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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.  Preoperative anxiolysis in pediatric population: A comparative study between oral midazolam and oral ketamine 
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.
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.
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.
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.
PMCID: PMC4173508
Anxiolysis; ketamine; midazolam; oral; sedation
3.  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.
PMCID: PMC3468288  PMID: 23050750
Propofol; Ketamine; Remifentanil; Deep sedation; TIVA
4.  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.
PMCID: PMC3657020  PMID: 23404347
Zolpidem; Zopiclone; Zaleplon; Poisoning; Analysis
5.  High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens 
Psychopharmacology  2012;223(1):1-15.
Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM.
This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam.
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.
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.
High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin.
PMCID: PMC3652430  PMID: 22526529
Dextromethorphan; Triazolam; Dose effects; Hallucinogen; Psychedelic; Entheogen; Drug abuse; Subjective effects; Mystical experience; Humans
6.  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
7.  Comparative evaluation of midazolam and butorphanol as oral premedication in pediatric patients 
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.
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.
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.
PMCID: PMC3275967  PMID: 22345942
Anxiolysis; oral midazolam; oral butorphanol; premedication; pediatric anesthesia; sedation
8.  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
9.  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.
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.
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.
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.
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)
PMCID: PMC3607964  PMID: 23170921
Balanced propofol sedation; Alfentanil; Fentanyl; Deep sedation; Diagnostic endoscopy; Cost benefit
10.  Effect of two Different Concentrations of Propofol and Ketamine Combinations (Ketofol) in Pediatric Patients under Lumbar Puncture or Bone Marrow Aspiration 
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.
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.
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
11.  Sedation Depth During Spinal Anesthesia and the Development of Postoperative Delirium in Elderly Patients Undergoing Hip Fracture Repair 
Mayo Clinic Proceedings  2010;85(1):18-26.
OBJECTIVE: To determine whether limiting intraoperative sedation depth during spinal anesthesia for hip fracture repair in elderly patients can decrease the prevalence of postoperative delirium.
PATIENTS AND METHODS: We performed a double-blind, randomized controlled trial at an academic medical center of elderly patients (≥65 years) without preoperative delirium or severe dementia who underwent hip fracture repair under spinal anesthesia with propofol sedation. Sedation depth was titrated using processed electroencephalography with the bispectral index (BIS), and patients were randomized to receive either deep (BIS, approximately 50) or light (BIS, ≥80) sedation. Postoperative delirium was assessed as defined by Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) criteria using the Confusion Assessment Method beginning at any time from the second day after surgery.
RESULTS: From April 2, 2005, through October 30, 2008, a total of 114 patients were randomized. The prevalence of postoperative delirium was significantly lower in the light sedation group (11/57 [19%] vs 23/57 [40%] in the deep sedation group; P=.02), indicating that 1 incident of delirium will be prevented for every 4.7 patients treated with light sedation. The mean ± SD number of days of delirium during hospitalization was lower in the light sedation group than in the deep sedation group (0.5±1.5 days vs 1.4±4.0 days; P=.01).
CONCLUSION: The use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation. Limiting depth of sedation during spinal anesthesia is a simple, safe, and cost-effective intervention for preventing postoperative delirium in elderly patients that could be widely and readily adopted.
Trial Registration: Identifier: NCT00590707
Use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation. Limiting depth of sedation during spinal anesthesia is a simple, safe, and cost-effective intervention for preventing postoperative delirium in elderly patients that could be widely and readily adopted.
PMCID: PMC2800291  PMID: 20042557
12.  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.
PMCID: PMC3891457  PMID: 24423419
Fospropofol; Midazolam; Moderate sedation; Outpatient surgery; IV conscious sedation; Benzodiazepine; Propofol
13.  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.
Many techniques are used for sedation of colonoscopies. Patient-controlled sedation (PCS) is utilizing many drugs or drug combinations.
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.
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.
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.
PMCID: PMC4268525  PMID: 25538518
Alfentanil; colonoscopy; patient-controlled sedation; remifentanil
14.  Comparison of three different sedative-anaesthetic protocols (ketamine, ketamine-medetomidine and alphaxalone) in common marmosets (Callithrix jacchus) 
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).
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.
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.
PMCID: PMC3686586  PMID: 23758836
Alphaxalone; Atipamezole; Common marmoset; Immobilisation; Induction; Ketamine; Medetomidine; Recovery; Sedation
15.  Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care 
Critical Care  2000;4(5):302-308.
The respiratory effects of dexmedetomidine were retrospectively examined in 33 postsurgical patients involved in a randomised, placebo-controlled trial after extubation in the intensive care unit (ICU). Morphine requirements were reduced by over 50% in patients receiving dexmedetomidine. There were no differences in respiratory rates, oxygen saturations, arterial pH and arterial partial carbon dioxide tension (PaCO2) between the groups. Interestingly the arterial partial oxygen tension (PaO2) : fractional inspired oxygen (FIO2) ratios were statistically significantly higher in the dexmedetomidine group. Dexmedetomidine provides important postsurgical analgesia and appears to have no clinically important adverse effects on respiration in the surgical patient who requires intensive care.
The α2-agonist dexmedetomidine is a new class of sedative drug that is being investigated for use in ICU settings. It is an effective agent for the management of sedation and analgesia after cardiac, general, orthopaedic, head and neck, oncological and vascular surgery in the ICU [1]. Cardiovascular stability was demonstrated, with significant reductions in rate-pressure product during sedation and over the extubation period.
Dexmedetomidine possesses several properties that may additionally benefit those critically ill patients who require sedation. In spontaneously breathing volunteers, intravenous dexmedetomidine caused marked sedation with only mild reductions in resting ventilation at higher doses [2]. Dexmedetomidine reduces the haemodynamic response to intubation and extubation [3,4,5] and attenuates the stress response to surgery [6], as a result of the α2-mediated reduction in sympathetic tone. Therefore, it should be possible to continue sedation with dexmedetomidine over the stressful extubation period without concerns over respiratory depression, while ensuring that haemodynamic stability is preserved.
The present study is a retrospective analysis of the respiratory response to dexmedetomidine in 33 postsurgical patients (who were involved in a randomized, double-blind, placebo-controlled trial [1]) after extubation in the ICU.
Patients who participated in the present study were admitted after surgery to our general or cardiothoracic ICUs, and were expected to receive at least 6 h of postsurgical sedation and artificial ventilation.
On arrival in the ICU after surgery, patients were randomized to receive either dexmedetomidine or placebo (normal saline) with rescue sedation and analgesia being provided, only if clinically needed, with midazolam and morphine boluses, respectively. Sedation was titrated to maintain a Ramsay Sedation Score [7] of 3 or greater while the patients were intubated, and infusions of study drug were continued for a maximum of 6 h after extubation to achieve a Ramsay Sedation Score of 2 or greater.
The patients were intubated and ventilated with oxygen-enriched air to attain acceptable arterial blood gases, and extubation occurred when clinically indicated. All patients received supplemental oxygen after extubation, which was delivered by a fixed performance device. Assessment of pain was by direct communication with the patient.
Results are expressed as mean ± standard deviation unless otherwise stated. Patient characteristics, operative details and morphine usage were analyzed using the Mann-Whitney U-test. Statistical differences for respiratory measurements between the two groups were determined using analysis of variance for repeated measures, with the Bonferroni test for post hoc comparisons.
Of the 40 patients who participated in the study, seven patients could not be included in the analysis of respiratory function because they did not receive a study drug infusion after extubation. Consequently, data from 33 patients are used in the analysis of respiratory function; 16 received dexmedetomidine and 17 placebo. Inadequate arterial blood gas analysis was available in five patients (two from the dexmedetomidine group, and three from the placebo group). There were no significant differences in patient characteristics and operative details between the groups.
Requirements for morphine were reduced by more than 50% in patients receiving dexmedetomidine when compared with placebo after extubation (0.003 ± 0.004 vs 0.008 ± 0.006 mg/kg per h; P= 0.040).
There were no statistically significant differences between placebo and dexmedetomidine for oxygen saturations measured by pulse oximetry (P= 0.26), respiratory rate (P= 0.16; Fig. 1), arterial pH (P= 0.77) and PaCO2 (P= 0.75; Fig. 2) for the 6 h after extubation.
The dexmedetomidine group showed significantly higher PaO2: FIO2 ratios throughout the 6-h intubation (P= 0.036) and extubation (P= 0.037) periods (Fig. 3). There were no adverse respiratory events seen in either the dexmedetomidine or placebo group.
Respiratory rate for the 6-h periods before and after extubation. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaCO2 (PCO2) for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaO2 : FIO2 ratio for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
Lack of respiratory depression in patients sedated with α2-adrenoceptor agonists was first reported by Maxwell [8] in a study investigating the respiratory effects of clonidine. However, more recent data suggests that clonidine may cause mild respiratory depression in humans [9], and α2-adrenoceptor agonists are well known to produce profound intraoperative hypoxaemia in sheep [10,11]. The effects of dexmedetomidine on other ventilation parameters also appear to be species specific [12].
Belleville et al [2] investigated the ventilatory effects of a 2-min intravenous infusion of dexmedetomidine on human volunteers. According to those investigators, minute ventilation and arterial PaCO2 were mildly decreased and increased, respectively. There was a rightward shift and depression of the hypercapnic response with infusions of 1.0 and 2.0 μg/kg.
Previous studies that investigated the respiratory effects of dexmedetomidine have only been performed in healthy human volunteers, who have received either single intramuscular injections or short (= 10 min) intravenous infusions of dexmedetomidine. It is therefore reassuring that no deleterious clinical effects on respiration and gas exchange were seen in the patients we studied, who were receiving long-term infusions. However, there are important limitations to the present results. No dose/response curve for dexmedetomidine can be formulated from the data, and further investigation is probably ethically difficult to achieve in the spontaneously ventilating intensive care patient. We also have no data on the ventilatory responses to hypercapnia and hypoxia, which would also be difficult to examine practically and ethically. The placebo group received more than twice as much morphine as patients receiving dexmedetomidine infusions after extubation, but there were no differences in respiratory rate or PaCO2 between the groups. We can not therefore determine from this study whether dexmedetomidine has any benefits over morphine from a respiratory perspective.
There were no differences in oxygen saturations between the groups because the administered oxygen concentration was adjusted to maintain satisfactory gas exchange. Interestingly, however, there were statistically significant higher PaO2 : FIO2 ratios in the dexmedetomidine group. This ratio allows for the variation in administered oxygen to patients during the study period, and gives some clinical indication of alveolar gas exchange. However, this variable was not a primary outcome variable for the present study, and may represent a type 1 error, although post hoc analysis reveals that the data have 80% power to detect a significant difference (α value 0.05). Further studies are obviously required.
Sedation continued over the extubation period, has been shown to reduce haemodynamic disturbances and myocardial ischaemia [13]. We have previously shown [1] that dexmedetomidine provides cardiovascular stability, with a reduction in rate-pressure product over the extubation period. A sedative agent that has analgesic properties, minimal effects on respiration and offers ischaemia protection would have enormous potential in the ICU. Dexmedetomidine may fulfill all of these roles, but at present we can only conclude that dexmedetomidine has no deleterious clinical effects on respiration when used in doses that are sufficient to provide adequate sedation and effective analgesia in the surgical population requiring intensive care.
PMCID: PMC29047  PMID: 11056756
α2-Adrenoceptor agonist; analgesia; dexmedetomidine; intensive care; postoperative; respiratory; sedation
16.  Should I eXtract Every Six dental trial (SIXES): study protocol for a randomized controlled trial 
Trials  2013;14:59.
Extraction of lower first permanent molars in children is common. There is uncertainty among clinicians as to whether a ‘compensating extraction’ (removal of the upper first permanent molar to prevent it over erupting) is necessary despite current guidelines recommending this. As a result, unnecessary dental extractions may be carried out or children may be failing to receive extractions required to achieve optimal long-term oral health. In addition, the decision to extract fewer or more teeth affects management options (local anesthetic injections alone, inhalation sedation or general anesthesia) needed to support the child with the surgical procedure(s).
The SIXES (Should I eXtract Every Six) dental trial investigates clinical effectiveness and quality of life for conventional treatment (following the guideline of compensation extraction of the upper first permanent molar) compared with the alternative intervention (removal of lower first permanent molars but no extraction of the upper).
This is a multicenter, two-arm parallel group randomized clinical trial. Allocation will be web-based randomization. Practitioners in primary and secondary care settings, reflecting the points of presentation and treatment of eligible patients, will recruit 400 children, aged 7 to 11 years requiring extraction of lower first permanent molars but who have upper first permanent molars of good prognosis. Baseline measures (prior to treatment) and outcome data (at one and five years, or when the patient reaches 14 years of age) will be assessed through study models and child/parent questionnaires.
The primary outcome measure is degree of tipping of the lower second permanent molar, (favorable outcome is tipping less than 15°).
The secondary outcomes are type of anesthetic/sedation used, residual spacing (between lower second premolar and second permanent molar), orthodontic treatment requirement, quality of life, and over-eruption in the intervention group. Assessors will be blinded where possible.
SIXES dental trial investigates whether compensating extraction of upper first permanent molars should be carried out following loss of lower first permanent molars. Currently dentists and orthodontists face a dilemma in clinical decision-making, relying on the lowest level of evidence - expert opinion. SIXES will provide evidence to support decision-making and inform practices and may result in reduced tooth extractions.
Trial registration
Clinical Identifier: NCT01591265
PMCID: PMC3602236  PMID: 23442547
First permanent molar; Compensating extraction; Orthodontics; Pediatric dentistry; Primary care; Randomized control trial; Dental; Oral health-related quality of life
17.  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
18.  Effect of Intrathecal Midazolam in the Severity of Pain in Cesarean Section: A Randomized Controlled Trail 
The benzodiazepines are used primarily for anxiolysis, amnesia and sedation. However, recent investigations have shown that some forms of this group of drugs have also direct effect on pain. This study aims to determine the effect of midazolam in reducing the severity of pain in women scheduled for elective cesarean section.
In a prospective, double blind randomized controlled trial, two groups parallel study, was conducted in Imam Reza/Moatazedi Hospital, an affiliate of Kermanshah University of Medical Sciences. Parturient women who met study inclusion criteria were consecutively assigned into either experimental (n=62) or control groups (n=62). Women in the experimental group received bupivacaine (10 mg) plus intrathecal midazolam (2 mg/ml) (BM) and those in the control group received bupivacaine plus normal saline (BNS). The outcome pain severity was measured by Verbal Numerical Rating Scale.
In comparison with the BNS group, mothers in the BM group reported a significant relief in pain (15 min and 120 min) after the surgery. There were no significant differences between the groups regarding the intensity of pain 5, 30, 60 and 240 min after the surgery. The average time until the first dose of additional analgesic, per mother’s request was 142.18±55.19 min in the BNS vs 178.06±77.33 min in the BM group.
Combination of bupivacaine plus intrathecal midazolam was an effective anesthetic technique to provide improvement in pain. The onset of sedation was faster in the BM group compared with the BNS group. The duration of effective analgesia, and the time for regression of sensory analgesia was the same in both groups in our study. However, incidence of nausea and vomiting was higher in the experimental group.
PMCID: PMC3398634  PMID: 22829986
Intrathecal; Bupivacaine; Midazolam; Cesarean Section; Pain
19.  The effects of preoperative anxiety on intravenous sedation. 
Anesthesia Progress  2004;51(2):46-51.
Anxiety is known to cause feelings of uneasiness, tension, and nervousness, and previous studies have noted that anxiety and its effects may have an effect on out-patient sedation for patients undergoing surgical procedures. In this study, we assess the effects of anxiety on 25 outpatients undergoing intravenous sedation for third molar extraction. Before the procedure, subjects completed the State-Trait Anxiety Inventory, and intraoperative patient movement was assessed using a subjective scale. We found that patients with a high level of preoperative anxiety had a greater degree of average intraoperative movement (P = .037) and also required a greater amount of propofol to maintain a clinically acceptable level of sedation (P = .0273) when compared with patients with less preoperative anxiety. Increased state anxiety and trait anxiety serve as predictors for an increased total dose requirement of propofol to maintain an acceptable level of sedation (r2 = 0.285, P = .0060, and r2 = 0.233, P = .0146, respectively). An increased level of trait anxiety was also a predictor of an increased degree of average intraoperative movement (r2 = 0.342, P = .0022). Patients who exhibit a high level of preoperative anxiety require a greater total dose of propofol to achieve and maintain a clinically acceptable level of sedation and are more prone to unwanted movement while under sedation.
PMCID: PMC2007471  PMID: 15366317
20.  Comparative evaluation of midazolam and clonidine as pediatric oral premedication 
Clonidine provides many desirable effects like sedation, analgesia, anxiolysis, and hemodynamic stability and these properties make it a potentially useful anesthetic premedication in the pediatric settings. The aim of this study was to compare oral midazolam (0.5 mg/kg), which is considered gold standard with oral clonidine (5 mcg/kg) as a premedication in pediatric patients.
Materials and Methods:
Sixty children classified as American Society of Anesthesiologists physical status I, aged between 2 and 12, who were scheduled to undergo an elective surgery, were enrolled for a prospective, randomized, and double blind controlled trial. They received either oral midazolam (Group M) or oral clonidine (Group C) 60 minutes before induction of anesthesia and were submitted to an evaluation of anxiety and sedation scores. We also evaluated secondary outcomes such as palatability, parental separation, effect on hemodynamic status, co-operation during venipuncture and facemask application, postoperative analgesic requirement, and recovery profile.
Oral midazolam had better efficacy in the preoperative period as sedative and anxiolytic (P < 0.001), allowed better cooperation during venipuncture and facemask application (P < 0.001), whereas, oral clonidine provided better palatability (P < 0.001), parental satisfaction (P < 0.001), stable perioperative hemodynamics (P < 0.001), better postoperative analgesia (P < 0.001), and night sleep pattern (P < 0.05) without any noticeable side effects (P > 0.05).
We conclude that under the conditions of this study, oral midazolam is a better medication than clonidine in children in preoperative period while clonidine is a better medication postoperatively with added advantage of palatability, hemodynamic stability, and no significant side effects.
PMCID: PMC4173523
Anxiolytics; oral clonidine; oral midazolam; pediatric anesthesia; premedication; sedation
21.  Aminophylline Fails to Reverse Conscious Sedation with Midazolam in Dentistry 
Anesthesia Progress  1986;33(3):152-154.
A double blind, randomized crossover study investigated whether aminophylline reverses the conscious sedation with midazolam in dentistry to result in quicker clinical recovery than when midazolam is used alone. Twenty-five patients between 17-30 years of age (ASA Grade 1) were sedated with midazolam for bilateral third molar extractions, one side being operated on one visit. Aminophylline or normal saline was given at the end of the surgical procedure on one visit and the alternative during the second visit. No significant difference in recovery was noted with either solution, suggesting that aminophylline does not produce significant reversal of sedation to achieve quicker clinical recovery. The majority of patients preferred to be alert following the operation while some (N = 5) wished to be drowsy, indicating the necessity to question the patient as to preference before deciding to administer a reversal agent.
PMCID: PMC2175479  PMID: 2943194
22.  Dose Effects of Triazolam and Scopolamine on Metamemory 
The present study compared the acute dose effects of the benzodiazepine triazolam and the anticholinergic scopolamine on metamemory (knowledge and awareness of one's own memory) in a two-phase paradigm designed to assess effects on both monitoring and control components of metamemory in both semantic (general knowledge) and episodic memory (cued recall) tasks. Placebo and two doses each of triazolam (0.125, 0.25 mg/70 kg, oral) and scopolamine (0.25, 0.50 mg/70 kg, subcutaneous) were administered to 80 healthy volunteers (16/group) in a double-blind, double-dummy, independent groups design. Both triazolam and scopolamine impaired episodic memory (quantity and accuracy) but not semantic memory. Results suggested that both drugs impaired monitoring as reflected in absolute accuracy measures (impaired calibration in the direction of overconfidence) and control sensitivity (the relationship between confidence and behavior). Overall, the results did not provide evidence for differences between triazolam and scopolamine in memory or metamemory. In addition to the clinical relevance of the observed effects, this study adds to the accumulating body of cognitive psychopharmacological research illustrating the usefulness of drug-induced amnesia as a vehicle to explore memory and metamemory.
PMCID: PMC2846306  PMID: 20158291
23.  Evaluation of the SEDline to improve the safety and efficiency of conscious sedation 
Brain function monitors have improved safety and efficiency in general anesthesia; however, they have not been adequately tested for guiding conscious sedation for periodontal surgical procedures. This study evaluated the patient state index (PSI) obtained from the SEDline monitor (Sedline Inc., San Diego, CA) to determine its capacity to improve the safety and efficiency of intravenous conscious sedation during outpatient periodontal surgery. Twenty-one patients at the periodontics clinic of Baylor College of Dentistry were admitted to the study in 2009 and sedated to a moderate level using midazolam and fentanyl during periodontal surgery. The PSI monitoring was blinded from the clinician, and the following data were collected: vital signs, Ramsay sedation scale (RSS), medications administered, adverse events, PSI, electroencephalography, and the patients' perspective through visual analogue scales. The data were correlated to evaluate the PSI's ability to assess the level of sedation. Results showed that the RSS and PSI did not correlate (r = −0.25) unless high values associated with electromyographical (EMG) activity were corrected (r = −0.47). Oxygen desaturation did not correlate with the PSI (r = −0.08). Satisfaction (r = −0.57) and amnesia (r = −0.55) both increased as the average PSI decreased. In conclusion, within the limits of this study, PSI appears to correlate with amnesia, allowing a practitioner to titrate medications to that effect. It did not provide advance warning of adverse events and had inherent inaccuracies due to EMG activity during oral surgery. The PSI has the potential to increase safety and efficiency in conscious sedation but requires further development to eliminate EMG activity from confounding the score.
PMCID: PMC3124903  PMID: 21738291
24.  Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713] 
Critical Care  2003;8(1):R1-R11.
This double-blind, randomized, multicentre study was conducted to compare the efficacy and safety of remifentanil and fentanyl for intensive care unit (ICU) sedation and analgesia.
Intubated cardiac, general postsurgical or medical patients (aged ≥ 18 years), who were mechanically ventilated for 12–72 hours, received remifentanil (9 μg/kg per hour; n = 77) or fentanyl (1.5 μg/kg per hour; n = 75). Initial opioid titration was supplemented with propofol (0.5 mg/kg per hour), if required, to achieve optimal sedation (i.e. a Sedation–Agitation Scale score of 4).
The mean percentages of time in optimal sedation were 88.3% for remifentanil and 89.3% for fentanyl (not significant). Patients with a Sedation–Agitation Scale score of 4 exhibited significantly less between-patient variability in optimal sedation on remifentanil (variance ratio of fentanyl to remifentanil 1.84; P = 0.009). Of patients who received fentanyl 40% required propofol, as compared with 35% of those who received remifentanil (median total doses 683 mg and 378 mg, respectively; P = 0.065). Recovery was rapid (median time to extubation: 1.1 hours for remifentanil and 1.3 hours for fentanyl; not significant). Remifentanil patients who experienced pain did so for significantly longer during extubation (6.5% of the time versus 1.4%; P = 0.013), postextubation (10.2% versus 3.6%; P = 0.001) and post-treatment (13.5% versus 5.1%; P = 0.001), but they exhibited similar haemodynamic stability with no significant differences in adverse event incidence.
Analgesia based sedation with remifentanil titrated to response provided effective sedation and rapid extubation without the need for propofol in most patients. Fentanyl was similar, probably because the dosing algorithm demanded frequent monitoring and adjustment, thereby preventing over-sedation. Rapid offset of analgesia with remifentanil resulted in a greater incidence of pain, highlighting the need for proactive pain management when transitioning to longer acting analgesics, which is difficult within a double-blind study but would be quite possible under normal circumstances.
PMCID: PMC420059  PMID: 14975049
analgesia; analgesia based sedation; critical care; fentanyl; propofol; remifentanil; renal function; sedation
25.  Quality of life following third molar removal under conscious sedation 
Aim: The aim of this study was to assess quality of life (QoL) and degree of satisfaction among outpatients subjected to surgical extraction of all four third molars under conscious sedation. A second objective was to describe the evolution of self-reported pain measured in a visual analogue scale (VAS) in the 7 days after extraction. Study design: Fifty patients received a questionnaire assessing social isolation, working isolation, eating and speaking ability, diet modifications, sleep impairment, changes in physical appearance, discomfort at suture removal and overall satisfaction at days 4 and 7 after surgery. Pain was recorded by patients on a 100-mm pain visual analogue scale (VAS) every day after extraction until day 7. Results: Thirty-nine patients fulfilled correctly the questionnaire. Postoperative pain values suffered small fluctuations until day 5 (range: 23 to 33 mm in a 100-mm VAS), when dicreased significantly. A positive association was observed between difficult ranked surgeries and higher postoperative pain levels. The average number of days for which the patient stopped working was 4.9. Conclusion: The removal of all third molars in a single appointment causes an important deterioration of the patient’s QoL during the first postoperative week, especially due to local pain and eating discomfort.
Key words:Third molar removal, quality of life, sedation.
PMCID: PMC3505722  PMID: 22926461

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