20, 30, 40%) were administered to 16 moderate drinkers (MDs) and 16 light drinkers (LDs) across four 3.5-h sessions. During experimental sessions, subjects first completed two 10-min sampling trials in which one of the nitrous oxide concentrations and placebo (100% oxygen) were inhaled. Subjective and psychomotor tests were given 5 min into each sampling trial. During the subsequent choice period, subjects were allowed to choose what they wanted to inhale (drug, placebo, or “drug-free air") on nine contiguous 5-min choice trials.
Choice of nitrous oxide was modulated by drinking status: MDs but not LDs chose nitrous oxide significantly more times than placebo, and MDs also chose nitrous oxide significantly more times than did LDs. At each active nitrous oxide concentration, MDs reported more abuse liability-related subjective effects, especially at the 20% and 30% concentrations.
The results of the present study provide more conclusive evidence that choice as well as subjective effects of nitrous oxide are modulated by alcohol-drinking status.
PMCID: PMC2566819  PMID: 18640794
Nitrous oxide; Preference; Choice; Reinforcing effects; Subjective effects; Psychomotor; Inhalants; Human
24.  Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial 
BMC Anesthesiology  2010;10:14.
Recent studies have questioned our previous understanding on the effect of nitrous oxide on muscle relaxants, since nitrous oxide has been shown to potentiate the action of bolus doses of mivacurium, rocuronium and vecuronium. This study was aimed to investigate the possible effect of nitrous oxide on the infusion requirements of cisatracurium.
70 ASA physical status I-III patients aged 18-75 years were enrolled in this randomized trial. The patients were undergoing elective surgery requiring general anesthesia with a duration of at least 90 minutes. Patients were randomized to receive propofol and remifentanil by target controlled infusion in combination with either a mixture of oxygen and nitrous oxide (Nitrous oxide/TIVA group) or oxygen in air (Air/TIVA group). A 0.1 mg/kg initial bolus of cisatracurium was administered before tracheal intubation, followed by a closed-loop computer controlled infusion of cisatracurium to produce and maintain a 90% neuromuscular block. Cumulative dose requirements of cisatracurium during the 90-min study period after bolus administration were measured and the asymptotic steady state rate of infusion to produce a constant 90% block was determined by applying nonlinear curve fitting to the data on the cumulative dose requirement during the study period.
Controller performance, i.e. the ability of the controller to maintain neuromuscular block constant at the setpoint and patient characteristics were similar in both groups. The administration of nitrous oxide did not affect cisatracurium infusion requirements. The mean steady-state rates of infusion were 0.072 +/- 0.018 and 0.066 +/- 0.017 mg * kg-1 * h-1 in Air/TIVA and Nitrous oxide/TIVA groups, respectively.
Nitrous oxide does not affect the infusion requirements of cisatracurium.
Trial registration NCT01152905; European Clinical Trials Database at
PMCID: PMC2931508  PMID: 20718983
25.  Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation 
Objectives—This study compared intranasal midazolam (INM) with a combination of intravenous ketamine and intravenous midazolam (IVKM) for sedation of children requiring minor procedures in the emergency department.
Method—A single blinded randomised clinical trial was conducted in the emergency department of a major urban paediatric hospital. Subjects requiring sedation for minor procedures were randomised to receive either INM (0.4 mg/kg) or intravenous ketamine (1 mg/kg) plus intravenous midazolam (0.1 mg/kg). Physiological variables and two independent measures of sedation (Sedation Score and Visual Analogue Sedation Scale) were recorded before sedation and at regular intervals during the procedure and recovery period. Times to adequate level of sedation and to discharge were compared.
Results—Fifty three patients were enrolled over a 10 month period. Sedation was sufficient to complete the procedures in all children receiving IVKM and in 24 of the 26 receiving INM. Onset of sedation was an average of 5.3 minutes quicker with IVKM than with INM (95%CI 3.2, 7.4 minutes, p<0.001). Children given INM were discharged an average of 19 minutes earlier than those given IVKM (95%CI 4, 33 minutes, p=0.02). Mean Sedation Scores and Visual Analogue Sedation Scale scores for the 30 minutes after drug administration were significantly better in children given IVKM compared with INM (2.4 and 1.8 versus 3.5 and 3.8, respectively). Both doctors and parents were more satisfied with sedation by intravenous ketamine and midazolam.
Conclusions—Intravenous ketamine plus midazolam used in an appropriate setting by experienced personnel provides an excellent means of achieving sedation suitable for most non-painful minor procedures for children in the emergency department. This combination is superior to INM in terms of speed of onset and consistency of effect. INM delivered via aerosol spray has a more variable effect but may still be adequate for the completion of many of these procedures.
PMCID: PMC1725505  PMID: 11310461

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