Changes in ocular measures due to benzodiazepines and alcohol consumption.

Changes in ocular measures due to benzodiazepines and alcohol consumption. Vanessa Wilkinson 1, Melinda Jackson 1,2, Bronwyn Stevens 1, Justine Westlake 1, Maree Barnes 1, Philip Swann 3, Mark Howard 1. 1 Institute for Breathing & Sleep, Department of Respiratory & Sleep Medicine, Austin Health 2 School of Psychology, Victoria University 3 Department Road Safety, VicRoads Ocular measures were found to change from baseline following benzodiazepine and alcohol consumption during a simulated driving task and were associated with decreased driving simulator performance and increased subjective sleepiness. Many participants underestimated their level of driving impairment following benzodiazepine administration. Ocular measures in this study were monitored using the Optalert Drowsiness Measurement System (ODMS), a device marketed to, and utilised by, commercial fleet to ensure alertness of drivers, despite minimal scientific validation. Ocular measures may have potential use in determining alcohol and drug-related impairment during driving. Background: Alcohol, sleepiness and drugs are leading contributing factors to road accidents. Benzodiazepine use is commonly detected in drivers injured in motor vehicle accidents (Ch ng et al., 2007) and is associated with a significantly increased risk of multiple accidents in commercial vehicle drivers (Howard et. al., 2004). Temazepam, a benzodiazepine, is the most frequently prescribed hypnotic in Australia (Hollingwoth & Siskind, 2010). MIMS consumer medication information advises individuals not to drive until they are aware of how Temazepam affects their driving ability. It is illegal to drive when impaired due to any cause; however, enforcement of laws about driving under the influence of legal drugs is difficult due to problems with real-time testing of benzodiazepine use. Changes in eyelid movements are known to occur in drowsy subjects, however less is known about changes in eyelid movements due to alcohol and legal drugs such as benzodiazepines. Changes in the frequency, amplitude and duration of blinks and occurrences of slow eye closure have been documented to occur in response to sleep deprivation (Tucker and Johns 2005; Wierwille and Ellsworth, 1994) and ocular measures are believed to have ability in measuring alertness, and thus improving safety, during on-road driving. We measured changes in eyelid movements following sleep restriction, alcohol and benzodiazepines using Optalert Drowsiness Measurement System (ODMS). ODMS is a real-time safety system designed to accurately detect the onset of driver drowsiness. ODMS is used commercially by transport drivers to continuously monitor their alertness, and delivers a warning to the driver when a level of drowsiness associated with increased accident risk is imminent.

Aims: To investigate the effect of benzodiazepines and alcohol on objective ocular drowsiness measures and subjective questionnaire responses during simulated driving. Methods: Participants (N=32) completed a 60 minute driving simulation task in a six condition randomised cross over design over three days at least one week apart. Participants were required to have a current driver s license and be over the age of 18. Participants were recruited from the public via means such as advertisements on clinical trial registries. Participants underwent a medical screening conducted by a consultant sleep physician to determine their suitability to participate, via assessment for sleep disorders (including a validated OSA screening questionnaire (Maislin et al., 1995)), excessive daytime sleepiness and contra-indications to alcohol, benzodiazepines or sleep restriction. Potential participants found to have a sleep disorder, excessive sleepiness or contra-indications to the experimental conditions were excluded from participating. Conditions were 1) baseline, 2) 0.05% blood alcohol concentration (0.05%BAC), 3) 0.08%BAC, 4) 20mg Temazepam (Temaze), 5) the morning (SR-AM) and 6) afternoon (SR- PM) following sleep restriction to four hours. Testing sessions (A, B, C) were conducted in a randomised order, but conditions remained in a consistent order within the particular session to allow for accumulation of BAC (testing session A) or sleepiness (testing session C). Testing sessions were: A (conditions 1, 2, 3), B (condition 4), and C (conditions 5, 6). Participants were randomised to the order of completing their baseline testing session; however it was always conducted prior to the 0.05%BAC and 0.08%BAC conditions. Participants were required to have at least eight hours in bed prior to session A and B to ensure they were rested. Participants slept from 0200-0600 on the night prior to session C. This was confirmed via actigraphy (conducted using SenseWear Body Monitoring System armband, Pittsburgh, USA). Participants were tested to ensure no alcohol or drugs were consumed prior to each testing session. BAC was measured using a calibrated Alcometer (model SD_400, Lion Laboratories, Glamorgan, UK). This instrument has an accuracy of ± 10%. The Dräger DrugTest 5000 Test Kit 6 Panel (Ref. 83 19 830, Lübeck, Germany) was used for qualitative detection of cocaine, opiates, benzodiazepines, THC, amphetamine and methamphetamine or their metabolites in human saliva. The Securetec DrugWipe Saliva Test (005-BZO, Brunnthal, Germany) was also used for the detection of benzodiazepines. Participants drank standard drinks of vodka (30ml of vodka mixed with orange juice) to achieve two target BACs (0.05% and 0.08% BAC, ±0.005%). Approximate alcohol required to reach the target BACs were calculated using the participant s gender, weight and age. BAC was measured using the Alcometer 15min after each drink, with participants blinded to their BAC. Performance measures were conducted in the afternoon of session A, once participants had achieved the target BACs (approximately three hours apart).

In the Temaze condition, participants were blinded to the type of tablet being taken, but were told it may or may not make them sleepy. Performance measures were then conducted two hours following administration of a 20 mg dose of Temazepam. Participants were able to withdraw from the study at any time and not all participants completed all test sessions. Driving ability was measured by average steering deviation (cm) on a driving simulator task. Variation in lane position was chosen as the primary outcome variable because it has previously been shown to be sensitive to the effect of both sleep restriction and alcohol using the AusEd driving simulator (Howard et al., 2007, Vakulin et al., 2007). Participants rated subjective sleepiness using the Sleepiness Symptoms Questionnaire (SSQ) and the Stop Driving Questionnaire (SDQ). Measures: AusEd Simulated Driving Task Participants undertook a 60-minute simulated driving task in a small, darkened, soundproofed room. The AusEd driving simulator consists of a computer display of a road and requires participants to use a steering wheel and foot pedals to simulate driving a car (Desai et al., 2007). The drive was a monotonous night-time drive on a two lane highway, which included standard lane divisions and road edges marked with reflective posts. A 60-minute drive was chosen because previous studies have demonstrated sleep-deprivation effects within this time frame (Vakulin et al., 2007). The drive included a series of curved and straight sections, and participants were instructed to brake in response to other vehicles. Participants were asked to maintain their position in the middle of the left-hand lane on the road (in accordance with Australian driving regulations) and keep their speed within 60-80 km/h on the speedometer. The road components and time of presentation of vehicles were identical for each drive session. The AusEd driving simulator was designed to assess fatigue in a clinical laboratory setting and has shown sensitivity to detecting individuals with diagnosed sleep disorders (Vakulin et al. 2011) as well as correlations with performance on currently used clinical tests for maintaining wakefulness (Maintenance of Wakefulness Test) that are used to determine whether drivers are sufficiently alert to possess a drivers license (Banks et al, 2005). Simulated driving tasks under sleep deprivation conditions have been shown to be comparable to real-life driving in variables such as line crossings and lane deviation (Philip et al. 2005). Optalert Drowsiness Measurement System (ODMS) ODMS (Optalert, Sleep Diagnostics Pty Ltd, Melbourne, Australia) is a device that measures the frequency and velocity of ocular movements, and is used to provide an objective measure of driver drowsiness. It consists of a pair of glasses and uses pulses of invisible infrared light from a light emitting diode positioned below and in front of the eye. Measures such as the duration of eyelid closure, of eyelids remaining closed and of reopening are calculated separately and automatically for each blink (Johns et al., 2007). Ocular measures included: Blink Total Duration (BTD): total duration of blinks (see Figure 1).

Negative Inter-Event Duration (IED): time between maximum closing/opening velocity of eyelid (see Figure 1). Johns Drowsiness Score (JDS, range 0-10): a composite measurement of fatigue based on several ocular characteristics. JDS is the fatigue measurement variable used in the commercially available version of the ODMS. Figure 1: Inter-Event Duration (IED) is measured from maximum closing velocity to maximum opening velocity during a blink (between arrows). Blink Total Duration (BTD) is measured from the start of closing to complete reopening during a blink (between arrows) (adapted from ODMS (Optalert ) manual). BTD, IED and JDS have been found to have good utility in detecting fatigue-related lapses in attention during baseline and sleep restricted conditions (Howard et al., 2011). Sleepiness Symptoms Questionnaire (SSQ) The SSQ is a self-administered questionnaire designed to measure sleepiness symptoms during driving. The respondents use a scale of one to seven to rate the frequency of eight symptoms of sleepiness. A score for each item, as well as an overall summed score of all symptoms is calculated, with higher scores indicating higher subjective sleepiness symptoms. Stop Driving Questionnaire (SDQ) Participants indicated whether they would continue to drive in a hypothetical on-road situation given their current state of sleepiness and using the SDQ (Appendix 1).

Statistical Analysis: STATA Version 11.2 (StataCorp, College Park, TX) was used for all statistical analyses. Results: The average age of participants was 42.9 (±14.0) with an average BMI of 29.3 (±5.9) and median Epworth Sleepiness Scale (Johns, 1991) of 5 (range 1-16). Means and standard deviations of measured BACs during each alcohol condition were: Baseline = 0.000 (± 0.000), 0.05% BAC = 0.048 (± 0.010), 0.08% BAC = 0.077 (± 0.014). Sleepiness Symptoms Questionnaire SSQ increased significantly from baseline in the 0.05%BAC (p=0.021), 0.08%BAC (p=0.013), Temaze (p=0.017), SR-AM (p=0.043), and SR-PM (p=0.031) conditions (Wilcoxon rank sum test, see Table 1). Baseline 0.05% BAC 0.08% BAC Temaze SR-AM SR-PM Median 22 31 40 31 29 31 IQR 19-30 24-40 30-50 23-42 23-42 26-45 Table 1: Sleepiness Symptoms Questionnaire (SSQ) (median and IQR). Simulated Driving Ability Driving ability, as measured by variation in lane position (steering deviation), was significantly worse than in a rested baseline condition in the 0.05%BAC (p=0.024), 0.08%BAC (p=0.001) and SR-PM (p=0.045) conditions, with a trend towards decreased driving ability in the Temaze (p=0.098) and SR-AM (p=0.524) (paired t-test) (see Graph 1). JDS JDS increased significantly from rested baseline due to alcohol in the 0.05%BAC condition (p=0.037) and there was a trend towards increased JDS due to Temaze and alcohol at 0.08%BAC (see Figure 2).

Steering deviation (cm) 160 140 120 100 80 60 40 4 3.5 3 2.5 2 1.5 1 JDS 20 0 Baseline 0.05%BAC 0.08%BAC Temaze SR AM SR PM 0.5 0 Steering deviation JDS Figure 2: JDS and steering deviation (mean, SEM). Linear regression found that increased mean JDS values during the one hour driving simulation were associated with decreased driving simulator performance (greater lane steering deviation) (p=0.003) and increased subjective sleepiness (SSQ) (p<0.001). IED and BTD IED and BTD had a trend towards increasing from baseline for each experimental condition (see Figure 3). BTD showed significant increases from baseline in the 0.05%BAC (p=0.034), 0.08%BAC (p=0.023) conditions, with a trend toward increased BTD in the Temaze condition (p=0.067, unpaired t test). The duration of blinks was far greater in the Temaze condition than other conditions. IED showed significant increases from baseline in the 0.05%BAC (p=0.019) and Temaze (p=0.029) with a trend towards increased IED in the other conditions (unpaired t-test). Time (s) 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Baseline 0.05%BAC 0.08%BAC Temaze SR AM SR PM IED BTD Figure 3: IED and BTD (mean, SEM).

Linear regression found that both increased mean BTD and increased mean IED values during the 60 minute simulated drive were independently associated with decreased driving performance (greater lane steering deviation) (p<0.001) and increased subjective sleepiness (SSQ) (p<0.001). Perception of Driving Ability: 42% of the participants in the Temaze condition (n=31) reported they would be willing to continue driving in a hypothetical on-road short suburban driving situation. Only 14% of participants (n=28) reported willingness to drive at 0.05%BAC. No participants (n=15) reported willingness to continue driving at 0.08%BAC. In the SR-AM condition (n=32) 44% were willing to drive whilst 48% were willing to drive in the SR-PM condition (n=31). Rested, baseline perception of driving ability data was available for 31 participants. Of the 23 participants who rated their driving simulator performance as impaired in the Temaze condition, 7 reported they would still be willing to drive in a real-life situation. 60% of participants performed worse in the Temaze condition than their 0.05%BAC performance. Perception of driving impairment was found to be underestimated in the Temaze condition with a substantial proportion of participants reporting willingness to drive in an on-road situation despite their simulated driving ability being deteriorated to a level greater than their performance in the 0.05%BAC condition (see Table 2). In comparison, a smaller proportion of participants were willing to drive after the SR-PM condition when they performed worse than 0.05%BAC. Temaze SR-PM Stop driving 58% 71% Continue driving 42% 29% N= 12 7 Table 2: Proportion of participants reporting they would stop driving or continue to undertake a short suburban drive after performing worse than during a 0.05%BAC driving simulation. When asked willingness to undertake a continuous long distance drive, more participants (29%) reported to be willing to drive during the Temaze condition than other experimental conditions (see Table 3). Baseline 0.05% BAC 0.08% BAC Temaze SR-AM SR-PM 53% 11% 0% 29% 23% 26% Table 3: Proportion of participants willing to undertake a continuous long distance drive in each condition

Conclusion: Ocular measures of drowsiness were altered by alcohol consumption and benzodiazepines. Different aspects of ocular measures were affected by alcohol (JDS, BTD, IED) than benzodiazepines (IED). These ocular changes correspond with increased subjective measures of drowsiness and decreased measures of driving simulator performance. The ODMS is designed for use during on-road driving and is marketed to commercial transport companies to ensure the alertness and safety of their drivers. The current study used a simulated driving task to infer driving ability and, at present, there are no published studies assessing the use of ODMS during on-road driving. We are currently conducting studies of on-road driving in a controlled environment to determine the utility of ocular measures to predict accident risk when impaired. Individuals did not accurately perceive their driving ability following Temazepam administration. 60% of participants performed worse in the Temaze simulated driving condition than their 0.05%BAC performance (a benchmark indicating impaired driving which increases accident risk). However, 42% of these participants responded that they would continue to drive in a hypothetical real-life suburban drive. Greater consumer guidelines may be required to warn of potential dangers of driving when impaired by legal drugs as individuals appear unable to accurately assess their own driving ability. Ocular measures may have potential in determining impairment due to benzodiazepine and alcohol consumption during on-road driving, in addition to their use in detecting impairment due to sleepiness and fatigue.

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Appendix 1: Stop Driving Questionnaire PART 1. With regards to how alert you feel, which one of the following statements best describes how you feel about driving for a short period in suburban traffic right now. (TICK ONE BOX) 1. I would continue driving 2. I would continue driving only if pressured to do so 3. I would stop driving now even if under pressure to continue 4. I would have stopped driving some time ago PART 2. With regards to how alert you feel, which one of the following statements best describes how you feel about driving for a continuous long distance right now. (TICK ONE BOX) 1. I would continue driving 2. I would continue driving only if pressured to do so 3. I would stop driving now even if under pressure to continue 4. I would have stopped driving some time ago