Subjective Sedation Research Articles

Selective effects of clonidine and temazepam on attention and memory

The present study compared the effects of clonidine and temazepam on performance on a range of tasks aiming to assess the role of central noradrenergic mechanisms in cognitive function. Fifteen healthy volunteers (seven male, eight female), aged 18-25 years, took part in a five-period crossover study in which they received placebo, temazepam (15 and 30 mg) and clonidine (150 and 300 microg) by mouth in counterbalanced order in sessions at least 4 days apart. A test battery was administered before treatment and at 45, 90 and 135 min after the dose. Performance on most tests was significantly impaired in a dose-related fashion, and subjective sedation was recorded for both drugs. The greatest impairments with clonidine were on attention in the presence of distractors. Clonidine did not affect the formation of new long-term memories, in contrast to temazepam, but did impair measures of working memory. Subjective effects, especially feelings of drunkenness and abnormality, were particularly marked with clonidine. These results support the suggestion that central noradrenergic function may be involved in preventing distraction, but do not confirm other reports suggesting that some aspects of performance are improved with clonidine.

Ambient isoflurane pollution and isoflurane consumption during intensive care unit sedation with the Anesthetic Conserving Device*

To examine ambient isoflurane pollution, scavenging efficacy, and isoflurane consumption using the Anesthetic Conserving Device (ACD) for prolonged isoflurane sedation in the intensive care unit. Prospective observational study. Multidisciplinary university intensive care unit. Fifteen adult ventilator-dependent intensive care unit patients sedated with isoflurane for 12-96 hrs. Isoflurane was infused to the ACD for sedation of study subjects. Changing of the ACD, isoflurane syringe, and opening of the respiratory circuit were performed in a standardized fashion according to investigator instructions. Active scavenging of waste gas from the ventilator was performed in ten patients; in five patients no active scavenging was performed. Continuous spectrophotometric measurement of ambient isoflurane pollution in parts per million (ppm) at 0.5 m from the patient's head and passive lapel dosimeter sampling for ten staff nurses over 8-hr shifts. Isoflurane requirement and agent consumption were registered in all patients. Spectrophotometric readings (0.1 +/- 0.2 ppm) were well below internationally recommended long-term exposure limits in all cases. Isoflurane peaks during nursing procedures were brief, infrequent, and of low amplitude. There was no observed difference between isoflurane trace levels with or without an active scavenging system in use. Passive dosimeter values were also low, ranging from undetectable to 0.16 ppm. Mean isoflurane consumption was 2.1 +/- 1.0 mL/hr. This is approximately one fourth of predicted and previously reported consumption of isoflurane with vaporizer-administered sedation in the intensive care unit setting. In the present setting, isoflurane via the ACD is an environmentally safe method of sedation provided users follow instructions for standardizing procedures with potential spillage of isoflurane. This method of sedation requires considerably less isoflurane than with traditional vaporizer technique.

Characteristics of sensing lower-jaw-position in patients with cerebral palsy during laughing gas-induced sedation

To clarify the effects of the applied during sedation with nitrous oxide (hereafter referred to as laughing gas) on the ability of muscles attached to the lower jaw to sense lower-jaw-position and on the sensation of muscle spindles attached to the lower jaw in patients with cerebral palsy (CP) using healthy adult subjects without functional abnormalities of the jaws and oral cavities as control subjects (hereafter referred to as healthy subjects). Experiments were performed under the following conditions: for each subject, before the inhalation of laughing gas (LG) and oxygen (air-inhalation condition: referred to as without LG inhalation) and during the inhalation of LG and oxygen (inhalation condition of LG and oxygen under LG-induced sedation: referred to as during LG inhalation). Subjects in the experiments were eight CP patients and eight healthy people as controls. The ability to discriminate lowerjaw- position was estimated by asking the subjects to determine whether the diameter of a test stick was larger or smaller than that of a reference stick after performing the following tasks: a) holding a reference stick between the central teeth of their upper and lower jaws for 5 s, and b) replacing the reference stick with a test stick and holding it at the same position for 5 s, and the test stick was then removed. The following findings were obtained. 1) In comparing discrimination ability in the absence of LG-induced sedation and that during LG-induced sedation of healthy control subjects, the rate of mis-estimation (RME) was significantly larger during LG-induced sedation than in the absence of LG-induced sedation for a test stick diameter (10.5 mm or 11.0 mm) larger than the reference stick diameter (10. 0mm) ( P < 0.05). No significant differences were observed for any other test sticks ( P > 0.05). 2) In comparing discrimination ability in the absence of LG-induced sedation and that during LG-induced sedation of CP patients, RME was significantly smaller during LG-induced sedation than in the absence of LG-induced sedation, when the test stick diameter (9.5 mm) was smaller than the reference stick diameter ( P < 0.05). No significant differences were observed for any other test sticks ( P > 0.05). These results indicate that neural functions are inhibited at the upper level of the central nervous system in CP patients, leading to the attenuation of sustained increase in muscle tonus that is characteristic of CP patients. In summary, it seems that the LG has some inhibitory effect on the activity of γ-motor neurons innervating muscle spindles attached to the lower jaw via the upper level of the central nervous system and that this inhibitory effect contributes to an improvement in the discrimination ability.

Prediction of responses to various stimuli during sedation: a comparison of three EEG variables

To compare the ability of the aepEX, a derivative of auditory evoked potentials, the bispectral index, and SEF95% to predict responses to various stimuli. Prospective clinical study. General Intensive Care Unit in a university hospital. Forty postsurgical, mechanically ventilated patients. Target concentrations of blood propofol were randomly set at 0.5 microg/ml, 1.0 microg/ml, 1.5 microg/ml, and 2.0 microg/ml, with a fixed fentanyl infusion rate between 0.5 microg.kg(-1).h(-1) and 1.5 microg.kg(-1).h(-1). Depth of sedation was subjectively assessed with the Ramsay Sedation Score. The aepEX was recorded using an auditory evoked potentials system. The bispectral index and SEF95% were measured using an Aspect A-1000 monitor. The aepEX, bispectral index, and SEF95% correlated with the Ramsay Sedation Score, the Pk value being greatest for the aepEX, followed by the bispectral index. All three variables could predict opening of the eyes in response to verbal commands or a glabellar tap, the aepEX being a better predictor than the bispectral index or SEF95%. All three EEG variables had Pk values >0.5 in predicting coughing or movement in response to tracheal suction, but they were unable to predict increases in heart rate or systolic blood pressure. The aepEX was the best predictor, followed by bispectral index. Although in most intensive care patients subjective sedation scales are sufficient to assess levels of sedation, the aepEX and bispectral index were potential alternatives to subjective scales when they do not work well in the setting of neuromuscular blockade or may not be sufficiently sensitive to evaluate very deep sedation.

Sparing of perceptual implicit memory despite suppression of the electrophysiological word repetition effect: a study with general anesthetic isoflurane

Objective: Much effort has been devoted to the search for the neurophysiological correlates of implicit memory. A commonly held view is that the early portion (250–500 ms) of the event-related potential (ERP) word repetition effect reflects processes important for perceptual implicit memory whereas the latter portion reflects processes implicated in explicit memory. It is, however, difficult to disentangle with certainty the relative contributions of each form of memory on ERPs since both forms co-exist in normal subjects. To dissociate ERP effect related to implicit and explicit memory, we used isoflurane sedation in normal subjects to suppress explicit remembering while sparing implicit memory. These ERPs were compared with those of non-medicated control subjects. Methods: Thirteen subjects performed an incidental encoding task for words presented auditorily during the inhalation of a subanesthetic dose of isoflurane. After termination of isoflurane administration, we assessed free recall and recorded ERPs during a syllable completion task (implicit memory) and during a passive listening task (ERP repetition effect). Eleven non-medicated control subjects were tested in a similar manner. Results: The controls showed robust early and late ERP repetition effect. The isoflurane group had implicit memory without free recall and showed no ERP repetition effect. Conclusions: These findings failed to show an association between any part of the repetition effect and perceptual implicit memory. The results are consistent with the view that processes linked to explicit memory contribute to the ERP repetition effect since there was a marked difference in free recall between the control and isoflurane groups. Significance: The present study shows that the reversible alterations of memory by general anesthetics can be used to study the neurophysiological correlates of memory processes.

Comparison of a New Bispectral Index (BIS) Algorithm to Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Scale in Moderate Sedation (MS)

Background: Assessment of sedation levels in endoscopy is crucial for patient safety. Sedation assessment is currently guided by indirect measures: vital signs, direct observation, and subjective sedation assessment like the MOAA/S scale. BIS monitoring is a mathematical evaluation of frontal cortex EEG activity used to improve general anesthetic titration and patient recovery. Current BIS algorithms do not differentiate various levels of MS. Aim: To compare the new BIS monitoring algorithm (BIS Revision 4.1) to MOAA/S scale for MS during elective endoscopy. Methods: 80 pts (43M/37F, mean age 61 yrs) were studied using a balanced cohort of procedures (20-EGD; 20-Colon; 20-ERCP; 20-EUS). IV MS (meperidine/midazolam) was administered. BIS levels and MOAA/S scores were recorded q 3 min. BIS level (0-100; 0=flatline EEG to 100=fully awake) and MOAA/S score (1-5; 1=unresponsive to shaking to 5=coherent). The mean BIS level and MOAA/S score were compared. Results: Levels of sedation achieved: 54 pts (67.5%) deep sedation and 26 pts (32.5%) mild to moderate sedation. The correlation coefficient between BIS level and MOAA/S score was 0.66 (p < 0.01; Graph). The new BIS algorithm had excellent correlation to mild/moderate sedation levels (MOAA/S 2-5; p < 0.001) but failed to discriminate between moderate/deep sedation levels (MOAA/S 1-2; p = 0.75). Conclusions: (1)Deep sedation occurs frequently during elective endoscopy. (2)The new BIS algorithm is successful in discriminating levels of mild/moderate sedation, but is no more effective than direct observation (MOAA/S score) at distinguishing between moderate/deep levels of sedation. Clinical implication: Since a large percentage of patients experience deep sedation during elective endoscopy, the new BIS algorithm needs to be refined to differentiate deeper levels of sedation.

Treatment Efficacy and Safety Related to the Use of Propofol vs. Conventional Sedation in the Performance of Colonoscopy: A Meta-Analysis of Published Randomized Controlled Trials

Background: Assessment of sedation levels in endoscopy is crucial for patient safety. Sedation assessment is currently guided by indirect measures: vital signs, direct observation, and subjective sedation assessment like the MOAA/S scale. BIS monitoring is a mathematical evaluation of frontal cortex EEG activity used to improve general anesthetic titration andpatient recovery. Current BIS algorithms do not differentiate various levels of MS. Aim: To compare the new BIS monitoring algorithm (BIS Revision 4.1) to MOAA/S scale for MS during elective endoscopy. Methods: 80 pts (43M/37F,mean age 61 yrs)were studied using a balanced cohort of procedures (20-EGD; 20-Colon; 20-ERCP; 20-EUS). IV MS (meperidine/midazolam) was administered. BIS levels and MOAA/S scores were recorded q 3 min. BIS level (0-100; 0=flatline EEG to 100=fully awake) and MOAA/S score (1-5; 1=unresponsive to shaking to5=coherent). ThemeanBIS level andMOAA/S score were compared. Results: Levels of sedation achieved: 54 pts (67.5%) deep sedation and 26 pts (32.5%) mild to moderate sedation. The correlation coefficient between BIS level and MOAA/S score was 0.66 (p < 0.01; Graph). The new BIS algorithm had excellent correlation tomild/moderate sedation levels (MOAA/S 2-5; p<0.001) but failed to discriminate betweenmoderate/deep sedation levels (MOAA/S 1-2; p= 0.75). Conclusions: (1)Deep sedation occurs frequently during elective endoscopy. (2)The new BIS algorithm is successful in discriminating levels of mild/moderate sedation, but is no more effective than direct observation (MOAA/S score) at distinguishing between moderate/deep levels of sedation. Clinical implication: Since a largepercentageofpatients experiencedeep sedationduringelective endoscopy, the new BIS algorithm needs to be refined to differentiate deeper levels of sedation. Treatment Efficacy and Safety Related to the Use of Propofol vs. Conventional Sedation in the Performance of Colonoscopy: A Meta-Analysis of Published Randomized Controlled Trials Neena S. Abraham, Maitreyi Raman, Kara Thompson Background and Aim: There is increasing interest in the use of propofol during the performance of colonoscopy. Our aim was to quantitatively evaluate the efficacy and safety of propofol as compared to conventional sedation in theperformance of routine colonoscopy. Methods: All randomized controlled trials evaluating propofol in colonoscopy, publishedas fullmanuscripts,were identifiedusing a standardized search and data abstraction policy. Comparisons between propofol and conventional sedationweremade in the areas of efficacy (pain control, patient satisfaction, recovery time) and risks (hypoxia, hypotension). A single combined estimate of treatment efficacy (ORwith 95%CI) was generated using a fixed effect model or random effects model if appropriate. When estimates could not be aggregated mathematically, a narrative systematic review was performed. Results: Eight studies were identified, however, twowere excluded for lack of control comparator. Aggregation of outcomes was impossible in all six studies due to lack of comparable outcome, failure to report a measure of variability or inability to dichotomize results. Recovery time post colonoscopy was substantially reduced using propofol when compared with conventional sedation (OR 18.25; 95% CI: 12.37 to 24.13). Hypoxic events occurred less frequently in the propofol arm, although this was not statistically significant (OR= 0.72; 95%CI: 0.72 to 2.37). Hypotension occurred less frequently using propofol, however, the heterogeneity in examination of this variablewas toogreat, rendering the result inconclusive. Pain and satisfaction were qualitatively reviewed due to heterogeneity in outcomes assessment andwere found equivalent or superior using propofol. Conclusions: There are a limited number of randomised controlled trials reporting on efficacy and safety of propofol during colonoscopy. Among the six published placebo controlled studies, there is a suggestion that propofol is superior to conventional sedationwith respect to recovery time, hypoxia, hypotension, pain control and patient satisfaction. The evidence for improved patient pain control and satisfaction is qualitative. Future studies require standardized assessment of these outcomes to allow quantitative aggregation of results. As more centers utilize propofol for routine colonoscopy, the cost-efficacy of reduced recovery time may become apparent.

Identification of factors that influence conscious sedation in gastrointestinal endoscopy.

Although several studies examined factors that influence conscious sedation, investigation was limited into the gender and age. The aim of this prospective study is to identify the clinical variables of successful conscious sedation during gastrointestinal endoscopy. A total of 300 subjects who underwent gastrointestinal endoscopy were enrolled in a prospective fashion. They completed a questionnaire to assess height, weight, drinking, smoking, education level, recent medication, past medical history, previous experience of conscious sedation, preprocedural anxiety, and apprehension about the procedure. Efficacy of sedation and amnesia were evaluated by the subject and the endoscopist. Amnesic and sedative effects were proportionally related with age (p<0.0001). Preprocedural anxiety level was higher in women (p=0.0062), younger subjects (p=0.035), slender subjects (p=0.041), and in those without previous experience of conscious sedation (p=0.0034). This anxiety level was also related to increased pain (p=0.0026) and alertness (p=0.0003) during the procedure. Lower dose of midazolam is needed for sedation in older subjects. Subjects with a high level of preprocedural anxiety such as women, younger subjects, slender subjects, and those without previous experience of conscious sedation should be sedated with great caution because generally, they complain of much more severe pain and alertness during the procedure.

Behavioral Undercontrol and Subjective Stimulant and Sedative Effects of Alcohol Intoxication: Independent Predictors of Drinking Habits?

Background: Previous studies have demonstrated relations between behavioral undercontrol (e.g., sensation seeking) and higher levels of alcohol use. The mechanism underlying this relation is not yet understood. In this article, we investigate the role of subjective stimulant and sedative effects of intoxication on drinking habits, and we test the possibility that these effects mediate or moderate relations between behavioral undercontrol and drinking habits. Methods: College drinkers (n= 91) consumed 0.85 ml/kg of alcohol (approximately four drinks) and completed self-report measures of stimulation and sedation at three time points: (1) before drinking; (2) 15 min after consumption, on the ascending limb of the blood alcohol curve; and (3) 45 min after consumption, on the descending limb of the curve. In addition, participants completed the MacAndrew Alcoholism and Sensation Seeking Scales, indices of behavioral undercontrol, and a self-report questionnaire of drinking habits (quantity, frequency, and maximum). Results: As expected, undercontrol was strongly related to drinking habits (p < 0.0005). Undercontrol was also significantly related to ascending limb stimulation (p < 0.005), which, in turn, was related to drinking habits (p < 0.005). Finally, stimulation was found to moderate the relations between undercontrol and drinking habits such that relations were stronger at higher levels of stimulation. Conclusions: These findings may help to better understand the variability in drinking behavior, and this may be critical in eventually developing and appropriately targeting prevention efforts.

Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery.

This paper describes the pharmacokinetics and effects of propofol in short-term sedated paediatric patients. Six mechanically ventilated children aged 1-5 years received a 6 h continuous infusion of propofol 6% at the rate of 2 or 3 mg kg-1 h-1 for sedation following cardiac surgery. A total of seven arterial blood samples was collected at various time points during and after the infusion in each patient. Pharmacokinetic modelling was performed using NONMEM. Effects were assessed on the basis of the Ramsay sedation score as well as a subjective sedation scale. The data were best described by a two-compartment pharmacokinetic model. In the model, body weight was a significant covariate for clearance. Pharmacokinetic parameters in the weight-proportional model were clearance (CL) = 35 ml kg-1 min-1, volume of central compartment (V1) = 12 l, intercompartmental clearance (Q) = 0.35 l min-1 and volume of peripheral compartment (V2) = 24 l. The interindividual variabilities for these parameters were 8%, < 1%, 11% and 35%, respectively. Compared with the population pharmacokinetics in adults following cardiac surgery and when normalized for body weight, statistically significant differences were observed the parameters CL and V1 (35 vs 29 ml kg-1 min-1 and 0.78 vs 0.26 l kg-1P < 0.05), whereas the values for Q and V2 were similar (23 vs 18 ml kg-1 min-1 and 1.6 vs 1.8 l kg-1, P > 0.05). In children, the percentage of adequately sedated patients was similar compared with adults (50% vs 67%) despite considerably higher propofol concentrations (1.3 +/- 0.10 vs 0.51 +/- 0.035 mg l-1, mean +/- s.e. mean), suggesting a lower pharmacodynamic sensitivity to propofol in children. In children aged 1-5 years, a pharmacokinetic model for propofol was described using sparse data. In contrast to adults, body weight was a significant covariate for clearance in children. The model may serve as a useful basis to study the role of covariates in the pharmacokinetics and pharmacodynamics of propofol in paediatric patients of different ages.

A New Computerized Test Battery to Evaluate Drug Effects on Psychomotor Performance. Lorazepam-induced Impaired Performance in Healthy Volunteers.

Objective: This study was performed to evaluate the sensitivity of a new computerized test battery which we developed for the detection of drug-induced impaired psychomotor performance.Methods: Twelve healthy male volunteers participated in this study. Lorazepam (0.5 or 1.0 mg oral), an antianxiety drug, or placebo was administered in a double-blind fashion with a Latin square design, with an interval of more than one week. The psychomotor performance tests were done before, and at 1 and 3 hours after drug administration. The test battery consisted of four different tasks ; a simple number copying test (SNCT), a continuous number addition test (CNAT), a number comparison test (NCT) and two types of reaction time tests (RTT). In SNCT, CNAT and NCT, percent changes in the number of keyed-in figures and the number of correctly keyed-in figures were automatically measured, and in RTT, the latency to respond was automatically recorded. To measurelorazepam-induced subjective sedative actions, visual analogue scales (VAS) were used.Results: The performance was impaired in SNCT and CNAT 1 hour after administration of 1.0 mg lorazepam, and in NCT 1 hour after administration of 0.5 and 1.0 mg lorazepam. There was no significant difference between lorazepam and placebo in RTT. The impaired psychomotor performance was observed irrespective of the absence of lorazepam-induced subjective sedative effects.Conclusion: The lorazepam-induced impaired psychomotor performance was objectively and sensitively detected in healthy volunteers by a new computerized test battery which we developed. This new objective method can be applied to sensitively detect minimal sedative effects of drugs in a situation similar to daily life.

Cognitive and sedative effects of benzodiazepine use.

This paper reviews the effects of benzodiazepines (BZs) on the performance of tasks measuring human cognitive abilities. The paper reviews the most common cognitive side effects of BZs: increased sedation, decreased attention, and anterograde amnesia. In particular, this paper focuses on recent findings regarding time course-related effects on BZ-induced deficits in explicit and implicit human memory performance. Specifically, we reviewed recent research indicating that both explicit memory and priming are impaired by BZs if the encoding task takes place near the time of the theoretical peak plasma concentrations of the drug. Although BZs also appear to increase objective and subjective sedation, as well as to impair attentional processing, these other cognitive impairments do not appear to fully account for the widespread memory deficits caused by BZ administration. The theoretical and clinical implications of benzodiazepine-induced memory impairments are discussed.

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10 mg (as a verum) and placebo in 10 healthy volunteers in a double-blind, randomised cross-over study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ). Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the difference with placebo reaching statistical significance on day 1, 8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05). These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10-20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.

The pharmacokinetics of dexmedetomidine in volunteers with severe renal impairment.

Dexmedetomidine, an alpha2-adrenergic agonist with sedative and analgesic properties, is mainly cleared by hepatic metabolism. Because the pharmacokinetics of dexmedetomidine have not been determined in humans with impaired renal function, we studied them in volunteers with severe renal disease and in control volunteers. Six volunteers with severe renal disease and six matched volunteers with normal renal function received dexmedetomidine, 0.6 microg/kg, over 10 min. Venous blood samples for the measurement of plasma dexmedetomidine concentrations were drawn before, during, and up to 12 h after the infusion. Two-compartmental pharmacokinetic models were fit to the drug concentration versus time data. We also determined its hemodynamic, respiratory, and sedative effects. There was no difference between Renal Disease and Control groups in either volume of distribution at steady state (1.81 +/- 0.55 and 1.54 +/- 0.08 L/kg, respectively; mean +/- SD) or elimination clearance (12.5 +/- 4.6 and 8.9 +/- 0.7 mL x min(-1) x kg(-1), respectively). However, elimination half-life was shortened in the Renal Disease group (113.4 +/- 11.3 vs 136.5 +/- 13.0 min; P < 0.05). A mild reduction in blood pressure occurred in most volunteers. Although most volunteers were sedated by dexmedetomidine, renal disease volunteers were sedated for a longer period of time. The pharmacokinetics of dexmedetomidine in volunteers with severe renal impairment differed little from those in volunteers with normal renal function. In addition, there were no clinically significant differences in the hemodynamic responses to dexmedetomidine. However, dexmedetomidine resulted in more prolonged sedation in subjects with renal disease.

Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo-controlled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

PQP1: LESSONS LEARNED FROM DEVELOPING A PSYCHOMETRICALLY BASED SEDATION QUESTIONNAIRE IN PHARMACOLOGICALLY PARALYZED CRITICALLY ILL PATIENTS

OBJECTIVE: To share lessons learned from developing a reliable and valid questionnaire for adequacy of sedation in pharmacologically paralyzed critically ill patients. METHODS: In phase 1, seven experts listed 21 characteristics describing anxiety in pharmacologically paralyzed patients. In phase 2, two scenarios were created illustrating the experience of paralysis: one with and one without receiving a sedative. A convenience sample of 30 people evaluated scenarios to determine the importance of characteristics obtained from phase 1 using a five-point scale. Items were reduced to the 10 most important characteristics (mean 3). Based on these results, the final instrument consisted of 12 questions: 2 categorical addressing memory of the experience and 10 referred to characteristics of anxiety. In phase 3, two groups of critically ill patients were administered the questionnaire: 1) sedated only and 2) sedated and pharmacologically paralyzed. The questionnaire was administered twice for reliability. Questionnaire results were compared to subjective and objective sedation monitoring tools for validity. Calculated sample size was 20 for each group. RESULTS: During six months, 21 patients consented to participate. Twelve patients died and nine patients (6 sedated, 3 sedated/paralyzed) were administered questionnaires. Five patients (3 sedated, 2 sedated/paralyzed) did not remember the intensive care unit experience. Two of three patients in the sedated group who answered the questionnaire found it difficult to remember over time. One sedated/paralyzed patient who answered the questionnaire received a sedative without amnesic properties and felt anxious during therapy. The distressful feeling of this patient was comparable to findings of the objective sedation tool. CONCLUSIONS: Mortality in this critically ill patient population was high. Due to amnestic properties of sedatives most patients did not remember the experience. Of patients who remembered, their memory deteriorated over time. Based on lessons learned, it may require 2–3 years to achieve the necessary sample size.

Acute effect of 3-(4-acetamido)-butyrril-lorazepam (DDS2700) on brain function assessed by PET at rest and during attentive tasks.

The aim of this study was to assess, by positron emission tomography (PET), the effect on cerebral functional activity of a new lorazepam-gamma-aminobutyric acid (GABA) conjugate [3-(4-acetamido)-butyrril lorazepam (DDS2700)]. Ten healthy volunteers were studied by PET and [18F]fluoro-deoxy-D-glucose ([18F]FDG) under baseline conditions and following the administration of DDS2700. Regional cerebral blood flow (rCBF) was measured by PET and 15O-water in three additional participants while they performed attentive tasks, before and after drug administration. DDS2700 induced a decrease in the regional cerebral metabolic rate of glucose (rCMRglu) in the thalamus (-17%), cerebellum (-11%) and caudate nucleus (-8%). The observed effects on glucose metabolism were probably related to the subjective sedation and tiredness reported by the participants. During the attentive tasks, rCBF increased in frontal and temporal regions associated with attentional processing of auditory material. These circuits were no longer active after DDS2700 administration, while rCBF increased in cingulate cortex, occipitoparietal regions, pons and cerebellum. These drug-induced activations might be directly related to intervening sleepiness and to the consequent effort in keeping attention focused on the tasks. The effects of DDS2700 on glucose metabolism at rest, and on rCBF during activation conditions, indicate a drug action on cerebral networks involved in alertness, vigilance and attention maintenance. PET assessment by [18F]FDG and water may provide complementary information in pharmacodynamic studies.

An investigation into the effects of cetirizine on cognitive function and psychomotor performance in healthy volunteers

The cognitive and psychomotor effects of 2.5, 5 and 10 mg cetirizine, a second-generation H1 receptor antagonist, were compared with loratadine 10, 20 and 40 mg, promethazine 25 mg and placebo in 24 healthy volunteers in a double-blind, randomised cross-over study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3 and 6 h post-dose. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking task (CTT) and assessment of subjective sedation (LARS). Cetirizine and loratadine at all doses tested were not significantly different from placebo in any of the tests used. However, as expected for a verum, all measures with the exception of CTT were significantly disrupted by promethazine (P < 0.05). Promethazine caused a reduction in CFF threshold at all test points; these differences were significant at 3 h and 6 h post-dose (P < 0.05). There was also a significant increase in total reaction time at 3 h post-promethazine administration. Subjective reports of sedation were significantly greater following the administration of promethazine at all time points (P < 0.05). These results allow the conclusion that cetirizine at its recommended therapeutic dose of 10 mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the positive control, promethazine 25 mg.

The Acute and Sub-chronic Effects of Levocetirizine, Cetirizine, Loratadine, Promethazine and Placebo on Cognitive Function, Psychomotor Performance, and Weal and Flare

SummaryAim: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (l-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments.Methods: Twenty healthy volunteers (18–50 years) received l-CTZ 5 mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100mg/ml histamine solution at baseline and at 1, 2, 3,4, 6,8,10 and 12 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit.Results: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). l-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, l-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4.Conclusions: In a study where the psychometric assessments were shown to be sensitive to impairment, l-CTZ 5 mg was found not only to be a potent inhibitor of the histamine-induced weal and flare reaction,

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

SummaryObjective:The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10mg (as averum) and placebo in 10 healthy volunteers in a double-blind, randomised crossover study.Methods: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ).Results: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the I difference with placebo reaching statistical significance on day 1,8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8 h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05).Conclusions: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10–20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.