342Tübingen Höhe Programmheft.doc

Program & Abstracts

Satellite Symposium at the Joint Congress of the Deutsche Physiologische Gesellschaft

(DPG, German Physiological Society)

held at

Tübingen on March 15, 2002

organized by the DPG-Working Group for Applied and Klinical Physiology and Pathophysiology (“AKP”)

Moderate and High Altitude Exposure –

Applied Physiology and Pathophysiology

Location:

Lecture hall of the Institute of Sports Science of the University of Tübingen (http://www.uni-tuebingen.de/IFS/) – Institut für Sportwissenschaft,

Wilhelmstraße 124, Hörsaal im 1. Stock (first floor)

edited by H.-V. Ulmer

Sportphysiologische Abteilung, FB Sport, Johannes Gutenberg-Universität (available at: http://www.uni-mainz.de/FB/Sport/physio/pdffiles/342Hoehetuebingen.pdf)

Mainz 2002

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Program & Contents Start: 10:00 a.m. In total 15 oral presentations for about 15 minutes

and 15 minutes discussion 10:00 Opening (H.-V. Ulmer, Mainz; H.-Ch. Gunga, Berlin) 10:15-12:15 Part 1: Adaptations to moderate altitude (1500-2500 m) (H.-V. Ulmer, NN) 10:15 1) AMAS-2000: Overview of the final results of a 3 weeks stay of

patients with metabolic syndrome at moderate altitude. Humpeler, E., M. Mittermayr, D. Fries, H.-Ch. Gunga, W. Schobersberger

10:45 2) AMAS-2000: Erythropoiesis and iron metabolism at moderate altitude. Fries, D., E. Humpeler, M. Mittermayr, E. Artner-Dworzak, H.-Ch. Gunga, W. Schobersberger

11:15 3) WMRS 2001 – The high- and low-pressure part of the circulation during 3 weeks of high altitude exposure (3800 m). Kirsch, K. A., H.-E. Koralewski, B. Johannes, M. Keck, H.-Ch. Gunga

11:45 4) Data acquisition and data management in complex field studies under extreme environmental conditions. Koralewski, H.-E., H.-Ch. Gunga, B. Johannes, K. A. Kirsch

12:15-13:30 Lunch break 13:30-17:00 Part 2: Adaptations to high altitude (>2500 m) (W. Schobersberger, NN) 13:30 5) Cardiorespiratory, renal and endocrinological reactions of

normotensive and hypertensive young men in moderate hypobaric hypoxia (4200 m) – Which parameters determine the tolerance for high-altitude hypoxia? Ledderhos, C., H. Pongratz, H.-Ch. Gunga, J. Exner, A. Gens, D. Roloff, A. Honig

14:00 6) Iron sequestration at high altitude – Relation to O2-transport. Behn, C., T. Viola, C. Hurtado, V. Penco, J. Cajigal, O. Araneda, D. Benitez, G. Celedón, G. González

14:30 7) Qualitative and quantitative changes of blood during prolonged intermittent exposure to hypoxia. Schmidt, W. F. J., N. Prommer, K. Heinicke, T. Viola, J. Cajigal, C. Behn

15:00 8) WMRS 2001 - Hematological changes and vascular endothelial growth factor during long-term high altitude exposure at 3800 m. Gunga, H.-Ch., R. Gossrau, M. Keck, E. Koralewski, L. Röcker, B. Johannes, K. A. Kirsch

15:30 9) WMRS 2001 – Changes of capillary density during long-term high altitude exposure (LTHAE) at 3800 m. Gossrau, R., H.-Ch. Gunga, H. Richter, G. Planitzer, M. Gutsmann

16:00 10) WMRS 2001 - Psychophysiology at high altitude. Johannes, B., H.-Ch. Gunga, E. Koralewski, K. A. Kirsch

16:30 11) Altitude adaptation in hemoglobin function – lessons from frogs and birds. Weber, R. E., A. Fago, H. Ostojic, L. Moens, C. Monge

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17:00-17:30 Break 17:30-19:30 Part 3: Pathophysiological Adaptations to altitude (H.-Ch. Gunga, NN) 17:30 12) Respiratory changes during exposure in an artificial air-space in

snow. Sumann, G., H. Brugger, W. Schobersberger, R. Meister, H.-Ch. Gunga, E. Koralewski, P. Mair, M. Falk

18:00 13) Frostbite – how to evaluate positive results of clinical cases treated with hyperbaric oxygen therapy – a study propasal. Gorjanc, J., B. I. Mekjavic

18:30 14) Hemostatic changes after a long-haul flight equivalent to 2400m altitude. Schobersberger, W., D. Fries, M. Mittermayr, P. Innerhofer, B. Hauer, G. Sumann, H.-Ch. Gunga

19:00 15) Simulation of a long-distance flight in patients with cystic fibrosis. Brückner, K., R. Fischer, S. Meyer, R. M. Huber

19:30 Final discussion and conclusions (preparation of written

remarks) H.-Ch. Gunga, W. Schobersberger, H.-V. Ulmer 20:00 Closing of the symposium 16) Poster presentation during the symposium: Gene expression in hypoxia. Lundby, C.

Evening Program: Moving to the Official Welcome Reception of the DPG.

Meeting afterwards in the HOTEL AM SCHLOSS, Burgsteige 18, Phone: 92940, (separate room reserved, warm meals until 22.30 p.m.)

Organization (Contact address: all 3 organizers) Privatdozent Dr. med. H.-Ch. Gunga, Institut für Physiologie, Arnimallee 22, D-14195 Berlin. gunga@zedat.fu-berlin.de Univ.-Dozent Dr. med. W. Schobersberger, Klinische Abteilung für Allgemeine und Chirurgische Intensivmedizin, Universitätsklinik Innsbruck, Anichstrasse 35, A-6020 Innsbruck. Wolfgang.Schobersberger@uibk.ac.at Prof. Dr. H.-V. Ulmer, Speaker of the DPG-Working Group for Applied and Klinical Physiology and Pathophysiology (“AKP”), Sportphysiologische Abteilung, FB 26, Albert-Schweitzer Strasse 22, D-55099 Mainz. Sportphysiologie@uni-mainz.de Acknowledgement The organizers say thanks to the Director and the staff of the Institute of Sport Science of the University of Tübingen for their hospitality and to the Mensa of the Eberhard-Karls-Universität and to Mrs. N. Albertini, M. Barra and C. Zein for organizational support.

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E-mail address list of speakers and chairmen with their program No. 6. Behn: cbehn@machi.med.uchile.cl 15. Brückner: kathrin.brueckner@medinn.med.uni-muenchen.de 2. Fries: dietmar.fries@uibk.ac.at 13. Gorjanc: jurij.gorjanc@mf.uni-lj.si 9. Gossrau: gossrau@ukbf.fu-berlin.de 8. Gunga: gunga@zedat.fu-berlin.de 1. Humpeler: humpeler@utanet.at 10. Johannes: bjohann@zedat.fu-berlin.de 3. Kirsch: kkirsch@zedat.fu-berlin.de 4. Koralewski: kora@zedat.fu-berlin.de 16. Lundby: Carsten@cmrc.dk 5. Ledderhos: CarlaLedderhos@bwb.org 7. Schmidt: Walter.Schmidt@uni-bayreuth.de 14. Schobersberger: wolfgang.schobersberger@uibk.ac.at 12. Sumann: guenther.sumann@uibk.ac.at Ulmer: sportphysiologie@uni-mainz.de 11. Weber: roy.weber@biology.au.dk

printed in the Universitätsdruckerei, Johannes Gutenberg-Universität Mainz

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 1

1) AMAS-2000: OVERVIEW OF THE FINAL RESULTS OF A 3 WEEKS STAY OF PATIENTS WITH METABOLIC SYNDROME AT MODERATE ALTITUDE.

Egon Humpeler1, Markus Mittermayr2, Dietmar Fries2, Hanns-Christian Gunga3, Wolfgang Schobersberger1,2

1IHS-Institut Humpeler-Schobersberger, Forschungsinstitut für Urlaubs- u. Freizeitmedizin sowie Gesund-heitstourismus, A-6900 Bregenz, Österreich, 2Klinische Abteilung für Allg. u. Chir. Intensivmedizin, Universität

Innsbruck, Österreich, 3Institut für Physiologie, Universitätsklinikum Benjamin Franklin, Berlin, Deutschland Introduction In Austria 10 million people visit moderate altitude regions (1500 m – 2500 m) every year, 40 million in the Alps, and 100 million worldwide. In contrast to the well-known physiological adaptations of healthy subjects, data how tourists with different diseases adapt to moderate hypoxia are rare. Even there are (unproven) recommendations for patients to avoid moderate hypoxia. The aim of this study was to investigate the influence of a 3-week stay at moderate altitude on patients with the „metabolic syndrome“ (obesity, hypertension, hyperlipidemia, glucose intolerance). We selected patients with metabolic syndrome because a) a large percentage of the millions of altitude visitors suffer – at least partially – from metabolic syndrome and b) metabolic syndrome may be a model for the investigation of interaction between altitude acclimatisation and sympathetic activity. We hypothesized that patients with metabolic syndrome might carry a higher cardiovascular risk even at moderate altitude and especially under exercise conditions. This was not investigated yet as was the differentiation between recreational and altitude specific effects. Methods The AMAS-2000 project consisted of two parts: part one was the pilot study for testing safety and feasibility and was conducted in Lech (Vorarlberg, Austria; 1700 m). On the basis of the Lech study results, part two was performed in Obertauern (Salzburg, Austria; 1700 m) and Bad Tatzmannsdorf (Burgenland, Austria; 200 m). Twenty-two male subjects with metabolic syndrome participated in the pilot-study, 36 subjects were enrolled for Obertauern and Bad Tatzmannsdorf, respectively. Baseline tests were performed in Innsbruck (500 m). During the 3 weeks the volunteers performed individually adjusted physical exercise (hiking 4-5 times/week for 4-5 hrs). During the three-week stay at moderate altitude (Lech, Obertauern) and Bad Tatzmannsdorf examinations were per-formed on days 1, 4, 9 and 19. Post-altitude tests were done a one and six weeks after return. The following physiological and clinical fields were examined: cardiovascular tests including blood pressure, pulse rate and ECG during rest and exercise and 24h monitoring; metabolic analyses of blood glucose (fasting and glucose tolerance test, oGTT), triglyceride, cholesterol, HDL, LDL; erythropoiesis, anthropometric parameters including fluid distribution and tissue thickness; and neuropsychological tests. As marker for oxidative stress plasma malondialdehyde was measured. Results The main findings were a significant decrease in blood pressure and pulse rate during rest and 24h holter monitoring during altitude exposure with a similar trend in patients at low altitude. No adverse cardiovascular events were observed at altitude. There were improvements in glycemic parameters and in lipid metabolism. Several neuropsychological tests revealed an improvement in well-being which was observed at both altitudes. Malondialdehyde was significantly reduced at the end of the moderate and low altitude sojourn. Conclusions All patients with metabolic syndrome tolerated the moderate altitude sojourn without any physical problems. These results indicate that a prolonged stay at moderate altitude may constitute a non-pharmacological intervention which reduces sympathetic nervous system activity, thus reducing cardiovascular and metabolic risk factors. For several parameters the time course was similar be-tween exposure to 1700 m and 500 m. Due to the favourable effects we had to reject our hypothe-sis of an increased risk for these tourists during a long lasting stay at moderate altitude. This study was supported by the Austrian Ministery of Economics, the Austrian State Departments of Tourism in Kärnten, Salzburg, Tirol, and Vorarlberg, Austrian Public Advertisment, the Austrian Tourism Organisation, and the village of Lech

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2) AMAS-2000: ERYTHROPOIESIS AND IRON METABOLISM AT MODERATE ALTITUDE

Dietmar Fries1, Egon Humpeler2, Markus Mittermayr1, Erika Artner-Dworzak3, Hanns-Christian

Gunga4, Wolfgang Schobersberger1,2 1Univ.-Klinik für Anästhesie und Intensivmedizin, Univ.-Klinik Innsbruck, Anichstrasse 35,

A-6020 Innsbruck, 2IHS-Institut Humpeler-Schobersberger GmbH, Forschungsinstitut für Urlaubs- und Freizeitmedizin sowie Gesundheitstourismus, Bregenz; 3Institut für Med. Chemie und

Biochemie, Innsbruck, Österreich; 4Institut für Physiologie, FU Berlin, Deutschland Introduction Among the millions of visitors of moderate altitude regions many suffer from chronic diseases. The effect of moderate altitude (1500 m-2500 m) has never been studies before in patients affected by the metabolic syndrome (obesity, hypertension, dyslipoproteinemia, insulin resistance). Exposure to altitude hypoxia induces the expression and release of erythropoietin (EPO) in healthy subjects thus stimulationg red cell production. The aim of this study was to investigate EPO, iron status and oxygen dissociation curve (ODC) in patients with the metabolic syndrome during a 3 weeks stay at moderate altitude. Methods The AMAS-2000 project consisted of two parts: part one was conducted in Lech (Vorarlberg, Aus-tria; 1700 m). On the basis of the Lech study results, part two was performed in Obertauern (Salz-burg, Austria; 1700 m) and Bad Tatzmannsdorf (Burgenland, Austria; 200 m). Twenty-two male subjects with metabolic syndrome participated in the pilot-study, 36 subjects were enrolled for Obertauern. Baseline tests were performed in Innsbruck (500 m). During the 3 weeks the volun-teers performed individually adjusted physical exercise (hiking 4-5 times/week for 4-5 hrs). During the three-week stay at moderate altitude blood was collected on days 1, 4, 9 and 19. Post-altitude tests were done one and six weeks after return. Following parameters were measured: Hemoglobin (Hb), hematocrit (PCV), reticulocytes, serum iron, transferrin, ferritin. In addition the P50 value (PO2 at 50%-saturation of Hb) as measure for the ODC was estimated. Statistics: Friedman-ANOVA fol-lowed by the Wilcoxon signed rank test. Level of significance p < 0.05. Results During the altitude sojourn only moderate changes in Hb, PCV and red cell count were found. In both studies EPO was already significantly elevated on day one at altitude and remained increased during the 3 weeks. A similar time course was measured for the reticulocyte count. Parameters of iron metabolism did not change at altitude. P50 was increased on the first day at altitude (+ 1mmHg; p < 0.001) still increasing until day 19 (+ 2.4 mmHg; p < 0.0001). Although P50 decreased after re-turn from altitude it remained above pre-altitude one week after descent (+ 1.1 mmHg; p < 0.01). Conclusions We conclude that moderate altitude stimulates erythropoiesis in patients with the metabolic syn-drome similar to healthy subjects as evidenced by a long lasting increase in serum EPO and in re-ticulocyte count. This moderate hypoxic stimulus was not sufficient to increase Hb, PCV and red cell count. The rightward shift in the ODC might be a beneficial adaptive response in patients with metabolic syndrome.

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3) WMRS 2001 – THE HIGH- AND LOW-PRESSURE PART OF THE CIRCULATION DURING 3 WEEKS OF HIGH ALTITUDE EXPOSURE (3800 M)

Karl August Kirsch*, Hans-Eberhard Koralewski*, Bernd Johannes*, Maike Keck*,

Hanns-Christian Gunga* *Center for Space Medicine Berlin, and Department of Physiology, Free University of Berlin, Arnimallee 22, 14195 Berlin, Germany

Introduction Under high altitude conditions an activation of the sympathetic nervous system occurs leading to an increase of the arterial blood pressure, heart rate and venoconstriction. How the latter affects cen-tral venous pressure (CVP) and peripheral venous pressures (PVP) on the long run is hard to pre-dict because intravascular volume is threatened by a negative water-balance in general and by ve-nous constriction which should lead to outward filtration. Long-term observations of venous pres-sures in high altitude were not yet done. Methods In 11 male subjects (age 26.6 ± 2.1 years, body height 1.79 ± 0.05 m, body mass 74.4 ± 10.7 kg, BMI 23.5 ± 3.5) arterial blood pressure (ABP), heart rate (HR), central and peripheral venous pres-sures were measured 12 - 16 hours and 20 days after arrival in high altitude. ABP and HR were measured with a wrist manometer during each session 5 times within 5 minutes. CVP was meas-ured applying the arm-down method (Cir.Res.4,1956 ,74), PVP was measured in the antecubital vein, the subjects resting in supine position for at least 20 minutes. Statistiscal analysis: MANOVA; SPSS 10.0 for WINDOWS. Results Self ratings of the subjects applying the acute mountain sickness (AMS) scores revealed that 4 out of the 11 subjects suffered from AMS. Their results must be seen separately from those of the other 7 subjects. Cluster analysis of the ABP and the venous pressure values confirmed the separation into two groups of subjects. At the average the systolic blood pressures of the AMS-subjects were higher by 6 to 10 mmHg at sea-level as well as in high altitude (p < 0.03) as compared to the sub-jects showing no symtoms of AMS. The same held for the diastolic values. In the AMS subjects HR were significantly lower (p< 0.04). In high altitude CVP and PVP values tended to increase in the AMS ridden subjects whereas in the normal subjects CVP and PVP decreased during their stay in high altitude. These patterns differed statistically significant (p<0.04). Conclusions In high alitude subjects suffering from AMS show higher ABP and increasing CVP and PVP values and lower heart rates. Their data should be treated separately from those subjects showing no symptoms of AMS. Sponsored by Deutsches Zentrum für Luft- und Raumfahrt (DLR/Cologne) (DLR-Project No 50-WB 0022, Free University of Berlin).

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4) DATA ACQUISITION AND DATA MANAGEMENT IN COMPLEX FIELD STUDIES UNDER EXTREME ENVIRONMENTAL CONDITIONS

Hans-Eberhard Koralewski, Hanns-Christian Gunga, Bernd Johannes and Karl August Kirsch

Center for Space Medicine Berlin, Department of Physiology, University Clinic - Benjamin Franklin - of the Free University Berlin, Arnimallee 22, 14195 Berlin

Introduction Due to the rapid development of microelectronics especially in the sensor and data management techniques more and more complex physiological tasks can be approached in the field, which means outside well equipped laboratories even under extreme environmental conditions. High precision and long term stability of modern semiconductor sensors can be achieved even with low energy consumption. New microprocessors work with high cycle frequencies, low voltages and low energy requirements. They can easily be fitted into complex systems. All these capabilities can be accomplished with light weighted, small and battery driven parts which can be connected to small sized data loggers. They are nowadays available on the market. Especially in field studies high demands are put on the systems. Besides high mechanical stability the systems must be easy to handle even by laymen. Our group has long lasting experience in the field of data acquisition especially in field studies (high altitude, tropical areas, space etc.) where for the purpose of those studies our own miniaturized data handling systems had to be developed. In this context our experience gained during several space missions (Spacelab1, D1, D2, MIR) needs to be mentioned. For these purposes we developed new and mobile data acquisition- and data handling systems for biological signals which can now be used for terrestrial studies under extreme field conditions as well. Based on these experiences the technical concept of - NeuroLab - was developed combining and integrating many small parts into one integrative system. The developments for this system started in the Russian Institute for Biomedical Problems (IBMP) in Moscow and the Bulgarian Space agency (BASA). In cooperation with the German space agency (DLR) this stationary system was installed in the MIR station and was used by Russian cosmonauts to test their physiological stability during their long term space missions. In continuation from 1996 on a mobile system called Heally was developed in Berlin with the same partners. In parallel since 1988 in our department a mobile data logger system called DALO was developed being tested and used for several studies under field conditions in extreme environments. Both systems were applied for noninvasive data acquisition and data storing of various physiologi-cal parameters which could be analysed on-line and presented on the screen. The on-line control of the data acquisition during those field studies is necessary because the experiments cannot be repeated later. If at all, they can be repeated or modified immediately during a running experiment which is time consuming and can only rarely be done. Time constraints are the most limiting fac-tors during those studies besides technological problems. Since 2000 both Systems were com-bined to the new HEALLY system under the concept – HEALTH LAB 2000 –. Hardware and Methods The hardware consisted of a core piece called Heally-Master connected with standardized minia-turized satellite modules for signal recordings. Heally-Master and the satellites were connected via an RS485 Interface. The Heally-Master was used as server and data logger and for the communication with a PC. It provided the power supply for the whole system. Two AA-batteries were enough to run the system for several hours. Exchangeable software allowed the decentralized use of the satellites when dis-connected from the core piece. Later the data collected by the satellites had to be synchronized with each other. If necessary for the on-line monitoring of the signals a PC could be used. Signal recording and a preliminary work-out could be done by the satellites. They contained their own micro controller with exchangeable software. Each satellite could handle 4 analogue signals together with several trigger-signals. Within the satellites a data reduction occured. The satellites as input/output systems could be controlled by the core piece Heally-Master. 6 satellites could be

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 5

handled simultaneously by the programs of core piece. The following satellites are already com-mercially available: 1. ECG, respiration, temperature, motion recording. 2. F0-Receiver for voice analysis. 3. Environment control : temperature, barometric pressure, humidity. 4. Pulse wave velocity, skin conductance, temperature. 5. EMG two channels. 6. EEG 4 channels 7. EOG 2 channels, skin conductance at the front. Step frequency and stride length for the estimation of the energy output and a satellite for venous pressure measurements are available. Satellite systems measure bio-impedance and calculate therefrom body composition. The oxygen saturation, evaporation and blood pressure can also be monitored by a satellite system. Data gen-erated from small transportable equipment for blood chemistry analysis can be fed into the data acquisition system and can be transfered to the core piece. As expert systems are available: 1. A psycho-physiological test battery to test the fitness of subjects under high altitude stress. 2. Subjective time perception with the help of a time reproduction test in conjunction with parame-ters under the control of the autonomic nervous system (ANS). 3. Heart- and Respiration rate Variability test and resting conditions and during exercise testing. Application and Results Recently the Heally-Systems were tested in a High Altitude Study in the White Mountains in Cali-fornia (USA) and during an Antarctic Study - MEDANTARKTICA -. It could be proven that the sys-tems were working excellently under hypobaric- as well as under cold arctic field conditions. All the data wanted could be obtained. Data monitoring and data workout in the field assured that no data were lost. Measurements could be repeated on a short term base. Data transfer in a condensed form could be managed via satellite and data were received on our server in Berlin without prob-lems. More difficult were the analyses of the blood parameters. Environmental temperatures and baro-metric pressures had be kept within narrow limits. Therefore the equipment had to be tested under simulated extreme conditions. Usually the hardware of the equipment was not a limiting factor. The preservation of the chemical substances created the most difficulties. Sponsored by Deutsches Zentrum für Luft- und Raumfahrt and the Free University of Berlin (DLR-Project No 50-WB 0022; Angiogenesis Project No. 2 and 8, Free University of Berlin).

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5) CARDIORESPIRATORY, RENAL AND ENDOCRINOLOGICAL REACTIONS OF NORMOTENSIVE AND HYPERTENSIVE YOUNG MEN IN MODERATE HYPOBARIC HYPOXIA (4200 M) – WHICH PARAMETERS DETERMINE THE TOLERANCE FOR

HIGH-ALTITUDE HYPOXIA? Carla Ledderhos+, Hans Pongratz+, Hanns-Christian Gunga*, Jürgen Exner#, Andre Gens+, Dieter

Roloff# and Arnold Honig#

+ German Air Force Institute of Aviation Medicine, Division III, Fuerstenfeldbruck * Center of Space Medicine Berlin and Department of Physiology , Free University of Berlin

# Institute of Physiology of the Ernst-Moritz-Arndt-University Greifswald Introduction Primary hypertensive humans have an enhanced reactivity and strong reflex effects of the arterial chemoreceptors as well as an exaggerated response of sympathetic nervous system in acute hy-poxic hypoxia. But it is unknown whether these phenomena influence their ability to tolerate sus-tained hypoxic hypoxia. So the aim of the experiments presented here was to determine whether or not primary hypertensive humans have a normal tolerance for high-altitude hypoxia. Methods Cardiorespiratory, renal and endocrinological parameters were measured during exposure to hypo-baric hypoxia in 18 young men with parental hypertension and office and 24-hour ambulatory blood pressure values in the upper normal or in the borderline hypertensive range, aging 20-27 years. 15 age-matched young men without any family background of essential hypertension and normoten-sive office and 24-hour ambulatory blood pressure values served as controls. All subjects experi-enced both a control and an altitude experiment, in which they underwent scheduled drinking each hour but no eating. In the altitude experiment they were exposed to hypobaric hypoxia in a low-pressure-chamber (4200 m) for eight hours. All parameters were determined at rest in supine posi-tion. Clearance technique during waterdiuresis was used to determine renal excretory function. Results All subjects tolerated the control experiment and all normotensives also the eight hours of altitude hypoxia. However, beginning after four hours of altitude exposure, eight out of 18 subjects with pa-rental essential hypertension had to be removed from the low-pressure chamber with symptoms of a mild acute mountain sickness like as headache, nausea and vomiting. Usually antidiuresis pre-ceded these symptoms. If compared to normotensives, subjects with parental essential hyperten-sion had better and more stable cardiorespiratory parameters at altitude. The reaction pattern of hormonal parameters (epinephrine, norepinephrine, renin, aldosteron, urodilatin und erythropoeitin) did not explain the different behaviour of both groups under hypoxic conditions. Conclusions The data support the hypothesis that primary hypertensive young men in acute high-altitude hy-poxia have strong respiratory and cardiovascular responses due to high excitability of their arterial chemoreceptors. But despite that their tolerance for high-altitude hypoxia was apperently not de-pendent of these parameters, for it was obviously much worse if compared to normotensives. The inability to develop high-altitude natriuresis and diuresis, probably because of an exaggerated re-sponse of their sympathetic nervous system, particularly of their efferent renal sympathetic nerves, limited the tolerance of primary hypertensives for high-altitude hypoxia . Acknowledgment This study was supported by the grant FV InSan I-0198-V-6700 from the Federal Ministry of de-fense (BMVg).

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 7

6) IRON SEQUESTRATION AT HIGH ALTITUDE – RELATION TO O2-TRANSPORT

Claus Behn1, Teresa Viola1, Carmen Hurtado2, Varinia Penco1, Jorge Cajigal3, Oscar Araneda1, Dixan Benítez1, Gloria Celedón4, Gustavo González5

1 Progr. Fisiología y Biofisica, ICBM, Fac. Medicina, Universidad de Chile, 2 Lab. Gastroenterología, Hosp. Clínico J. J. Aguirre, Fac.Medicina, Universidad de Chile, 3 Centro de Alto Rendimiento, ChileDeportes, Go-bierno de Chile, Santiago, 4 Departamento de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, 5

Inst. Química, Universidad Católica de Valparaíso, Valparaíso, Chile Introduction Serum iron concentration ([Fe]s) was decreased at HA as compared to sea level (SL) values in male Chilean Army recruits weekly commuting between the Chilean harbour of Arica and the Alti-plano village of Putre located at 3,600 m asl (Viola et al., 2001). [Fe]s decrement at HA inversely correlated with a concomitant decrease of maximal oxygen uptake, the latter being referred to maximal heart rate and expressed as maximal oxygen pulse in mlO2/beat (Viola et al., 2001). Via Fenton reaction, the transition metal Fe favours hydroxyl radical production, and, thus oxidative stress. Whether iron status changes on commuting between HA and SL may relate to plasma anti-oxidant capacity (AOCp) and thereby to availability of red cell membrane band 3 protein is investi-gated in the present work. As an anion exchanger involved in bicarbonate handling, band 3 protein changes may affect metabolic compensation of respiratory alkalosis and, thereby oxygen transport at HA. Methods Eight male Chilean Army recruits (19 yr), commuting for aprox 3 months between Arica at SL and Putre at HA, participated in the present study, after giving their informed consent to do so. Venous blood samples were obtained at HA after a week of the subjects continuously being exposed to that condition, as well as, 18 hrs after descending and having spent a night at SL. Immediately after obtained, the blood samples were centrifuged for plasma to be stored at - 40ºC and the red cells to be washed and lysed for membrane isolation and further processing according to techniques cur-rently in use (Celedón et al, 1998). Total antioxidant capacity (AOCp) as measured by luminol de-pendent chemiluminiscence, uric acid concentration as a main determinant of AOCp, and various iron status parameters were later on determined in the plasma samples. The isolated red cell membranes, being stored at - 70 ºC, were finally used to determine band 3 protein susceptibility to endogenous proteases as an evidence of the anion exchanger having been altered by oxidative stress (Celedón et al., 1998). Statistics: Spearman correlation coefficient; SPSS 10.0 for Windows. Results None of above parameters showed clearcut differences between HA and SL in the present study. HA and SL values taken together (n =16), however, evidenced correlations between AOCp and [Ua]p (r = 0.7; p < 0.001), AOCp and [Fe]p (r = - 0.48; p < 0.06), AOCp and transferrin saturation (r = - 0.55; p<0.05), AOCp and ferritin (r = - 0.77; p< 0.001). AOCp, as well as, [Ua]p respectively cor-related (r = 0.74; p<0.002 and r = 0.53; p<0.05) with protease susceptibility of band 3 protein. Conclusions Rather than determining AOCp, eventual acute HA related changes in iron status appear to depend on it. Available band 3 protein also depending on AOCp, the latter may influence bicarbonate han-dling, and thereby, oxygen transport at HA. References Celedón G, Gonzáles G, Sotomayor CP, Behn C. (1998) Membrane lipid diffusion and band 3 pro-tein changes in human erythrocytes due to acute hypobaric hypoxia Am. J. Physiol. 275 (Cell Physiol. 44): C1429-C1431 Viola T, Cajigal J, Hurtado C, Heinicke K, Prommer N, Schmidt W, Behn, C (2001) Iron sink pre-serves oxygen delivery at high altitude. Proc. IUPS Congress NZ Acknowledgements: This work was funded by FONDECYT 1000858 and by CONICYT-DAAD agreement.

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7) QUALITATIVE AND QUANTITATIVE CHANGES OF BLOOD DURING PROLONGED INTERMITTENT EXPOSURE TO HYPOXIA

#Walter F. J. Schmidt, #Nicole Prommer, #Katja Heinicke, *Teresa Viola, *Jorge Cajigal,

*Claus Behn #Dept. Of Sports Medicine / Sports Physiology, University of Bayreuth, Germany;

*Faculty of Medicine, University of Chile, Santiago, Chile Introduction In their daily life many residents of South American and Central Asian countries frequently have to move between near sea level and high altitudes. Until now, there is only little data available dealing with this kind of intermittent hypoxia. Our group had the opportunity to investigate the physical per-formance, acid base status and blood volumes in soldiers of the Chilean army who were members of a regiment regularly stationed at one of the highest military base camps (3550 m) in the world. Methods Mainly two groups were investigated: one consisted of young soldiers born at sea level who for 6 months regularly spent 11 days at 3550 m followed by 3 days at sea level (Gr. I). The second group were sub-officials who for more than 20 years regularly spent 3.5 days at 3550 m followed by 3.5 days at sea level (Gr. II). In addition to the longitudinal observation of one hypoxic/ normoxic cycle of both groups we compared their data with that of young soldiers living exclusively at sea level and with that of a group of residents native to 3550 m (indigenous Aymaras) whose antecedents lived at that altitude for generations. The aim of this protocol was to evaluate, whether relatively short-term (6 months) or long-term (> 20 years) intermittent hypoxic periods would lead to similar adaptations as occurring under chronic hypoxia and whether frequent movement from one environment to the other would produce regular short term adaptations to the prevailing situation. In a follow-up study on a second group of young soldiers also accustomed to intermittent hypoxia for 6 months, we de-termined changes of the electrolyte and water status as well as responses of the cardio-respiratory system to submaximal exercise during one hypoxic/normoxic cycle. Results and Discussion The acid-base-status in the blood of the soldiers adapted for 6 months as well as for >20 years was still characterized by remarkable oscillations of all parameters (pH, pCO2, BE). The arterial pO2 rapidly decreased immediately after ascent (50.8 mmHg in both groups) and markedly increased until day 4, which was more pronounced in the younger (58.1 ± 3.2 mmHg) than in the more ex-perienced soldiers (54.1 ± 2.2 mmHg). The changes in the acid-base-status with highest pH on day 2 (pH in both groups: 7.47 ± 0.01) and possibly also alterations in red cell 2,3-BPG concentrations shifted the oxygen dissociation curve (here characterised by the P50 of Gr. I) from 25.9 ± 0.4 mmHg after 3 days at sea level slightly to the left side at the first day at altitude (P50 25.2 ± 0.5 mmHg) and later on markedly to the right (P50 27.3 ± 1.2 mmHg at day 11). In some individuals the oxygen satu-ration of the arterial blood was very low (82 %) during the first days at altitude and increased in all subjects to more than 87 % until day 11. Arterial pO2 and sO2 measured after 3 min of intensive exercise (160 Watts) continuously increased from the first to the last day at altitude (pO2 from 57.3 ± 6.5 mmHg to 64.8 ± 4,0 mmHg, sO2 from 81.8 ± 3.5 % to 85.8 ± 2.9 %). The corresponding arterial pCO2 and the ventilation, however, did not differ during the whole exposure at altitude indicating that the respiratory response to exercise under hypoxia is only slightly influenced by normoxic episodes. Heart rate under resting as well as under submaximal exercise conditions increased immediately after arrival at altitude, declined under both conditions during the following days, and reached near sea level values at the last day at altitude. Maximum heart rate, however, measured the 4th day at altitude was markedly decreased compared to the maximum values obtained after 3 days at sea level.

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 9

When subjects are exposed to acute hypoxia they generally react with increased erythropoietin secretion during the first few days. This response decreases within one or two weeks of continuous exposure to hypoxia. Thus, the altitude residents investigated in this study showed similar plasma EPO concentrations (5.2 ± 3.8 mU/ml) as the lowlanders (6.4 ± 3.4 mU/ml). Both of the groups ex-posed to intermittent hypoxia increased their plasma EPO concentration about 6-fold by the second day at altitude, which was followed by a continuous decline until EPO reached sea level values again after 11 days (Gr. I). Our data underlines that the EPO system completely adapts under con-tinuous hypoxic exposure. When the hypoxic stimulus, however, is interrupted by only three days the sensitivity of this system completely recovers even after more than 20 years of intermittent hy-poxia. In this study we firstly determined the total hemoglobin mass (tHb), the red cell volume (RCV) as well as the plasma volume (PV) and the total blood volume (BV) during long term intermittent expo-sure to hypoxia. After six months of adaptation, tHb and red cell mass were already increased by 11 % when compared with that of the soldiers from sea level (tHb: 751 ± 72 g vs. 836 ± 103 g). This elevated tHb was nearly identical to that we measured in soldiers after >20 years of intermittently hypoxic exposure (832 ± 80 g) and also to that of the altitude residents (857 ± 81 g). In contrast to tHb and RCV, plasma volume and total blood volume markedly changed when our subjects moved from the normoxic to the hypoxic environment. In the group (Gr. I) that had adapted for 6 months, BV measured at sea level was similar (5548 ± 570 ml) to that of the lowlanders (5787 ± 566 ml) and decreased by about 580 ml until day 11 under hypoxia. Also in the long-term adapted group we still found a decrease of 280 ml until the 4th day at altitude. This reduction in BV is due to a lower plasma volume caused by an enhanced hypoxia-induced diuretic activity at altitude. The body weight of the young soldiers decreased by 1.1 kg until the 4th day, which corresponded to an in-crease in urine flow during the whole hypoxic exposure (from 1.0 ± 0.3 ml/min at sea level to 2.0 ± 0.8 ml/min on day 4 and 1.7 ± 0.9 ml/min on the last day at altitude). Because the diuresis was well associated with a pronounced natriuresis, we assume that hypoxia-related alterations of sodium regulating hormones are the cause. As a result of the higher red cell mass, the hemoglobin concen-tration and hematocrit values were already elevated when staying at sea level. Because of de-creasing plasma volume both parameters regularly increased during the stay at altitude partly over-reaching the values of the native population. Conclusion Based on these results we conclude that this form of intermittent exposure to hypoxia which is very common in the South American Andes produces long-term adaptations (e. g. in red cell mass) as are observed in populations native to altitude. Many physiological functions, however, like the regu-lation of the acid-base-status, the sympathetic activation, erythropoietin secretion, and the regula-tion of the electrolyte and water status including the blood volume are not desensibilized, neither against the hypoxic, nor against the normoxic environment. The resulting adaptations and de-adaptations also occur in subjects who have been accustomed to regular intermittent hypoxia for more than two decades. Supported by Deutscher Akademischer Austauschdienst (DAAD), Comision Nacional de Investiga-cion Cientifica y Technologia, Chile (CONICYT), and by the Deutsche Gesellschaft für Sport-medizin und Prävention (DGSP).

10 AKP-Symposium "High Altitude" Tübingen, 15.3.2002

8) WMRS 2001 - HEMATOLOGICAL CHANGES AND VASCULAR ENDOTHELIAL GROWTH FACTOR DURING LONG-TERM HIGH ALTITUDE EXPOSURE AT 3800 M

Hanns-Christian Gunga*, Reinhart Gossrau**, Maike Keck*, Eberhard Koralewski*, Lothar

Röcker*, Bernd Johannes*, Karl Kirsch* *Center for Space Medicine Berlin, and Department of Physiology, Free University of Berlin, Arnimallee 22, 14195 Berlin, Germany

**Department of Anatomy II, Free University of Berlin, Königin-Luise-Str. 15, D-14195 Berlin, Germany

Introduction The hypoxic-hypobaric environment reduces the overall physical performance of humans. Already today, under real micro-g conditions astronauts/cosmonauts are frequently exposed to an artifical hypobaric-hypoxic environment during extravehicular activities (EVA). Furthermore, it can be as-sumed that in future during long-term space flights and/or for base camps on planets like Mars the environmental conditions in the spacecrafts and habitats at the landing side will be hypobaric-hypoxic ones due to financial and logistic reasons. Therefore it is necessary to analyze the acute, intermittent and long-term effects of hypobaric-hypoxic exposure on the human body. In the course of the WHITE MOUNTAIN RESEARCH STUDY 2001 we investigated the human long-term adaptation to an altitude of approximately 3800 m above sea-level (Barcroft Facility, California, USA). It was the aim to study the changes regarding body composition (lean body mass, fat mass, total body water), circulation, blood physiology, muscle metabolism, capillary density and psycho-physiology. We will present here prelimary data regarding the haematological adaptations and the changes of capillary density in muscle fibers (musculus vastus lateralis) due to the long-term high altitude stay. Methods 11 male subjects (age 26.6 ± 2.1 years, body height 1.79 ± 0.05 m, body mass 74.4 ± 10.7 kg, BMI 23.5 ± 3.5) were studied. Five blood samples (before, during, and after) and 2 muscle biopsies were taken (before and after) the in total five weeks lasting study. Statistiscal analysis: MANOVA; SPSS 10.0 für WINDOWS. Results Packed cell volume [PCV], hemoglobin concentrations [HB], transferrin-receptors [Tfr-R], and erythropoietin [EPO] concentrations increased significantly during the exposure (p<0.01). Ferritin [FER] significantly decreased (p<0.01) and the circulating vascular endothelial growth factor [VEGF] concentrations remained unchanged, although the capillary density increased significantly by approximately 24 % (p<0.01). Conclusions The preliminary data show that a permanent exposure to high altitude (3800 m) causes a transient increase in [EPO] and the concomitantly [FER] decrease, and [PCV], [HB], and [Tfr-R] increase indicate a sustained stimulation of erythropoiesis combined with a stimulated angiogenesis as shown by the increase in capillary density. It is concluded that during long-term space flights a hypobaric-hypoxic environment inside the space craft or habitats could be used to trigger erythro-poiesis and angiogenesis. Sponsored by Deutsches Zentrum für Luft- und Raumfahrt and the Free University of Berlin (DLR-Project No 50-WB 0022; Angiogenesis Project No. 2 and 8, Free University of Berlin).

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 11

9) WMRS 2001- CHANGES OF CAPILLARY DENSITY DURING LONG-TERM HIGH ALTITUDE EXPOSURE (LTHAE) AT 3800 M

Reinhart Gossrau1, Hanns-Christian Gunga2, Heidrun Richter1, Gerit Planitzer1,

Martina Gutsmann1 1Department of Anatomy II, Free University of Berlin, Königin-Luise-Str. 15, D-14195 Berlin,

2Center for Space Medicine Berlin and Department of Physiology, Free University of Berlin, Arni-mallee 22, D-14195 Berlin, Germany

Introduction Laboratory studies have shown that hypoxic-hypobaric conditions increase capillary density (CD) in human skeletal muscles. However, this type of investigation differs from the natural environment, and no information is available whether and which angiogenic events are responsible for the in-creased CD, where CD increases in the heterogenous capillary bed (CB) and which cell types and molecules may be involved as driving forces for the formation of new and more capillaries. Here, we report on CD findings obtained with muscle biopsies from a field study during LTHAE at 3800 m. Subjects and Methods Biopsies were taken from the vastus lateralis (VL) muscle of 11 male subjects before and after LTHAE, frozen in isopentan-cooled N2 and cryosectioned. The cryosections were used for enzyme and lectin histochemistry as well as immunohistochemistry followed by quantification using com-puterized image analysis. Results Using non-specific alkaline phosphatase (NALP) as marker molecule for arterial and transitory cap-illary endothelial cells (CEC), capillary supply (C:F ratio) was increased by 24 % (p<0.01), with en-dothelial nitric oxide synthase (eNOS, NOS-3) for arterial, venous and/or transitory CEC by 13 % (p<0.01) and with Ulex lectin as marker molecule for all types of CEC by 7.2 % (p<0.01) after LTHAE. Dipeptidyl peptidase IV which is only expressed in venous CEC appeared to be also in-creased. However, further experiments have to substantiate this tendency. Pericytes visualized by smooth muscle cell (SMC)-α-actin showed an increase of 11.8 % (p<0.01). Sarcolemma-associated NOS-1 (nNOS) activity appeared to be also increased after LTHAE. The proangiogenic molecule vascular endothelial cell growth factor (VEGF)-1 was found in CEC, extracellular matrix cells (ECM) and in the subsarcolemma region of muscle fibers and VEGF receptor (R)-2 (FLK/KDR) in arteriolar SMC and CEC without significant differences before and after LTHAE. Other molecules such as mitochondrial succinate dehydrogenase, NADH reductase, myosin heavy chain (MHC) in slow (S, type I) and fast (F, type II) fibers as well as α1-integrin in CEC and the sarcolemma region appeared to be unchanged as was the size of type I and type II muscle fibers before and after LTHAE. Conclusions After LTHAE capillary supply is significantly increased as shown by NALP, Ulex lectin and NOS-3 histochemistry and concerns the total CB of human VL muscle. This increase is not caused by the decreased size of muscle fibers as shown by their unchanged diameter. Despite their partial dislo-calization the presence of VEGF-1 and VEGFR-2 and our first positive data for hypoxia-inducible factor (HIF)-1α inducing VEGF and VEGFR as well as for certain VEGF-activated matrix metallo-proteinases (MMPs) suggest that the increased CD is caused by VEGF/VEGFR-driven angiogene-sis.This process may be modulated by NOS-1 and NOS-3 generated NO as shown for some ex-tramuscular tissues. The absence of significant differences between the VEGF/VEGFR system be-fore and after LTHAE could be explained by the initial upregulation of these molecules and their downregulation 3 weeks after beginning of hypoxic-hypobaric LTHAE, when the biopsies were taken. Finally, the increase of pericytes which may be involved in capillary sprouting as one of the steps in angiogenesis points to the participation of these cells in the formation of new capillaries induced by LTHAE.

Supported by Deutsches Zentrum für Luft- und Raumfahrt and the Free University of Berlin (DLR-Project No. 50-WB 0022; Angiogenesis Projects No. 2 and 8, Free University of Berlin)

12 AKP-Symposium "High Altitude" Tübingen, 15.3.2002

10) WMRS 2001 – PSYCHOPHYSIOLOGY AT HIGH ALTITUDE

Bernd Johannes, Hanns-Christian Gunga, Hans-Eberhard Koralewski, Karl August Kirsch Center for Space Medicin Berlin (ZWMB), Dept. of Physiology, FU Berlin

Introduction The experiment „REGULATION“ was designed to assess the actual psychophysiological state of cosmonauts on board the space station MIR. Based on clinical reference data it provides a com-mon classification of complex regulatory changes besides the obvious single-channel information. With the measurement system NEUROLAB-B specially developed for this experiment it was possi-ble to run the fully computerized psychological stimulation procedure and to measure simultane-ously a set of physiological parameters that should particularly mirror the activity of the central nervous system, the autonomic nervous system and the cardiovascular system. As a spin-off from space research the same standardized protocol and equipment could be used in two scientific high altitude expeditions. The acute adaptation to high altitude provokes individually different reactions of the autonomic nervous system. Caused by insufficient time for adaptation occur symptoms of the Acute Mountain Sickness (AMS). In the presented study was successfully tried to find predictors for the AMS risk within the pre-altitude measures. Methods 17 male miners in Collahuasi, Chile, 3800 m and 11 male sportsmen in Barcroft, White Mountain, 3800 m were examined three days prior to going to high altitudes, on the second day of their stay at high altitudes and two/three days after returning to sea level. The protocol of the experiment was designed to evoke a series of changes between psychologically load-enhancing situations and re-laxation phases under physically calm and inactivity conditions. The fully computerized psychologi-cal stimulation procedure was run measuring simultaneously the electrocardiogram (ECG), the ar-terial blood pressure (BP), the electromyogram (EMG) from the right forearm, finger skin tempera-ture and the skin conductance response (SCR) from the right hand fingers. Based on data from former clinical studies in Berlin/Germany the subjects were grouped into different types of psycho-physiological reactivity (Autonomic Outlet Types, AOT). The subjects were divided by their AOT at altitude. For these altitude subgroups the pre-altitude data were reanalyzed. Results Well known differences in physiological data between sea-level and high altitude as increases in blood pressure, heart rate and respiration rate, decreases of heart rate variability could be con-firmed. Significant differences in pulse wave velocity, reactivity of the EMG were found but not in the reactivity of skin conductance or periphery skin temperature. Furthermore no general differ-ences in voice pitch and voice pitch reactivity were found. The separation of AOT’s at high altitude provided two main groups, one with 19 autonomically stable subjects, the other with 7 subjects, described as hypertensives and subjectively also suffering from AMS symptoms. No general differ-ences in the pre-altitude data of these subgroups were found for the separately analyzed parame-ters. But we could find a discriminant function, considering all single data together as a pattern, which reproduced the subgroups by 100 %. Conclusions The development of a statistical function for the prediction of the AMS risk before exposure to alti-tude would be of high importance. In the present study could be shown that such an approach has high chance to succeed if one looks more at the whole reactivity pattern than at single channel data. The found discriminant function needs to be repeated and confirmed by independent data. That should be one goal of future research. This study was supported by the FONDEF D 97 11068 and DLR grant 50WP0022.

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 13

11) ALTITUDE ADAPTATION IN HEMOGLOBIN FUNCTION – LESSONS FROM FROGS AND BIRDS

Roy E. Weber*, , Angela Fago*, Hrvoy Ostojic¶, Luc Moens$ and Carlos Monge& *Zoophysiology Department, University of Aarhus, DK 8000 Aarhus C, Denmark;

¶Clinicum, Laboratorio Automatizado, Iquique, Chile; $Biochemistry Department, University of Antwerp, Belgium;

&Laboratorio de Transporte de Oxígeno, Universidad Cayetano Heredia, Lima 31, Peru. Introduction Compared to endothermic birds and mammals little is known about the molecular adaptations that secure O2 transport at high altitude in lower vertebrates. The adaptations encountered in vertebrate animals may favour either O2 loading at the respiratory surfaces or O2 unloading in the tissues. The mechanisms implicate changes in either the intrinsic O2 affinity of the hemoglobin (Hb) (cf. llamas) or in the effects of erythrocytic anions, like organic phosphates (cf. human at high altitude) and chloride that lower Hb-O2 binding in the red cells. The hypoxic challenge at altitude is greater in ectothermic and aquatic animals. We studied the molecular mechanisms determining blood-O2 af-finity in the high-altitude, skin-breathing, aquatic frog Telmatobius peruvianus (from 3800 m in the North Chilean Andes) and compared these with those found in the lowland, aquatic amphibian, Xenopus laevis, and high-altitude birds. Methods Hb solutions were prepared and analysed as previously described (1). IsoHb components were separated by preparative isoelectrofocusing. O2 equilibria including extreme O2 saturations (<2 % and >98 %) were analyzed by end-weighted fitting (1) of the two-state Monod-Wyman-Changeux (MWC) equation to the data. Results and Conclusions The strategies in amphibians and birds show marked differences. In the Barheaded and Andean geese (that fly at ~9000 and ~5000 meters in the Himalayan and Andes Mountains, respectively), high intrinsic Hb-O2 affinities result from the substitution of two amino acid residues (α119 and β55, respectively), which are opposite poles of the same intramolecular contact that otherwise (in low-land geese and humans) constrains Hb in the “tense” (low-affinity, deoxygenated) conformational state (2). In contrast, ‘stripped’ (effector-free) Telmatobius Hb shows similar intrinsic properties (O2 affinity and phosphate sensitivities) as in Xenopus laevis Hb. However, in the presence of chloride ions Telmatobius Hb shows a markedly higher affinity, indicating that its high blood affinity results from a reduction in chloride sensitivity (3). The amino acid sequences show conservation of the β-chain chloride-binding sites that appear to play a dominant role in human Hb, but reveal specific changes at the α-chain chloride-binding sites that thus appear to play a key role in anuran high-altitude adaptation. (1) Weber, R.E., Fago, A., Val, A.L.,Bang, A., Van Hauwaert, M.L., De Wilde, S., Zal, F. and Moens, L. J. Biol. Chem. 275, 17297-17305, 2000. (2) Weber, R. E., T.-H. Jessen, H. Malte, and J. Tame. J. Appl. Physiol. 75: 2646-2655, 1993. (3) Weber, R. E., H. Ostojic, A. Fago, S. DeWilde, L. van Hauwert, L. Moens and C. Monge, Sub-mitted. Supported by the Danish Natural Science Research Council

14 AKP-Symposium "High Altitude" Tübingen, 15.3.2002

12) RESPIRATORY CHANGES DURING EXPOSURE IN AN ARTIFICIAL AIR-SPACE IN SNOW

Günther Sumann1, Hermann Brugger2, Wolfgang Schobersberger1, Roland Meister3,

Hanns-Christian Gunga4, Eberhard Koralewski4, Peter Mair1, Markus Falk5 1 Dept. of Anesthesiology and Intensive Care Medicine, University hospital of Innsbruck,

Anichstr. 35, A-6020 Innsbruck, Austria 2 International Commission for Mountain Emergency Medicine, Europastraße 17, Bruneck, Italy

3 Swiss Federal Institute for Snow and Avalanche Research, Flüelastraße 11, Davos, Switzerland 4 Department of Physiology, Free University of Berlin, Arnimallee 22, Germany

5 Biostatistician, Inova Q, Siemens Straße 19, Bozen, Italy Introduction Decisive factors governing survival following complete burial under a snow avalanche (snow cover-age of head and chest, at least) are extrication speed and presence of an air pocket, which is de-fined as any space surrounding mouth and nose, and free airways. Brugger and Falk calculated in 1994 that the survival probability for persons completely buried in an avalanche dropped precipi-tously from 92 % at 15 min to 30 % at 35 min due to acute asphyxiation of victims without an air pocket, with a further drop from 27 % at 90 min to 3 % at 130 min. Based on this report, avalanche survival beyond 35 min is dependent on the presence of an air pocket. However, documented in-formation on air pockets is lacking and previous experimental findings were contradictory. While breathing into an air pocket the victim suffers from hypoxia and hypercapnia. We introduce a model of an artificial air pocket in snow for the investigation of ventilation and acid-base status of avalanche victims. During the test the volunteer is sitting under open-air and does not need to be buried. Methods We undertook a prospective randomised field study in a simple 2x2 cross-over design with 12 sub-jects breathing in two test series and 28 tests into air pockets of different volumes (1 l or 2 l) and in snow of different density. The subjects sat outside a snow wall and breathed by means of a her-metically-placed facial mask through a tube into an artificial air pocket in snow. Non-invasive pa-rameters were measured (SpO2, blood pressure, respiratory rate, ECG and etCO2) and capillary blood samples were taken from hyperaemised fingertips for blood gas analysis. We also recorded the gas-concentrations within the air pockets and the snow density and temperature. Statistical analysis: Wilcoxon Test, Mann-Whitney U test Results The tests showed that during respiration into the air pockets oxygen saturation decreased signifi-cantly within 4 min to 88 % (range 71 %-94 %), dependent on air pocket volume (inverse) and snow density. Simultaneously, end-tidal carbon dioxide rose significantly from 38 mmHg to 51 mmHg (range 44-62) and respiratory acidosis developed. The air pocket O2-concentration dropped from 21 % to 11,5 % (range 8,9-13,1 %), whilst the CO2-concentration rose from 0-4,2 % (range 3,4-5,6 %). Conclusions Although contributing factors of snow burial like the influence of snow pressure on chest and venti-lation, hypothermia and stress cannot be assessed in this simulatory model we were able to eluci-tate the respiratory changes while breathing into air pockets in snow. The rapid development of hypoxia and hypercapnia is remarkable and appears to be in contradiction to the long survival times in some cases of avalanche burial. The air pocket model has proved to be useful and will be applied to future investigations. Sponsored by MFF Tirol

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 15

13) FROSTBITE – HOW TO EVALUATE POSITIVE RESULTS OF CLINICAL CASES TREATED WITH HYPERBARIC OXYGEN THERAPY

– A STUDY PROPOSAL

Jurij Gorjanc* , B. Igor Mekjavic** *General hospital Slovenj Gradec, Slovenia; Faculty of Medicine, Ljubljana, Slovenia **Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, UK;

Institute Jozef Stefan, Ljubljana, Slovenia Introduction Frostbite is an acute traumatic peripheral ischaemia (ATPI). Hypoxia and trauma are common to all ATPIs (frostbite, burns, crush injury, compartment syndrome, threatened flaps, replantations). Hy-perbaric oxygen therapy (HBOT) is advocated as an effective adjunct therapy for all ATPIs, except for frostbite. There is insufficient clinical evidence regarding the effectiveness of HBOT in freezing and non-freezing cold injury to advocate its acceptance as an adjunct therapy. Methods Five cases of frostbitten toes have been treated in recent years by HBOT as an adjunct therapy in Slovenia, all with good results. The before and after examination of the patients was performed, including clinical measuring of vital skin proportions of the total toe length before and after HBOT. HBOT comprised 90 min exposures to 2.5 ATA in a hyperbaric chamber, during which the patient breathed pure oxygen via an oro-nasal mask. A total of 20 treatments were conducted over a 1 month period DSA and Tc 99 scintigraphy were performed clinically in order to shorten the waiting period for am-putation. A case report of a climber of the Si. mobil Skieverest 2000 Expedition is presented as a pattern of diagnostics and treatment. Results Our clinical experience of using hyperbaric oxygen treatment of frostbite can be summarized as follows: 1) HBOT is an adjunctive therapy and should not replace any conventional treatments. 2) HBOT should be initiated immediatelly. 3) Further data is required to determine the optimal dosage of hyperbaric oxygen. Our present protocol of daily treatments for 20 days may not be optimal. 4) In all patients treated to date, the demarcation line moved distally during HBOT. 5) All subjects re-ported feeling a tingling and burning sensation during the therapy. 6) HBOT provides enhanced healing of post-surgical wounds and prevents wound infection. Conclusions Clinical benefits of prompt hyperbaric oxygen treatment were observed in all cases treated up to now. Lack of exact and consistent evaluation of benefits of HBOT in frostbite leads us toward a controlled study in animals.

16 AKP-Symposium "High Altitude" Tübingen, 15.3.2002

14) HEMOSTATIC CHANGES AFTER A LONG HAUL FLIGHT EQUIVALENT TO 2400 M ALTITUDE

Wolfgang Schobersberger1,2, Dietmar Fries1, Markus Mittermayr1, Petra Innerhofer1,

Beatrix Hauer2, Günther Sumann1, Hanns-Christian Gunga3 1Univ.-Klinik für Anästhesie und Intensivmedizin, Universität Innsbruck, Anichstrasse 35,

A-6020 Innsbruck, 2IHS-Institut Humpeler-Schobersberger GmbH, Forschungsinstitut für Urlaubs-und Freizeitmedizin sowie Gesundheitstourismus, Bregenz, Österreich;

3Institut für Physiologie, FU Berlin, Deutschland Introduction World wide approximately 1.5 billion passengers travel by aircrafts yearly. Deep venous thrombosis (DVT) and pulmonary embolism are severe complications of long-haul flights, also termed „econ-omy class syndrome (ECS)“. Based on Virchow´s triad it has been postulated that besides sitting in a cramped position DVT may be caused by aircraft-specific factors, i.e. low humidity, relative hy-poxia and dehydration. Whether under these conditions coagulation plays a crucial role is unknown. Until now hemostasis has not been investigated during and after a real long haul flight. The goal of the project ECS-2001 was to determine the influence of a long-haul flight on the coagulation sys-tem. Methods Blood was collected from 20 volunteers, 10 with low risk (mean age 29.7 yrs, BMI 23.6) and 10 with moderate risk (mean age 43.5 yrs, BMI 33.4) for DVT before, during an 9h flight (Vienna-Washington), on the flight back, and one and three days after return. Following parameters were measured: PT, aPTT, maximal clot firmness (MCT) and α-ankle (roTEG), thrombin-antithrombinIII-(TAT) complexes, D-dimer, plasmin-α2-antiplasmin (PAP), t-PA, PAI-1, factors VII and VIII, protein C and S. Statistics: Manova for repeated measures. Level of significance, P < 0.05. Results PT did not change, but aPTT was significantly reduced after the flight. MCF and α-ankle were in-creased during and after the flights. TAT, D-dimer and PAP remained unchanged. T-PA was de-creased after the flights and PAI-1 was increased, the t-PA-PAI-1 ratio dropped. Coagulation fac-tors VII and VIII were elevated during and after the flights. No change was found for protein C and S. Conclusions We conclude that the long-haul flight induced a hypercoagulable state independent of the risk pro-file for DVT as evidenced by thromelastographic measurements and analysis of FVII and VIII. In addition the fibrinolytic potential was significantly suppressed. Since we could not find differences in the measured coagulation parameters between both risk groups we speculate that in the presence of additional risk factors these hemostatic changes may trigger DVT in passengers during long-haul flights.

AKP-Symposium "High Altitude" Tübingen, 15.3.2002 17

15) SIMULATION OF A LONG-DISTANCE FLIGHT IN PATIENTS WITH CYSTIC FIBROSIS

Kathrin Brückner, Rainald Fischer, Susanne Meyer, Rudolf M. Huber

Pneumology, Medizinische Klinik Innenstadt, Ludwig-Maximilians-University, Ziemssenstrasse 1, 80336 Munich (altitude 500 m), Germany

Introduction Due to the increasing age and mobility of patients with cystic fibrosis, the number patients perform-ing long-distance flights increases. There are limited data about the cardio-pulmonary risk of an exposition for several hours to an altitude of approximately 2600 m in these patients, equivalent to the pressurized cabin of an aircraft at cruising altitude. Methods We examined patients with cystic fibrosis at an altitude of 2660 m over a period of 8 hours, per-forming lung function tests, capillary blood gas analysis and echocardiography at rest. To evaluate the effect of moderate exercise at altitude, we draw additional blood gas samples during cycling at 60 watt. Results We included 34 patients in the study, average age 30.1 years (19 – 47), 14 women. variable (mean values)

500 m 2660 m, at arrival

2660 m, after 8h

moderate exercise,2660 m

FEV1 % Soll 66.3 71.1 70.4 R tot (kpa*s/l) 0.4 0.35 0.37 ITGV % 118.4 133.5 136.8 VC max (l) 3.97 3.96 3.95 PEF % Soll 71 84.9 82.2 MEF25 % Soll 25.96 32.52 30.33 PaO2 (mmHg) 75.9 52.8 52.8 47.8 PaCO2 (mmHg) 38.3 35.2 37.8 34.2 32 % of our patients had a PaO2 of 50 mmHg or lower at rest after 8 h. However, none of them had to be treated with oxygen or felt subjectively sick. We found no significant increase in pulmonary pressure signs in echocardiography. The correlation coefficient between low altitude PaO2 and high altitude PaO2 was 0.69 (p<0.01). In multivariate analysis, MEF25 (percent predicted) was the best predictor of PaO2 at altitude. Conclusion Even with moderate exercise, patients with cystic fibrosis are able to tolerate PaO2-values below 50 mmHg over a period of up to 8 hours. Therefore, some of the international guidelines concerning fitness to fly in these patients may be too rigorous.

18 AKP-Symposium "High Altitude" Tübingen, 15.3.2002

16) GENE EXPRESSION IN HYPOXIA.

Carsten Lundby The Copenhagen Muscle Research Centre, 9 Blegdamsvej, section 7652, 2100 Copenhagen Ø,

Denmark. Carsten@cmrc.dk

Introduction Exposure to high altitude induces several adaptive responses to ensure an adequate oxygen sup-ply to the cells. Hypoxia-inducible factor 1 (HIF-1) is the transcription factor for many genes that are augmented in hypoxic environments, and which main purpose is to increase either O2 delivery or the metabolic capacity of the cells (Semenza 2000). Examples of such genes are 1) erythropoietin, that induces erythropoiesis and thus increased oxygen transport capacity 2) VEGF, that induces angiogenesis, and thereby allows a more efficient oxygen extraction by the cells, and 3) glucose transporters and glycolytic enzymes which together allow an increased glycolytic flux in the cell. To date the HIF-1a response in humans exposed to chronic hypoxic environments is unknown, and therefore the purpose of the present study was to investigate the effects of chronic hypobaric hy-poxia on HIF-1a and VEGF at the mRNA level. For this, 8 Danish lowlanders were investigated at sea level, and after 2 and 8 weeks of exposure to 4100 m altitude. Also 7 high altitude native Ay-mara Indians were studied after life long residents at high altitude.

Methods Resting biopsies were obtained from the middle portion of the vastus lateralis muscle from the above-mentioned groups. The biopsy was immediately frozen in liquid nitrogen, and stored at –50 °C for later analysis. Total mRNA was isolated and analysed for HIF-1a and VEGF by RT-PCR (Pilegaard et al., 2000).

Results No differences in HIF-1a or VEGF expression were observed between the Danes at any point of time, and also the Aymara Indians showed no differences compared to the Danes (fig 1).

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Figure 1. HIF-1a and VEGF mRNA levels in high altitude Aymara natives, and in Danish lowlanders at sea level (SL), and after 2 and 8 weeks at 4100 m. No differences were found between any data point. Conclusion We hypothesized that HIF-1a and VEGF mRNA levels would increase in hypoxia, however, this was not the case. Although the mRNA levels were unchanged, it cannot be ruled out that HIF-1a and VEGF protein content are in fact elevated during hypoxic exposure, as protein levels are regu-lated at multiple sites.

References Pillegaard H, Ordway GA, Saltin B, Neufer PD. Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab 279: 806-814, 2000.