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Changes in the loco-regional cerebral blood flow (r.C.B.F.) during a simulation of weightlessness
Acta Astronaatica Vol. 9, No. II. pp. 689-690, 1982 Printed in Great Britain.
0094-5765/821110689-02503.0010 Pergamon Press Ltd.
Academy Transactions Note CHANGES IN THE LOCO-REGIONAL CEREBRAL BLOOD FLOW (r.C.B.F.) DURING A SIMULATION OF WEIGHTLESSNESS A. GUELL, PH. DUPUI, M. BARRERE,G. FANJAUDand A. BES Department of Neurology, CHU Rangueil, Toulouse, France and
A. KOTOWSKAIA Moscow Institute for Medico-BiologicalProblems, Moscow, U.S.S.R. (Communicated by O. G. GAZENKO'tand L. F. DIETLEIN~;received 10 November 1981)
Abstract--Experiments of prolonged bedrest in antiorthostatic position are conducted in order to simulate cardio-circulatory modificationsobserved in weightlessness.Until now, no studies of r.C.B.F, have been effected in these conditions. Six young, healthy volunteers (average age 23.8) were placed in strict bedrest and in antiorthostatic position - 4 ° for 7 days. The r.C.B.F, measurements were studied by mXe inhalation method using a 32 detectors system. Studies were made first in basal conditions, then between the 6th and 12th hr, and finallybetween the 72nd and the 78th hr after the beginning of the experiment. Three of the subjects received 0.450mg of Clonidine daily during the experiment. In the subjects having taken no Clonidine, we observed a constant increase in r.C.B.F. (12, 17 and 16% respectively) in the first 12 hr; at the 72nd hour, all values had returned to basal state. This findingsagrees with the well known notion of a rapid correction of hemodynamicdisturbances observed in the first days of weightlessness. In the subjects treated with Clonidine, the increase of r.C.B.F, did not occur. Several mechanicsms of action are possible; the Clonidine affecting either the heart by inhibiting volemic atrial receptors, or the brain by direct vasoconstriction. i. INTRODUCTION Space flights cause an important redistribution of the circulating blood mass in the human cardio-vascular system; this redistribution goes from the infracardiac regions towards the cephalic region[3]. On Earth, it is impossible to simulate weightlessness. There are however a few conditions such as immersion[6], prolonged bedrest[8] and antiorthostatism[7] that allow us to recreate in a much weaker way, some of the changes that occur in space, and those, accidentally that concern the cardio-vascular system. In this work, we studied the possible cephalic circulatory changes by means of following the variations of the regional Cerebral Blood Flow (r.C.B.F.) during simulated 0-gravity.
2. MATERIALS AND METHODS
Six young healthy volunteers (median age: 24yr-+ 4.1yr) were placed in bedrest and in a -4 ° antiorthostatic position (head down) for 7 days; they were not allowed to raise their head from the level of the bed but they were stillallowed to move laterally.Three of these subjects received, after their consent and for the entire length of the experiment CIonidine, 0.450 mg per day in
tAcademy Member (Section 3). :~AcademyCorresponding Member (Section 3).
three doses, for to block the Gauer's reflex[5]. To measure the possible variations of the r.C.B.F., we used a multidetector apparatus that was equiped with 16 scintillation detectors for each hemisphere which was based on the t33Xe inhalation technique that Obrist and Risberg have perfected[10, 11]. The subject inhales in a closed circuit system, during one minute, a gaz mixture containing t33Xe (2.5 mC/1 or a total of 15-20 mC per patient and per examination), after what he breathes ambient air. For 10min, we recorded on one hand, the cerebral radioactivity of the exhaled air at the end of each expiration. A computerized program allows bicompartimental analysis of them clearance curves, therefore giving results which correspond to the fast compartiment (r.C.B.F.) in the grey matter: FI in ml/100g/nm with corrections depending on the tracer's arterial recirculation. Each cerebral hemisphere is divided in to 7 regions in front of which 2 or 3 scintillation detectors are placed. The calculated results appear on a printing board: a hemispheral reconstruction is also possible on a TV screen calibrated to a color scale that is information of the flow. Three r.C.B.F, determinations were performed on each of the volunteers: --the first one, before bedrest began and before receiving Clonidine, --the second one, between the 6th and the 9th hr after the beginning of the experiment, --finally, the third one, 72 hr after bedrest began.
689
690
A. Gt EI,I et al. C,B,F. (ml/lO0
120
g/mn)
No C lonidine
Clonidine
ii0 90 80 70
oh ~'h
7~h ~h ~h
I
.h
Time
(hours)
Fig. 1. Effects of prolonged bedrest in - 4 ° antiorthostatic position on C.B.F. action of Clonidine.
3. RESULTS Among the 3 subjects who did not receive Clonidine, there was a constant increase in the r.C.B.F. (Fl: Flow in grey matter) between the 6th and the 9th hr after the beginning of the experiment: +13, +16 and +17% respectively (Fig. I). 72 hours after bedrest began, the r.C.B.F, does not show any significant variation with the results obtained before bedrest. Among the 3 subjects who received 0.450 mg of Clonidine, per day, during the time of the experiment, we did not notice any significant variation in the r.C.B.F.; not even during the second measure (between the 6th and the 9th hr after bedrest began) (Fig. 1). Finally, we noted that the subjects who did not receive Clonidine showed objective signs of cephalic "venous congestion" (feeling of a full head, nasal congestion, facial and most of all palpebral edema, etc...). These symptoms appear 2 hr the beginning of bedrest and reach their peak around the 48th hr. On the contrary, those who received Clonidine hardly presented any such symptoms during the experiment, and when they appeared, they only did so towards the end of the experiment. 4. DISCUSSIONANDCONCLUSION It is well established that prolonged bedrest in antiorthostatic position causes a redistribution of the circulating blood mass in favor of the thoraco-cephalic region and most of all towards the head where a venous stasis will appear [4, 7]. This stasis will be responsible for a great variety of objective and subjective symptoms: feeling of head fulness, and nasal congestion, buccal and gingival mucosal turgescence, retinal venous dilatation, slight papilary blur, important facial and palpebral edema. The symptoms are present among the subjects that did not receive Clonidine and they are classically common among all astronauts. One can suppose that this venous stasis is responsible for a venous pressure in the intra-cerebral veins; CO2 would then be less well eliminated and the cortical pCO2 would tend to increase; this, in return could cause a vasodilatation in the arterial territory, thus, an increase in the C.B.F.[I]. In favor of this hypothesis, one can recall the results of certain authors, found during animal
experimentation, concerning the arterial vasodilatation of pial arteries after an increase of venous pressure[12]. When given, Clonidine will mask the increase in C.B.F. that occurs in the other three patients by diminishing the cardiac output and by stimulating the local alpha2 adrenergic receptors. It therefore appears that the experiments using prolonged bedrest in antiorthostatic position can be considered to be good experimental models for on the ground simulation of cephalic circulatory modifications that occur during space flight. One must however realise that on Earth, these changes are only quite temporary because they disappear after the 4th day whereas during long term space flights, they persist for several weeks. It is therefore absolutely necessary to be able to study not only cerebral hemodynamics but also the entire cardio vascular system (neuro-endocrine regulation included) in weightlessness, so that one can well understand all the consequences that are due to the important shift of liquid caused by 0-gravity. As a result of such research it should be possible to create a space pharmacopeia that could care for, and prevent the customary problems that occur. REFERENCES 1. Bes A.. Rrgulation de la Circulation Crr~brale. J. d'Enseignement et d'Actualit~s Neurologiques (Edited by Chibret and Clermont-Ferrand), p. 35, France (1980). 2. Bolme P., Forsyth R., Ishizaki T. and Melmon L., Hemodynamic effects of systemic and central administration of Clonidinein the monkey. Am. J. Phys. 222, 1276-1279(1975). 3. Dietlein L. F.. Space flights deconditioning and overview of manned space flights results? NASA, SP, 269, 1-26 (1971). 4. Guell A., Braak L., Arne-Bes M. C., Fanjaud G. and Bes A., Simulation d'absence de pesanteur: modifications circutatoires au niveau de I'extr~mit6 crphalique. Circulation C#~brale (Edited by A. Bes and G. Geraud), p. 271, Toulouse, France (1979). 5. Guell A., Colombani J. C., Gharrib CI., Montastruc P. and Bes A., Effets de la Clonidine sur le mrtabolisme hydro61ectrolytique chez des sujets placrs en drcubitus prolong6 et en position anti-orthostatique. XXIXth Int. Cong. Aviation and Space Medicine, Nancy, France 7-11 Septembre 1981. 6. Hood W. B., Murray R. H., Urshel C. W., Bowers J. A. and Goldman J., Effects of water immersion upon human subjects. Aerospace Med. 39, 579-584 (1948). 7. Kakurin L. I., Lobanik V. I., MikhailouM. and Senkevich Y. A., Anti-orthostatichypokinesia as method of weightlessness simulation. Aviation Space Environn. Med. 47, 1083-1086 (1976). 8. Kotovskaya A. R., Kakurin L I., Konova N. 1., Simpura S. F. and Grishiwa I. S., Effects of prolonged hypokinesia on human resistance to G. Forces. In Problems in Space Biology, Vol. 4, p. 17, A.T.D., Press Washington,D.C. (1%5). 9. Montastruc P., Montastruc J. L. and Dang-TranL., Clonidine inhibits negative pressure breating (or left atrial distension) induced diuresis: evidence for involvement of central 2 mechanisms, J. Pharmacol. (Paris) 13, 317-327 (1982). 10. Obrist W., Thompson H. and King C., Determinationof CBF by inhalation of 133 Xenon. Circulation Res. 20, 124-135 (1%7). 11. RisbergJ., Ali Z., Wilson E., Wills E. and Halsey J., Regional Cerebral Blood Flow by 133 Xenon Inhalation. Stroke 6, 142-148 (1975). 12. Wet E. P. and Kontos H. A., Responses of pial arterioles to increased venous pressure. J. CBF and Metabolism l, Suppl. 1. 329-330 (1981).
0094-5765/821110689-02503.0010 Pergamon Press Ltd.
Academy Transactions Note CHANGES IN THE LOCO-REGIONAL CEREBRAL BLOOD FLOW (r.C.B.F.) DURING A SIMULATION OF WEIGHTLESSNESS A. GUELL, PH. DUPUI, M. BARRERE,G. FANJAUDand A. BES Department of Neurology, CHU Rangueil, Toulouse, France and
A. KOTOWSKAIA Moscow Institute for Medico-BiologicalProblems, Moscow, U.S.S.R. (Communicated by O. G. GAZENKO'tand L. F. DIETLEIN~;received 10 November 1981)
Abstract--Experiments of prolonged bedrest in antiorthostatic position are conducted in order to simulate cardio-circulatory modificationsobserved in weightlessness.Until now, no studies of r.C.B.F, have been effected in these conditions. Six young, healthy volunteers (average age 23.8) were placed in strict bedrest and in antiorthostatic position - 4 ° for 7 days. The r.C.B.F, measurements were studied by mXe inhalation method using a 32 detectors system. Studies were made first in basal conditions, then between the 6th and 12th hr, and finallybetween the 72nd and the 78th hr after the beginning of the experiment. Three of the subjects received 0.450mg of Clonidine daily during the experiment. In the subjects having taken no Clonidine, we observed a constant increase in r.C.B.F. (12, 17 and 16% respectively) in the first 12 hr; at the 72nd hour, all values had returned to basal state. This findingsagrees with the well known notion of a rapid correction of hemodynamicdisturbances observed in the first days of weightlessness. In the subjects treated with Clonidine, the increase of r.C.B.F, did not occur. Several mechanicsms of action are possible; the Clonidine affecting either the heart by inhibiting volemic atrial receptors, or the brain by direct vasoconstriction. i. INTRODUCTION Space flights cause an important redistribution of the circulating blood mass in the human cardio-vascular system; this redistribution goes from the infracardiac regions towards the cephalic region[3]. On Earth, it is impossible to simulate weightlessness. There are however a few conditions such as immersion[6], prolonged bedrest[8] and antiorthostatism[7] that allow us to recreate in a much weaker way, some of the changes that occur in space, and those, accidentally that concern the cardio-vascular system. In this work, we studied the possible cephalic circulatory changes by means of following the variations of the regional Cerebral Blood Flow (r.C.B.F.) during simulated 0-gravity.
2. MATERIALS AND METHODS
Six young healthy volunteers (median age: 24yr-+ 4.1yr) were placed in bedrest and in a -4 ° antiorthostatic position (head down) for 7 days; they were not allowed to raise their head from the level of the bed but they were stillallowed to move laterally.Three of these subjects received, after their consent and for the entire length of the experiment CIonidine, 0.450 mg per day in
tAcademy Member (Section 3). :~AcademyCorresponding Member (Section 3).
three doses, for to block the Gauer's reflex[5]. To measure the possible variations of the r.C.B.F., we used a multidetector apparatus that was equiped with 16 scintillation detectors for each hemisphere which was based on the t33Xe inhalation technique that Obrist and Risberg have perfected[10, 11]. The subject inhales in a closed circuit system, during one minute, a gaz mixture containing t33Xe (2.5 mC/1 or a total of 15-20 mC per patient and per examination), after what he breathes ambient air. For 10min, we recorded on one hand, the cerebral radioactivity of the exhaled air at the end of each expiration. A computerized program allows bicompartimental analysis of them clearance curves, therefore giving results which correspond to the fast compartiment (r.C.B.F.) in the grey matter: FI in ml/100g/nm with corrections depending on the tracer's arterial recirculation. Each cerebral hemisphere is divided in to 7 regions in front of which 2 or 3 scintillation detectors are placed. The calculated results appear on a printing board: a hemispheral reconstruction is also possible on a TV screen calibrated to a color scale that is information of the flow. Three r.C.B.F, determinations were performed on each of the volunteers: --the first one, before bedrest began and before receiving Clonidine, --the second one, between the 6th and the 9th hr after the beginning of the experiment, --finally, the third one, 72 hr after bedrest began.
689
690
A. Gt EI,I et al. C,B,F. (ml/lO0
120
g/mn)
No C lonidine
Clonidine
ii0 90 80 70
oh ~'h
7~h ~h ~h
I
.h
Time
(hours)
Fig. 1. Effects of prolonged bedrest in - 4 ° antiorthostatic position on C.B.F. action of Clonidine.
3. RESULTS Among the 3 subjects who did not receive Clonidine, there was a constant increase in the r.C.B.F. (Fl: Flow in grey matter) between the 6th and the 9th hr after the beginning of the experiment: +13, +16 and +17% respectively (Fig. I). 72 hours after bedrest began, the r.C.B.F, does not show any significant variation with the results obtained before bedrest. Among the 3 subjects who received 0.450 mg of Clonidine, per day, during the time of the experiment, we did not notice any significant variation in the r.C.B.F.; not even during the second measure (between the 6th and the 9th hr after bedrest began) (Fig. 1). Finally, we noted that the subjects who did not receive Clonidine showed objective signs of cephalic "venous congestion" (feeling of a full head, nasal congestion, facial and most of all palpebral edema, etc...). These symptoms appear 2 hr the beginning of bedrest and reach their peak around the 48th hr. On the contrary, those who received Clonidine hardly presented any such symptoms during the experiment, and when they appeared, they only did so towards the end of the experiment. 4. DISCUSSIONANDCONCLUSION It is well established that prolonged bedrest in antiorthostatic position causes a redistribution of the circulating blood mass in favor of the thoraco-cephalic region and most of all towards the head where a venous stasis will appear [4, 7]. This stasis will be responsible for a great variety of objective and subjective symptoms: feeling of head fulness, and nasal congestion, buccal and gingival mucosal turgescence, retinal venous dilatation, slight papilary blur, important facial and palpebral edema. The symptoms are present among the subjects that did not receive Clonidine and they are classically common among all astronauts. One can suppose that this venous stasis is responsible for a venous pressure in the intra-cerebral veins; CO2 would then be less well eliminated and the cortical pCO2 would tend to increase; this, in return could cause a vasodilatation in the arterial territory, thus, an increase in the C.B.F.[I]. In favor of this hypothesis, one can recall the results of certain authors, found during animal
experimentation, concerning the arterial vasodilatation of pial arteries after an increase of venous pressure[12]. When given, Clonidine will mask the increase in C.B.F. that occurs in the other three patients by diminishing the cardiac output and by stimulating the local alpha2 adrenergic receptors. It therefore appears that the experiments using prolonged bedrest in antiorthostatic position can be considered to be good experimental models for on the ground simulation of cephalic circulatory modifications that occur during space flight. One must however realise that on Earth, these changes are only quite temporary because they disappear after the 4th day whereas during long term space flights, they persist for several weeks. It is therefore absolutely necessary to be able to study not only cerebral hemodynamics but also the entire cardio vascular system (neuro-endocrine regulation included) in weightlessness, so that one can well understand all the consequences that are due to the important shift of liquid caused by 0-gravity. As a result of such research it should be possible to create a space pharmacopeia that could care for, and prevent the customary problems that occur. REFERENCES 1. Bes A.. Rrgulation de la Circulation Crr~brale. J. d'Enseignement et d'Actualit~s Neurologiques (Edited by Chibret and Clermont-Ferrand), p. 35, France (1980). 2. Bolme P., Forsyth R., Ishizaki T. and Melmon L., Hemodynamic effects of systemic and central administration of Clonidinein the monkey. Am. J. Phys. 222, 1276-1279(1975). 3. Dietlein L. F.. Space flights deconditioning and overview of manned space flights results? NASA, SP, 269, 1-26 (1971). 4. Guell A., Braak L., Arne-Bes M. C., Fanjaud G. and Bes A., Simulation d'absence de pesanteur: modifications circutatoires au niveau de I'extr~mit6 crphalique. Circulation C#~brale (Edited by A. Bes and G. Geraud), p. 271, Toulouse, France (1979). 5. Guell A., Colombani J. C., Gharrib CI., Montastruc P. and Bes A., Effets de la Clonidine sur le mrtabolisme hydro61ectrolytique chez des sujets placrs en drcubitus prolong6 et en position anti-orthostatique. XXIXth Int. Cong. Aviation and Space Medicine, Nancy, France 7-11 Septembre 1981. 6. Hood W. B., Murray R. H., Urshel C. W., Bowers J. A. and Goldman J., Effects of water immersion upon human subjects. Aerospace Med. 39, 579-584 (1948). 7. Kakurin L. I., Lobanik V. I., MikhailouM. and Senkevich Y. A., Anti-orthostatichypokinesia as method of weightlessness simulation. Aviation Space Environn. Med. 47, 1083-1086 (1976). 8. Kotovskaya A. R., Kakurin L I., Konova N. 1., Simpura S. F. and Grishiwa I. S., Effects of prolonged hypokinesia on human resistance to G. Forces. In Problems in Space Biology, Vol. 4, p. 17, A.T.D., Press Washington,D.C. (1%5). 9. Montastruc P., Montastruc J. L. and Dang-TranL., Clonidine inhibits negative pressure breating (or left atrial distension) induced diuresis: evidence for involvement of central 2 mechanisms, J. Pharmacol. (Paris) 13, 317-327 (1982). 10. Obrist W., Thompson H. and King C., Determinationof CBF by inhalation of 133 Xenon. Circulation Res. 20, 124-135 (1%7). 11. RisbergJ., Ali Z., Wilson E., Wills E. and Halsey J., Regional Cerebral Blood Flow by 133 Xenon Inhalation. Stroke 6, 142-148 (1975). 12. Wet E. P. and Kontos H. A., Responses of pial arterioles to increased venous pressure. J. CBF and Metabolism l, Suppl. 1. 329-330 (1981).