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1.  Oral triazolam pretreatment for intravenous sedation. 
Anesthesia Progress  1993;40(4):117-121.
This double-blind, controlled clinical trial assessed the anxiety relief provided by oral triazolam given before intravenous sedation. Twenty-two healthy adults undergoing third-molar surgery with intravenous sedation were enrolled in this study. Subjects were randomly assigned to receive either 0.25 mg of triazolam p.o. or an identically appearing placebo 45 to 60 min before venipuncture. Immediately before test drug administration, subjects completed the Corah Anxiety Scale, a Visual Analog Scale (VAS) assessing state anxiety, and the Interval Scale of Anxiety Response (ISAR). The VAS and ISAR were repeated immediately before venipuncture. Intravenous sedation medications consisted of fentanyl, midazolam, and methohexital. At 24 hr, assessments of the venipuncture and global experience were obtained. Results indicated that the characteristics of the triazolam and placebo patients were similar at baseline. With triazolam pretreatment, both the VAS and ISAR scores decreased significantly. Dose requirements for conscious sedation medications were decreased in the triazolam group. Patients rated the venipuncture experience significantly less unpleasant when pretreated with triazolam, and global ratings of the overall surgical experience favored triazolam. An oral-intravenous combination sedation technique using 0.25 mg of triazolam may have a significant therapeutic advantage for outpatient oral surgery.
PMCID: PMC2148582  PMID: 7943920
2.  Investigation of the usefulness of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function 
Background
Military operation personnel often suffer from sleep difficulty because of their work requirements. In this study, we investigated the efficacy of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function; we subsequently established the optimal dosage regimen for military operation personnel.
Methods
Twenty-two healthy young male volunteers were recruited for the study. Eight subjects took 10 mg or 15 mg of zaleplon and placebo alternately and then were exposed to noise. Changes in polysomnography (PSG) indices, including sleep latency (SL), sleep efficiency (SE) and sleep structure, were recorded after drug administration. After awakening, the volunteers’ subjective judgments of sleep quality and sleepiness were measured. Eight volunteers underwent 3 psychomotor performance tests at a one-week interval, and the psychomotor performance tests were conducted before and after taking zaleplon and placebo. Six volunteers participated in the vestibular function test session, and parameters, including optokinetic nystagmus (OKN), vestibular ocular reflex (VOR), visual-vestibular ocular reflex (VVOR) and vestibular ocular reflex fixation suppression (VOR-Fix), were detected by the same experimental design as described above. The data of sleep observations were subjected to one-way variance analysis.
Results
Compared with the placebo group, SL was shortened significantly, and the scores of subjective sleep quality and sleep depth were clearly increased in the zaleplon 10 mg group (P < 0.05). Moreover, the SE and the percent of REM (rapid eye movement) sleep were increased remarkably in the zaleplon 15 mg group (P < 0.01). Furthermore, the SE, percent of REM sleep and scores of subjective sleep depth in the zaleplon 15 mg group were significantly higher than in the zaleplon 10 mg group (P < 0.05). The psychomotor performance did not change significantly after ingestion of 10 mg or 15 mg of zaleplon, whereas the OKN and VOR gains were lower in the two dose groups of zaleplon (P < 0.05) and restored to normal 3 h after drug ingestion.
Conclusion
Zaleplon is an ideal hypnotic for military personnel, and its hypnotic efficiency is dose-related under noise interference; a 15 mg dose of zaleplon could provide significantly better sleep than a 10 mg dose of zaleplon.
doi:10.1186/s40779-016-0075-4
PMCID: PMC4774104  PMID: 26937286
Insomnia; Sleep; Hypnotic; Zaleplon; Psychomotor performance; Vestibular function
3.  The Clinical and Forensic Toxicology of Z-drugs 
Journal of Medical Toxicology  2013;9(2):155-162.
The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1–7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography–mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.
doi:10.1007/s13181-013-0292-0
PMCID: PMC3657020  PMID: 23404347
Zolpidem; Zopiclone; Zaleplon; Poisoning; Analysis
4.  Preoperative anxiolysis in pediatric population: A comparative study between oral midazolam and oral ketamine 
Context:
Preoperative anxiety is synonymous with pediatric surgery. Anxiolysis is of crucial importance and poses a significant challenge to the pediatric anesthesiologist. Orally administered midazolam and ketamine can be used as anxiolytic premedication in children.
Aim:
To compare the efficacy of orally administered midazolam and ketamine for preoperative sedation and anxiolysis in children and determine the minimum interval required between premedication and parental separation.
Setting and Design:
Prospective, randomized, double-blind study.
Materials and Methods:
A total of 70 children aged 2-8 years, belonging to ASA grade 1 and 2, scheduled to undergo elective infraumbilical and peripheral surgeries were randomized into two groups of 35 each to receive either midazolam (0.5 mg/kg) or ketamine (5 mg/kg) orally. They were assessed at an interval of 5 minutes up to 40 minutes, at the time of parental separation, intravenous cannulation, and application of face mask for ventilation. Sedation was noted according to Ramsay Sedation Scale and anxiolysis was noted according to Anxiolysis Scores used in previous published studies.
Statistical Analysis Used:
Skewed data between groups were analyzed by Mann Whitney U Test. Data within a group were analyzed using Friedman's Analysis of variance and a post hoc test.
Results:
No statistically significant difference in sedation and anxiolysis scores were obtained between the groups at any point of time. Maximum sedation score was achieved at 20 minutes in both the groups, with no statistically significant difference with scores obtained thereafter. Statistically significant difference occurred in anxiolysis score at study points in group receiving midazolam.
Conclusion:
The study documents the rapid achievement of preoperative sedation and anxiolysis in children with orally administered midazolam or ketamine, with the latter producing a superior quality of anxiolysis. An interval of 20 minutes is sufficient between premedication and parental separation.
doi:10.4103/0259-1162.118960
PMCID: PMC4173508  PMID: 25885833
Anxiolysis; ketamine; midazolam; oral; sedation
5.  Comparison of Propofol-Remifentanil Versus Propofol-Ketamine Deep Sedation for Third Molar Surgery 
Anesthesia Progress  2012;59(3):107-117.
This study aimed to compare continuous intravenous infusion combinations of propofol-remifentanil and propofol-ketamine for deep sedation for surgical extraction of all 4 third molars. In a prospective, randomized, double-blinded controlled study, participants received 1 of 2 sedative combinations for deep sedation for the surgery. Both groups initially received midazolam 0.03 mg/kg for baseline sedation. The control group then received a combination of propofol-remifentanil in a ratio of 10 mg propofol to 5 μg of remifentanil per milliliter, and the experimental group received a combination of propofol-ketamine in a ratio of 10 mg of propofol to 2.5 mg of ketamine per milliliter; both were given at an initial propofol infusion rate of 100 μg/kg/min. Each group received an induction loading bolus of 500 μg/kg of the assigned propofol combination along with the appropriate continuous infusion combination . Measured outcomes included emergence and recovery times, various sedation parameters, hemodynamic and respiratory stability, patient and surgeon satisfaction, postoperative course, and associated drug costs. Thirty-seven participants were enrolled in the study. Both groups demonstrated similar sedation parameters and hemodynamic and respiratory stability; however, the ketamine group had prolonged emergence (13.6 ± 6.6 versus 7.1 ± 3.7 minutes, P = .0009) and recovery (42.9 ± 18.7 versus 24.7 ± 7.6 minutes, P = .0004) times. The prolonged recovery profile of continuously infused propofol-ketamine may limit its effectiveness as an alternative to propofol-remifentanil for deep sedation for third molar extraction and perhaps other short oral surgical procedures, especially in the ambulatory dental setting.
doi:10.2344/12-00001.1
PMCID: PMC3468288  PMID: 23050750
Propofol; Ketamine; Remifentanil; Deep sedation; TIVA
6.  Use of triazolam and alprazolam as premedication for general anesthesia 
Korean Journal of Anesthesiology  2015;68(4):346-351.
Background
Triazolam has similar pharmacological properties as other benzodiazepines and is generally used as a sedative to treat insomnia. Alprazolam represents a possible alternative to midazolam for the premedication of surgical patients. The purpose of this study was to evaluate the anxiolytic, sedative, and amnestic properties of triazolam and alprazolam as pre-anesthetic medications.
Methods
Sixty adult patients were randomly allocated to receive oral triazolam 0.25 mg or alprazolam 0.5 mg one hour prior to surgery. A structured assessment interview was performed in the operating room (OR), the recovery room, and the ward. The levels of anxiety and sedation were assessed on a 7-point scale (0 = relaxation to 6 = very severe anxiety) and a 5-point scale (0 = alert to 4 = lack of responsiveness), respectively. The psychomotor performance was estimated using a digit symbol substitution test. As a memory test, we asked the patients the day after the surgery if they remembered being moved from the ward to the OR, and what object we had shown them in the OR.
Results
There were no significant differences between the groups with respect to anxiety and sedation. The postoperative interviews showed that 22.2% of the triazolam-treated patients experienced a loss of memory in the OR, against a 0% memory loss in the alprazolam-treated patients. In comparison with alprazolam 0.5 mg, triazolam 0.25 mg produced a higher incidence of amnesia without causing respiratory depression.
Conclusions
Oral triazolam 0.25 mg can be an effective preanesthetic medication for psychomotor performance.
doi:10.4097/kjae.2015.68.4.346
PMCID: PMC4524932  PMID: 26257846
Alprazolam; Amnesia; Premedication; Triazolam
7.  High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens 
Psychopharmacology  2012;223(1):1-15.
Rationale
Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM.
Objective
This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam.
Methods
Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg/70kg), and placebo were administered to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 hours.
Results
Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis, increases in observer-rated effects typical of classic hallucinogens (e.g. distance from reality, visual effects with eyes open and closed, joy, anxiety), and participant ratings of stimulation (e.g. jittery, nervous), somatic effects (e.g. tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g. psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow up volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences.
Conclusions
High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin.
doi:10.1007/s00213-012-2680-6
PMCID: PMC3652430  PMID: 22526529
Dextromethorphan; Triazolam; Dose effects; Hallucinogen; Psychedelic; Entheogen; Drug abuse; Subjective effects; Mystical experience; Humans
8.  Use of sevoflurane inhalation sedation for outpatient third molar surgery. 
Anesthesia Progress  1999;46(1):21-29.
This study attempted to determine if sevoflurane in oxygen inhaled via a nasal hood as a sole sedative agent would provide an appropriate level of deep sedation for outpatient third molar surgery. Twenty-four patients scheduled for third molar removal were randomly assigned to receive either nasal hood inhalation sevoflurane or an intravenous deep sedation using midazolam and fentanyl followed by a propofol infusion. In addition to measuring patient, surgeon, and dentist anesthesiologist subjective satisfaction with the technique, physiological parameters, amnesia, and psychomotor recovery were also assessed. No statistically significant difference was found between the sevoflurane and midazolam-fentanyl-propofol sedative groups in physiological parameters, degree of amnesia, reported quality of sedation, or patient willingness to again undergo a similar deep sedation. A trend toward earlier recovery in the sevoflurane group was identified. Sevoflurane can be successfully employed as a deep sedative rather than a general anesthetic for extraction of third molars in healthy subjects.
PMCID: PMC2148884  PMID: 10551056
9.  Comparative evaluation of midazolam and butorphanol as oral premedication in pediatric patients 
Background:
To compare oral midazolam (0.5 mg/kg) with oral butorphanol (0.2 mg/kg) as a premedication in 60 pediatric patients with regards to sedation, anxiolysis, rescue analgesic requirement, and recovery profile.
Materials and Methods:
In a double blinded study design, 60 pediatric patients belonging to ASA class I and II between the age group of 2–12 years scheduled for elective surgery were randomized to receive either oral midazolam (group I) or oral butorphanol (group II) 30 min before induction of anesthesia. The children were evaluated for levels of sedation and anxiety at the time of separation from the parents, venepuncture, and at the time of facemask application for induction of anesthesia. Rescue analgesic requirement, postoperative recovery, and complications were also recorded.
Results:
Butorphanol had better sedation potential than oral midazolam with comparable anxiolysis at the time of separation of children from their parents. Midazolam proved to be a better anxiolytic during venepuncture and facemask application. Butorphanol reduced need for supplemental analgesics perioperatively without an increase in side effects such as nausea, vomiting, or unpleasant postoperative recovery.
Conclusion:
Oral butorphanol is a better premedication than midazolam in children in view of its excellent sedative and analgesic properties. It does not increase side effects significantly.
doi:10.4103/0970-9185.92431
PMCID: PMC3275967  PMID: 22345942
Anxiolysis; oral midazolam; oral butorphanol; premedication; pediatric anesthesia; sedation
10.  Noise-induced sleep maintenance insomnia: hypnotic and residual effects of zaleplon 
Aims
The primary objective of the study was to assess the residual effects of zaleplon in the morning, 4 h after a middle-of-the-night administration. The secondary objective was to investigate the effectiveness of zaleplon in promoting sleep in healthy volunteers with noise-induced sleep maintenance insomnia.
Methods
Thirteen healthy male and female volunteers (aged 20–30 years) with normal hearing, who were sensitive to the sleep-disrupting effects of noise, participated in a double-blind, placebo-and active-drug controlled, four-period cross-over study. The subjects were permitted to sleep for 5 h (22.45–03.45 h) in a quiet environment before they were awoken. At 04.00 h they ingested 10 mg zaleplon, 20 mg zaleplon, 7.5 mg zopiclone (active control), or placebo before a second period of sleep (04.00–08.00 h), during which they were exposed to an 80 dB(A) 1 kHz pure tone pulse with an inter-tone interval of 1 s and a duration of 50 ms. The sound stimulus was stopped after 10 min of persistent sleep or after 2 h if the subject had not fallen asleep. Residual effects were assessed at 08.00 h (4 h after drug administration) using the digit symbol substitution test (DSST), choice reaction time (CRT), critical flicker fusion (CFF), and immediate and delayed free recall of a 20 word list. The data were analysed by analysis of variance. A Bonferroni adjustment was made for the three active treatments compared with placebo.
Results
There were no residual effects of zaleplon (10 and 20 mg) compared with placebo. Zopiclone impaired memory by delaying the free recall of words (P = 0.001) and attenuated performance on DSST (P = 0.004) and CRT (P = 0.001), compared with placebo. Zaleplon reduced the latency to persistent sleep (10 mg, P = 0.001; 20 mg, P = 0.014) and the 20 mg dose reduced stage 1 sleep (P = 0.012) compared with placebo. Zopiclone reduced stage 1 sleep (P = 0.001), increased stage 3 sleep (P = 0.0001) and increased total sleep time (P = 0.003), compared with placebo.
Conclusions
Zaleplon (10 mg and 20 mg), administered in the middle of the night 4 h before arising, shortens sleep onset without impairing next-day performance.
doi:10.1046/j.-5251.2001.01520.x
PMCID: PMC1874295  PMID: 11851645
insomnia; noise; residual effects; sleep maintenance; zaleplon; zopiclone
11.  A Randomized Double-Blind Pilot Study to Compare Conscious Sedation Produced by Diazepam Against Sufentanil 
Anesthesia Progress  1987;34(4):137-141.
Intravenous sufentanil, an analog of fentanyl, was compared to diazepam for conscious sedation in ambulatory dental outpatients. Ten patients undergoing the surgical removal of impacted third molars served as subjects in a double-blind, within-subject, single crossover study. Sedation was achieved with a combination of 30% nitrous oxide/70% oxygen by nasal mask and either diazepam (0.05—0.15 mg/kg) or sufentanic (0.05—0.15 μg/kg) titrated to a clinical endpoint of altered speech and relaxation. Intraoperative physiologic monitoring, patients' and the oral surgeon's subjective estimates of efficacy and psychomotor recovery were used to compare the two treatments. Both patients (eight of 10) and surgeons (six of 10) preferred sufentanil sedation. No significant differences were noted between treatments for psychomotor recovery. These preliminary data in a small sample suggest that sufentanil produces adequate conscious sedation in dental outpatients and should be evaluated further with larger patient samples.
PMCID: PMC2186288  PMID: 2964215
12.  Comparison between the recovery time of alfentanil and fentanyl in balanced propofol sedation for gastrointestinal and colonoscopy: a prospective, randomized study 
BMC Gastroenterology  2012;12:164.
Background
There is increasing interest in balanced propofol sedation (BPS) titrated to moderate sedation (conscious sedation) for endoscopic procedures. However, few controlled studies on BPS targeted to deep sedation for diagnostic endoscopy were found. Alfentanil, a rapid and short-acting synthetic analog of fentanyl, appears to offer clinically significant advantages over fentanyl during outpatient anesthesia.
It is reasonable to hypothesize that low dose of alfentanil used in BPS might also result in more rapid recovery as compared with fentanyl.
Methods
A prospective, randomized and double-blinded clinical trial of alfentanil, midazolam and propofol versus fentanyl, midazolam and propofol in 272 outpatients undergoing diagnostic esophagogastroduodenal endoscopy (EGD) and colonoscopy for health examination were enrolled. Randomization was achieved by using the computer-generated random sequence. Each combination regimen was titrated to deep sedation. The recovery time, patient satisfaction, safety and the efficacy and cost benefit between groups were compared.
Results
260 participants were analyzed, 129 in alfentanil group and 131 in fentanyl group. There is no significant difference in sex, age, body weight, BMI and ASA distribution between two groups. Also, there is no significant difference in recovery time, satisfaction score from patients, propofol consumption, awake time from sedation, and sedation-related cardiopulmonary complications between two groups. Though deep sedation was targeted, all cardiopulmonary complications were minor and transient (10.8%, 28/260). No serious adverse events including the use of flumazenil, assisted ventilation, permanent injury or death, and temporary or permanent interruption of procedure were found in both groups. However, fentanyl is New Taiwan Dollar (NT$) 103 (approximate US$ 4) cheaper than alfentanil, leading to a significant difference in total cost between two groups.
Conclusions
This randomized, double-blinded clinical trial showed that there is no significant difference in the recovery time, satisfaction score from patients, propofol consumption, awake time from sedation, and sedation-related cardiopulmonary complications between the two most common sedation regimens for EGD and colonoscopy in our hospital. However, fentanyl is NT$103 (US$ 4) cheaper than alfentanil in each case.
Trial registration
Institutional Review Board of Buddhist Tzu Chi General Hospital (IRB097-18) and Chinese Clinical Trial Registry (ChiCTR-TRC-12002575)
doi:10.1186/1471-230X-12-164
PMCID: PMC3607964  PMID: 23170921
Balanced propofol sedation; Alfentanil; Fentanyl; Deep sedation; Diagnostic endoscopy; Cost benefit
13.  Effect of two Different Concentrations of Propofol and Ketamine Combinations (Ketofol) in Pediatric Patients under Lumbar Puncture or Bone Marrow Aspiration 
Background
Ketamine is an anesthetic drug that is importantly analgesic without respiratory depression. Ketamine increases blood pressure and heart rate. Propofol is an anesthetic drug with good sedation, rapid recovery, but it causes respiratory depression, low heart rate and low blood pressure. Combination of Ketamine and Propofol provides sedation, analgesia and rapid recovery with hemodynamic stability and minimal respiratory depression. The aim of this study was to compare two different combinations of these two drugs to reach necessary sedation scale for the Lp or BMA in pediatric with ALL.
Materials and Methods
This randomized, double blinded study was designed to compare the quality of sedation and side effects of intravenous Ketofol on 60 patients of both gender. Patients received titrated injection of a solution containing combination of one part of Ketamine and two parts of Propofol (1:2) (group I) or one part of Ketamine and three parts of Propofol (1:3) (group II) to reach almost near 5 sedation level (using Ramsay Sedation Scale). Respiratory and hemodynamic profiles, amount of drug injected and side effects were recorded.
Results
These drug combinations were used on 60 children with a median age of 6.2 years. In this study, recovery time and hallucination was significantly high in group I, but in both groups hemodynamic were stable, amnesia was enough, and there was no respiratory depression.
Conclusion
Lower doses of Ketamine in these combinations have lower psycho mimetic side effects, and shorter recovery time.
PMCID: PMC3915440  PMID: 24575262
Ketamine; Propofol; Spinal Puncture; Pediatrics
14.  A Comparison of Fospropofol to Midazolam for Moderate Sedation During Outpatient Dental Procedures 
Anesthesia Progress  2013;60(4):162-177.
Moderate intravenous (IV) sedation combined with local anesthesia is common for outpatient oral surgery procedures. An ideal sedative agent must be safe and well tolerated by patients and practitioners. This study evaluated fospropofol, a relatively new sedative/hypnotic, in comparison to midazolam, a commonly used benzodiazepine, for IV moderate sedation during oral and maxillofacial surgery. Sixty patients were randomly assigned to either the fospropofol or the midazolam group. Each participant received 1 μg/kg of fentanyl prior to administration of the selected sedative. Those in the fospropofol group received an initial dose of 6.5 mg/kg, with 1.6 mg/kg supplemental doses as needed. Those in the midazolam group received initial doses of 0.05 mg/kg, followed by 0.02 mg/kg supplemental doses. The quality of sedation in each patient was evaluated with regard to (a) onset of sedation, maintenance, and recovery profile; (b) patient and surgeon satisfaction; and (c) hemodynamic stability and adverse effects. The fospropofol group demonstrated shorter physical recovery times than midazolam patients, taking a mean of 11.6 minutes versus 18.4 minutes for physical recovery (P = .007). Cognitive recovery comparison did not find any difference with a mean of 7.5 minutes versus 8.8 minutes between the 2 drug groups (P = .123). The fospropofol group had a higher rate of local anesthetic injection recall (90.5 vs 44.4%, P = .004). Other parameters of recall were comparable. Two adverse effects demonstrated significance, with more patients in the midazolam group experiencing tachycardia (48.2 vs 9.4%, P = .001), and more patients in the fospropofol group experiencing perineal discomfort (40.6 vs 0, P < .001). No significant difference was found in any other measures of sedation safety, maintenance, or satisfaction. Fospropofol, when administered intravenously by a dentist anesthesiologist at the indicated dose in this study, appears to be a safe, well-tolerated alternative to midazolam for intravenous moderate sedation during minor oral surgery procedures.
doi:10.2344/0003-3006-60.4.162
PMCID: PMC3891457  PMID: 24423419
Fospropofol; Midazolam; Moderate sedation; Outpatient surgery; IV conscious sedation; Benzodiazepine; Propofol
15.  Patient-controlled sedation with propofol/remifentanil versus propofol/alfentanil for patients undergoing outpatient colonoscopy, a randomized, controlled double-blind study 
Saudi Journal of Anaesthesia  2014;8(Suppl 1):S36-S40.
Context:
Many techniques are used for sedation of colonoscopies. Patient-controlled sedation (PCS) is utilizing many drugs or drug combinations.
Aims:
The aim of this study is to compare the safety and feasibility of propofol/remifentanil versus propofol/alfentanil given to sedate patients undergoing outpatient colonoscopies through a patient-controlled technique.
Settings and Design:
Controlled randomized and double-blind study.
Materials and Methods:
A total of 80 patients were randomly divided into two groups; PA group received a combination of propofol/alfentanil and PR group received propofol/remifentanil combination. Patients were monitored for heart rate (HR), blood pressure (BP), oxygen saturation, and Ramsay sedation scale (RSS). Times of the following events were recorded; initiation of sedation, insertion and removal of the colonoscope, recovery and discharge. Five intervals were calculated; time to sedation, procedure time, postprocedure time, procedure room time, and postanesthesia care unit (PACU) time. Endoscopist and patient satisfaction scores were obtained.
Statistical Analysis Used:
Unpaired Student's t-test was used to compare between the two groups. Paired Student's t-test was used to compare baseline readings with readings after 30 min of sedation in the same group when needed.
Results:
Both groups showed slowing of the HR and decrease in mean arterial BP. HR and mean arterial BP were significantly lower 5 and 10 min after initiation of sedation in PR group when compared with PA group. Both HR and mean arterial BP returned to presedation readings 30 min after initiation of sedation in PR group but not in PA group. No differences between the two groups concerning oxygen saturation, RSS, endoscopist and patient satisfaction scores. Postprocedure and PACU times were significantly prolonged in PA group.
Conclusion:
PCS with either remifentanil/propofol or alfentanil/propofol for patients undergoing outpatient colonoscopy is safe and feasible. Remifentanil/proofol has more beneficial advantages in this setting secondary to its more rapid clearance.
doi:10.4103/1658-354X.144068
PMCID: PMC4268525  PMID: 25538518
Alfentanil; colonoscopy; patient-controlled sedation; remifentanil
16.  Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism  
1 The interaction between triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double-blind, randomized crossover study of three phases.
2 Twelve healthy young volunteers received 100 mg fluconazole, 250 mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25 mg dose of triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17 h after the intake of triazolam.
3 Fluconazole increased the area under the triazolam concentration time-curve more than twofold (P<0.001) and prolonged the elimination half-life of triazolam nearly twofold (P<0.001). The peak concentration of triazolam was also increased significantly (P<0.05) by fluconazole.
4 During the fluconazole phase pharmacodynamic effects of triazolam (e.g. digit symbol substitution test, body sway and drowsiness) were enhanced significantly (P<0.05) when compared with the placebo phase.
5 Terbinafine did not change significantly the pharmacokinetics or pharmacodynamics of triazolam.
6 Care should be taken when triazolam is prescribed to patients using fluconazole. Although the interaction is not as strong as that of triazolam with ketoconazole or itraconazole, it is clinically significant. Triazolam and probably other drugs metabolized by CYP3A4 can be used in normal doses with terbinafine.
doi:10.1046/j.1365-2125.1996.03189.x
PMCID: PMC2042590  PMID: 8730978
triazolam; fluconazole; terbinafine; interaction; pharmacokinetics; pharmacodynamics
17.  The Anxiolytic Effect of Midazolam in Third Molar Extraction: A Systematic Review 
PLoS ONE  2015;10(4):e0121410.
Purpose
To assess the efficacy of midazolam for anxiety control in third molar extraction surgery.
Methods
Electronic retrievals were conducted in Medline (via PubMed, 1950-2013.12), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), Embase (via OVID 1974-2013.12), and the System for Information on Grey Literature in Europe (SIGLE). The bibliographies of relevant clinical trials were also checked. Randomized controlled trials satisfying the inclusion criteria were evaluated, with data extraction done independently by two well-trained investigators. Disagreements were resolved by discussion or by consultation with a third member of the review team.
Results
Ten studies were included, but meta-analysis could not be conducted because of the significant differences among articles. All but one article demonstrated that midazolam could relieve anxiety. One article demonstrated that propofol offered superior anxiolysis, with more rapid recovery than with midazolam. Compared with lorazepam and diazepam, midazolam did not distinctly dominate in its sedative effect, but was safer. Two articles used midazolam in multidrug intravenous sedation and proved it to be more effective than midazolam alone.
Conclusion
It was found, by comparison and analysis, that midazolam might be effective for use for anxiety control during third molar extraction and can be safely administered by a dedicated staff member. It can also be used with other drugs to obtain better sedative effects, but the patient’s respiratory function must be monitored closely, because multidrug sedation is also more risky.
doi:10.1371/journal.pone.0121410
PMCID: PMC4388717  PMID: 25849859
18.  Comparison of three different sedative-anaesthetic protocols (ketamine, ketamine-medetomidine and alphaxalone) in common marmosets (Callithrix jacchus) 
Background
Handling of common marmoset (Callithrix jacchus) usually requires chemical restraint. Ketamine has been associated with muscle damage in primates, while common marmosets, compared to other primates, additionally display an exceptional high sensitivity to ketamine-associated side-effects. Notably, muscle twitching movements of limbs and hands, and a marked increase in salivation are observed. We investigated two alternative intramuscular (i.m.) immobilisation protocols against ketamine (50 mg/kg; protocol 1) in a double-blind randomised crossover study in ten healthy adult common marmosets for use as a safe reliable, short-term immobilisation and sedation. These protocols comprised: alphaxalone (12 mg/kg; protocol 2) and 25 mg/kg ketamine combined with 0.50 mg/kg medetomidine (reversal with 2.5 mg/kg atipamezole; protocol 3A). Following completion and unblinding, the project was extended with an additional protocol (3B), comprising 25 mg/kg ketamine combined with 0.05 mg/kg medetomidine (reversal with 0.25 mg/kg atipamezole, twice with 35 min interval).
Results
All protocols in this study provided rapid onset (induction times <5 min) of immobilisation and sedation. Duration of immobilisation was 31.23 ± 22.39 min, 53.72 ± 13.08 min, 19.73 ± 5.74 min, and 22.78 ± 22.37 min for protocol 1, 2, 3A, and 3B, respectively. Recovery times were 135.84 ± 39.19 min, 55.79 ± 11.02 min, 405.46 ± 29.81 min, and 291.91 ± 80.34 min, respectively. Regarding the quality, and reliability (judged by pedal withdrawal reflex, palpebral reflex and muscle tension) of all protocols, protocol 2 was the most optimal. Monitored vital parameters were within clinically acceptable limits during all protocols and there were no fatalities. Indication of muscle damage as assessed by AST, LDH and CK values was most prominent elevated in protocol 1, 3A, and 3B.
Conclusions
We conclude that intramuscular administration of 12 mg/kg alphaxalone to common marmosets is preferred over other protocols studied. Protocol 2 resulted in at least comparable immobilisation quality with acceptable and less frequent side effects and superior recovery quality. In all protocols, supportive therapy, such as external heat support, remains mandatory. Notably, an unacceptable long recovery period in both ketamine/medetomidine protocols (subsequently reversed with atipamezole) was observed, showing that α-2 adrenoreceptor agonists in the used dose and dosing regime is not the first choice for sedation in common marmosets in a standard research setting.
doi:10.1186/1746-6148-9-113
PMCID: PMC3686586  PMID: 23758836
Alphaxalone; Atipamezole; Common marmoset; Immobilisation; Induction; Ketamine; Medetomidine; Recovery; Sedation
19.  Development and validation of the PROcedural Sedation Assessment Survey (PROSAS) for assessment of procedural sedation quality 
Gastrointestinal endoscopy  2014;81(1):194-203.e1.
Background
Over 20 million invasive procedures are performed annually in the United States. The vast majority are performed with moderate sedation or deep sedation yet there is limited understanding of drivers of sedation quality and patient satisfaction. Currently, the major gap in quality assurance for invasive procedures is the lack of procedural sedation quality measures.
Objective
To develop and validate a robust, patient-centered measure of procedural sedation quality, the PROcedural Sedation Assessment Survey (PROSAS).
Design
Through a series of interviews with patients, proceduralists, nurses and anesthesiologists, and an interactive patient focus group, major domains influencing procedural sedation quality were used to create a multipart survey. The pilot survey was administered and revised in sequential cohorts of adults receiving moderate sedation for GI endoscopy. After revision, the PROSAS was administered to a validation cohort.
Setting
GI endoscopy unit.
Patients
A expert panel of proceduralists, nurses and anesthesiologists, an initial survey development cohort of 40 patients, and a validation cohort of 858 patients undergoing sedation for outpatient GI endoscopy with additional surveys completed by the gastroenterologist, procedure nurse and recovery nurse.
Main Outcomes and Measures
Survey characteristics of the PROSAS.
Results
Patients were able to independently complete the PROSAS after procedural sedation before discharge. 91.6% of patients reported minimal discomfort; however, 8.4% of patients reported significant discomfort and 2.4% of patients experienced hemodynamic and/or respiratory instability. There was a high correlation between patient reported intraprocedure discomfort and both clinician assessments of procedural discomfort and patient recall of procedural pain 24 to 48 hours postprocedure (p<0.001 for all), suggesting high external validity.
Limitations
Single-center study, variability of sedation technique between providers, inclusion of patients with chronic pain on analgesics
Conclusions
The PROSAS is a clinically relevant, patient-centered, easily administered instrument that allows for standardized evaluation of procedural sedation quality. The PROSAS may be useful in both research and clinical settings.
doi:10.1016/j.gie.2014.07.062
PMCID: PMC4272880  PMID: 25293829
Endoscopy; Sedation; Quality; Safety; Patient Satisfaction; Patient Reported Outcome
20.  Oral midazolam for conscious sedation of children during minor procedures. 
OBJECTIVE: To compare the safety and efficacy of two doses of oral midazolam, and to assess the drug induced amnesia obtained, when used for conscious sedation of children undergoing minor procedures in the accident and emergency (A&E) setting. METHODS: A two stage trial was completed: an initial prospective, double blinded, randomised trial comparing 0.2 mg/kg midazolam suspension with 0.5 mg/kg, followed by further data collection on the higher dose. Children whom staff and parents felt required sedation for accurate and humane completion of minor procedures were selected. Anxiety was measured using physiological parameters, a behavioural anxiety score, a parental visual analogue scale, and a telephone questionnaire at 2-7 days after the procedure. RESULTS: Fifty patients in total were recruited. Randomisation between two doses ceased after 20 patients since staff, despite being "blinded", perceived there to be a wide variation in response to midazolam and attributed that to the difference in doses. On breaking the code these suspicions were partly supported. Due to reluctance to continue with the lower dose all children subsequently received 0.5 mg/kg. At this higher dose oral midazolam had an onset of action of 15 minutes and was effective in 76% of children (as measured by anxiety score and/or subsequent amnesia). Amnesia was reported in 66% of children. There were no adverse side effects except paradoxical hyperagitation in three (6%); this did not require any specific treatment. General anaesthesia was avoided in at least eight children in whom the procedure would not have been attempted without midazolam. Altogether 90% of parents said they would like it to be used again should similar circumstances arise. CONCLUSIONS: At 0.5 mg/kg oral midazolam appears safe and is effective in sedating most children for minor procedures. Its use should be considered by all A&E departments dealing with children.
PMCID: PMC1343135  PMID: 9681307
21.  Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis 
BMJ : British Medical Journal  2002;324(7330):144.
Objectives
To compare the efficacy and tolerability of butterbur (Petasites hybridus) with cetirizine in patients with seasonal allergic rhinitis (hay fever).
Design
Randomised, double blind, parallel group comparison.
Setting
Four outpatient general medicine and allergy clinics in Switzerland and Germany.
Participants
131 patients were screened for seasonal allergic rhinitis and 125 patients were randomised (butterbur 61; cetirizine 64).
Interventions
Butterbur (carbon dioxide extract tablets, ZE 339) one tablet, four times daily, or cetirizine, one tablet in the evening, both given for two consecutive weeks.
Main outcome measures
Scores on SF-36 questionnaire and clinical global impression scale.
Results
Improvement in SF-36 score was similar in the two treatment groups for all items tested hierarchically. Butterbur and cetirizine were also similarly effective with regard to global improvement scores on the clinical global impression scale (median score 3 in both groups). Both treatments were well tolerated. In the cetirizine group, two thirds (8/12) of reported adverse events were associated with sedative effects (drowsiness and fatigue) despite the drug being considered a non-sedating antihistamine.
Conclusions
The effects of butterbur are similar to those of cetirizine in patients with seasonal allergic rhinitis when evaluated blindly by patients and doctors. Butterbur should be considered for treating seasonal allergic rhinitis when the sedative effects of antihistamines need to be avoided.
What is already known on this topicSeasonal allergic rhinitis (hay fever) is common in countries with temperate climates.Most patients have their symptoms treated for short periods, particularly during peaks in atmospheric pollen countWhat this study addsAfter two weeks, the effects of butterbur and cetirizine were comparable in patients with hay feverButterbur produced fewer sedating effects than cetirizineButterbur should be considered when the sedating effects of antihistamines must be avoided
PMCID: PMC64514  PMID: 11799030
22.  Anterograde Amnesia as a Possible Postoperative Complication of Midazolam as an Agent for Intravenous Conscious Sedation 
Anesthesia Progress  1988;35(4):160-162.
Anterograde amnesia is often considered to be a beneficial effect of intravenous conscious sedation. The recently introduced benzodiazepine, midazolam, has associated with its administration a significant anterograde amnesic period. In the case presented here, a healthy young female presented for third molar extraction under midazolam conscious sedation and local anesthesia. After uncomplicated removal of the teeth and clinically adequate recovery from sedation, it was noted that the patient had swallowed the postsurgical gauze packs. Efforts at recovery of the gauze packs were futile. Follow-up discussion with the patient revealed a complete lack of recall of all events occurring for up to an hour or more after the administration of intravenous midazolam. The need for written and oral postoperative instructions to both the patient and his/her escort is emphasized.
PMCID: PMC2167955  PMID: 3166354
23.  Triazolam compared with nitrazepam and with oxazepam in insomnia 
British Journal of Clinical Pharmacology  1981;11(Suppl 1):43S-49S.
1 In two double-blind, crossover studies, general practitioners compared the hypnotic activity of triazolam 0.50 mg with that of nitrazepam 5 mg or oxazepam 50 mg in outpatient insomniacs.
2 The patients' preferences served as the main criterion, and were processed by sequential analysis.
3 More patients (P<0.05) preferred triazolam to nitrazepam (triazolam 28; nitrazepam 11; no preference 9).
4 The numbers of patients who preferred triazolam or oxazepam did not differ significantly.
5 Triazolam and oxazepam affected sleep parameters similarly except for onset of sleep and feeling in the morning, for which triazolam seemed to be superior to oxazepam.
PMCID: PMC1401639  PMID: 6133534
24.  A Visual ERP Study of Impulse Inhibition following a Zaleplon-Induced Nap after Sleep Deprivation 
PLoS ONE  2014;9(5):e95653.
The side effects of a zaleplon-induced nap as a countermeasure in the reduction of impulse inhibition function decline following 30 h of sleep deprivation (SD) were examined by event-related brain potentials. Sixteen adult participants performed a Go/NoGo task at five time points: (1) baseline; (2) after 30 h of SD; (3) upon sudden awakening, also called 2 h post-drug; (4) 4 h post-drug; and (5) 6 h post-drug. Behavior results show an increase in both reaction time and false alarm rates after SD and sudden awakening, and a marked decrease at 4 h and 6 h post-drug in zaleplon and placebo conditions. However, no difference was observed between the zaleplon condition and the placebo condition. In event-related potential (ERP) reults compared with results obtained under control conditions, NoGo-P3 latencies significantly increased, whereas the Nogo-P3 amplitude decreased after 30 h of SD and sudden awakening in both the zaleplon condition and the placebo condition. These results indicate that SD attenuates resource allocation and error monitoring for NoGo stimuli. In addition, NoGo-P3 latencies were longer in the zaleplon condition compared with the placebo condition at sudden awakening. Additionally, the NoGo-P3 latencies were shorter in the zaleplon condition than in the placebo condition at 4 h and 6 h post-drug. These results indicate that zaleplon at a dose of 10 mg/day may help subjects achieve a better recovery or maintain better impulse inhibition function, although the side effects of zaleplon last at least 2 h post-drug.
doi:10.1371/journal.pone.0095653
PMCID: PMC4012989  PMID: 24806263
25.  A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening 
Aims
To compare the duration of the residual hypnotic and sedative effects of zaleplon with those of zolpidem and placebo following nocturnal administration at various times before morning awakening.
Methods
Zaleplon 10 mg, zolpidem 10 mg, or placebo was administered double-blind to 36 healthy subjects under standardized conditions in a six-period, incomplete-block, crossover study. Subjects were gently awakened and given medication at predetermined times 5, 4, 3, or 2 h before morning awakening, which occurred 8 h after bedtime. When the subjects awoke in the morning, a battery of subjective and objective assessments of residual effects of hypnotics was administered.
Results
No residual effects were demonstrated after zaleplon 10 mg, when administered as little as 2 h before waking, on either subjective or objective assessments, whereas zolpidem 10 mg showed significant residual effects on DSST and memory (immediate and delayed free recall) after administration up to 5 h before waking and choice reaction time, critical flicker fusion threshold and Sternberg memory scanning after administration up to 4 h before waking. Residual effects of zolpidem were apparent in all objective and subjective measurements when the drug was administered later in the night.
Conclusions
The present results demonstrate that zaleplon at the dose of 10 mg is free of residual hypnotic or sedative effects when administered nocturnally as little as 2 h before waking in normal subjects. In contrast, residual effects of zolpidem are still apparent on objective assessments up to 5 h after nocturnal administration, longer than has been reported from studies involving daytime administration.
doi:10.1046/j.1365-2125.1999.00024.x
PMCID: PMC2014318  PMID: 10510148
hypnotic; residual effects; sedative; zaleplon; zolpidem

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