Preparation, Implementation and Execution of Human Cardiovascular Experiments in Space

3.1 CVP experiment

The CVP experiment was originally planned to be done on two of the Spacelab D2 astronauts, but for some technical reasons, it was only accomplished in one. The experimental plan was to shortly before launch insert a long catheter with a pressure transducer at the end into the vein directly leading into the right atrial chamber of the heart through a peripheral arm vein and connect it to a preamplifier and a recording system. The test astronaut would thus be inserted with the catheter and wear the CVP monitoring system until 3 hours into the mission following launch. Thereafter the catheter would be withdrawn. Before the launch of the Space Shuttle, control measurements in different body postures were performed.

The equipment used for measurements of central venous pressure during the Spacelab D2 mission in one astronaut is depicted in Figure 1. The central venous catheter (1) with a pressure transducer placed at one end and a connector box at the other was plugged into a preamplifier (2) that was connected to a recording unit (3). A calibration piston (4) could be connected to the reference opening of the catheter and thus induce predetermined pressure changes on the backside of the transducer membrane. In this way, it was tested to what degree the calibration characteristics of the pressure transducer might have changed over time after being inserted into the astronaut. Following the spaceflight, the catheter was brought back to the investigators and tested for change in drift of the tip transducer.

3.2 Urinary excretion experiment

Before the spaceflight, four test astronauts would, over a 4.5-h period, empty their urine bladders in either supine or seated posture, on an hourly basis after being infused through a peripheral vein with isotonic saline in an amount of 2% of their body weight. About a week into the flight, the same would be done following a similar infusion while they thus would be free floating in the space vehicle. Blood was sampled on ground and during flight for determination of water-, salt- and blood pressure-regulating hormones. The volume of urine was measured after each void and samples taken for determination of salt (sodium and potassium) concentrations. In space, the volume of urine was determined by a urine monitoring system delivered by NASA, which was connected to the toilet. If the voids were felt by the subjects to be small, the bladders were emptied into bags and returned to Earth through the trash system on the Shuttle. The saline infusion was conducted over some 20 min by manually inflating a cuff-pressure system, and the amount varied on an average between 1.7 and 1.8 litres.

5.1 Proposal

The first step for performing experiments in space is to develop a proposal and respond to a space agency solicitation from, e.g. the European Space Agency (ESA) or National Aeronautics and Space Administration (NASA). ESA’s topics are usually broader than NASA’s, because the latter are mostly focused on operational aspects. In both cases the proposal formats are rather similar and the subsequent selection process very much like the way it is done at the national levels with peer review panels and scientific merit scorings. In order for a proposal to be successful, the following criteria must generally be fulfilled:

1. Qualified research team with experimental experience from a university or a recognised company. Most proposals are from universities, and experience in space research is an advantage but not a requirement.

2. Clearly written proposal, which fulfils the requirements stated in the call.

3. Adherence to all of the rules and instructions—otherwise the proposals will be rejected upon receipt, and this includes adhering to the stated deadlines for submission.

4. Relevancy for utilising spaceflight meaning that what is proposed to be measured should be responsive to the flight environment (e.g. weightlessness).

One thing to keep in mind when writing a proposal is to formulate it so that non-experts in the field can also get something meaningful out of it, because at the time of selection and thereafter, decision-makers who may not be scientists might make a judgement as to the appropriateness of spending resources in space for this particular experiment.

5.2 Selection

When a proposal is submitted in response to a research announcement, the first step is that it will be evaluated by scientists appointed by the space agency or a group of space agencies. The scientists—or peer reviewers—are usually experts within the field of the topic of the solicitation, who are not involved in collaborations with the proposers. The peer review panels are usually led by an agency representative, and the panel will score each proposal on a scale between zero and 100. Scores between 90 and 100 are categorised as “Excellent” or “Outstanding”, 80 and 89 as “Very Good”, 70 and 79 as “Good”, 50 and 69 as “Fair” and below 50 as “Poor”. The score threshold for selection may vary between space agencies, but usually no proposals are selected with a score lower than 70.

The next step for the space agency representatives is to—based on the peer review scores—perform final selections. In this case, not only the scientific merit scores play a role but also the relevancy of the proposal for the agency. Usually a subset of the highest scientifically scoring proposals are selected, but sometimes even proposals with the highest scores may not be finally selected because of less relevancy for the operational purposes of the agency. In this regard, there are different policies between the space agencies. For NASA, deep space explorations are the main drivers, while ESA usually focuses almost entirely on the scientific merit and the proposal’s ability to produce new fundamental knowledge to the scientific community.

5.3 Funding

In order for a selected proposal to be executed in space, funding has to be obtained. This can either be done by grants from local and national authorities or from the space agency itself. The problem in particular for European researchers is that for ESA to consider selection of a proposal, it is advantageous to have obtained national funding or a declaration of intention of funding already before submission. In many cases, national authorities will only indicate intention of funding, should the proposal be selected, but they usually will not guarantee it. This can sometimes create a hen and an egg problem: The space agency will—before it actually finally selects a proposal—require guaranteed funding from a national authority, whereas the national authority requires that the agency selects the proposal. The proposers usually obtain intention for funding in letters from the national funding authorities, and usually the space agency will accept that. In our case, when the research team was supported for selected experiments, we referred to an existing grant that could overlap with selection of a new proposal.

Funding of a grant for experiments in space usually only covers the expenses incurred by the experimental research team. The space infrastructure, such as access to a space vehicle and its astronauts (e.g. the Space Shuttle), is delivered by the space agencies.

5.4 Feasibility

When selection and funding are obtained, the space agency will conduct a feasibility study to evaluate whether the experiment can be implemented in space and whether there are technical or other obstacles. If these cannot be overcome, the proposal will be de-selected. Usually the experiment is modified, if obstacles are detected. An obstacle for implementation may not just be technical such as lack of availability of a technique or equipment but may also be lack of astronaut crew time for execution of the experiment. In that case, the experiment is usually modified in close collaboration with the research team. If the experiment changes considerably, the space agency may require an additional scientific peer review to evaluate whether the scientific quality is still high enough, but this is not the usual process.

5.5 Implementation

When the space agency feasibility assessment has been successfully completed, meaning that the experiment can be conducted in space, the implementation process begins. All of our previous research team’s selected experiments (10 in total) have been somehow modified during the feasibility assessment and implementation processes. The renal experiment on the Spacelab D2 mission in 1993 was changed by decreasing the number of inflight sessions from two to one, because of limited crew time. The purpose was as previously described to evaluate the effects of applying an intravenous saline fluid load to the test astronauts on renal excretion rates of fluid and sodium. We had originally planned a session with infusion and a session without, but only the infusion session could be implemented in space. Otherwise the experiment was kept intact except that it was actually improved by changing our proposed saline loading from an oral saltwater load to intravenous infusion. This was done because an experimental complement was created for the space mission, whereby several experiments were to be executed in an integrated fashion, and a US experiment had suggested to use saline loading by infusion. Thus, this intravenous infusion of isotonic saline was planned to be done for the first time ever in space.

Although the urinary experiment was not difficult to implement from a technical point of view, it was totally different regarding the CVP experiment. After selection of this experiment, many managers within ESA and NASA thought it would be impossible to be allowed to conduct such an invasive study. We succeeded anyway, which was because of one important thing: the backing of the appointed payload commander. Without this support for the experiment, it would never have been executed. The reason for the astronaut support was because of thrust in our research group’s ability to conduct the study, which we obtained by always being well prepared for pre-flight briefings of the astronauts as well as for the pre-flight control studies. We always made sure that as much of the data that had been collected were properly analysed between the different ground tests and that the data were presented to the astronauts during the subsequent tests so that they together with the investigators could follow the progress of the study throughout the pre-flight period.

5.6 Execution

During the Spacelab D2 mission, I was standing in the mission control centre in Oberpfaffenhofen near Munich in Germany holding my breath and watching the big screen. All investigators followed the executions of their experiments from the mission control centre, and just before initiation of our renal experiment, which as described earlier was integrated into one complement, a valve was stuck in some of the equipment. If the valve problem was not solved, we would all risk that none of the experiments in the complement would be conducted. It was a tense moment, when the payload commander after directions from mission control finally got the valve to work and initiated the flow of measurements. What a relief!

During execution of our urinary excretion experiment a mistake did happen, whereby urine bags, which were to be collected after flight directly from the trash can in the Space Shuttle, were not correctly labelled. It meant that we could not readily identify, from which crew members the urine in the bags derived. The way the problem of identification was solved was by measuring the concentrations of five different substances in each urine bag and comparing them to samples that had been collected inflight from each bag before trash storage. Each of the samples had been correctly labelled. Since each crew member had a unique pattern of concentrations of the selected substances, the matching and identification of the bags with the samples were possible.

Spaceflight experimentation often requires creative solutions to unexpected problems.

The CVP experiment went well in one astronaut. Originally, we had planned for two astronauts to be instrumented, but unfortunately the catheter broke in one during an extended prelaunch period, where the catheters had been successfully inserted into two astronauts, but where the prelaunch period was extended for 2 days over a weekend because of a failure in one of the shuttle’s navigation systems that had to be changed. During some leisure activities, it broke and was withdrawn before launch.

During execution of the experiment on ground before the flight, which is called the baseline data collection to which all inflight data were to be compared, the biggest obstacle occurred during the execution process of one of the pre-flight test sessions on the ground. The obstacle demonstrated that it is not only a challenge to implement and execute an experiment during the flight phase but that ground tests can be limiting factors too. What happened is that the gas analyser used for rebreathing experiments to determine cardiac output and respiratory variables (Figure 3) for some reason did not work. Even though these measurements were not directly involved with our urinary experiment, it sent our experiment to jeopardy, because it was totally integrated into an experimental complement to be executed in concert. The breakdown happened at the Aerospace Medical Institute at the German space centre, DLR, and since the astronauts’ test time was extremely limited with many other obligations, it was made clear to the experimental team that the astronauts would withdraw from the experiments, if the equipment was not working the next morning. We knew then that we were in trouble!

We were otherwise all ready to conduct the baseline data collections the next day, and if the gas analyser could not be fixed, it would mean that all of our experimental efforts would go down the drain. What could we do?

Ingenuity, imagination and thinking out of the box are usually essential in solving unexpected problems associated with spaceflight. In fact, this is what characterises this discipline. To my disappointment most of the officials and investigators gave up immediately. It was late afternoon, and the experiments were to be commenced early next morning at 07.00 am. The payload commander had left with a statement that he and his astronaut team would show up on time the next morning, and if the equipment did not work, the experimental complement would be deleted from the mission.

I and one of our ESA representatives soon conferred with each other, and we promised that we would demonstrate to the payload commander that this problem could be fixed in time. The only question was how? At the time we did not know that the problem was a burned capacitor, so we planned to have a technician immediately flown down from the company, Innovision A/S, in Denmark, which had developed and built the equipment.

What we did was risky, unusual and not according to the normal rules and regulations, but we were running out of time. We had to rent a private airplane within a few hours, because there were no commercial flights at that time. We had to establish an ESA guarantee for payment to the airline company, and we—above all—had to get in contact with the technician in Denmark. It soon turned out that he was available and the money for renting the airplane could be secured (after tough negotiations with ESA) and everything seemed possible.

The technician was late at night transported by taxi to a nearby local airport some 200 km away, from where he lived, entered the plane and came to Cologne around 4 am in the morning. We picked him up at the airport in Cologne and brought him to the aerospace facility, and by a miracle, he quickly identified the problem to be a burned capacitor and substituted it by another from a similar equipment.

At exactly 07.00 am before the baseline data collection was to begin, we were ready. The astronauts entered with the expectation that the tests would be cancelled. We could inform them otherwise, and with a rare expression of facial recognition, the payload commander and his fellow astronauts professionally moved ahead to be ready for the tests.

Everything went smoothly!

This as well as the inflight incident with the stuck valve were pivotal obstacles for the outcome of many of the physiological experiments during the Spacelab D2 mission. Had they not been overcome, I would probably not have been able to continue my space physiology career for the next 30 years.

5.7 Data analysis

It is pivotal to make sure that the data collected are correct. One basic rule is for the principal investigator to always be present or to have proper representation at each of the pre- and post-flight experimental sessions and to be monitoring how the data collections are done during flight—preferably from a mission control centre. If that is not made sure of by the investigators of a study, one cannot be sure that the circumstances surrounding the collections are fully understood and that handling of blood samples is done correctly and according to specifications. Furthermore, the investigators have to make sure to be readily available during executions of their experiment should inquiries from space agency representatives need acute responses and interventions. Otherwise, it is unlikely that the data can be trusted.

The investigators must also be proactive and tenacious in obtaining the collected data in space that usually are stored on inflight computers. One way to make sure that the data are correctly handled is to push the mission controllers to download as much as possible from space to ground as soon as the data are collected, because no one knows what could happen afterwards to the storage. Usually, it is not a problem should downloading not be possible, but in this case, it can also delay the post-flight analysis of the data because of bureaucratic impediments to obtain it.

During the very sad and unfortunate accident of the STS-107 mission on February 1, 2003, where the Space Shuttle, Columbia, and crew were lost during re-entry in the atmosphere, I was in charge of an experiment. We conducted inflight cardiac output rebreathing experiments as well as blood pressure monitoring. The data were downloaded to the mission control centre during the mission, which made it possible for us to publish the data so that the experiments—despite the very sad circumstances—were not done in vain.

During the Euromir 95 mission, which was a long-duration mission on the Russian space station Mir, where the ESA astronaut, Thomas Reiter, stayed for 179 days in space, I was in charge of a urinary collection experiment following an oral water load. I obtained the inflight data directly from Thomas Reiter himself shortly after his flight, which is unusual, but we did so to bypass the bureaucracy. Otherwise it could have taken weeks to obtain it.

5.8 Publication

The most important part of all investigations including those in conjunction with human spaceflights is to publish the results in as widely distributed scientific journals as possible. The whole purpose of obtaining the data is to gain new knowledge, and by publishing in science journals with external peer review, there is a certain guarantee for data quality and interpretation. It usually takes 2 years after the end of a spaceflight mission to have the data published, but many times, it takes longer. The investigators, however, owe it to everybody involved as well as society in general to produce a scientific publication as fast as possible.

From the Spacelab D2 mission in 1993, our research team succeeded in publishing three papers within 3 years of the mission [1, 2, 3]. During later missions on the Russian space station Mir, the Space Shuttle Columbia (STS-107) and the International Space Station, we conducted five additional experiments focusing on how the human cardiovascular system adapts to short- and long-duration flights [6, 7, 8, 9, 10]. This is important for understanding the long-duration health effects of future deep space missions that may last up to 3 years on a mission to Mars.

7.1 Spacelab D2 mission

From the Spacelab D2 mission, our CVP and urinary experiments showed us a new mechanism as to how blood and fluid are shifted from the lower to the upper portions of the body in weightlessness and that the excretion rate of a saline load is not faster than on Earth. Both results were surprising and revealed new insight. Likewise, it was a surprise that the agitating (sympathetic) part of the autonomous nervous system was stimulated during weightlessness and that it was not—as expected—supressed. In ground-based simulation studies using 6⁰ head-down bed rest or acute seated head-out water immersion, the opposite is usually seen. Thus, there is a difference in effects of weightlessness in space and the simulation models on the ground.

Despite the upward blood shift to the heart and head, CVP was measured to decrease in space compared to being horizontal supine on the ground (see Figure 5). We had expected it to be increased. The data we obtained were only from one astronaut, but a US-led team during two other missions also measured CVP directly with invasive catheters and found decreases. We thereafter performed a parabolic flight study and measured CVP with same technology as during the D2 mission and found similar acute decreases during the 20 s of weightlessness [11]. However, we also observed that the heart was expanded despite the decreased CVP, because simultaneously the oesophageal pressure also decreased and even more so. From ultrasound images taken of the heart during the parabolic weightless period, we observed an expansion of the cardiac chambers, so the ostensible discrepancy between the decrease in CVP and the expanded heart could be reconciled by the expansion of the thorax that further stretches the heart and gives an erroneous impression of the change in its feeding pressure (CVP, Figure 6).

7.2 Subsequent space missions

From our later inflight experiments [6, 7, 8, 9, 10] following the Spacelab D2 mission, the main conclusions can be briefly summarised as follows:

• Cardiac output and stroke volume increase by some 35–40% during months of flight in space, which is caused by the weightlessness-induced upward fluid shift.

• The arterial resistance vessels dilate and decrease the circulatory resistance by some 40% and blood pressure by 10 mm Hg.

• The sympathetic nervous activity is not decreased in space and is at the level of being upright on ground, which is supported by the attenuated urinary excretion rates of fluid and sodium.

• The dilatation of the arteries and the high sympathetic nervous activity is in contradiction to each other, and the mechanism is not yet known (Figure 7).

Thus, to our experience, experiments in space have revealed some new insight and mechanisms into human physiology, which could be of importance in interpreting the health consequences of long-duration flights in the future. By comparing the effects of long-duration (3–6 months) spaceflight on the International Space Station [12] with those of short-term shuttle flights [8], there are at least two important and surprising observations: (1) The shift of blood and fluid from the lower body segments into the heart, which increases cardiac output, is even bigger, and (2) blood pressure is more decreased by a more pronounced peripheral vasodilation (Figures 6 and 7).