Driving performance and neurocognitive skills of long-term users of sedating antidepressants

Objective: To assess driving performance and neurocognitive skills of long‐term users of sedating antidepressants, in comparison to healthy controls. Methods: Thirty‐eight long‐term (>6 months) users of amitriptyline (n = 13) and mirtazapine (n = 25) were compared to 65 healthy controls. Driving performance was assessed using a 1‐h standardised highway driving test in actual traffic, with road‐tracking error (standard deviation of lateral position [SDLP]) being the primary measure. Secondary measures included neurocognitive tasks related to driving. Performance differences between groups were compared to those of blood alcohol concentrations of 0.5 mg/ml to determine clinical relevance. Results: Compared to controls, mean increase in SDLP of all antidepressant users was not significant, nor clinically relevant (+0.75 cm, 95% CI: - 0.83 cm; +2.33 cm). However, users treated less than 3 years (n = 20) did show a significant and clinically relevant increase in SDLP (+2.05 cm). No significant effects were observed on neurocognitive tasks for any user group, although large individual differences were present. Most results from neurocognitive tests were inconclusive, while a few parameters confirmed non‐inferiority for users treated longer than 3 years. Conclusion: The impairing effects of antidepressant treatment on driving performance and neurocognition mitigate over time following long‐term use of 3 years

The influence of alcohol (0.5‰) on the control and manoeuvring level of driving behaviour, finding measures to assess driving impairment:A simulator study

Objective: The influence of psychoactive substances on driving performance and traffic safety has been extensively studied. Research on the influence of alcohol at the control level of behaviour (i.e. automated processes) has been well established and has shown that the ability to operate a vehicle decreases with rising alcohol levels. However, results one level higher at the manoeuvring level (i.e. conscious processes), are inconsistent. The current study aimed to replicate findings on the influence of alcohol on the control level of behaviour and investigate effects on the manoeuvring level in order to find suitable measures to assess driving impairment. Method: The study was double-blind, placebo-controlled with a counterbalanced treatment order and a two-way crossover design. Thirty participants performed tasks in a driving simulator under the influence of alcohol (0.5‰) and a placebo. In the driving tasks the control level of behaviour (swerving, average speed, and speed variation) was investigated, as well as the manoeuvring level of behaviour (distance to other traffic during an overtaking manoeuvre, reaction time to a traffic light turning amber, and response to a suddenly merging car). Results: As expected, alcohol affected the control level of behaviour negatively. Participants swerved more and showed more speed variation after alcohol intake. The manoeuvring level of driving behaviour was also affected by alcohol. The distance to other drivers during an overtaking manoeuvre was smaller under the influence of alcohol. Results on reaction time were however less straightforward. Reaction time increased significantly under the influence of alcohol when reacting to a traffic light but not in reaction to a car unexpectedly merging into traffic. When analysing behaviour in reaction to these different events in more detail it became clear that they were responded to in varying manners, making it difficult to find an average impairment measure. Conclusions: The deteriorating effect of alcohol at the control level of driving behaviour was replicated, confirming the suitability of the standard deviation of lateral position and the variation in speed as measures of impairment. At the manoeuvring level, the kept distance to the leading car during an overtaking manoeuvre appeared to be a suitable measure to assess impairment as well as reaction time to a traffic light. The current study also confirms the difficulties in evaluating complex driving behaviour and the need for more research on this subject

Brachio-cephalic ('Gracz') fistula use for continuous hemofiltration in a hemodynamically unstable hemodialysis patient without venous vascular access: a case report

Even in patients with chronic renal failure and chronic intermittent hemodialysis, continuous venovenous hemofiltration (CVVH) is the most often practiced renal replacement technique in the intensive care unit. Although patients show less hemodynamic instability during CVVH than during hemodialysis, it requires a blood flow exceeding 200 ml/min in the extracorporeal circuit necessitating the use of large bore catheters. Vascular access in critically ill septic and edematous patients is sometimes difficult, or even impossible

Assessing fitness to drive:A validation study on patients with mild cognitive impairment

Objectives: There is no consensus yet on how to determine which patients with cognitive impairment are able to drive a car safely and which are not. Recently, a strategy was composed for the assessment of fitness to drive, consisting of clinical interviews, a neuropsychological assessment, and driving simulator rides, which was compared with the outcome of an expert evaluation of an on-road driving assessment. A selection of tests and parameters of the new approach revealed a predictive accuracy of 97.4% for the prediction of practical fitness to drive on an initial sample of patients with Alzheimer's dementia. The aim of the present study was to explore whether the selected variables would be equally predictive (i.e., valid) for a closely related group of patients; that is, patients with mild cognitive impairment (MCI).Methods: Eighteen patients with mild cognitive impairment completed the proposed approach to the measurement of fitness to drive, including clinical interviews, a neuropsychological assessment, and driving simulator rides. The criterion fitness to drive was again assessed by means of an on-road driving evaluation. The predictive validity of the fitness to drive assessment strategy was evaluated by receiver operating characteristic (ROC) analyses.Results: Twelve patients with MCI (66.7%) passed and 6 patients (33.3%) failed the on-road driving assessment. The previously proposed approach to the measurement of fitness to drive achieved an overall predictive accuracy of 94.4% in these patients. The application of an optimal cutoff resulted in a diagnostic accuracy of 100% sensitivity toward unfit to drive and 83.3% specificity toward fit to drive. Further analyses revealed that the neuropsychological assessment and the driving simulator rides produced rather stable prediction rates, whereas clinical interviews were not significantly predictive for practical fitness to drive in the MCI patient sample.Conclusions: The selected measures of the previously proposed approach revealed adequate accuracy in identifying fitness to drive in patients with MCI. Furthermore, a combination of neuropsychological test performance and simulated driving behavior proved to be the most valid predictor of practical fitness to drive.</p

An explorative approach to understanding individual differences in driving performance and neurocognition in long-term benzodiazepine users

Objective: Previous research reported cognitive and psychomotor impairments in long‐term users of benzodiazepine receptor agonists (BZRAs). This article explores the role of acute intoxication and clinical complaints. Methods: Neurocognitive and on‐road driving performance of 19 long‐term (≥6 months) regular (≥twice weekly) BZRA users with estimated plasma concentrations, based on self‐reported use, exceeding the therapeutic threshold (CBZRA+), and 31 long‐term regular BZRA users below (CBZRA−), was compared to that of 76 controls. Results: BZRA users performed worse on tasks of response speed, processing speed, and sustained attention. Age, but not CBZRA or self‐reported clinical complaints, was a significant covariate. Road‐tracking performance was explained by CBZRA only. The CBZRA + group exhibited increased mean standard deviation of lateral position comparable to that at blood‐alcohol concentrations of 0.5 g/L. Conclusions: Functional impairments in long‐term BZRA users are not attributable to self‐reported clinical complaints or estimated BZRA concentrations, except for road‐tracking, which was impaired in CBZRA + users. Limitations to address are the lack of assessment of objective clinical complaints, acute task related stress, and actual BZRA plasma concentrations. In conclusion, the results confirm previous findings that demonstrate inferior performance across several psychomotor and neurocognitive domains in long‐term BZRA users

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets

Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (Tmax) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another. Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant “safe space” for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the “safe space” for dissolution. Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy. Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the “safe space” based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem. Conclusions: A PBPK/PD model indicates that current BCS biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling