We have made significant progress over the past year on possible mechanisms of Spaceflight Associated Neuro-ocular Syndrome (SANS); all approvals were received and experimental schedules were optimized. We have completed most of our project NNX13AJ12G entitled “Fluid Distribution before, during and after Prolonged Space Flight” NASA Experimental Document and its revision. Likewise, we have updated and renewed our University of California - San Diego (UCSD) Institutional Review Board (IRB) approval.
To date, all pre/in/post-flight data collection has been completed on 12 subjects for this experiment. The final subject will require 1 more post-flight session, which will mark the completion of data collection for this study. This is expected to be completed by November 2020. Partial results from our space flight and other related investigation are available as part of three publications and one abstract.
The Fluid Shifts flight study was funded starting in 2012 and resulted from the combination of three selected grant proposals into a single study (Principal Investigators: Mike Stenger/Cardiovascular and Vision Laboratory-JSC; Alan Hargens/University of California-San Diego; and Scott Dulchavsky/Henry Ford Health System). In 2013, the Cardiovascular & Vision Laboratory (CVL) portion of the project budget was re-scoped at the request of Human Health Countermeasures (HHC) management to increase the grant from 3 years to 7 years. Data collection on 10 subjects began in 2014, and 3 additional subjects were added to the CVL scope of work in 2017. This international investigation included astronauts from NASA, the European Space Agency (ESA), and the Japan Aerospace Exploration Agency (JAXA) , as well as Russian Cosmonauts.
The primary goal of this study was to (1) characterize the fluid shift that occurs during space flight, (2) determine if measurements obtained preflight could be used to predict ocular changes during space flight, and (3) evaluate the effectiveness of lower body negative pressure (LBNP) during space flight to acutely reverse the headward fluid shift.
Subjects were studied before (L-90), during (FD45, FD150), and after (R+10, R+30, R+180) space flight. Before and after space flight subjects were studied in the seated, supine, and 15° head-down tilt postures; before flight also included a posture of 15° head-down tilt plus 25 mmHg lower body negative pressure (LBNP). During space flight subjects were studied during nominal weightlessness, and again during use of 25 mmHg LBNP using the Russian Chibis device. Outcome measures included a variety of vascular, cardiac, and ocular ultrasound measures, noninvasive estimates of intracranial pressure, eye structural measures with optical coherence tomography, and intraocular pressure.
Fluid distribution measures included assessment of plasma volume (pre- and post-flight, supine), total body water, and intracellular and extracellular fluid volumes.
Magnetic resonance imaging (MRI) of the brain and eyes was obtained pre- and post-flight in the seated, supine, and 15° head-down tilt postures.
Data collected in the Fluid Shifts study have been published as part of two manuscripts, with multiple additional manuscripts being planned.
Early Signs of Optic Disc Edema: Optical coherence tomography (OCT) imaging provides quantitative measures of retinal thickness that can be used to identify the earliest signs of optic disc edema. We published a subset of the data collected in this study collected on ~flight day 30 and, combined with the same measures obtained in the Ocular Health study, compared to the same data collected in subjects exposed to 30 days of strict head-down tilt bed rest. This publication in the journal JAMA Ophthalmology highlighted similarities and differences in ocular changes between astronauts exposed to space flight and subjects exposed to a space flight analog.
Venous Thrombosis in Spaceflight. During a test session with a Fluid Shifts subject on ISS our ultrasound team discovered a venous thrombosis in the left internal jugular vein (IJV) of an astronaut participating in the Fluid Shifts study. This unexpected finding resulted in the PI team reviewing images of prior subjects and determined that a second earlier Fluid Shift subject also had an unconfirmed IJV thrombosis. These findings, along with IJV cross-sectional area and pressure data, were published in the journal JAMA Network. In addition to 2 of 11 subjects demonstrating thrombosis in the left IJV, this publication also revealed that IJV cross-sectional area during space flight is similar to that in the supine posture on Earth and that there are IJV flow pattern abnormalities during weightlessness that do not occur on Earth. These findings highlight that cerebral venous congestion occurs in weightlessness and underscore the need for additional characterization of all cerebral venous outflow pathways, including both left and right IJVs and left and right vertebral veins.
Cardiovascular Responses to LBNP during Space Flight
While use of LBNP during space flight has been studied in astronauts during short-duration space flight missions, long-duration astronauts have not been systematically evaluated during exposure to a sustained mild level of LBNP during space flight. Russian Cosmonauts routinely use LBNP during various research studies, as well as during the final 21 days of space flight as a countermeasures to prepare for re-adaptation to gravity. A key question being investigated here was how the cardiovascular system would respond to up to 60 minutes of LBNP during weightlessness during long-duration space flight when there are known musculoskeletal and cardiovascular changes that could limit the physiological responses to the LBNP stressor. The preliminary data will be included in an upcoming manuscript.
LBNP reduces venous return to the heart, thereby lowering cardiac output and ultimately arterial blood pressure. To compensate, heart rate increases in order to maintain appropriate blood pressure levels. If the negative pressure is increased far enough, or the physiological responses designed to prevent a fall in blood pressure are inadequate, syncope can occur. Here we report preliminary data on the change in mean arterial pressure (MAP) and heart rate (HR) during exposure to 25 mmHg LBNP in 12 subjects throughout long-duration space flight missions. These preliminary data reveal that all subjects tolerated the LBNP sessions without a substantial fall in MAP, yet HR was elevated in all subjects. During FY21 our team will continue analysis of these preliminary data and draft a manuscript with these and other data to highlight the similarities and differences in the LBNP response during space flight, compared to that with occurs in a gravitational environment on Earth.
Data collection will be completed on the final Fluid Shifts subjects in early FY21, and the continued analysis and reporting of findings are anticipated to continue through FY21 and FY22. Due to the international collaborations that make up the Fluid Shifts team, we are planning to hold a data summit to discuss data products and identify how multiple data sets link together to develop a comprehensive picture about (1) the fluid shift that occurs during long-duration space flight, (2) the ability for LBNP to reverse the fluid shift, and (3) if there are anatomic, physiologic, or other factors that can provide insight into which subjects may be most at risk for developing SANS findings.
OTHER RECENT RESULTS
FLUID DISTRIBUTION AND COMPARTMENTALIZATION DURING LONG-DURATION SPACE FLIGHT
INTRODUCTION. Visual acuity changes observed after short-duration missions are largely transient, but now up to 70% of ISS astronauts returning from long-duration missions demonstrate ocular structural changes such as optic disc edema, globe flattening, and/or choroidal folds. These structural and functional changes are referred to as the Spaceflight Associated Neuro-ocular Syndrome (SANS). The purpose of this study is to characterize the fluid distribution and compartmentalization associated with long-duration space flight and to determine whether a relationship exists between these fluid distribution measures and the ocular structural and functional changes associated with SANS. We also seek to determine whether headward fluid shifts during space flight, as well as any SANS-related effects of those shifts, can be predicted by preflight responses to acute hemodynamic manipulations, including posture changes with and without lower body negative pressure (LBNP).
METHODS. A variety of physiologic were investigated in 13 long-duration ISS crewmembers. Measures include (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by carbon monoxide rebreathe, interstitial fluid by calculation); (2) upper and lower body skin tissue thickness by ultrasound; (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography; intraocular pressure; 2-dimensional ultrasound including optic nerve sheath diameter, globe anterior-posterior diameter, and retina-choroid thickness; Doppler ultrasound of ophthalmic and retinal arteries and veins); (6) cardiac variables by ultrasound (inferior vena cava, stroke volume, right heart dimensions and function, four-chamber views); and (7) noninvasive ICP measures (tympanic membrane displacement, otoacoustic emissions). Before and after space flight, tests during acute posture changes included supine and head-down tilt (HDT) to induce headward fluid shifts, whereas LBNP (only preflight) will oppose these shifts. Through interventions applied before, during, and after flight, we intend to evaluate the relationship between headward fluid shifts, SANS, and possible SANS countermeasures.
DISCUSSION. Twelve subjects have completed all testing and all subjects have completed the flight phase of this experiment. Preliminary results suggest that relative to the seated posture, jugular vein cross-sectional area and pressure, intraocular pressure, and noninvasive indices of ICP increase in the supine and HDT conditions, yet choroid thickness does not change. Measures obtained during space flight generally are similar to supine values on Earth, but the choroid is thicker in weightlessness. Use of 25 mmHg LBNP appears to be partially effective in reducing the cephalad fluid shift both on Earth and in space, but does not affect choroid thickness measured within the first 15 min of LBNP. Analyses of the following outcomes are expected this year: blood pressure and heart rate responses to LBNP during space flight; total body water and extracellular fluid volume; optic nerve head morphology changes and their relationship to other variables; magnetic resonance imaging (MRI) of cerebral venous compartment; and MRI metrics of globe flattening.
JUGULAR, MIDDLE CEREBRAL AND PORTAL VEIN RESPONSES TO SIX MONTHS ISS SPACEFLIGHT AT REST AND WITH LBNP
BACKGROUND. Cephalad fluid shifts are suspected to cause ocular edema and increase ocular and intracranial pressures, likely resulting in the development of the SANS. Lower body negative pressure (LBNP) can be used as a method to shift fluid towards the legs in the absence of gravity. Our hypothesis was that inflight jugular and portal vein volumes would increase due to the fluid shift and that intracranial vein velocity would increase due a narrowing of the vessel lumen from increased intracranial pressure. LBNP was tested to restore these variables to preflight levels.
METHODS. During 6-month ISS spaceflights 13 astronauts performed echographic investigations with verbal remote guidance assistance from the ground. Jugular vein volume (JV vol, cm3), portal vein cross-sectional area (PV cm²), and intracranial vein velocity (MCV; cm/s) were measured pre-flight, in-flight (FD45, FD150), and post-flight (R+40, R+180), at rest and during 25 mmHg LBNP with the Russian Chibis device.
RESULTS. With space flight, JV vol increased from pre-flight supine and seated values (46±48% from supine at FR45 & FD150) and 520±291%, from seated at FD45 & FD150. P<0.05), MCV increased (43±19% from supine and 109±110% from seated on FD45 and FD150, P<0.05). PV tended to increase but was not significant. Inflight LBNP of 25 mmHg restored JV vol, and MCV to pre-flight supine levels (P<0.05).
CONCLUSION. The increase in JV vol confirms the sustained headward fluid shift during the 6-month ISS flight. MCV increased, probably by compression of the vein (lumen reduction) or reduction in backpressure/interstitial resistance as neither cerebral nor carotid flows changed in space flight. The application of LBNP during the flight restored JV and MCV to pre-flight supine levels.
Articles in Peer-reviewed Journals
Garrett-Bakelman FE, Darshi M, Green SJ, Gur RC, Lin L, Macias BR, McKenna MJ, Meydan C, Mishra T, Nasrini J, Piening BD, Rizzardi LF, Sharma K, Siamwala JH, Taylor L, Vitaterna MH, Afkarian M, Afshinnekoo E, Ahadi S, Ambati A, Arya M, Bezdan D, Callahan CM, Chen S, Choi AMK, Chlipala GE, Contrepois K, Covington M, Crucian BE, De Vivo I, Dinges DF, Ebert DJ, Feinberg JI, Gandara JA, George KA, Goutsias J, Grills GS, Hargens AR, Heer M, Hillary RP, Hoofnagle AN, Hook VYH, Jenkinson G, Jiang P, Keshavarzian A, Laurie SS, Lee-McMullen B, Lumpkins SB, MacKay M, Maienschein-Cline MG, Melnick AM, Moore TM, Nakahira K, Patel HH, Pietrzyk R, Rao V, Saito R, Salins DN, Schilling JM, Sears DD, Sheridan CK, Stenger MB, Tryggvadottir R, Urban AE, Vaisar T, Van Espen B, Zhang J, Ziegler MG, Zwart SR, Charles JB, Kundrot CE, Scott GBI, Bailey SM, Basner M, Feinberg AP, Lee SMC, Mason CE, Mignot E, Rana BK, Smith SM, Snyder MP, Turek FW. "The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight." Science. 2019 Apr 12;364(6436):eaau8650. https://science.sciencemag.org/content/364/6436/eaau8650.long ; PMID: 30975860; PMCID: PMC7580864 , Apr-2019