Makowski AL, Lindgren K, Locke JP. Visual side effects of scopolamine/dextroamphetamine among parabolic fliers. Aviat Space Environ Med 2011; 82:683–8.
Introduction: Scopolamine/dextroamphetamine has been used to combat motion sickness generated aboard research aircraft for decades. While it has shown to be effective, previous studies differ as to the presence of visual side effects secondary to scopolamine's anticholinergic properties. This study sought to quantify any such effects in order to determine if they are operationally significant. Methods: Fliers in NASA's Reduced Gravity Program received a weight-based dose of scopolamine/dextroamphetamine prior to boarding the aircraft. Measurements of pupil size, visual acuity, and accommodation were taken in identical conditions using subjects' dominant eyes prior to medication administration and again after landing. We enrolled 131 subjects ages 18–48. Pre- and postflight measurements of pupil size and acuity were available for 125 subjects. Results: Average pupil size increased by 1.1 mm (95% CI 0.9–1.2). Only 1.6% of subjects experienced a change in visual acuity of greater than 10 ft. The average near-point accommodation changed from 8.61 to 7.84 diopters, a difference of −0.77 (−1.01 to −0.53) diopters or 1.34 cm (0.87–1.81). Increasing age also correlated significantly with worsening change in accommodation. Discussion: This study found statistically significant changes in pupil size and near point accommodation that do not appear to be clinically important. No significant decrement in acuity was noted. While direct effects on in-flight performance could not be assessed, the use of scopolamine/dextroamphetamine among fliers aboard research aircraft does not appear to yield visual side effects sufficient to compromise later ground operations.Keywords
MOTION SICKNESS resulting from rough seas has plagued mariners since ancient times. The advent of aviation and the subsequent generation of hypergravity environments have produced increasingly nauseogenic stimuli while simultaneously requiring heightened levels of performance from affected personnel. NASA's Reduced Gravity Program typically produces forces alternating among 1.8, 0, and 1.0 g as a DC-9 aircraft flies parabolic trajectories yielding approximately 25 s of simulated microgravity at a time. Typical flights involve 40-60 such parabolas and the incidence of motion sickness among non-medicated first time fliers is roughly 70% (Locke JP. Personal communication, October 2010). The introduction of prophylactic antiemetics has reduced this rate considerably, but there remains concern for operationally significant side effects.
The pharmacologic agent offered to fliers is a preparation of scopolamine (hyoscine bromide) and dextroamphetamine. Scopolamine is a belladonna alkaloid similar to atropine with strong anticholinergic properties while dextroamphetamine functions as a sympathomimetic. Scopolamine's mechanism of action is thought to arise from competitive blockade of postganglionic muscarinic receptors, which hinders neurotransmission and communication between the vestibular apparatus and the vomiting center located in the medulla (15,30). Its efficacy in the prevention of motion sickness has been known since World War II (12) and has been demonstrated repeatedly (2,10,24). A 2007 Cochrane review of 14 studies involving 1025 subjects found scopolamine to be better than placebo in preventing symptoms (27). Very little research has been done into the visual effects of dextroamphetamine when given alone, but a 1983 study found a small yet significant mydriatic effect vs. placebo when given at doses of 10 mg. Doses of 5 mg trended toward significance, but failed to achieve it (11).
Scopolamine is available in many preparations, including oral tablets, IV/IM injection (4), buccal tabs (24), intranasal sprays (18), and transdermal patches (2,10). Among the most popular is transdermal therapeutic system scopolamine (TTS-S), which contains a 1.5-mg reservoir of scopolamine hydrobromide that is released at 5 μg · h−1 over 72 h (6). The oral preparation has been favored for parabolic flight given the transient nature of the stimulus and the desire to minimize prolonged side effects. When administered by mouth, scopolamine reaches peak serum levels 1 h after administration and has a measured half-life between 3.25 and 4.5 h (7,26). It has central sedative activity that depresses cortical function, which may result in lightheadedness and drowsiness. For that reason, it is often administered with dextroamphetamine to combat fatigue that could affect performance. The sympathomimetic action of d-amphetamine at noradrenergic receptors is synergistic with scopolamine's anticholinergic effects and the two drugs combat both the sympathetic and parasympathetic stimuli that are thought to activate the vomiting center (29).
Like other anticholinergics, scopolamine can be associated with adverse effects that reflect suppression of parasympathetic activity—mainly mydriasis, cycloplegia (loss of accommodation), dry mouth, drowsiness (3,6,21), and rarely, confusion or psychosis (22). Visual effects are thought to be the result of scopolamine's activity as a competitive antagonist at muscarinic receptor sites, resulting in diminished parasympathetic neurotransmission from the third nerve nucleus to the ciliary body and the sphincter muscles of the iris. The subsequent paralysis of the ciliary body results in reduced ability to focus on nearby objects (1). Loss of accommodation or changes in acuity represent potential obstacles to scopolamine's use as an antiemetic on research aircraft. Most previous studies were focused on establishing the efficacy of oral or transdermal scopolamine in response to rough seas (2,5,12) or provocative stimulation testing (9,13,29) and surveyed participants as to the presence or absence of particular side effects, including blurred vision. Other studies gathered similar qualitative data, but were focused on different primary outcomes (4,16,25). Those which attempted to quantify visual effects used small populations and were unable to draw conclusions regarding effects of doses of 0.8 mg or more via transdermal (1,8), oral (3,30), or combined route dosing (20). Given NASA's routine use of doses of or exceeding 0.8 mg, it has become increasingly important to identify the presence of any operationally significant visual side effects of scopolamine that could affect fliers' abilities to operate equipment, decipher text, or operate a motor vehicle postflight.
The study protocol was approved in advance by the IRB at Johnson Space Center and all participants provided written informed consent. Potential subjects were enrolled prior to the standard preflight instruction and administration of the scopolamine/dextroamphetamine combination on the date of their flight. Those flying on more than one occasion were given additional opportunities to participate, but only the data from their initial flight were analyzed. Individuals had already passed an Air Force Class III physical exam and were free of cardiovascular, renal, ophthalmic, psychiatric, and neuromuscular disorders. Pregnancy and the use of prescription or over-the-counter medications were also exclusion criteria. Those who elected to participate in the study supplied demographic and historical information, including age, sex, use of visual correction devices, history of refractive surgery, and medication use.
The investigators helped subjects identify their dominant eyes using a simple cover/uncover test. The contralateral orbit was covered with a patch and all objective measurements were taken using only the dominant eye. Subjects who wore corrective lenses were asked to continue using them. Near visual acuity was measured using a miniature Snellen eye chart held 38 cm from the eye. A standard pupillary size chart with black spots measuring 2-10 mm held next to the uncovered eye was used to estimate pupillary size to the nearest millimeter. Near-point accommodation was measured using a Prince rule—a ruler with a track on which a movable slide containing a card with text of uniform font and size is mounted. Subjects were instructed to hold the Prince rule against their cheek below the uncovered eye with the slide in its closest position. They were then asked to slide the card away from their cheek slowly and to stop when they were first able to resolve the text. This point of legibility without perfect clarity was defined as the near-point accommodation (19). To account for the variability of individual measurements, subjects were asked to repeat the procedure three times.
After collection of the premedication vision measurements, subjects were given scopolamine/dextroamphetamine using the pre-existing weight-based nomogram. Flyers weighing less than 50 kg (110 lb) received scopolamine 0.4 mg/dextroamphetamine 5 mg, flyers weighing 51-91 kg (111-200 lb) received 0.8 mg/5 mg, and those weighing greater than 91 kg received 1.2 mg/5 mg. Subjects generally flew 40 parabolas divided into 4 groups of 10. Each group was separated by approximately 10 min of level flight. Many flights also concluded with single parabolas simulating lunar and Martian gravity. During the flight, subjects were asked to carry out their assigned duties to the best of their ability. Subjects feeling ill were advised to strap in to a seat or to lay parallel to the direction of flight during the 1.8-g pull-up to minimize perceived angular acceleration (21). Those who became incapacitated by emesis were given a single 25-mg IM injection of promethazine. Initial measurements were taken prior to the 0800 medication briefing and subjects recorded their own medication dosages and times of ingestion. All measurements were performed under constant lighting conditions in the same room after at least 5 min time to adjust to indoor ambient lighting. Comparison data (including an additional three measurements of near-point accommodation) were taken approximately 3.75 h later following the postflight briefing. At that time, subjects were also asked if they felt nauseous or became ill during the flight.
Pupil sizes pre- and postflight were compared using a Wilcoxon signed-rank test and measurements of near-point accommodation were compared via paired t-test. Calculations were carried out using Stata data reduction software (2005; Stata Statistical Software, Release 8; StataCorp, College Station, TX).
A total of 131 subjects were enrolled in the study during the preflight briefings. Six subjects were lost to follow-up because they did not attend the postflight briefing and no comparison data could be gathered. Three subjects stated they were unable to bring the text into focus at any distance on the Prince rule and no numerical value could be assigned to their near-point accommodation by our research protocol either pre- or postflight. One subject was excluded because he informed the investigator after flying that he had misunderstood the directions and measured the farthest point on the Prince rule at which he could read the text. Thus, no preflight measurement of near-point accommodation was ever made. This left 121 subjects with both pre- and postflight measurements of near-point accommodation. Even when accommodation data were unavailable, measurements of pupil size and acuity were still taken and compared.
The average age of the subjects was 24.7 yr with a range of 18 to 48; 34% were women. Of the subjects, 52% reported no use of corrective lenses, 19% used eyeglasses, 26% used contact lenses, and 2% had reported undergoing corrective surgery. Sixty-three percent were right eye dominant. All subjects took medication. An average of 3.75 h elapsed between the ingestion of medication and the postflight measurements. Of the subjects, 10% took 0.4 mg scopolamine, 76% took 0.8 mg, and 12% took 1.2 mg.
The average near-point accommodation amplitude preflight was 8.61 diopters (12.64 cm) and 7.84 diopters (13.98 cm) postflight. This corresponds to a worsening of -0.77 diopters (95% CI -1.01 to -0.53) and 1.34 cm (95% 0.87 to 1.81), P < 0.001. (Fig. 1) Two subjects measured unusually poor accommodation amplitudes of 2.4 diopters (42 cm) before medication. They were 20 and 42 yr old with otherwise unremarkable acuities, pupil sizes, and similar powers of accommodation after medication. There were also two subjects, ages 33 and 22 yr, with significantly larger changes in accommodation (−6.9 and −7.0 diopters, respectively) than the mean. While exclusion of these individuals as outliers would enable the population to better approximate a normal distribution, the significance of the result would remain unchanged. Consequently, no data were excluded. The relationship between near-point accommodation and age both pre- and post-medication is depicted graphically in Fig. 2.
Average pupil size increased from 5.3 to 6.4 mm, a difference of +1.1 mm (95% CI 0.9–1.2, z = −8.6) with a P-value of P < 0.001 (Fig. 3). Of the subjects, 79% (N = 125) had no change in their visual acuity while an additional 19.4% of subjects experienced a change of 10 ft. A paired t-test (2-tailed, paired distribution, 120 degrees of freedom) was used to determine the difference in near-point accommodation pre- and postflight. A Wilcoxon signed-rank test was used to test and reject the null hypothesis, that the median change in pupil size was zero.
There were 38% of the subjects who reported experiencing signs of motion sickness while 21% vomited at least once during flight. Those that developed motion sickness or vomiting were not found to have larger changes in accommodation. No correlation between changes in accommodation and pupil size was found. Gender and medication dose were also found to have no effect on accommodation or pupil size. A Kendall's Tau test showed a weak positive correlation between age and change in accommodation with Tau equal to 0.136 (95% CI 0.013-0.259) and a value of zero, corresponding to no correlation. Thus, there is a trend toward larger changes in accommodation after scopolamine at increasing ages (P = 0.03). Of the five subjects with the largest changes in accommodation (−7.0, −6.9, −4.6, −4.3, and −4.1 diopters), however, four of them were younger than the mean (ages 22, 33, 20, 20, and 20, respectively).
Multiple previous studies have explored the anticholinergic side effects of scopolamine. Dry mouth (4–6,12) and drowsiness (29,30) have been reported, but dextroamphetamine has been shown to help alleviate the latter (16,29). Most studies using psychomotor tests have failed to show degradation after administration of oral (3,28,30) or transdermal scopolamine (8), but some limited effects have been observed when given without dextroamphetamine (17,25). Repeated oral or transdermal dosing has been shown to increase the prevalence of anticholinergic side effects due to muscarinic supersensitivity, a process by which receptor sensitivity is increased above normal levels (1,13,25). The presence of statistically significant mydriasis is well described in the literature and while some previous studies have failed to find any changes in visual acuity, others have noted a decrement (1,9).
Reports of blurred vision secondary to scopolamine use abound in the literature. Some studies have reported significant prevalence among test subjects (5,13,16,29) while others have failed to do so (2,3,9,12,25). A 2007 Cochrane review of 14 studies found scopolamine to be no more likely to cause blurred vision, drowsiness, or dizziness when compared to other agents (27). There have only been a handful of studies to attempt to quantify the presence of blurred vision in terms of near-point accommodation. Nachum found no difference in accommodation among 25 subjects given a transdermal patch and 0, 0.3, and 0.6 mg oral scopolamine, but no reference was made to baseline measurement or placebo (23). Gordon found no change in accommodation in 23 subjects following transdermal dosing and Brand found none among 60 subjects after ingesting 0.1, 0.42, and 0.7 mg oral scopolamine (4,8). A crossover study comparing the effects of IM vs. PO scopolamine in six subjects showed a significant difference when 1 mg was delivered intramuscularly, but not orally (20). In 1972, Wood reported on a series of double-blind placebo controlled experiments involving healthy college students and Navy personnel who had been given a wide range of antiemetics and subjected to centrifuge, sea, and aerial acrobatics. Oral scopolamine 0.6 mg with dextroamphetamine 10 mg was found to be the preferred preparation (with scopolamine/dextroamphetamine 1.2 mg/20 mg yielding 46% more drowsiness and dry mouth with only a marginal increase in effectiveness), with no significant alteration in near vision, far vision, or depth perception found (30).
In 1995, Alhalel et al. published a study measuring the ocular effects of double dose transdermal scopolamine and assessed whether pyridostigmine, a carbamate which reversibly inhibits acetylcholinesterase, could obviate scopolamine's peripheral anticholinergic side effects. The 15 young men receiving double dose TTS-S plus placebo pyridostigmine had a statistically significant change of approximately 4 diopters near-point accommodation, whereas the 16 subjects given double dose TTS-S plus 30 mg pyridostigmine did not. Interestingly, the 16 men who took placebos of both drugs also had a significant worsening of accommodation (by roughly 2.5 diopters) on days 2 and 3 of the experiment. A significant decrement in acuity and increase in pupil size were also noted among the 15 men given only double dose TTS-S (1).
This study enrolled 131 subjects, a substantially greater population than previous efforts to quantify the visual side effects of scopolamine. Other studies may not have been sufficiently powered to detect the subtle change in near-point accommodation detected in this study. A difference of −0.77 diopters (1.34 cm), while more than statistically significant, is not clinically important in most instances. The presence of a real but relatively minor change in accommodation may explain the mixed findings of “blurred vision” in some earlier studies. The presence of significant mydriasis has been well established and was anticipated. Hamilton found that coadministration of 5 mg dextroamphetamine did not significantly alter pupil size, but its effect on other visual parameters has never been definitively established (11).
Our study did not find the large changes in near visual acuity or the 4-diopter change in accommodation noted by Alhalel et al. This is likely due to several factors. First, the use of single dose oral scopolamine in this study negates the receptor supersensitivity which tends to worsens scopolamine's peripheral effects (13,25). Secondly, they noted a gradual worsening of acuity and accommodation each day and a persistent effect after patch removal. This suggests a possible accumulation of the drug within or near the ciliary body that would not be present in our protocol (1). Third, variation in measurement technique such as our use of the dominant eye only, Prince rule, etc. may play a role.
We would have considered the change of 4 diopters measured by Alhalel et al. to be quite significant. No correlation between the five subjects in our study with changes in accommodation larger than 4 diopters and any other variable could be found. Given the correlation between increasing age and worsening accommodation, we were surprised to find that four of the five were younger than the mean age of 24.7 yr. Two subjects, ages 20 and 42, measured uncharacteristically poor accommodation amplitudes of approximately 2.4 diopters (42cm) before medication (Fig. 2A). Their post-medication measurements were similar and their other visual parameters were entirely unremarkable. It remains unknown if they, like one subject we excluded, inadvertently measured the farthest point on the Prince rule at which they could resolve text. Four subjects had large changes in pupil size (+3 mm). All were 20-25 yr old, two wore corrective lenses, and three had no change in acuity or accommodation. One subject did experience a change in acuity of +5 ft and a change in accommodation of −2.4 diopters. Only two participants experienced large changes (≥ 20 ft) in acuity. Both were refracted and in their 40s, but neither experienced a large change in accommodation and while one reported a worsening by 20 ft, the other reported an improvement by 45 ft. Thus, despite careful analysis, no common characteristics among outliers could be found.
Scopolamine is a competitive antagonist of muscarinic receptors that results in diminished parasympathetic activity. Previous study has shown that the G-transition maneuvers during parabolic flight activate the sympathetic nervous system (14). This study could not discern the relative contributions of these effects on pupillary size and accommodation. A more rigorous time-based data sampling (e.g., before ingestion, 1, 2, 3, and 4 h after ingestion), both on the ground and in-flight, would help delineate these effects. While such a study design was initially envisioned, subjects would have been too busy with their own research activities aboard the aircraft to participate in repetitive data collection. The expense of in-flight subjects dedicated solely to a vision study would be cost-prohibitive and, consequently, an observational study of fliers using the existing protocol was selected. An alternative design would be a placebo-controlled in-flight experiment, but the success of the current scopolamine/dextroamphetamine regimen (roughly 70% reduction in motion sickness) is widely known among parabolic flight participants and few are likely to consent to forgo medication, particularly since doing so could compromise in-flight performance of their primary research objectives.
The design of this study contained additional limitations. While most subjects continued research on the DC-9 or in the hangar for several days after participating, there was no official contact with investigators after their postflight measurements. Thus, any difficulty they may have had operating a vehicle or deciphering road signs was not formally assessed. Anecdotally, however, this medication has been used in the Reduced Gravity Program for over 40 yr with many subjects flying on several consecutive days and there have not been complaints of impaired vision or difficulty driving. No measurements of far-point accommodation were made at any time, though significant change would not be expected given that the ciliary body paralysis induced by anticholinergics tends to affect one's ability to bring nearby objects into focus. In addition, all flights took place in the morning, when diurnal variations in the cholinergic system may make scopolamine more effective (13). It is unknown if the efficacy of the drug or the severity of its side effects would change with afternoon stimuli or dosing. While most previous studies assessed visual effects by survey, this study gathered only quantifiable data. It is possible that participants may have experienced subjectively blurred vision that was not assessed in the postflight interview.
Most importantly, however, this study contained a relatively small number of subjects over the age of 40. Near-point accommodation increases significantly over age 40 and our study was underpowered to detect significant changes in presbyopes. While there was a statistically significant positive correlation with increasing age, it remains unknown if older individuals would experience changes in accommodation that become clinically important. In addition, many of the oldest participants were members of the astronaut corps and may not have a baseline presbyopia similar to that of their age-matched peers.
The lack of meaningful changes in visual parameters suggests that scopolamine can continue to be used safely for prophylaxis of motion sickness in fliers in the Reduced Gravity Program. Its short duration of action also makes it useful aboard other research aircraft and in aeromedical flight programs. While it is sometimes taken on orbiter missions after main engine cut-off, it is generally not used beyond that as repeated dosing can increase the prevalence of side effects due to muscarinic receptor supersensitivity (5,21,25). Transdermal patches release a relatively constant amount of drug over a long period of time, but the 6-8 h needed to achieve therapeutic plasma concentration versus less than 1 h with oral dosing makes them less practical for immediate use aboard research aircraft (23). Transdermal patching has been used extensively aboard sea-faring vessels and is better suited for situations involving extended exposure to nauseogenic stimuli. The relatively rapid onset and short duration of the oral preparation may better serve commercial airline passengers, amusement park participants, and automobile passengers. Its apparent lack of operationally significant side effects suggest that crew aboard aeromedical transport helicopters are also unlikely to be impaired visually when performing procedures, referencing protocols or drug manuals, or attending to patients. Additional studies using this specific population are needed.
We would like to thank Dr. Alan H. Feiveson, Ph.D., statistician at NASA JSC in the Human Adaptations and Countermeasures Division of the Science Directorate, for his assistance with statistical advice and operations.
Authors and affiliations: Andrew L. Makowski, M.D., Department of Emergency Medicine, St. Joseph Regional Medical Center, Milwaukee, WI; and Kjell Lindgren, M.D., Astronaut Office, and James P. Locke, M.D., NASA Flight Surgeon, Medical Operation Branch, NASA Johnson Space Center, Houston, TX.