Pharmaceuticals in Space Medicine

by Charles A. Berry, MD

pharmaceuticals

in space medicine

358

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

A ll of our astronauts arc aircraft " pilot s and routinely fly high performance aircraft as a portion of their continuing training program . " 'e are thus faced with an aviation m edicine problem as well as a space medicine problem in the u se of pharmaceuticals. There h as been a general policy, certainly \",ithin the military, that a pilot requiring drug therapy sh ould not be tlying. In the civilian situation the poli cy is not that clear-cut for the control of the flight crew or the individual pi lot is not that direct. There is no d()ubt the simplest way t o handle the problem is t o say there should be n o combination of drugs and flying. H oweyer , we knO\~; that thi s is not realistic in many situations and , therefore, our life becomes comp1icated. .\ panel discussion on drugs and fl ying pe rsonnel at an FAA advanced aviation medical seminar in San Franci sco ob sen 'ed that drugs mi ght be used in instances where they could improve an airman 's skill. An example would be the use of aspirin t o clear a headache, thus enabling an individual to fly better than he might with the headache. The second grou p involved drugs tha t would be h azardou s to flying if t he flyi ng occurred while the pilot was under the effect s of the m edication , but there woul d be no hazard in volved after a period of time. A harbitura te was used as an exam ple of thi s group . The third grou p invoh 'ed drugs \,vhich m ay or may not be h azards of them selves. ~fost of the inst ances involve this group and in m an y of t he cases the underlying medical condition would preclude the flyi ng while the drug itself might be fai rly h armless in its effects. FAA h as realized t h at som e illnesses or symptom s migh t not preclude flying or ground traffic control work and may be benefited by appropriat e drugs. The fli ght surgeon is t hen face d wi th determinin g

Ast rona ut Edward H. Wh ite II , during the third orbit of the Gemini-Titan 4 flight , performed his spectacular walk in space secured to the spacecraft by a 25-foot umbilical line and a 23-foot tether line, both wrapped together with gold tape to form one cord. Becoming the first A merican astronaut to egress from his spacecraft while in orbit, White remained outside the capsule a total of 21 minutes. He is holding a selfmaneuvering unit for moving about in the weightless environment; on his chest is an emergency oxygen supply pack . In command of the ship which completed 62 revolutions in four days was Astronaut James A . McDivitt.

* Adapted from a p r "'sentation t o t h e industr ial pharmacy section at t h e an nua l m eeting of the AMER IC AN PHAR M ACEUT I CAL ASSOCIATION in New York City , August 4 , 1964.

the safet y of t he particular drug in relation to aviation . A guide to drug hazards in aviation medicine has been pre pared by F AA and is of u se in m aking this det ermin ation . l Even in cases where the drug may n ot seem t o be contraindicated in the flying situation , possible drug reaction or allergy must be con sidered . This is even true with the antibiotics . In our own situa tion we have found that the fewer the flight crew the easier the control and this factor is helpful in det ermining our action s concerning drug thera py and fl ying. The M ercury program has proved that man is capable of performin g not only marginally but very well in t he spaceflight environment. This was so well sh own in the Mercury program that the Gemini and Apollo spacecraft launch vehicl e combinations have been designed with man as an integral part of the control loo p. His activity has, in m an y instan ces, becom e primary ra ther than an equipment failure override. In our :34-h our missions the only outstanding problem h as been the a ppearance of postflight orthost atic h y potension . This h as pe rsisted for periods of 9 t o 17 h ours and in the case of .\ stronau t Coo per resulted in a near faint on the carrier deck . It must be em ph asized tha t we are not at all con vinced tha t orthost a tic h y poten sion is a prima ry effect of weigh tlessnes!3 for there are m an y other fact ors involved , such as confinemen t and deh ydration . In fact the M ercury astronauts were su bjected to a number of stresses (T able I). In spite of these stresses and our fu rther continuou s observation of the fligh t crew in the prefli ght, fli gh t and postfligh t periods, little has been observed in the way of abnorm al ph ysiologic activity . \\'e h ave observed elevated pulse rates and rhy thm and pacem aker activity changes on the ECG . These h ave all been easily relat ed t o specific fli ght events or activity and are considered norm al under t hese circumst ances. 2

table I mercury spaceflight stresses Full pressure suit Confinement and restraint 100% oxygen 5 psi atmosphere Changing cabin pressure (launch and entry) Varying cabin and suit temperature Acceleration Weightlessness Vibration Dehydration Flight plan pe rformance Sleep need Alertness need Changing illumination Diminished food intake

" A-OK " from Lt. Col. Charles A . Berry gave James Mc Divitt and Edward White the goahead signal from a health standpoint when the astronauts took their four-day Gemin v flight in June . The chief of the medical operations office at the Houston , Texas. NASA manned spacecraft center has been connected with the space program almost from the time it began. He had a hand in selecting the original seven astronauts and served as technical advisor for the " Men into Space " TV series . In 1959 he was. chosen as an aeromedical monitor for Proj ect Mercury fli g ht operations and on Jun e 17, 1960 he qualified for duty as a " space surgeon ." A graduate of the University of California , Berry was decorated for his. services during World War II and has been presented with the Arnold D. Tuttle award for original research , the USAF certificate of achievement and the AMA speci al aero space medicin e honor citation .

Early in the m anned spacefli ght program it \,v as decided t o adhere t o t he basic concept developed in avia tion- no drugs were to be u sed as routine measures for extendin g man 's capability Lut drugs woul d be made available for certain emergency u ses. An immedi a te problem was posed in the selection of not only the m edi cations to be used Lut the m ethods fo r a dministerin g these medication s in the spacefli ght environ ment. The opera tion al situa tion required that the full pressure suit Le \\-orn during the en tire mission . Any possible inj ection was thus h ampered by the body's being covered with t he sui t, primarily, and , second arily, Ly the h ands' being encased in gloves which m igh t be pressu rized . F ine movemen ts thus ,,'ould be somewhat more diffic ul t than if the h and s were ungloved . Inj ectors were developed which could deliye r t heir con tents throu gh the pressure suit an d into the astronau t's Vol. NS 5, No .7 , July 1965

359

Fig u r e I-G 0 r don Cooper carried these injectors and medication case on his MA-9 mission. He used the in jector to administer d extro-a mph eta min e sulfate to himself in flight.

Figure 2-Special measures were used for packaging the medication. The tablets were broken and placed in capsules which were sewn with a single-thread on a velcro flap in an aluminum con tainer. The capsule could easily be bitten off and ingested as necessary.

thigh (Figure 1) . They were fired by removing the pin from one end of the injector, thus arming it and then placing the other end against the thigh with some pressure . This caused the needle to fire through the suit into the thigh and inject the material all in one motion . During the first four space missions the drug5 made available in the injectors included an anodyne , an antimotioll sickness drug, a stimulant and a vaso constrictor for treatment of shock . I n the later missions these were reduced to an injector containing an anti motion sickness drug and one carrying an anodyne. Injectors were made available both in a pocket on the suit and in the survival kit. These in jectors have performed very satisfactorily in all their testing and were routinely returned to the contractor for evaluation following the flight. An evaluation of the longer missi()n programmed for MA-9 (Gordon Cooper's flight) led to the decision to make certain tablet type medications available both on the suit and in the survival kit. The medications chosen were dextro-amphetamine sulfate, an antimotion sickness drug and an antihistamine tablet. Again the spaceflight environment and the gloved hands called for the development of special measures for packaging these tablets for use in the weightless en vironment. The pill case developed (Figure 2) consisted of an aluminum container lined with velcro and having a velcro top flap which could be lifted easily from either end with a gloved hand . The tablets were broken and 360

placed in capsules which were then sewn with a single thread to the velcro flap. As the flap was lifted back, the individual capsule could be easily bitten off and ingested. In the flight program to date, we have not had to utilize any medications pre- or postflight and have utilized medication in flight on only one occasion, when the dextro-amphetamine sulfate was administered during Gordon Cooper's flight. The astronaut's mental and physical integrity was never in doubt during this mlSSlOn. However, as the time for retrofire approached, a review of the mission tasks made it evident that the astronaut had undergone a long and a rigorous work schedule from which he might be expected to experience considerable fatigue, even under ideal environmental conditions and with full benefit from restful sleep. Knowing that neither of the latter conditions prevailed, the astronaut was requested to ingest the dextro-amphetamine sulfate tablet prior to the initiation of retro-sequence. While at the time he received this instruction he was not convinced it was necessary, he did take the medication and within 15 minutes noticed a marked change in his mental attitude and a lifting of the sensation of fatigue. It is our feeling that such drugs should be available both during flight and in the survival kit for postflight use should the occasion arise. In the use of any such medications it is extremely important to carry out a pretesting program and thus assay the effect of the given drug on the particular

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

astronaut. This was done in our program and, in fact, the medication for pain contained in the injector was changed on the last mission as the astronaut was found to be sensitive to the medication which had been used on previous flights . The Gemini and Apollo missions will bring us more prolonged exposures to the spaceflight environment for greater numbers of flight crew. These longer exposures may provide us with more problems. We still do not have the answer to the postflight orthostatic hypotension problem. The bone de calcification which has been observed in bedrest studies, but not yet in our flights, may be seen as a result of these longer missions. Man has been made a vital part of the system in these ad vanced projects and his vital role is amply demonstrated in the necessity for his conduct of mid-course corrections. full manual control of lunar touchdown and docking maneuvers in these programs . These activities call for highl y trained astronauts in excellent control of physical and mental capabilities. The longer mission duration, the number in the crew and the lunar operation phase have called for a careful evaluation of the needs for medical supplies on these missions. Early suggestions included rather elaborate equi pmen t lists, even calling for emergency surgery equipment. More careful eval uation has led to a more austere and reasonable list based on the following considerations~the ~the

Apollo mission profile high probability of water landing with 6- to 72-hour access ~the fact that crewmen will remain aboard the spacecraft ~the severe limitation of weight and volume.

It is currently planned that a single medical kit will be located in the command module, accessible during flight and easily removable in case of leaving this module. At the current stage of planning items in the kit include analgesic tablets, antibiotic capsules, antifatigue tablets, antiemetic capsules, general purpose ointment, decongestant inhaler, bandaids, dressings and injectors of an antimotion sickness drug and an anodyne. Space will be left for elective medications. In the lunar excursion module only six tablets will be carried, four analgesic and two antifatigue. 3 As we look forward to 7- and I-t-day missions and indeed on to missions of :30, 60, 90 days and even longer, we naturally speculate on the means of extending man's natural capability . Concern has been expressed that the environment may stress man beyond his physiological tolerances unless we do (continued on page 378)

physiological feats . This would, indeed, sound like an ideal spaceman. Since this optimum man is not now available, what can we consider in the way of drugs to extend man's performance? The conceivable uses can be classified into three broad categ()ries~

1. those drugs used for the treatment of some present loss or deficit such as aspirin for a headache 2. those drugs used for the prophylaxis of some anticipated deficit such as antibiotics, antihistamines or radiation drugs 3. those drugs used to enhance natural capability such as stimulants, hypnotics or energizers.

,r M edical supplies carried on first Gemini twoman mission launched by NASA.

pharmaceuticals in space (rontinlfed from j)age 360)

something to help make up the difference. Traditionally we have used protective devices and equipment and made few attempts to alter man himself. Every efIort has been made to assure the provision of a "natural man," as near a perfect physical specimen as possible, and one on whom it would be difficult to improve if he is in his normal, natural state. Is it possible to modify man in any meaningful manner, particularly by the use of drugs? Freedman recently discussed easing the spacecraft design engineer's problem by trying to change man instead of constantly adding protective equipment- and thus weight requirements- to the spacecraft. It was suggested that, perhaps, normal man or natural man was not the optimum man. It would be nice if we could have man maintain a normal temperature range in spite of large variations in the environment, use little or no oxygen, react only to massive doses of radiation, perform at peak intellectual and physical efficiency on four hours sleep and other such seemingly outlandish 378

The idea of drug usage in spaceflight is not new for Oberth, as early as 1929, recommended use of scopolamine for the treatment of space sickness. More recent suggestions have included the use of tranquilizers to allay anxiety prior to or during spaceflight. These drugs do produce a less than normal individual with unpredictable mental attitudes. They may alter judgment and change orientation to reality. In addition it has been shown that the tranquilizers reduce tolerance to stress of several types such as altitude and acceleration. 6 This would certainly be an undesirable side effect. The use of stimulants has been suggested in the longer flights and at various critical points in flight. The need for increased vigilance in a fatigued pilot at such critical times as re-entry or landing can hardly be questioned. Research has shown that amphetamines are capable of mitigating fatigue and improving ability at psychomotor tasks. They appear to be useful in increasing and maintaining alertness. I feel that missions and equipment should always be planned within the capabilities of the crew but, if it becomes absolutely necessary to extend the crew's performance further, drugs such as amphetamines may be used at crucial points if they are carefully controlled. Repetitive use should be avoided for it is not possible to create a superman with these drugs and it is possible to overextend man. In the future it may even be feasible to efIect some control over diurnal or work-rest cycles by the use of improved sedatives and stimulants. The requirement for adequate work-rest cycles in such prolonged missions as the lunar landing and lunar surface activity requires investigation of these technics. To reduce metabolism and thus diminish the amounts of oxygen and food necessary on very prolonged interplanetary missions, the use of hypothermia has been suggested. Some basic studies have been done stemming from the use of hypothermia in surgery. The development of a metabolism-

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

lowering drug to either aiel or to supplant the hypothermia has been projected as a possibility. Certainly for any of our missions in the foreseeable future, the hypothermia technic would appear to still be in the "Buck Rogers" status. In considering our longer missions it is worthwhile to observe research efforts in the hope that they may determine some drugs which would be useful in spaceflight. The overall mission phases might be viewed in line with trying to note areas where such activity might be concentrated. In the preflight period there is a need for adequate rest and perhaps for the adjustment of workrest cycles during this hectic period. Hypnotics have been used prior to aircraft missions to make sure astronauts secure adequate rest but performance decrement has been reported for as long as 15 hours postingestion. Careful consideration should be given to the use of any such agent. To date our missions have required no preflight or postflight medication. As we approach longer missions, the limited attempts at reduction in personal contacts during the preflight period which have been effective on our short missions must be reconsidered. It is quite possible that exposure during the preflight period could result in the development of disease during a prolonged mission, such as a 14-day flight. The use of antibiotics for prophylactic reasons has been suggested and might be considered along with modifications of the preflight period to provide some modicum of crew isolation. This is a controversial and difficult area for the crew is required to partici pa te in numerous preflight checks during this period and any real isolation appears to be rather impractical at the present time. Some drugs have shown increased animal tolerance to acceleration and deceleration but further studies are certainl y in order. During the orbital mission phase we have been concerned with the development of acute emergencies and the possibility of motion sickness. We have certainly seen no evidence of either and while we still carry the antimotion sickness drugs, they are most likely to be used in the postflight water landing situation. Consideration might be given to tablets for meal supplements and vitamins and also for the use of antifatigue drugs at critical periods. The possibility of exposure to radiation on certain flights in the future, suggested by the presence of the radiation belts, indicates that an antiradiation drug would be a valuable item in the spaceflight armamentarium. While much work is being done in this area, to date there is no one acceptable drug available. The energy sinks such as the sulfhydryl drugs have been

ballistic missiles, air craft and submarines. The pulse mode transducer (}'igure 3, above, page 372) "acquires" and "tracks" the blood vessel of interest, while measuring its cross-sectional dimneter from moment to moment. The Doppler mode transducer (Figure 3, below, page 372) measures blood flow velocity in the vessel by detennining the Doppler shift in pulse repetition frequency caused by blood flow. Figure 4 illustrates the idealized waveforms for the pulse mode transducer and the Dop-

biomed ica I i nstru mentation (continued from page 372)

figuration for measurement of volumetric blood flow. The instrumentation employs ultrasonic traveling waves which are modulated in a pulse mode. The signal modulation concepts and information extraction methods utilized in this system are nlethods that have been developed and successfully employed in modern radar and sonar systems for detecting and tracking

Figure 4- This diagram shows idealized waveforms for the (a) "pulse mode" transducer and (b) Doppler mode transducer. The "pulse mode" transducer "acquires" and "tracks" the blood vessel of interest while measuring blood vessel diameter from moment to moment. The Doppler mode transducer measures blood flow velocity . From the two transducers volumetric blood flow is computed automatically from moment to moment.

"P ULSE MODE" TRANSDUCER VOLTAGES

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J I

-

TIME

I

SCATTERED SIGNAL AT FREQUENCY to

-

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A\

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:

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( b)

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Figure 5-This roentgenogram of a Rhesus monkey was prepared for continuous measurement of cardiac output, electrocardiogram, respiratory rate and effort and electroencephalogram.

VESSEL WALL PAIR

R"ElVEO RAYLEIGH SCA TTERE 0 SlGNAL

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PULSE

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"DOPPLER MODE" TRANSDUCER VOLTAGES

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9

pharmaceuticals in space (continued from preceding page)

toxic in protective doses and have given variable response. Further work is certainly indicated in this area. In the re-entry and recovery phase an timotion sickness drugs and the antifatigue drugs may prove to be useful, particularly if we continue our sea landings. Early studies with the Gemini spacecraft have been quite efIective in producing motion sickness with the spacecraft in the water. The postflight orthostatic hypotension and bone demineralization may lend themselves to amelioration through drug therapy. This should certainly be in vestiga ted. In the current drug climate one cannot help but worry about exactly

J!:Td~. ~'CO~~

-

TIM E

what drugs do and particularly about efIects of which we may not be aware . It is imperative that if we do something with drugs, it must be for the good and betterment of the flight crew and not something harmful. Every attempt must be made to know the actual effect of the drugs, their mode of action, any side effects and the effect on performance of man in the space situation or, at least, space simulated situation. Our medical selection and maintenance program with the preventive medicine activities has precluded generally the development of in-flight ills. We still tend to feel that a carefully selected and trained astronaut would better accomplish his mission without the use of drugs, thereby adhering to the natural man theory. However, as we look forward to more prolonged

pIer mode transducer. From the output of these two transducers volumetric blood flow is computed automatically. Such a device will find general medical usefulness not only in evaluating and managing patients with cardiac and vascular disease but in ra pidl y, (continued on page 380)

mISSIons, it is obvious that man will need assistance and he might obtain this through a careful choice of drugs . • references 1.

2.

3.

4.

5. 6.

Cutting, W .C., Guide to Drug Hazards in Aviation 111 ed., Fed. Aviation Agency, Aviation Med. Serv., Washington, D .C., U.S. Govt. Printing Office (1962). Berry, C.A., "Aeromedical Preparations ," .11 ercury Proj . Sum. including R esults of the Fourth AI anned Orbital Flight, JI ay 15 and May 16, 1963, NASA Manned Spacecraft Center, 199. BetTY, C.A., Space Aled. Expel'. and Applications to Apollo, presented at Amer. Astronautical Soc. meeting , New York, N.Y., May 1964. Freedman, T., and Linder , G .S., Can A1an Be Modified?, pt'esented at 17th annual Amer. Rocket Soc. meeting, Los Angeles, Calif., Nov. 13-18, 1962. Berry, C.A. , "l\Ian, Drugs and Spaceflight," A nnals of Otology, Rhinology and Laryngology, 70, 418 (June 1961) . l\IcGuire, T . , and Leary, F.J., "Tmnquilizing DI-ugs and StJ-ess Tolerance ," WADC Tech. Rpt., Wright Patterson AFB, 58 (Oct. 1958).

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379