1 TEMAZEPAM, BUT NOT ZOLPIDEM, CAUSES ORTHOSTATIC HYPOTENSION IN ASTRONAUTS AFTER SPACEFLIGHT KATHLEEN M. GARCIA, B.S.,' AND JANICE V. SHANG-JIN SHI, M.D., PH.D.,1 MECK, PH.D.2 2fohnson Space Center, National 'Wyle Laboratories, Houston, Texas 77058; and Aeronautics and Space Administration, Houston, Texas 77058 Address for correspondence: Janice V. Meek, Ph.D. Space Life Sciences Research Laboratories Lyndon B. Johnson Space Center, SD361 National Aeronautics and Space Administration Houston, Texas 77058 Phone: 281-244-5405 Fax: 281-483-4181 Email: jmeckems.j sc.nasa.gov Running head: Effect of Hypnotics on Astronauts This research was supported by NASA Grant NRA OLMSA96-01-051. 1 ABSTRACT Many astronauts do not sleep well due to the difficult environment in Background space. Hypnotics such as temazepam or zolpidem are often taken while in space and/or the night prior to returning to Earth. Until now, no data have illustrated the effect of these sleeping medications on postflight hemodynamic responses. The purpose of this study was to determine if the use of different hypnotics during flight has any effect on cardiovascular responses to standing in astronauts upon returning to Earth's gravity. Astronauts were separated into three groups: control group (n = 40), Methods (5 or 10 mg; n = 8). In this temazepam group (15 or 30 mg; n 9), and zolpidem group study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand test before spaceflight and on landing day. Systolic blood pressure decreased and heart rate increased significantly in the Results temazepam group when compared with the control group on landing day. However, systolic blood pressure and heart rate were not different between zolpidem and control groups. 2 Temazepam may aggravate orthostatic hypotension after spaceflight. Conclusions Zolpidem may be a better choice as a sleep aid while in space. Key words: astronaut, spaceflight, orthostatic hypotension, temazepam, zolpidem, 3 4 INTRODUCTION Many astronauts experience difficulty sleeping during spaceflight.' Because sleep deprivation affects performance and can cause other medical and operational problems, the in-flight use of sedative-hypnotics as sleeping aids is common. 4 Two hypnotics, temazepam (Restoril, a benzodiazepine) and zolpidem (Ambien, an imidazopyridine), are used by astronauts during their missions, including the night prior to shuttle landings. Some sedative-hypnotics have side effects that affect the cardiovascular system by decreasing arterial blood pressure and increasing heart rate. 5 After spaceflight, astronauts experience orthostatic hypotension68 due to, among other things,- reduction of plasma volume and autonomic dysfunction. It is possible that the use of these hypnotics is an additional contributor. Temazepam belongs to the benzodiazepine family that causes sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity.9 Zolpidem is an imidazopyridine that differs structurally from the benzodiazepines.'° It has sedative-hypnotic properties, but has only minor anxiolytic 1l2 and anticonvulsant properties, and no myorelaxant Although the National Aeronautics and Space Administration (NASA) began using temazepam and zolpidem as 4 5 inflight sleeping aids in 1990 and 1994, respectively, the ettects ot these medications on cardiovascular responses to upright posture have not been documented. Therefore, the purpose of this study was to assess whether hypnotics exacerbate orthostatic intolerance in astronauts on landing day. METHODS This study was conducted in two parts. The first part was a prospective study in laboratory volunteers on the effects of temazepam on cardiovascular responses to standing. Based on those results, a retrospective analysis was performed on astronauts' preflight stand test, and postflight stand tests with and without the influence of temazepam or zolpidem. Subjects. The NASA Johnson Space Center Committee for the Protection at Human Subjects approved these protocols. There were two sets of subjects: astronauts and non- astronauts. Ground-based Study. All subjects (non-astronauts) had passed an Air Force Class III physical exam before their participation and signed written informed consent. Ten 6 subjects were studied before and ten hours after a single, 30 mg oral dose of temazepam. Subjects abstained from caffeine, alcohol, and any medications for 12 hours prior to each study and ate a.light breakfast before reporting to the laboratory. Testing on the first day began at 8 AM. After the test session, subjects were given 30 mg of temazepam which they ingested orally at 10 PM that night. They were studied again at 8 AM the following morning, ten hours after taking the drug. For each test, subjects were placed on a bed in a quiet, air-conditioned room where the temperature was 23-25 °C. After 20 minutes of supine rest, baseline arterial blood pressure and heart rate were recorded. Then a tightly sealing Silastic chamber, connected to a computer-controlled bellows, was strapped to the anterior neck.'3 During held expiration, and triggered by successive R-waves, the pressure in the neck chamber was increased to +40 mmHg for four heart beats and then reduced to, +25, +10, -5, -20, -35, -50, and -65 mmHg, and then returned to ambient pressure. This sequence was repeated seven times. R-R intervals were plotted against carotid distending pressures (systolic blood pressure minus chamber pressure). After the neck suction protocol was completed, a stand test was performed. Subjects were assisted to a standing position by three investigators who lifted them behind both shoulders and 6 7 swept their feet off the bed. This helped to minimize artifactual arterial blood pressure changes with the effort of standing. Subjects remained standing without support for ten minutes unless presyncopal symptoms necessitated the termination of the test. Their heart rates were recorded with electrocardiogram (SpaceLabs, Redmond, WA), and systolic and diastolic blood pressures were measured manually with sphygmomanometer every minute. Finger arterial blood pressure was measured by a beat-to-beat pressure detector (Finapres, Ohmeda, Tewksburi, MA). Flight-based Study. Informed consent was obtained according to the guidelines set forth by the Committee for the Protection at Human Subjects at the NASA Johnson Space Center. The astronaut subjects were separated into three different groups: those who took no medication the night before landing (n = 40), those who took oral temazepam (15 or 30 mg) the night before landing (n = 9), and those who took oral zolpidem (5 or 10 mg) the night before landing (n = 8). No astronaut took either medication before flight and no additional medications other than the hypnotics were taken before landing. This retrospective analysis encompasses a 7-year period from January 1990 until December 1996. Stand tests were performed according to the same protocol described above, ten 7 8 uays before launch and two to four hours after landing. All preflight stand tests were conducted at Johnson Space Center in Houston, Texas, and landing day stand tests were conducted either at Kennedy Space Center, Florida, or Dryden Flight Research Center at Edwards Air Force Base, California. Data Analysis - Carotid Baroreceptor-Cardiac Reflex Response. All electrocardiograms and neck pressures were recorded on digital tape for subsequent analysis. R-R intervals were measured from the electrocardiogram. Carotid-cardiac baroreflex responses were determined off-line using standard data acquisition and analysis packages. Responses to baroreflex were reduced to the following set of parameters for analysis: range of R-R response, maximum slope, and operational point. Maximum slopes were identified with linear regression analyses applied to each set of three consecutive data pairs on the stimulus-response relation. Operational points were defined as [(R-R interval at 0 mmHg neck pressure - minimum R-R interval) / (R-R interval range)] x 100%. The operational point is a measure of the amount of buffering capacity above and below baseline systolic blood pressure due to increases or decreases in cardiac-vagal outflow, respectively. 8 9 Data Analysis - Stand Tests. The stand portion of the test assessed the systolic and diastolic blood pressures and heart rates pre- and post-temazepam and zolpidem. Both systolic and diastolic blood pressures and heart rates were measured every minute for six minutes supine and ten minutes standing. Systolic and diastolic blood pressures and heart rates were stable in the supine position, so only the last supine measurement was reported. Statistics. All data are presented as mean ± SE. A Kruskal-Walljs one-way analysis of variance (ANOVA) on Ranks was used for between groups comparison (i.e. control group vs. temazepam or zolpidem group). A paired t-test was used for within-group comparisons (i.e. pre- vs. post-temazepam). For all tests, significance was set at P < 0.05. RESULTS The anthropometric data for all subjects are presented in Table 1. Age, body weight, and height did not differ significantly among any of the groups. Between January 1990 and December 1996, 13.7% of astronauts took temazepam and 4.6% took zolpidem 9 10 during flight. Therefore, astronauts took temazepam three times more than zolpidem during this period. Ground-based Results. In non-astronauts, one subject who had not become presyncopal before taking temazepam became presyncopal during standing after taking it. Two additional subjects reported feeling lightheaded and dizzy the morning after taking temazepam but before reporting to the laboratory. These two subjects did not become presyncopal during their stand tests. Fig. I shows that finger arterial blood pressures and heart rates decreased in the subject who became presyncopal after taking temazepam. Before temazepam (upper panel), arterial systolic blood pressure was maintained the entire time of standing. After temazepam, systolic blood pressure dropped to 70 mmHg (bottom panel) and the subject became presyncopal. Standing heart rate post-temazepam was 15 bpm higher than pre-temazepam until presyncope occurred. Fig. 2 represents supine and standing arterial blood pressures and heart rates before and after 30 mg of temazepam in the ground-based subjects. As a group, there was no effect of temazepam on supine or standing arterial blood pressures. Supine heart rates 10