NASA Technical Memorandum 112212

Water Metabolism and Fluid Compartment Volumes in Humans at Altitude

A compendium of Research (1914-1996)

J. L. Chou, N. J. Stad, E. Gay, G. I. West and P. R. Barnes, California State University at San Francisco

J. E. Greenleaf, Ames Research Center, Moffett Field, California

October 1997

National Aeronautics and Space Administration Ames Research Center Moffett Field, California 94035-1000

Contents Page

Summary ...... iv Introduction ...... v

Abstracts and Synopses ...... 1 Additional Selected Bibliography ...... 97 Author Index ...... 103

Keyword Index ...... 111

iii Summary

This compendium includes abstracts and synopses of clinical observations and of more basic studies involving physiological mechanisms concerning interaction of metabolism and fluid compartment volumes in humans during altitude exposure. If the author's abstract or summary was appropriate, it was included. In other cases a more detailed synopsis of the paper was prepared under the subheadings Purpose, Methods, Results, and Conclusions. Author and subject indices are provided, plus an additional selected bibliography of related work and of those papers received after the volume was being prepared for publication. This volume includes material published from 1914 through 1995.

iv Introduction

The purpose of this compendium is to present summaries of clinical observations and results from more basic studies that help to elucidate physiological mechanisms for control of water balance and fluid compartment volumes at altitude in humans. If the author's abstract or summary was appropriate, it was utilized. In some cases a more detailed synopsis was provided under the subheadings Purpose, Methods, Results, and Conclusions. This volume includes studies published from 1914 through 1995. Author and subject indices are provided. The material is listed in alphabetical order by first author and numbered consecutively by abstract number, not page number. We thank our many colleagues who sent us reprints, and apologize to those whose work we have inadvertently overlooked. The authors thank Esther Johnson for valuable technical assistance.

J.E.G.

1. Abbrecht PH and JK Littell. output was chiefly due to decrease in stroke Plasma in men and mice volume. Though volume was less at during acclimatization to different high altitude, acute plasma volume expansion altitudes. with dextran in two subjects failed to restore Journal of Applied Physiology 32:54- stroke volume to sea-level values. The 58, 1972. reduction of stroke volume was apparently not Authors' Abstract a result of altered blood pH, pulmonary Repeated measurements of plasma hypertension and right ventricular overload, erythropoietin concentration were made in five depletion of myocardial norepinephrine stores, men before and during 10 days stay at 14,300 diminished sympathetic nervous activity, or ft. Serial determinations of plasma reduction in blood volume and ventricular erythropoietin concentration over a 10-day filling pressures. Myocardial function was period were also made in mice during exposure probably depressed by hypoxia secondary to to air pressures of 510, 440, or 360 mm Hg, lowered coronary arterial oxygen tension, equivalent to altitudes of 10,500, 14,500, and reduced coronary blood flow, or both. 19,000 ft, respectively. Calibration curves using a standard erythropoietin preparation 3. Anand IS, Y Chandrashekhar, SK were done with all assays, so that Rao, RM Malhotra, R Ferrari, J erythropoietin concentration could be expressed Chandana, B Ramesh, KJ Shetty in standard units per milliliter. In human and MS Boparai. beings, erythropoietin concentration reached compartments, renal blood maximum values from 19- to 39-hr hypoxia, flow, and hormones at 6,000 m in and then decreased rapidly without a significant normal subjects. change in hematocrit or blood hemoglobin Journal of Applied Physiology concentration. Maximum erythropoietin values 74:1234-1239, 1993. in mice were measured at 12- to 18-hr hypoxic Authors' Abstract exposure, with the earlier peak occurring at the We previously described a syndrome of highest altitude. In all cases, erythropoietin congestive failure occurring in healthy concentration had decreased to values not young men at extreme altitude (Anand et al. significantly different from prehypoxic control Lancet 335: 561-565, 1990). The values by the 10 _ day at altitude. There was pathogenesis of this condition is unclear. We good correlation between maximum therefore measured body fluid compartments, erythropoietin concentration and estimated PO 2 renal blood flow, and a variety of plasma in mice. hormones in 10 asymptomatic young men staying above 6,000 m for > 10 wk and 2. Alexander JK, LIt Hartley, M compared the results with controls at sea level. Modeiski and RF Grover. Body compartments were measured with Reduction of stroke volume during isotope dilution techniques and renal blood exercise in man following ascent to flow with o-[_25I]iodohippurate sodium. There 3,100 m altitude. was a marked expansion of all the fluid spaces: Journal of Applied Physiology 23:849- total body sodium was 14% above normal 858, 1967. (P<0.05), total body water was 18% above Authors' Abstract normal (P<0.05), plasma volume was 33% The cardiac output response to submaximal above normal (P<0.05), and blood volume was supine leg exercise was determined in eight 84.5% above normal (P<0.001). The effective normal subjects, first at sea level and again renal plasma flow was lower than normal by after 10 days at 3,100 m. Using the direct Fick 55% (P<0.001), but the reduction in the method for oxygen, cardiac output was effective renal blood flow was 37% below measured at rest and during four work loads normal (P<0.001) because the hematocrit was requiring oxygen uptakes of 600-1,600 ml/min high (41.6% above normal). Plasma at both altitudes. At rest and at each level of norepinephrine was nearly 3 times normal exercise, cardiac output was less at 3,100 m, (P<0.01), cortisol 3 times normal (P<0.001), by as much as 2 liters/min. Reduced cardiac and growth hormone 18 times normal (P<0.01). Aldosteronewastwice normal hypoxia on CO, MAP, GFR, SV, and renal (P<0.03). Plasmaepinephrine,atrial blood flow in hypophysectomized animals was natriureticpeptide,andplasmareninactivity the same as in intact animals. In contrast to wereunchanged.Thedegreeof fluid retention intact animals, however, hypoxia did not in thesenormalsubjectswassimilarto thatin induce a significant antidiuresis in patientswith severeuntreatedcongestiveheart hypophysectomized animals (Uo, m from 72 to failure(Anandet al. Circulation 80:299-305, 82 mosmol/kg H20 ). To delineate the afferent 1989), whereas sodium retention and reduction pathway for hypoxia-stimulated in effective renal blood flow were less. Serum release, hypoxia was induced in dogs with was less in our normal subjects either chemo- or barorecptor denervation. The than in patients with congestive heart failure. effect of hypoxia on CO, MAP, GFR, SV, and Our findings suggest that a prolonged stay at renal blood flow in the denervated animals was extreme altitude can cause salt and water the same as in nondenervated animals. retention to an extent approximately similar to Hypoxia resulted in an anti-diuresis in that in untreated congestive heart failure. It is chemoreceptor (Uo_ from 113 to 357 likely that the stress of hypobaric hypoxia, mosmol/kg H20, P<0.001) but not in cold, and exertion at high altitude increases baroreceptor (Uo, mfrom 116 to 138 mosmol/kg catecholamines, which reduce renal blood flow H20, NS) denervated animals. To determine if and lead to a congestive state in normal subjects hypoxia alters renal response to vasopressin, at extreme altitude. exogenous vasopressin was administered to normoxic and hypoxic groups of dogs. The 4. Anderson R J, RG Pluss, AS Berns, antidiuretic effect of vasopressin was no JT Jackson, PE Arnold, RW different in these two groups. These results Schrier and KM McDonald. demonstrate that hypoxia induces an Mechanism of effect of hypoxia on antidiuresis which is independent of alterations renal water excretion. in CO, MAP, SV, fraction, renal Journal of Clinical Investigation nerves, or renal response to vasopressin and 62:769-777, 1978. occurs through baroreceptor-mediated Authors' Abstract vasopressin release. The nature of the The effect of lowering the pressure of baroreceptor stimulation remains to be elucidated. oxygen from 80 to 34 mm Hg was examined in anesthetized dogs that were undergoing a water diuresis. This degree of hypoxia was 5. Antezana A-M, J-P Richalet, I associated with an antidiuresis as Noriega, M Galarza and G Antezana. osmolality (Uo, m) increased from 107 to 316 mosmol/kg H20 (P<0.001) and plasma Hormonal changes in normal and arginine vasopressin increased from 0.06 to polycythemic high-altitude natives. Journal of Applied Physiology 79:795- 7.5 gU/ml, (P<0.05). However, hypoxia was 800, 1995. not associated with significant changes in Authors' Abstract cardiac output (CO, from 4.2 to 4.7 liters/min), Acute and chronic exposure to high-altitude mean arterial pressure (MAP, from 143 to 149 (HA) hypoxia inhibits the -angiotensin- mm Hg), glomerular filtration rate (GFR, from aldosterone system and may modify the release 46 to 42 ml/min), solute excretion rate (SV, of atrial natriuretic peptide (ANP) in sea-level from 302 to 297 mosmol/min), or filtration (SL) natives. In HA natives, the release of fraction (from 0.26 to 0.27, NS). Hypoxia these hormones could be influenced by changes was associated with an increase in renal in blood volume or pulmonary arterial vascular resistance (from 0.49 to 0.58 mm pressure. Twenty-four men residing in La Paz, Hg/ml per rain, P<0.01). The magnitude of Bolivia, at 3,600 m were separated into two hypoxia-induced antidiuresis was the same in groups: one normocythemic (HA.N; with innervated kidneys and denervated kidneys. hematocrit < 57%; n = 13) and the other To further examine the role of vasopressin in polycythemic (HAP; with hematocrit > 57%; n this antidiuresis, hypoxia was induced in = 11). A control group of 9 SL residents was hypophysectomized animals. The effect of studiedin normoxia(SLN)aswell asafter4 substitution test (DSST) were administered 4 daysspentat 4,350m (SLH). Thegroups times daily. At sea level, a significant decrease weretestedfor plasmaactiverenin(PAR), in body weight with furosemide did not affect plasmaaldosteroneconcentration,ANP,and symptom or DSST scores. All subjects potassiumandnorepineprineconcentrationsat reported an increase in symptoms at altitude. restandafteramaximalexercise.Pulmonary Although the state of body hydration was arterialsystolicpressurewasassessedby a significantly different after furosemide Dopplertechnique.It wasobservedthatPAR treatment, the severity of symptoms and DSST andplasmaaldosteroneconcentrationat rest scores were the same as in the other groups. andafterexercisewerelowerin theSLHthan in theSLN group. PARandnorepineprine 7. Arnaud J, N Gutierrez, GW Tellez concentrationwerehigheramonghighlanders and H Vergnes. thanin the SLN group. Reninresponseto Haematology and erythrocyte exercisewasnormalamongtheHAN group metabolism in man at high altitude: An andslightly decreasedamongtheHAPgroup, Aymara-Quechua comparison. andanexercise-inducedincreasein aldosterone American Journal of Physical wasattenuatedin bothHA groups. Anthropology 67:279-284, 1985. Aldosteroneresponseto reninwasmaintained Authors' Abstract amongtheSLH groupbutwasattenuatedin the In the course of haematological and HA groups,possiblyowing to aprotective biological investigations among Aymara and mechanismagainstsaltandwaterretention. Quechua populations in Bolivia, an RestingandexerciseANP waslowerin theHA anthropological study of the erythrocytary groupsthanin theSLN group. In theHAP respiratory function was carried out on the two group,apositiverelationshipwasfound groups at two altitudes: 3,600 m and 450 m. betweenANP andpulmonaryarterialpressure A difference in the intensity of the atrest. Evidenceof lowerplasmaANPin HA biological variations of the two populations is nativesdespitehigherpulmonarypressure observed at high altitude. couldbeexplainedby anadaptationto chronic In the Quechuas, as in any lowland native, distensionof atrialstretchreceptorsinvolvedin the adaptative phenomena are totally and centralbloodvolumeregulation. quickly reversible. In the Aymaras, we detected the existence 6. Aoki VS and SM Robinson. of more marked haematological and Body hydrationandtheincidenceand biochemical characters: moderate polycythemia, severityof acutemountainsickness. hyperhaemoglobinemia, microcytosis, Journal of Applied Physiology 31:363- metabolical hyperactivity with accumulation of 367, 1971. 2-3 di-phosphoglycerate and ATP, and Authors' Abstract methaemoglobinemia with a drop in the activity The possible influence of the state of body of the methaemoglobin reductases. The hydration on the development of acute Aymaras preserve some of those characters mountain sickness (AMS) was suggested by (methaemoglobinemia excepted) when they the reports that , such as acetazolamide settle in lowlands. and furosemide, prevented or relieved the symptoms. To study this possibility, 12 8. Arnaud J, JC Quilici, N Gutierrez, J subjects were exposed to altitude during 3 Beard and H Vergnes. separate sessions 2 weeks apart. Each session Methaemoglobin and erythrocyte consisted of 3 days at sea level and 2 days at a reducing systems in high-altitude simulated altitude of 14,000 ft. At sea level, natives. water deficits were corrected with an oral water Annals of Human Biology 6:585-592, load. The subjects were then given either 1) 1979. placebo, 2) vasopressin-in-oil to maintain Authors' Summary hydration, or 3) furosemide to produce The stress of chronic hypobaric hypoxia moderate dehydration. Symptom present at high altitudes induces a series of questionnaires and a digit-symbol adaptive changes in the intermediate metabolismin erythrocytesof high-altitude no changes occurred in U v, urine Na ÷ natives.Aymarasof thehighAndeanPlateau concentration, glomemlar filtration rate, plasma areshownto havewithin erythrocytes:(a) or urine bradykinin concentration, serum increasedactivity of NADH2(GAPDH) angiotensin-converting enzyme activity, plasma generatingstages,(b)decreasedactivityof renin activity, plasma aldosterone NADH2(LDH) consumingsteps,(c) concentration, plasma arginine vasopressin significantlyincreasedmethaemoglobin concentration, or plasma norepinephrine content,and(d)a largeincreasein thelevelof concentration. Two subjects with hypoxia reducedglutathione.Thesealterationsoccur (PO 2 43 and 36 ton') showed antidiuresis (U v alsoin personsof thesameethnicgroup decreased > 50%), associated with nausea in residingatlow altitude. Thereis, however, one and with decreases in mean blood pressure only amoderateelevationof classic (16% and 21%) and increases in arginine haematologicalparameters(erythrocytecount, vasopressin levels ( 50 pg/ml) in both. This haemoglobinandhaematocrit)in highland study confirms our previous observation that natives.Thefunctionalimplicationsof these hypoxia in normal individuals has no direct metabolicchangesarediscussedwith respectto effect on hormonal or renal parameters thought regulationof erythrocytemetabolism. to affect water excretion; increases in plasma arginine vasopressin levels (two subjects) were 9. Ashack R, MO Farber, MH induced by nausea or hypotension or both. Weinberger, GL Robertson, NS The new data relate to plasma angiotensin- Fineberg and F Manfredi. converting enzyme and to plasma and urine Renal and hormonal responses to acute kinin levels, none of which was affected by the hypoxia in normal individuals. hypoxic exposure. Journal of Laboratory and Clinical Medicine 106:12-16, 1985. 10. Asmussen E and FC Consolazio. Authors' Abstract The circulation in rest and work on We studied, in normal volunteers, the Mount Evans (4,300 m). effects of 1 hour of hypoxia on the American Journal of Physiology concentration of angiotensin-converting 132:555-563, 1941. enzyme and bradykinins, along with previously Authors' Summary measured parameters of renal and endocrine Two subjects were studied in rest and work function. Ten men, 18 to 42 years of age, during a sojourn of 15 days at the summit of undergoing water diuresis, breathed a low- Mt. Evans, Colorado (elev. 4,300 m). In both oxygen (five breathed 10.5% O 2 and subjects an increase in the resting cardiac five 12% 02); all breathed 21% O 2 on a control output of about 100 per cent occurred during day. Measurements included mean blood the first 4 to 5 days, later followed by a return pressure and heart rate every 2 to 3 minutes; to values still well above sea-level values. plasma levels of renin activity, aldosterone, The blood volume decreased considerably arginine vasopressin, norepinephrine, and the first 3 or 4 days, then increased to a level bradykinin, and angiotensin-converting enzyme still below the sea-level values. The percentage activity, before and at the end of gas breathing; O2-capacity was increased already the first day, and urine volume (Uv), creatinine, Na ÷, and presumably as a result of withdrawal of fluid bradykinin concentration. Arterial blood gases from the blood. Determinations of the total 02 - and effective renal plasma flow were capacity showed that an increased formation of determined at the end of gas breathing only. red cells first occurred after a latency of 4 to 5 Mean values + SEM for arterial blood gases days. with low 02 were pH 7.39 + 0.02, PO 2 46 + 2 In work the cardiac output was ton., PCO 2 39 + 2 Torr (12 % O2) and 7.48 + considerably higher the first days than later on, 0.01, 35 + 1 Torr, 33 + 1 Torr (10.5% O2). but even then it was still higher than at sea- Responses were otherwise identical in both level. The decline in cardiac output after about groups, and data were combined for analysis. a week at high altitude is presumably related to With hypoxia, heart rate and effective renal the concomitant increase in blood volume and plasma flow increased significantly, P< 0.005; total O2-capacity. The chemosensible reflexes were active 12. Ayres PJ, RC Hurter and ES during the whole sojourn at Mt. Evans. If the Williams. acclimatized subjects breathed an air mixture Aldosterone excretion and potassium enriched with 0 2, the cardiac output both in rest retention in subjects living at high and during work fell to values lower than the altitude. corresponding sea-level values. Nature 191:78-80, 1961. The findings are discussed and brought into Annotation relation with other results on the regulation of Purpose the circulation. To observe changes in body composition during exposure to high altitude. 11. Asmussen E and M Nielsen. Methods Studies on the initial increase in 02 Members of the Middlesex Hospital capacity of the blood at low 02 Medical School High Altitude Physiological pressure. Expedition spent 24 days at 14,300 ft.on Mont. Acta Physiologica Scandinavica 9:75- Blanc. 24 hr urine collections were made from 87, 1945. several subjects. Aldosterone, sodium and Authors' Summary potassium contents were determined. During Determinations of red volumes, plasma the study the diet of the subjects consisted of , blood volumes and water balance dehydrated food stuffs. To establish the effect were made in a low pressure chamber at 435- of the diet on the results, a one-subject control 450 mm Hg barometric pressure. It was found experiment was conducted at sea level. that the increase in cell volume - and O 2 Results capacity during the first days at low pressure Urine analysis showed a drop in was due to a diminished plasma volume, and aldosterone and potassium excretion in the days paralleled by an increase in plasma immediately following ascent, along with an concentration. A similar concentration of the increase in Na + excretion which tended to blood was found during fasting (40 hours) at retum to normal values with time. normal barometric pressure, but a much greater Conclusion concentration of the blood was observed when Changes in body electrolyte composition the subjects fasted at low barometric pressure. showed a marked acclimatization effect. In two of the three subjects the increased concentration of the blood at low pressure was 13. Baertschi A J, J-H Jiao, DE accompanied by an extra loss of water from the Carlson, RW Campbell, WG body. From an estimation of the part played by Teague, D Willson and DS the extracellular water in this loss, it was Gann. found, that about one half of the concentration Neural control of ANF release in of the blood was caused by loss of extracellular hypoxia and pulmonary hypertension. . The other part of the concentration American Journal of Physiology of the blood and, in the third subject, the whole 259:H735-H744, 1990. extra concentration at low pressure was due to Authors' Abstract a leaking-out of fluid from the , Hypoxia causes the release of atrial presumably caused by the increased natriuretic factor (ANF), but the mechanisms blood pressure and an increased permeability of are not yet understood. This study examined the capillary walls at low O 2 pressure. While the relative contribution of pulmonary arterial the excess filtration out of the blood no doubt is hypertension, neural pathways, increased heart a sign of insufficiency of the capillaries, rate, or increased atrial size to the ANF incidentally increasing the oxygen capacity of response. Alveolar hypoxia [fractional the blood, it is difficult to decide whether the concentration of 02 in inspired gas (FIO 2) = excess excretion of water (increased diuresis) is 0.1] or pulmonary arterial hypertension (25-45 the result of a regulation, serving the oxygen mmHg) was induced for 10 min in four series supply, or whether it is due to other causes. (n = 4-12 each) of anesthetized, mechanically ventilated pigs. During hypoxia, plasma ANF concentrations increased by 29 +52 (SE) pg/ml (or 271+105%) over baseline (35 +7 pg/ml; hypoxia and cold appear to be the most unusual P<0.01) (series 1). There was also a environmental stresses. Results to date show a significant increase of pulmonary arterial high birth rate and a high death rate, the death pressure, heart rate, central venous pressure, rate for females, both postnatal and prenatal (as and pulmonary capillary wedge pressure. inferred from the sex ratio at birth), being Repeated pulmonary hypertension induced by unusually high. Birth weights are low, while intravenous air infusion caused a repeated and placenta weights are high. Postnatal growth is reversible quite slow relative to the rate for other 125 +14% increase (P<0.001) of plasma ANF, populations throughout the world, and the and this response was totally abolished by adolescent growth spurt is less than that for lesion of the cervical vagosympathetic trunks other groups. The maximum oxygen (series 2). Lesion of these nerves 1 h before consumption (and thus the capacity for hypoxia also decreased the ANF response to sustained work) of adult males is high despite hypoxia by 45-58% (P<0.01), whereas the reduced atmospheric pressure at high responses of heart rate and atrial pressures altitude. All lowland groups brought to this were unchanged (series 3). The ANF response altitude showed significant reductions in to hypoxia, expressed in percent of baseline, maximum oxygen consumption. The Nufioa was not affected by 0.2 mg/kg propranolol native's responses to cold exposure also differ (PR) (no PR: 145 +63%; PR: 151 +82%; not from those of the lowlander, apparently significantly different from series 1 and because blood flow to his extremities is high control, series 3), although the increase in heart during exposure to cold. The disease patterns rate (no PR: 61+15 beats/min) was almost are not well known: respiratory diseases appear abolished (PR: 17 +_.5beats/min) (series 4). common, whereas there seems to be almost no Hypoxia caused no significant changes in right cardiovascular disease among adults. Systemic and left atrial peak volume regardless of blood pressures are very low, particularly those propranolol, as measured with an electrical of individuals living in traditional native conductance catheter. The results indicate that fashion. Nutrition appears to be good, but a new neural reflex of probably pulmonary analysis of the nutrition studies is continuing. arterial origin mediates 50% of the ANF The results of theses studies are interpreted response to hypoxia. The remaining ANF as showing that some aspects of the natives' response remains to be explored further and adaptation to high altitudes require lifelong cannot be explained by conventional release exposure to the environmental conditions and mechanisms such as atrial stretch and pulsatility may be based on a genetic structure different alone. from that of lowlanders.

14. Baker PT. 15. Banchero N and JC Cruz. Human adaptation to high altitude. Hemodynamic changes in the Andean Science 163:1149-1156, 1969. native after two years at sea level. Author's Abstract Aerospace Medicine 41:849-853, The high-altitude areas of South America 1970. are in many ways favorable for human Authors' Abstract habitation, and they have supported a large Eleven healthy high altitude natives were native population for millennia. Despite these studied by right heart catheterization in facts, immigrant lowland populations have not Morococha, Peru, at 4,540 m altitude. They become predominant in these areas as in other were restudied in Lima, at 150 m, after 2 years parts of the New World, and lowlanders of continuous residence at this level. experience a number of biological difficulties Intravascular pressures and cardiac output were on going to this region. measured at rest and during exercise on a In order to learn more about the adaptations bicycle ergometer at a work load of 300 Kg- which enable the native to survive at high m/min/m E. altitudes, an intensive study of a native A significant decrease in heart rate was population is being carried out in the district of observed after two years at sea level (p<0.01). Nufioa in the Peruvian Altiplano. In this area Resting cardiac output increased from 3.83

6 L/min/m2athighaltitudeto 4.45L/min/m2at altitude (LA) and with 103 _+6 W 4-7 h after sealeveldueto ahighly significantincreasein arrival at 4,559 m or high altitude (HA). Mean strokeindex(p<0.001). However,no changes heart rates during exercise at both altitudes and in meansystemicarterialpressurewerefound during active ascent to HA were similar. atsealeveldueto afall in systemicvascular Exercise-induced changes at LA did not differ resistance.Pulmonaryarterypressureand significantly between the eight subjects who pulmonaryvascularresistancedecreased stayed well and the nine subjects who significantly(p<0.001)after2yearsat sea developed AMS during a 3-day sojourn at level. At sealevelchangesin meanpulmonary 4,559 m. At HA, 02 saturation before (71 +2 arterypressureduring supineexercisewere vs. 83 +_2%, P<0.01) and during exercise ( 67 significantlylessthatthoseobservedat high +_2 vs. 72 +1%, P<0.025) was lower and altitudebut largerthanthoseseenin normalsea exercise-induced increase of plasma levelresidents.This latterfindingappearsto aldosterone (617 +116 vs. 233 +42 pmolfl, berelatedtoincompleteregressionof the P<0.025) and plasma antidiuretic hormone anatomiccharacteristicsof thepulmonary (23.8 +14.4 vs. 3.4 +1.8 pmol/1, P<0.05) was vasculature. greater in the AMS group, whereas exercise- induced rise of plasma atrial natriuretic factor 16. Barer AS and EV Yakovleva. and changes of hematocrit, potassium, and Changes of the concentration of sodium osmolality in plasma were similar in both and potassium ions in the human urine groups. In the AMS group, exercise at HA and saliva during elevations in a was associated with a fall in mean blood barochamber to the altitude of 5,000 pressure (-13 +2 vs. 0 +5 Torr, P<0.05) and a and 6,000 m. greater rise of plasma norepinephrine Bulletin of Experimental Biology and (14.6 +1.6 vs. 8.9 +1.3 nmol/1, P = 0.01) and Medicine 53:63-65, 1962. adrenocorticotropic hormone (30.9 +13.8 vs. Authors' Abstract 7.9 +2.8 pmol/1, P = 0.07), which most likely The method of flame photometry was used accounted for the higher plasma aldosterone and antidiuretic hormone levels after exercise. for studying the sodium and potassium concentration in the saliva and urine of man These results demonstrate that exercise at HA elevated in a barochamber to the altitude of performed at a work load comparable with the 5,000 and 6,000 metres. A definite regularity efforts of mountaineering results in a hormonal was noted in the shifts of concentration of the constellation that favors greater water and salt substances studied. The concentration of retention in subjects subsequently developing potassium ions has a tendency to rise, while AMS compared with those who stay well. that of sodium--to drop. In repeated elevations these shifts become more smooth. 18. B/irtsch P, N Pfluger, M Aud6tat, S Shaw, P Weidmann, P Vock, 17. B/irtsch P, M Maggiorini, W W Vetter, D Rennie and O Oelz. Effects of slow ascent to 4,559 m on Schobersberger, S Shaw, W Rascher, J Girard, P Weidmann fluid homeostasis. and O Oeiz. Aviation, Space, and Environmental Enhanced exercise-induced rise of Medicine 62:105-110, 1991. aldosterone and vasopressin preceding Authors' Abstract mountain sickness. Since acute mountain sickness (AMS) is Journal of Applied Physiology 71:136- associated with rapid ascent and with fluid 143, 1991. retention, we assessed clinical status and fluid Authors' Abstract homeaostasis in men slowly ascending on foot A possible contribution of exercise to the over 3 d to 4559 m and remaining at this fluid retention associated with acute mountain altitude 5 d. We studied 15 male mountaineers, sickness (AMS) was investigated in 17 6 of whom had previously had repeated, severe mountaineers who underwent an exercise test AMS or high altitude pulmonary for 30 rain on a bicycle ergometer with a (HAPE), at 1170 m, 3611 m, and 4559 m. We constant work load of 148 _+9(SE) W at low found that four of the six subjects with previousAMS orHAPEcomparedwith none established. The association of AMS with of ninewith no suchhistory,developedthese facial (P<0.005) and pulmonary edema conditions. Thosewhoremainedwell hada (P<0.05) is compatible with the hypothesis that diuresisthatcouldnotbeovercomeby ANP may contribute to edema formation by its increasingfluid intakeandnochangein renin action on transcapillary fluid exchange. activity,plasmaaldosterone,or atrialnatriuretic peptide(ANP). Thosewhobecameill showed 20. B_irtsch P, S Shaw, P Weidmann, considerableweightgainindependentof fluid M Franciolli, M Maggiorini and intake,andagreatincreasein ANPwhich O Oelz. correlatedwith measurementsof right atrial Aldosterone, antidiuretic hormone and crosssection.We concludethatmountaineers atrial natriuretic peptide in acute whohavepreviouslyexperiencedrepeated mountain sickness. AMS or HAPEgetfluid retentiondespiteslow In: Hypoxia and Mountain Medicine. ascentandthatthis is associatedwith widening Proceedings of the 7'h International of theatriumandanincreasein ANP. Symposium, edited by JR Sutton, G Coates, and CS Houston. New York: 19. Biirtsch P, S Shaw, M Franciolli, Pergamon Press, 1992. p. 73-81. MP Gniidinger and P Weidmann. Annotation Atrial natriuretic peptide in acute Purpose mountain sickness. Summarizes the major findings of two Journal of Applied Physiology studies, comparing changes of diuresis and 65:1929-1937, 1988. natriuresis with those of plasma levels of Authors' Abstract aldosterone, antidiuretic hormone and atrial To test the hypothesis that elevated atrial natfiuretic peptide between subjects with and natriuretic peptide (ANP) may be involved in without acute mountain sickness upon acute altered fluid homeostasis at high altitude, we exposure to an altitude of 4,559 m. examined 25 mountaineers at an altitude of 550 Methods m and 6, 18, and 42 h after arrival at an altitude Different subjects participated in the two of 4,559 m, which was climbed in 24 h starting studies. They were investigated prospectively from 3,220 m. In 14 subjects, symptoms of before ascent and during a sojourn of 3 or 4 acute mountain sickness (AMS) were absent or days at the high altitude research laboratory mild (group A), whereas 11 subjects had located in the Capanna Regina Margherita severe AMS (group B). Fluid intake was (4,559 m). The ascent lasted 20-22 h including similar in both groups. In group B, urine flow transportation by cable car from 1,170 to 3,220 decreased from 61 +8 (base line) to 36 +_3 (SE) m and an overnight stay at 3,611 m. The ml/h (maximal decrease) (P<0.05), and sodium subjects climbed for 2 h (from 3,220 to 3,611 excretion from 7.9 _+0.9 to 4.6 _+0.7) mmol 11 m) on the first day of ascent and 4-5 h (from h "1(P<0.05); ANP increased from 31 +4 to 87 3,611 to 4,559 m) on the second day. In +_26 pmol/1 (P<0.001), plasma aldosterone 1986, 25 subjects (age 23-64 y) stayed for 3 from 191 +_27 to 283 +55 pmolll (P<0.01 days and in 1988, 17 subjects (ages 25-62 y) compared with group A), and antidiuretic remained 4 days at 4,559 m; they were hormone (ADH) from 1.0 _+0.1 to 2.9 +1.2 examined after 50 min. of rest in the supine pmol/1 (P = 0.08 compared with group A). position, first at low altitude and 3 times during These variables did not change significantly in the stay at high altitude. group A, with the exception of a decrease in In the latter study, an exercise bout of 30 plasma aldosterone from 189 +19 to 111 +17 rain on a cycle ergometer was performed at low pmol/l (P<0.01). There were no measurable altitude and within 4 to 8 hours after arrival at effects of elevated ANP on natriuresis, cortisol, 4,559 m. or blood pressure. The reduced diuresis in Results AMS may be explained by increased plasma In 1986, 11 of 25 subjects developed acute aldosterone and ADH overriding the expected mountain sickness. Six subjects having acute renal action of ANP. The significance of mountain sickness and two lacking this elevated ANP in AMS remains to be condition developed high altitude pulmonary edema.In 1988five casesof highaltitude and the development of acute mountain pulmonaryedemadevelopedin 9 of the17 sickness. subjectswhichhadacutemountainsickness. In bothstudiesfluid intakewascomparable 21. Baylis PH, RA Stockley and DA betweenthegroupswith andwithoutacute Heath. mountainsickness.In bothstudiesurine Effect of acute hypoxaemia on plasma outputandnatriuresiswerelowerin thegroups arginine vasopressin in conscious man. havingacutemountainsickness.In both Clinical Science and Molecular studiessubjectswith acutemountainsickness Medicine 53:401-404, 1977. hadsignificantlyhigherplasmaaldosteroneat Authors' Abstract highaltitudecomparedto thosewithoutthis 1. Acute hypoxaemia has been reported to condition. No statisticallysignificantchanges stimulate vasopressin release in animals. occurredin eithergroupwith regardto ADH in 2. Hypoxaemia induced by breathing 9.3% plasmaor to plasmaosmolality.PlasmaANP oxygen for 15-20 rain failed to produce a rise wassignificantlyelevatedin theacutemountain in plasma arginine vasopressin concentration in sicknessgroupascomparedto non- six out of eight healthy human subjects. The symptomaticsubjects.Plasmalevelsof renin, two subjects who developed an increase in norepinephrineandcortisolwerealsohigherin plasma arginine vasopressin concentration had theacutemountainsicknessgroup. However, a significant rise in serum cortisol. therewereno changesin plasmasodiumand 3. Breathing 100% nitrogen until adrenocorticotropinlevels. impairment of consciousness caused no rise in Exerciseathighaltitudeproduced plasma arginine vasopressin concentration. significantlyhigherlevelsof plasma aldosterone,ADH, renin,norepinephrine, 22. Becker EL, JA Schilling and RB cortisol,andACTH in theacutemountain Harvey. sicknessgroup,whereasincreasesof Renal function in man acclimatized to osmolality,plasmasodium,potassium, high altitude. protein,andhematocritweresimilarin both Journal of Applied Physiology 10:79- groups.Meanarterialoxygensaturationprior 80, 1957. to exercisewas71+_3%in theacutemountain Authors' Abstract sicknessgroup,83 +_2%in thenon-acute Studies were carried out at the Andean mountainsicknessgroup,andfell during Institute of Biology, Morococha, Peru (altitude exerciseto 67 +_2%and71+_2%,respectively. 15,000 ft.) on natives who for generations Conclusions have been living at high altitude. These Increased plasma levels of aldosterone at acclimatized individuals represent a climato- rest and a greater exercise-induced increase of physiological variety of the human race aldosterone and ADH in subjects developing different from sea level dwellers. The mean acute mountain sickness may explain their data on all subjects showed an 11% decrease in water and salt retention which was independent filtration rate, a 52% decrease in effective renal of the amount of fluid intake. The hormonal plasma flow, and an 89% increase in filtration alterations favoring enhanced water and salt fraction, with a 44% increase in hematocrit as retention could result from more severe compared to normal sea level values taken from hypoxemia due to decreased ventilatory drive the literature. giving rise to stress and hypotensive noradrenergic reactions. Alternatively, the 23. Behm R. authors cannot exclude that a primary increase Role of the peripheral arterial in hormonal response to exercise with chemoreceptors in electrolyte subsequent fluid retention could lead to homeostasis and cardiovascular interstitial pulmonary edema and account for regulation. the observed differences in oxygen saturation. In: Hypoxia and Mountain Medicine. Further investigations are needed to determine Proceedings of the 7'h International the cause and effect relation between changes in Symposium, edited by JR Sutton JR, G hormonal response, alterations in gas exchange Coates, andCSHouston.New York: appear to be the cause of the reduction of renal PergamonPress,1992.p.50-60. plasma flow nor the retention of salt and water Author's Abstract observed in congestive heart failure. In recentyears,therehasbeengrowing interestin theroleof peripheralarterial 25. Bharadwaj H. chemoreceptorsin theregulationof sodium Effect of prolonged stay at high altitude homeostasis,especiallyin hypertensive on body fat content An anthropometric mammals.Similarmorphological,biochemical evaluation. andfunctionalalterationsof arterial Human Biology 44:303-316, 1972. chemoreceptorshavebeendescribedin both Author's Abstract hypertensiveandhypoxicanimals.In The effect of 10-months' continuous stay at normotensiverats, moderate hypobaric hypoxia high altitudes on body fat content was leads to transient decreases in salt and water evaluated on troops drawn from two ethnic intake and slight reductions in arterial blood groups. Body fat content was measured by pressure. In contrast, in spontaneously anthropometric techniques, and it was observed hypertensive rats, hypoxia induces a sustained that it declined significantly on prolonged suppression of voluntary salt intake and a exposure to high altitudes. Since lean body marked reduction in blood pressure. Water weight increased after exposure to high intake is similarly affected by hypoxia in altitudes, body weight change was much hypertensive and normotensive rats. The effect smaller than what had been observed in acute on salt, but not water intake, is inhibited by exposures to high altitude by other carotid body denervation in hypertensive rats. investigators. Fluctuations in the body fat The decrease in blood pressure is attenuated by content at high altitudes could be seasonal. access to additional dietary salt and augmented by carotid body denervation. Hypoxia is 26. Bharadwaj H, SC Jain and HS further associated with significant renal sodium Nayar. retention, although this effect may depend on Body composition of high altitude the salt content of the diet. Hypoxia-induced natives on descent to the plains: A renal sodium retention is more pronounced in densitometric, hydrometric, and chemodenervated than in intact rats. anthropometric evaluation. These data suggest that peripheral arterial Journal of Applied Physiology 47:65- chemoreceptors can play a major role in sodium 72, 1981. homeostasis and blood pressure. Presently, Authors' Abstract the exact mechanisms of interaction between Body density was experimentally hypoxia and chemoreceptor activation on the determined at a field location at 3,920 m on 32 one hand and sodium homeostasis and blood medically fit and active high altitude native pressure on the other hand are not completely males using a water displacement technique. understood and warrant further investigations. Stature, body weight and the bony widths at the elbow, wrist, knee, and ankles; and 24. Berger EY, M Galdston and SA thickness of skin folds at eight sites were Horwitz. measured. Based on body density and bony The effect of anoxic anoxia on the widths, body fat, total body water (TBW), human . mineral mass and total cell solids (TCS) were Journal of Clinical Investigation calculated. 28:648-652, 1949. Similar measurements were made on Authors' Abstract another group of 16 high altitude natives after Renal plasma flow in man did not decrease one months stay in Dehli (200m). TBW of 11 under situations of anoxia where arterial of these subjects was experimentally oxygen tension was lowered to about 50 into determined by the oral administration of Hg. The most pronounced effect of lowered 200 Ci of tritiated water. This group of oxygen tension on renal tissue was the subjects was physically less active in Delhi. At increased excretion of sodium and chloride. high altitude the natives consumed a balanced Anoxic anoxia alone, therefore, does not diet which provided 20.21 M J, but in the plains

I0 thedietprovidedonly 15.69MJ thoughit was m, after 4 weeks of their stay at those altitudes. nutritionallybalanced. Body composition changes have been inferred In spiteof thereducedcalorieintakethis from the changes in body measurements, and groupshowedgreaterfat contentin Delhi than soft tissue X-rays of the upper arm. thegrouplocatedathighaltitude.Thesemen werealsohyperhydrated.Hyperhydrationof 28. Bharadwaj H, AP Singh and MS theleanbodycouldbean adaptiveresponseof Malhotra. thehighaltitudenativesto thenew Body composition of the high-altitude environment.Dueto thedisturbedstateof natives of Ladakh: A comparison with hydrationof theleanbodyof thesemenin the sea-level residents. plains,useof Siri's formulafor the Human Biology 45:423-434, 1973. computationof totalbodyfat is questioned. Authors' Abstract Using anthropometric techniques, body 27. Bharadwaj H and MS Malhotra. composition was evaluated in three groups of Body composition changes after 4 week young soldiers; 30 Tamilians at sea level, 45 acclimatization to high altitude: Ladakhis at altitude and 17 Tamilians after a anthropometric and 10-month stay at 3960 m altitude, were roentgenogrammetric evaluation. studied. In the Tamilians at sea level, the body Zeitschrifi fiir Morphologie und mass (mean 55.93 +5.67 kg) was composed of Anthropologie 65:285-292, 1974. 11.85 +4.51% body fat, 5.52 _+0.62% bone Authors' Abstract mineral, 65.76 +4.56% body water and 16.87 Body composition changes were studied by +2.14% cell solids. Among Ladakhis (mean Surks et al. (1966) on subjects abruptly body weight 55.54 +4.82 kg), fat constituted exposed to high altitude (4,300 m) for 8 days. 10.58 +2.73%, bone mineral 5.79 _-_+0.38%, They attributed body weight loss to loss of fat. body water 66.93 +4.12% and cell solids Though total proteins remained unaltered, the 16.69 +__2.92% of the total body weight. Bone authors noticed significant shifts in proteins mineral was significantly greater in the from muscle to non-muscle fraction. Harmon Ladakhis due to their wider bi-iliac, wrist, knee et al. (1969) observed reduced thickness of and ankle widths. After 10 months' stay at skin folds, and smaller circumferences of the high altitude, the Tamilians lost 0.89 kg body limbs of eight college women exposed to 4,300 fat and 0.58 kg cell solids. Body water m altitude for two and a half months. increased by 0.56 kg. Changes in bone Consolazio et al. (1968) observed negative mineral, however, were not significant. nitrogen and water balance after 4-week In spite of prolonged exposure to high exposure to 4,300 m altitude, and Krzywicki et altitude, the Tamilians were unable to adjust the al. (1969) have reported losses in body fat, oxygen transport mechanism like the natives. protein, water and mineral contents in subjects Structural changes in the skeletal system of the exposed for 12 days at the same altitude. high-altitude natives are obviously meant for Hannon (1969), while reviewing the subject of better haemopoietic activity. water balance at high altitude, concluded that there was no hypohydration during brief 29. Bharadwaj H, MV Singh, SB exposure to high altitude, but only a shift of Rawal, T Zachariah, S Kishnani, water from the extra-cellular into the SN Pramanik, A Gupta and RM intracellular space. This view has, however, Rai. been recently contradicted by Krzywicki et al. Hydration and tissue solid content of (1971) who observed 2.25 kg water loss the lean body on prolonged exposure to during 6-day exposure to 4,300 m altitude. altitude. Significant water loss took place exclusively International Journal of from the intracellular space, whereas Biometeorology 33:27-31, 1989. extracellular space increased significantly. Authors' Abstract In view of these conflicting results adaptive Using densitometric, hydrometric and changes in body composition have been studied anthropometric techniques, body fat, tissue on lowlanders at altitudes ranging 3962 to 4115 solids, water and mineral content were

11 quantitativelymeasuredon twogroupseachof phosphokinase indicate that the density of the 26 youngandhealthyIndiansoldiersof mixed lean body had increased owing to elevated ethniccomposition.Theexperimentalgroup protein synthesis and its retention in the wasexposedto 3500m altitudefor 2 yearsand intracellular spaces during this period. Increase theexperimentswerecarriedoutafter48 hand in the density of the lean body without 3weeksrehabilitationin Delhi (300m). The significant change in its volume would comply controlgroupwasneverexposedto high with experimental observations. altitudes.In spiteof theexperimentalgroup beingfedwith superiorrationsat highaltitude, 31. Bharadwaj H, SS Verma, T thisgroupshowedsignificantlyhyperhydrated Zachariah, MR Bhatia, S leanbodywith reducedtissuesolidsin Kishnani and MS Malhotra. comparisonto thecontrolgroupwhichwasfed Estimation of body density and lean with identicalrationsin Delhi. Thecalculated body weight from body measurements meandensit2(of thefat freebodyhaddeclined at high altitude. to 0.092x10°kg/m3. The 3weekstayat low European Journal of Applied altitudehadlittle influenceon body Physiology 36:141-150, 1977. composition.Hyperhydration,with reduced Authors' Abstract tissuesolids,wouldcausereductionin the Body density and other anthropometric data densityof fat freebody,andwould thus were obtained on 101 Indian soldiers who were interferewith theestimatesof totalbodyfat continuously staying at high altitude (3920 m) basedon densitometricproceduresalone.In for more than 10 months. Use was made of a thehyperhydratedstate,Siri's formula volumeter, and body density was overestimatedfat by 22.8%of thetruevalue. calculated from observed body weight and volume. Measurements were taken on the 30. Bharadwaj H, KK Srivastava and body using standard techniques. A stepwise MS Malhotra. linear regression analysis was performed to Body composition changes in the plains establish possible relationships of 36 body on descent from high altitude. measurements with density and lean body Human Biology 46:43-55, 1974. weight. Thigh anterior, juxta-nipple skin folds Authors' Abstract and forearm and ankle circumferences were Body composition and serum metabolites selected in the regression equation predicting were studied in 24 subjects at 4000 m and body density. Multiple correlation coefficient again after the first week and fourth week of (R) equal to 0.765 was obtained for this rehabilitation in Delhi (216 m) when the level equation. For the predicted lean body weight, of physical activity and nutrition was R equaled 0.930. The regression equations considerably reduced. Significant gain in body included body weight, thigh anterior and juxta- weight was observed after one week of nipple skin fold thicknesses, and forearm rehabilitation. This included significant gains circumference. Contribution of other body in fat, cell solids and mineral content of the measurements in the regression of these body. Body water, however, did not increase parameters was not significant. The analysis significantly. Gain in fat content was also revealed that a new set of coefficients is supported by significant increase in skinfold required for the measurements included in the thickness during the first week. Skinfolds published regression equations. which are determinants of total body fat, continued to increase significantly throughout 32. Bircher HP, U Eichenberger, M the rehabilitation period. Thickness of the skin Maggiorini, O Oelz and P folds at the extremities, however, tended to Biirtsch. decline after the first week. Relationship of mountain sickness to The increase in the cell solids after one physical fitness and exercise intensity week of rehabilitation was unexpectedly larger during ascent. than the total increase in the lean body weight. Journal of Wilderness Medicine The changes in the levels of serum alanine and 5:302-311, 1994. aspartate amino-transferases as well as creatine

12 Authors' Abstract prolonged exposure to high altitude may result Thepurposeof thestudywasto investigate in persistent impairment of osmoregulation, whethersusceptibilityto acutemountain caused in part by an inappropriate arginine- sickness(AMS) andhigh-altitude pulmonary vasopressin response to hyperosmolality. edema (HAPE) is related to differences of physical fitness and/or the level of exercise 34. Bouissou P, CY Guezennec, FX during ascent. Work capacity at a heart rate of Galen, G Defer, J Fiet and PC 170 min 1 (PWC170) was assessed on a bicycle Pesquies. ergometer prior to high-altitude exposure, and Dissociated response of aldosterone the heart rate was continuously registered from plasma renin activity during during the ascent from 3610 to 4559 m in 41 prolonged exercise under hypoxia. mountaineers. During the subsequent stay of 3 Hormone and Metabolic Research days at 4559 m, 12 subjects developed AMS, 20:517-521, 1988. 13 subjects showed radiographic evidence of Authors' Abstract HAPE, and 16 subjects remained without Six healthy male subjects on a fixed salt- significant illness. PWCI70 (group means diet performed 1 hour ergocycle exercise at between 238 and 247 W) and heart rate during 65% of VO 2 max in normoxic (N) and ascent (group means between 134 and 141 n_ 1) hypoxic (H) conditions. Blood samples were did not significantly differ between these taken at intervals for estimations of plasma groups. PWC_70correlated negatively with two aldosterone (PAC), angiotensin converting independent symptoms scores (clinical score, enzyme (ACE), adrenocortiotrophic hormone environmental symptom questionnaire) on day (ACTH) and catecholamine concentrations. 3 at 4559 m, whereas heart rate during ascent Plasma volume reductions with exercise were correlated positively only with clinical score on similar in N (4.3 +1%) and H (4.0 +1%). days 2 and 3 at 4559 m. Correlations, PRA response to exercise was increased by however, were minor, with correlation hypoxia while PAC and plasma catecholamine coefficients of r = 0.32-0.43 (p<0.05-0.01). rose to a similar extent in both conditions. These results indicate that physical fitness or Increases in ACTH concentration occurred at exercise intensity during ascent were of minor the end of exercise but no difference was found importance for the development of AMS and between high and low altitudes. Plasma ACE HAPE in our subjects. remained unchanged throughout exercise in either condition. These results indicate that 33. Blume FD, SJ Boyer, LE hypoxemia interferes with PRA-mediated Braverman, A Cohen, J Dirkse aldosterone secretion. The variations in plasma and JP Mordes. ACTH levels during exercise in hypoxia do not Impaired osmoregulation at high appear responsible for this interference. altitude. Journal of the American Medical 35. Bouissou P, F Peronnet, G Association 252:524-526, 1984. Brisson, R Helle and M Ledoux. Authors' Abstract Fluid-electrolyte shift and renin- Osmoregulation was studied in 13 aldosterone responses to exercise under mountaineers who had experienced long-term hypoxia. exposure to high altitude on Mt. Everest. Hormone and Metabolic Research Serum osmolality rose from 290 +1 mOsmNg 19:331-334, 1987. to 295 +_2 mOsrn/kg at 5,400 m and finally to Authors' Abstract 302 +4 mOsm/kg at 6,300 m after a mean of In order to describe fluid-electrolyte shift 26.5 days above 5,400 m. Despite this degree and endocrine response to exercise under of osmoconcentration, plasma arginine- moderate acute hypoxia, 8 healthy male vasopressin concentration remained unchanged: subjects (24 +_3 years old) were evaluated at 1.1 +-0.1 U/re& at sea level, 0.8 + 0.1 U/mL 40, 60, 80 and 100% _'O 2 max in normoxic at 5,400 m, and 0.9 + U/mL at 6,300 m. (N) and hypoxic (H) conditions (14.5% 02). Urinary vasopressin excretion was also similar at all three altitudes. We conclude that VO 2 max decreased from 55.5 +_1.3 to 45.8

13 _+1.4 ml/kg x min in H condition. Plasma subjects, and xylose excretion decreased volume reductions with increasing relative 24.3% in six of seven subjects at 6,300 m workloads were similar in N (9.4%) and H relative to sea level. It appears that muscle (9.9%) conditions. The rise in plasma catabolism and malabsorption contribute osmolality was in part related to blood lactate significantly to weight loss at high altitude. accumulation which occurred in both High percent body fat does not protect against conditions. However, variations in plasma loss of muscle tissue. Sherpas do not appear solute content and osmolality suggested that susceptible to some of the changes affecting exercise under hypoxia results in a greater Caucasians. electrolyte loss from vascular space and in a greater K ÷ loss from working skeletal muscles. 37. Brahmachari HD, MS Maihotra, Increase in catecholamine concentrations were K Ramachandran and U similar in normoxic and hypoxic conditions Radhakrishnan. except for lower maximal norepinephrine Progressive changes in plasma cortisol, concentration under hypoxia. Finally, although antidiuretic hormone and urinary plasma retain activity increased with workload volume of normal lowlanders during in both conditions, plasma aldosterone did not short stay at high altitude. significantly change. This dissociation Indian Journal of Experimental between renin and aldosterone suggests that Biology 11:454-455, 1973. aldosterone release during exercise might Authors' Abstract depend upon other factors. However, changes Lowlanders taken to high altitude of 11,500 in plasma potassium concentration do not ft showed a rise in blood cortisol level within appear as an important stimulus for aldosterone 3-9 days of arrival which returned to normal secretion during exercise. sea level in 13 days. Antidiuretic hormone showed a rise in 4 days and remained at a 36. Boyer SJ and FD Blume. higher level despite the occurrence of diuresis Weight loss and changes in body in the subjects. Within 5 days of return to composition at high altitude. plains the plasma cortisol again showed a rise Journal of Applied Physiology while the antidiuretic hormone reached normal 57:1580-1585, 1984. level. Urine volume showed a rise with the Authors' Abstract antidiuretic at the same time, when the cortisol Little is known about weight loss and and ADH levels were highest. The cortisol changes in body composition at extreme response to hypoxic stress appears to be altitude. As part of the American Medical connected with the occurrence of acute Research Expedition to Everest in 1981 we mountain sickness. measured body weight, body fat, limb circumferences, dietary intake, 72-h stool fats, and 5-h urine xylose excretion at various 38. Burrill MW, S Freeman and AC altitudes on Caucasian and Sherpa expedition Ivy. members. In Caucasians, loss of body fat Sodium, potassium, and chloride accounted for 70.5% of the mean 1.9-kg excretion of human subjects exposed to weight loss during the approach march at a simulated altitude of eighteen moderate altitude, but for only 27.2% of the thousand feet. mean 4.0 kg weight loss during residence Journal of Biological Chemistry above 5,400 m. There was significant 157:297-302, 1945. proportionate decrease in arm and leg Authors' Abstract circumferences during residence above 5,400 Exposure to reduced pressure, under the m (1.5 and 2.9 cm, respectively). On the other conditions of the experiment, caused a hand, Sherpas, who arrived in Base Camp with temporary rise in the excretion of sodium, half as much body fat as Caucasian members potassium, and chloride. Following exposure (9.1% vs. 18.4%), maintained weight and limb the excretion of these was circumferences during residence above 5,400 compensatorily reduced so that total excretion m. Fat absorption decreased 48.5% in three during the 24 hours was not altered. A

14 temporaryrisein urinevolumewasalsofound interaction of many of the indirect effects of to accompanyexposure. hypoxia usually served to stabilize caloric It is possiblethat areducedoxygentension intake at levels comparable to those found at in theatmospheremaydirectlyor indirectly sea level for the man performing like amounts influencetheexcretionof sodiumand of work. In studies using well-condition track potassiumin theurine;yet thereis surprisingly athletes, there was a 10% reduction in caloric little informationon thissubjectin the intake with exposure to hypoxia, and this literature.Thepossibilitythattherequirements reduction was corrected within 3-4 days. for theseelementsmight bealteredin aviators Physical activity increases water requirements, or othersmaintainedathighaltitudesledto the particularly in warm and hot environments and studyof thisquestionin humansubjectsunder at high altitude. About 13 mg of water vapor conditionsof simulatedhighaltitude. are lost for every liter of air expired if the vapor pressure gradient exceeds 20 mm Hg from the 39. Buskirk ER and J Mendez. mouth and nose to ambient air. In a temperate Nutrition, environment and work environment when man is hypohydrated and performance with special reference to subsequently exercises, his deep body altitude. temperature increases. This reaction reduces Federation Proceedings 26:1760- heat tolerance. As the body becomes 1767, 1967. hypohydrated, urine flow is reduced and the Annotation urine is maximally concentrated at about 1,400 Purpose milliosmols/liter with a daily urine volume of This report deals with gross calorie and 500 ml or less. water requirements for resting and working Conclusions man under environmental conditions of climate In the absence of abnormal climate and altitude. situations and gross disturbances in thermal Methods balance, the most important factor for A brief graphic review was made of both determining caloric requirements is physical old and more recent efforts to relate food and activity; for water requirements the important water requirements to variables associated with factors are environmental conditions including climate and physical work. Attention was paid water vapor pressure plus physical activity. only to the young man of average body build and stature who works in various 40. Butterfield GE, J Gates, S environments. Fleming, GA Brooks, JR Sutton Results and JT Reeves. Increased energy intake minimizes Studies during World War II indicated; as weight loss in men at high altitude. the environmental temperature decreases, that caloric intake increases, but considerations Journal of Applied Physiology 72:1741-1748, 1992. were given to variations in activity level. Studies undertaken in the late 1950's used the Authors' Abstract inclusion of body weight as a reference and the The hypothesis that high-altitude weight results showed that increasing physical activity loss can be prevented by increasing energy clearly increased caloric intake in all intake to meet energy requirement was tested in environments. On the basis of studies in 1964, seven men, 23.7 +4.3 (SD) yr, taken to 4,300 the evidence suggested that no more than a 2- m for 21 days. Energy intake required to 5% increase in caloric allowance need be maintain body weight at sea level was found to be 3,118 +300 kcal/day, as confirmed by provided for adequately clothed persons in cold climates. If a caloric allowance adjustment is nitrogen balance. Basal metabolic rate (BMR), made for hot climates, it has been estimated that determined by indirect calorimetry, increased a 0.5% per degree centigrade increase is a 27% on day 2 at altitude and then decreased sufficient adjustment for climates above 30°C and reached a plateau at 17% above the sea ambient temperature. After reviewing several level BMR by day 10. Energy expended investigations designed to evaluate caloric during strenuous activities was 37% lower at altitude than at sea level. Fecal excretion of requirements at altitude, it was apparent that the

15 energy,nitrogen,totalfiber,andtotalvolatile Authors' Abstract fatty acidsasnot significantlyaffectedby Twenty subjects each were rapidly inducted altitude. Energyintakeataltitudewasadjusted by road to 3200 and 3771 m. Serum and after 1wk, on thebasisof theincreasedBMR, urinary sodium, potassium, calcium, and to 3,452+452 kcal/day. Mean nitrogen magnesium were measured during 10 d at high balance at altitude was negative (-0.25 _+0.71 altitude. At 3200 m, only serum potassium g/day) before energy intake was adjusted but increased significantly on the 10_ day. At rose significantly thereafter (0.02 _+0.71 and 3,771 m serum potassium did not increase. 0.44 _+0.66 g/day during weeks 2 and 3). Serum sodium generally remained low, serum Mean body weight decreased 2.1 +1.0 kg over magnesium increased, while calcium decreased the 3 wk of the study, but the rate of weight significantly. Urinary volume over 24 h loss was significantly diminished after the decreased more and for longer duration at 3771 increase in energy intake (201 _+75 vs. 72 _+48 m than at 3200 m. Urinary cations did not g/day). Individual regression lines drawn change significantly at 3200 m. At 3771 m, through 7-day segments of body weight sodium and potassium excretion decreased on showed that in four of seven subjects the days 1 and 3 and later returned towards slopes of body weight were not significantly preinduction levels. Magnesium and calcium different from zero after the 2 _dwk. Thus decreased throughout the high-altitude stay. weight loss ceased in four of seven men in Significant changes were noticed in serum and whom increased BMR at altitude was urinary cations on exposure to high altitude compensated with increased energy intake. when adequate caloric intakes were not This study demonstrates that weight loss at ensured. altitude can be minimized or even halted by increasing energy intake to meet increased 43. Claybaugh JR, DP Brooks and A energy need. Cymerman. Hormonal control of fluid and 41. Carmena At, N Garcia de Testa electrolyte balance at high altitude in and FL Frias. normal subjects. In: Hypoxia and Urinary erythropoietin in men subjected Mountain Medicine. Proceedings of to acute hypoxia. the 7'h International Symposium, Proceedings of the Society for edited by JR Sutton, G Coates, and CS Experimental Biology and Medicine Houston. New York: Pergamon Press, 125:441-443, 1967. 1992. p.61-72. Authors' Abstract Authors' Abstract The urinary erythropoietin content of Ascent to high altitude results in imbalances residents at sea level was measured during a 5- of body fluids and electrolytes. The magnitude day sojourn at 14,900 feet. We found an early and direction of the imbalances are not EP rise with the peak on the 2nd-3 _ day of consistent between studies because of the exposure. Thereafter, activity declined. The various schedules of ascent, severity and rapid increase in activity is considered to reflect duration of hypoxia, prophylactic measures for the response to a severe hypoxic stimulus, and prevention of high altitude sickness, and diet the subsequent decrease, to utilization of the employed by investigators. Nonetheless, most hormone by an active erythroid bone marrow. studies indicate a loss in total body water. The body water is reduced as a consequence of 42. Chatterji JC, VC Ohri, KS Chadha, increased insensible water loss, relatively BK Das, M Akhtar, SC Tewari, constant urine output and a reduction in water P Bhattacharji and A Wadhwa. intake resulting from decreased thirst. Thus, a Serum and urinary cation changes on transient negative water balance exists for the acute induction to high altitude (3200 first 3-5 days at high altitude, resulting in a and 3771 metres). deficit of about 2 L in body water for up to 12 Aviation, Space, and Environmental days. Decreased appetite also usually occurs Medicine 53:576-579, 1982. upon ascent to high altitude, resulting in decrements of caloric intake of 1500 Kcal/day.

16 ConsequentlyNa andK intakesarereduced, 45. Claybaugh JR, CE Wade and SA andincreasesin plasmareninactivityand Cucinell. aldosteroneconcentrationareobservedseveral Fluid and electrolyte balance and daysafterascent.Whenappetitelossis less hormonal response to the hypoxic severe,reninlevelsareusuallyunchangedand environment. aldosteronelevelsarereduced,reflectingwhat In: Hormonal Regulation of Fluids appearsto beamoreaccurateresponseto and Electrolytes, edited by JR hypoxemiaperse. Theantidiuretichormone Claybaugh and CE Wade. New York: responseto highaltitudeiscomplicatedby an Plenum Press, 1989. p.187-214. alterationin circadianrhythm. Most Authors' Abstract antidiuretichormoneresponsesat highaltitude High altitude exposure results in a negative areprobablyindirectresponsesto the water balance. This is in part due to increased hypoxemiaandthemechanismsarediscussed. insensible water loss, decreased thirst, an inappropriately maintained urine flow despite 44. Claybaugh JR, JE Hansen and DB the decreased thirst, and a decreased appetite. Wozniak. The hormonal involvement in these responses Response of antidiuretic hormone to is unclear. For instance, no clear cut role for acute exposure to mild and severe any hormone system has been established for hypoxia in man. the decreased thirst. Similarly, the maintenance Journal of Endocrinology 77:157-160, of urine flow despite decreased intake is not 1978. reflected in the short term by an alteration in the Authors' Abstract to plasma ADH relationship. Eight men, 19-35 years of age, breathed However, evidence after prolonged exposure 20.9% (normal oxygen), 13.9% (mild suggests that the ADH response to increased hypoxia) or 11.1% (severe hypoxia) oxygen in osmolality is reduced. Also, increased cortisol nitrogen gas during three 20 min and ANF levels may be contributing to the periods, which were separated by 1 h recovery relative diuresis. periods. The order in which the gas mixtures When dietary intake is controlled, high were breathed was random. The partial altitude is associated with a retention of pressure of oxygen decreased from a mean of potassium and a tendency to lose sodium. 93.5 during exposure to normal oxygen to 53.9 These responses are consistent with the and 36.7 mmHg during mild and severe reduced aldosterone levels which in turn are a hypoxia, respectively. There were result of a reduced responsiveness of corresponding decreases in haemoglobin aldosterone to renin. The mechanism of the saturation. The partial pressure of carbon latter is still unresolved. dioxide was lower and the pH higher during The responses of ADH to hypoxia are very severe hypoxia than during exposure to normal complex and have led to considerable oxygen. There were no changes in the plasma confusion. We have tried to describe the osmolality or in the concentrations of sodium differences in experimental designs that or potassium in the plasma. There was a probably account for the reports of different tendency for both the renin activity and the responses. Clearly, degree of hypoxia, time of concentration of aldosterone in the plasma to exposure, and whether or not the experiment decrease progressively as the percentage of allowed for spontaneous hyperventilation, are oxygen breathed decreased. Unlike severe important considerations in comparing ADH hypoxia, mild hypoxia suppressed the responses from different studies. concentration of antidiuretic hormone (ADH) in The potential for hormonal involvement in the plasma of all subjects by about 59%; during acute mountain sickness, high altitude severe hypoxia the reduction was not pulmonary edema, and cerebral edema significant, being only about 33%. These data continues as an important avenue of research are consistent with the suggestion that the effect aimed toward prevention and cure of these of hypoxia on the release of ADH is dependent diseases. Lack of an animal model displaying on the level of hypoxia. these responses, and the present inability to use certain drugs in human studies has impaired

17 progress.With eventualdevelopmentof ANF 35 yr (group 2) on normal and low-salt diets by antagonists,andapprovalto useADH having the subjects breathe hypoxic gas. The antagonists,moreinsightinto thesehigh fractional inspired O 2 of the hypoxic gas was altitudeafflictionswill beobtained. regulated so that group 1 hemoglobin saturations fell to 90% for 1 h. Group 2 46. Claybaugh JR, CE Wade, AK Sato, subjects had desaturation to 90% for 1 h SA Cucinell, JC Lane and JT followed by desaturation to 80% for a 2"d h. Maher. Plasma renin activity (PRA), angiotensin- Antidiuretic hormone responses to converting enzyme activity (ACE), and plasma eucapnic and hypocapnic hypoxia in cortisol levels did not change during humans. hypoxemia. Plasma aldosterone levels fell in Journal of Applied Physiology 53:815- both groups during the 1st h of hypoxemia. 823, 1982. Decreases were greatest during salt restriction Authors' Abstract and were significant (P<0.01) for the combined Urinary excretion rate of antidiuretic groups. Plasma aldosterone levels plateaued hormone (UAD HV) was studied in male during the 2 ndh of more severe hypoxemia in volunteers in response to hypobaric hypoxia. group 2. Hepatic blood flow, measured by The first series consisted of three groups. The indocyanine green , and the adrenal chamber was decompressed to 465,495, and response to exogenous adrenocorticotropic 438 Torr during high-altitude (HA) exposure hormone, measured by changes in plasma cortisol and aldosterone, were not changed by for groups I (n = 5), II (n = 5) and III (n = 4), hypoxemia in group 2 subjects. These results respectively. In group I, the chamber air indicate that plasma aldosterone falls during contained 3.77% CO 2 to prevent alkalosis. The hypoxemia despite unchanged PRA, ACE, level of hypoxemia was similar in groups I and hepatic blood flow, and adrenal function. II. Mean 24-h UAt)H was unchanged in group I, but increased 96% (P<0.05) and 180% 48. Colice GL and G Ramirez. (P<0.05) in groups II and III, respectively, on Aldosterone response to angiotensin II day 1 at HA and was normal during subsequent during hypoxemia. days at HA regardless of symptoms of acute mountain sickness. Shorter sampling intervals Journal of Applied Physiology 61:150- 154, 1986. employed in a second series of experiments conducted at 495 Torr revealed a twofold Authors' Abstract Exercise in humans causes increases in increase in UADH"V"(P<0.05) 8-12 h after plasma renin activity (PRA) and plasma ascent in eight asymptomatic subjects; UAOH aldosterone concentrations (PAC) except when returned to base line within 9 h and remained performed at high altitude or while the subjects low. The symptomatic subjects both had breathe hypoxic gas. Under those conditions, increased UAt_H_" (3- and 8-fold from base PRA increases with exercise but PAC does not. line) between 2 and 4 h after ascent. Increased We speculated that the PAC suppression during UADH'v" in asymptomatic subjects may be a hypoxemic exercise was due to hypoxemia- induced release of a circulating inhibitor of result of the concomitant decrease in plasma volume, both of which appeared to be angiotensin H-mediated aldosterone secretion. eliminated by CO 2 supplementation. To test this hypothesis, we measured the PAC response to graded infusions of angiotensin II 47. Colice GL and G Ramirez. during hypoxemia and normoxemia. Eight Effect of hypoxemia on the renin- normal volunteers were given increasin_ doses angiotensin-aldosterone system in of angiotensin II (first 2 ng• kg ' • min and humans. then 4, 8, and finally 12 ng' kg _ • min _, each Journal of Applied Physiology 58:724- for 20-min periods) on 2 separate days, once 730, 1985. while breathing room air and the other day Authors' Abstract while breathing hypoxic gas adjusted to maintain the subjects' hemoglobin saturation at Hypoxemia was induced in five subjects 90%. The PAC response to different doses of older than 40 (group 1) and five younger than

18 angiotensinII did notsignificantlydiffer during 50. Consolazio CF, HL Johnson and hypoxemiafrom normoxemia.Weconclude HJ Krzywicki. thatour modelof hypoxemiadoesnotcause Body fluids, body composition, and releaseof aninhibitor of angiotesinN-mediated metabolic aspects of high-altitude aldosteronerelease. adaptation. In: Physiological Adaptations-Desert 49. Consolazio CF, LO Matoush, H and Mountain, edited by MK Yousef, Johnson and TA Daws. SM Horvath and RW Bullard. New Energy, nitrogen, and water York: Academic Press. Chap. 16, requirements on normal adults residing 1972. p.227-241. at 4,300 m for 28 days. Authors' Abstract Denver, CO: Fitzsimons General Anorexia accompanied by body weight Hospital. losses and negative water and nitrogen balances U.S. Army Medical Research and were observed in the 1964 and 1967 studies. Nutritional Laboratory Report In the 1967 and 1968 studies, AMS was No.308, July, 1967.22p. drastically reduced. The dally caloric Authors' Abstract consumption in human subjects can be Balance studies were conducted on three maintained after abrupt exposure to high groups of young, healthy adults between the altitude, providing the men have reduced ages of 18-24 years. After control studies, severity of AMS and are in good physical Group I was taken to 4,300 meters gradually, condition prior to and during altitude exposure. Group II was taken to 4300 meters abruptly, This study indicates that (a) positive nitrogen and Group llI remained at sea level during the balances can be achieved during altitude entire study. One-half of each group was exposure; (b) body weight losses can be greatly physically conditioned. No significant reduced; (c) mineral balances are positive; (d) differences were observed in nitrogen, and blood electrolyte levels are normal; and (e) fluid balances between (a) the groups that were fasting levels and glucose tolerance taken to altitude gradually or abruptly, or (b) curves are normal. Normal digestion and between the groups that were physically absorption occurred during acute altitude conditioned, and those who did not exercise. exposure. It appears that many of the As a result, the respective groups were biochemical changes that occur during abrupt combined for comparative purposes. high altitude exposure, previously attributed to Three factors were prominent during the hypoxia, may be the result of anorexia and the 28-day high altitude exposure to 4300 meters subsequent caloric restriction. that included (a) a decrease in food intake Since total body water and intracellular which is probably due to anorexia caused by water are significantly decreased during acute the clinical symptoms, (b) a negative nitrogen altitude exposure, it appears that hypohydration balance which may be due to the decreased and a natural diuresis occurs. This appears to nutrient intake and the increased requirement be an adaptive mechanism that may reduce for energy, and (c) a negative due cerebrospinal pressure, and cerebral edema, the to involuntary dehydration and other presence of which reduces the severity of undetermined factors. These factors appeared AMS. The severity of AMS during abrupt to be somewhat less in Group I who ascended altitude exposure can be greatly reduced to altitude gradually, and suggests the without the use of drug therapy. The following beneficial effects of ascending to high altitude conditions appear to be highly beneficial; (a) gradually. heavy physical activity and physical These and other related problems require conditioning prior to altitude exposure; (b) the considerable investigation in the near future. consumption of a minimal quantity of carbohydrate (at least 320 gm/day), (c) the maintenance of a normal food intake at altitude, and (d) a natural "cold" diuresis, with a subsequent decrease in total body water and intracellular water.

19 (age, 35.0 +1.8 years) by history and physical 51. Consolazio CF, LO Matoush, HL examination and was confirmed by a Johnson and TA Daws. characteristic chest radiogram showing alveolar Protein and water balances of young infiltrates associated with a normal cardiac adults during prolonged exposure to silhouette. Five healthy age- and sex-matched high altitude (4,300 meters). subjects with similar physical activity at the The American Journal of Clinical same altitude served as controls. Plasma Nutrition 21:154-161, 1968. sodium was 135.0 +1.5 mmol/L in the acutely Authors' Abstract ill patients compared with 144.0 +_3.3 mmol/L Balance studies were conducted on three in the controls (P<0.025). Mean plasma atrial groups of young healthy adults between the natriuretic factor immunoreactivity averaged ages of 18 and 24. After control studies, group 17.6 +_.5.6pmol/L in patients with high-altitude 1 was taken to 4,300 m gradually, group 2 was pulmonary edema compared with 6.8 _+0.7 taken to 4,300 m abruptly, and group 3 pmol/L in the controls at the same altitude remained at sea level during the entire study. (P<0.05). Elevated atrial natriuretic factor One-half of each group was physically levels normalized to 7.5 +1.9 pmol/L (P<0.05) conditioned. No significant differences were during recovery in Denver (altitude, 1600 observed in nitrogen and fluid balances meters) 24 hours later. Plasma arginine between a) the groups that were taken to vasopressin levels were 1.8 _+0.37 pmol/L in altitude gradually or abruptly, or b) between the patients with high-altitude pulmonary edema at subgroups that were physically conditioned and diagnosis compared with 0.92 _+0.28 pmol/L in those who did not exercise. The exercisers and controls (P--0.07). The inappropriately nonexercisers in each group were combined for elevated arginine vasopressin levels decreased statistical comparisons. to 1.29 _+0.37 pmol/L during recovery The two factors which were prominent (P<0.025), but the lowered plasma sodium during the 28-day high-altitude exposure to concentration had not normalized by discharge 4,300 m by groups 1 and 2 were a) negative within 24-hours of transfer to Denver and nitrogen balances which may have been due to averaged 135.8 +1.2 mmol/L. The the decreased utilization of protein and the pathophysiologic implications of these findings increased requirement for energy, the possible are discussed. decrease in protein synthesis at altitude, or a combination of these; and b) negative fluid 53. Cunningham WL, EJ Becker and F balances due to involuntary dehydration and Kreuzer. other undetermined factors. The negative Catecholamines in plasma and urine at nitrogen balance appeared to be somewhat less high altitude. in group 1, which ascended to altitude Journal of Applied Physiology 20:607- gradually, and this suggests the beneficial 610, 1965. effects of ascending gradually to high altitude. Authors' Abstract Group 3, which remained at sea level during The concentration of free epinephrine and the entire study, was in nitrogen and fluid norepinephrine in plasma and 24-hr urine balance during the entire study. samples, collected from members of the Dutch Monte Rosa expedition (July 1963) was 52. Cosby RL, AM Sophocles, JA investigated during 17 days at various altitudes Durr, CL Perrinjaquet, B Yee up to 4,560 m. The results indicate that the and RW Schrier. levels of both plasma and urine catecholamines Elevated plasma atrial natriuretic factor were elevated during the expedition, the plasma and vasopressin in high altitude levels reaching a maximum towards the end of pulmonary edema. the 12 days sojourn at 4,560 m. In general there was a twofold increase in total Annals of Internal Medicine 109:796- 799, 1988. catecholamine concentration in the samples Authors' Abstract collected at high altitude as compared to control A diagnosis of acute high-altitude values at sea level. This difference was due to pulmonary edema was made in five male skiers a significant increase in the norepinephrine

20 concentration;therewaslittle changein comparison. Since CV did not change at epinephrinelevel. altitude, Hct Vvalues obtained on eight occasions at altitude were used to calculate PV 54. Delamare JP. at altitude. The mean Hct v increased 3.7% at Birmingham Medical Research altitude, which corresponds to a decrease of Expeditionary Society 1977 Expedition: 6.6% in PV. The mean decrease in body Changes in renal function observed weight, BW, was 21. In the runners BV in during a trek to high altitude. relation to BW was 21% greater than in 48 Postgraduate Medical Journal 55:487- non-athletes. Approximately one-third of this 491, 1979. larger BV is accounted for by the lower body Authors' Abstract fat of the runners. Cell volume, PV and total Changes in renal function were observed in Hb, all in relation to BW, were greater in the 17 subjects during the course of a trek to high runners than in the non-athletes by 18, 24, and altitude. Comparison was made between these 16%, respectively. Consistent with the changes and the clinical assessment of acute difference in PV and in CV, Hb concentration mountain sickness (AMS). was 4% lower in the runners. It is concluded Periods of natriuresis occurred during that endurance athletes have thin blood, but so ascent and descent, that during ascent being much of it that their total Hb exceeds that of related to a fall in plasma aldosterone. non-athletes. Aerobic power was dependent in Alterations in serum and urinary potassium part on Hb/kg not only in the runners but also suggested that potassium retention occurred in gift swimmers. during the ascent to altitude. No significant correlation occurred between 56. Dill DB, FG Hall, KD Hall, C changes in renal function and the severity of Dawson and JL Newton. AMS before the illness being clinically Blood, plasma, and red cell volumes: apparent. When this was so, the severity of age, exercise, and environment. AMS correlated with a decreasing urine output, Journal of Applied Physiology 21:597- increasing positive fluid balance and a 602, 1966. decreasing excretion of sodium and potassium; Authors' Abstract these changes were produced in part by a Observations have been made on blood decrease in glomerular filtration rate. components of seven men in the hot desert and on two of them at 3,800 m 1 week after leaving 55. Dill DB, K Braithwaite, WC the desert. Similar observations made in the Adams and EM Bernauer. desert on Dill 32 years before are recorded. No Blood volume of middle-distance notable change occurred in blood components runners: effect of 2,300-m altitude and at rest during the fn'st days in the desert; even comparison with non-athletes. in a bout of exercise there generally were no Medicine and Science in Sports and changes. In two men who engaged in frequent Exercise 6:1-7, 1974. strenuous exercise during a 5-week period, Authors' Abstract their was a decline in total red cell volume and Concurrent with the study of performance an increase in plasma volume with no change in and aerobic power of 12 highly trained, blood volume. These two men, Phillips age 34 superior middle-distance runners before, and Dill age 73, then made the transition to the during and after 3 weeks of strenuous training Barcroft laboratory with a decrease in at 2,300-m altitude, observations were made barometric pressure from 694 to 485 mm Hg pre- and post-altitude on blood volume, BV, and in maximum temperature from above 40 tO plasma volume, PV, cell volume, CV, about 15 C. Phillips showed an increase in hematocrit, Hct V,and the concentration and hemoglobin concentration and a decrease in amount of hemoglobin, Hb. For comparative plasma volume. Dill had a decrease in purposes, the same componenets were hemoglobin concentration and an increase in measured in 21 non-athletic young men at or plasma volume. In the light of this and other near sea level. Similar data on 27 black and evidence it appears that the response of plasma white sharecroppers also were available for volume in the first clays at high altitude is to

21 declinein youthandto increasein age. From neutralize fixed acids. The increase in age41 to age73,Dill's plasmavolumehas hemoglobin and decrease in alkaline reserve decreasedaboutone-sixthandredcell volume occur slowly; months may be required for about6%. hemoglobin to reach a maximum and arterial CO: content, a minimum. 57. Dill DB, SM Horvath, TE Dahms, The electrolytes of serum at high altitude RE Parker and JR Lynch. were found to undergo one major change, Hemoconcentration at altitude. whether measured in milli-equivalents or in per Journal of Applied Physiology 27:514- cent of the sea-level value. This is the decrease 518, 1969. in bicarbonate. At 5.34 km. this may be 8 Authors' Abstract milli-equivalents, while the CI increase is 4 Concentration of hemoglobin in blood milli-equivalents and the Na decrease, 2 milli- ((Hb)b), blood volume (BV), and related equivalents, leaving an unexplained anion observations were made on 12 men, aged 18 to deficit of about 2 milli-equivalents. Other ions 77 years, during 2-6 weeks at 3,800 m. are remarkable for their stability. Concentration of hemoglobin in red cells A synthetic description is given of the ((Hb)c) and red cell volume (CV) remained blood of fully adapted workmen living at 5.34 constant at altitude although in some men CV kin. and working at 5.80 kin. increased postaltitude. With (Hb)c and CV constant, plasma volume (PV) could be 59. Durkot M J, RW Hoyt, A calculated from (Hb) b. Mean (Hb) b increased Darrigrand, LJ Hubbard, GH 17% in 2 weeks; PV decreased. However, in Kamimori and A Cymerman. Dill, aged 77 years, during the first week (Hb)b Chronic hypobaric hypoxia decreases decreased and PV increased and in ERN, aged intracellular and total body water in 26 years, (Hb)b was nearly unchanged for 8 microswine. days. Neither increases nor decreased in (Hb) b Comparative Biochemistry and correlated with changes in body weight which Physiology 114A:117-121, 1996. presumably reflected changes in body water. Authors' Abstract While concentration of plasma protein (P)s The effects of hypobaric hypoxia on body generally increased in the first weeks at fluid distribution were studied in five altitude, total plasma protein did not change unanesthetized immature microswine (body consistently. Within 24 hr postaltitude (Hb) b, weight 17.1 +1.5 kg, mean +SEM) at sea level PV, and (P)s returned to, or nearly to, and after 23 days of simulated altitude exposure prealtitude values. (427 Torr, 4600 m, 24°C, 50% RH). Total body water (TBW), volume 58. Dill DB, JH Talbott and WV (ECF), and plasma volume (PV) were Consolazio. determined with D:O, NaBr, and indocyanine Blood as a physicochemical system. green, respectively. Intracellular fluid volume XII. Man at high altitudes. (ICF = TBW - ECF) and interstitial fluid Journal of Biological Chemistry volume (ISF = ECF - PV) were calculated. 118:649-666, 1937. Hypoxia resulted in characteristic decreases Authors' Abstract (P<0.05) in arterial PO 2 and PCO 2, and an The distribution of combined CO 2 between increase in hemoglobin concentration. Chronic arterial cells and serum is unchanged at high exposure to hypobaric hypoxia elicited altitudes aside from the responses due to significant (P<0.05) decrements in body changes in pH and per cent saturation with weight gain (-14%), TBW (-11%, 12.5 vs oxygen. There appears to be a decreased 11.3 L), ICF volume (-13%, 8.9 vs. 7.8 L) proportion of chloride in cells (Fig. 1). Owing and PV (-28%, 0.82 vs. 0.57 L). Although the to increase in the proportion of red cells, the ECF was unaffected (3.66 vs. 3.57 L), the ISF buffer value of blood is increased; the pH, was significantly increased (+6%, 2.83 vs. change in the respiratory cycle is one-fourth 3.22 L) (P<0.05). Decreased TBW accounted less. At the same time the decreased alkaline for 51% of the expected reduction in body reserve reduces the capacity of the body to mass. These results suggest that the

22 suppressionin bodyweightgainis partially during hypoxia were significantly elevated after accountedfor by decreasesin TBW, ICF, and 114 and 84 min (3,000 and 4,000 m), rising PV. In addition,theapparentelevationof ISF thereafter continuously for the period occurring concurrently with decreases in ICF investigated. Mean values increased from 16.0 and PV may be related to the development of to 22.5 mU/ml (3,000 m) and from 16.7 to edema, which can accompany exposure to high 28.0 mU/ml (4,000 m). This rise in EPO altitude. levels corresponds to 1.8-fold (3,000 m) and 3.0-fold (4,000 m) increases in the calculated 60. du Souich P, C Saunier, D production rate of the hormone. After Hartemann, A Sautegeau, H termination of hypoxia, EPO levels continued Ong, P Larose and R Babini. to rise for 1.5 h and after 3 h declined Effect of moderate hypoxemia on atrial exponentially with an average half-life time of natriuretic factor and arginine 5.2 h. vasopressin in normal man. Biochemical and Biophysical 62. Eckardt K-U, J Dittmer, R Research Communications 148:906- Neumann, C Bauer and A Kurtz. 912, 1987. Decline of erythropoietin formation at Authors' Abstract continuous hypoxia is not due to feedback inhibition. The object of this study was to assess the effect of moderate acute hypoxemia on plasma American Journal of Physiology concentrations of atrial natriuretic factor 258:F1432-F1437, 1990. (ANF), arginine vasopressin (AVP), plasma Authors' Abstract renin activity (PRA) and urinary excretion of Serum erythropoietin (EPO) levels in response to hypoxia are known to decline E 2 (UpcE2 V). Eight volunteers before an increase in blood oxygen carrying were exposed for 2 hours to a gas mixture capacity. To define the possible mechanisms containing 10% 02 4.5% CO 2 and 85.5% N 2. underlying this phenomenon, we have Hypoxia increased cliastolic blood pressure and investigated 1) how renal EPO mRNA content free water clearance. Hypoxia did not change and EPO production rate underlying the early the AVP, PRA, or UprE2 V, although increased kinetics of serum EPO levels change under ANF from 17.7 +3.4 pg/ml to 27.2 +_1.7 pg/ml different degrees of normobaric hypoxia, and (p<0.005) at 120 minutes. ANF changes were 2) if a feedback inhibition of either EPO closely associated with the rise in blood formation or EPO survival in the circulation pressure. exists by the hormone itself. We found that serum immunoreactive EPO levels in rats 61. Eckardt K-U, U Boutellier, A peaked after 12-h exposure to 7.5 or 9% Kurtz, M Schopen, EA Koller oxygen (2,949 +600 and 756 +_108 mU/ml, and C Bauer. respectively, mean +_SE) and declined to 29 and Rate of erythropoietin formation in 64% of peak levels, respectively, after 36 h of humans in response to acute hypobaric hypoxia. EPO levels in response to 11.5% hypoxia. oxygen showed no consistent change between Journal of Applied Physiology 12 (122 +_21 mU/ml, mean +SE) and 36 h (182 66:1785-1788, 1989. +_35 mU/ml) of hypoxia. The decline in EPO Authors' Abstract levels under severe hypoxia (7.5% 02) was This study was carried out to investigate the paralleled by a marked reduction in renal EPO early changes in erythropoietin (EPO) mRNA content, indicating that it was primarily formation in humans in response to hypoxia. a result of diminished hormone production. Six volunteers were exposed to simulated The observed reductions in serum EPO after 36 altitudes of 3,000 and 4,000 m in a h corresponded to preceding declines of decompression chamber for 5.5 h. EPO was calculated EPO production rates from 163- to measured by radioimmunoassay in serum 62-fold (7.5% 02) and 36- to 25-fold (9% 02) samples withdrawn every 30 min during basal values. Application of 50 IU altitude exposure and also in two subjects after recombinant human EPO to rats 12 h, 6 h, or termination of hypoxia (4,000 m). EPO levels

23 immediatelybeforehypoxicexposuretomimic oxygen at reduced total barometric pressure theearlyincreasein EPOlevelsdidnotaffect (258 mmHg) (hyperoxia) on plasma renin endogenousEPOformationduringa activity (PRA), urinary aldosterone excretion subsequenthypoxicexposureof 12h. These (AER), and sodium homeostasis were assessed resultsindicatethattheearlydecreasein EPO in eight normal male subjects. Renal sodium productionatcontinuoushypoxiaisnot conservation during hyperoxia, as assessed by mediatedby anegativefeedbackcontrol days to balance following dietary sodium throughtheeffectof EPOonits production restriction, was similar to control (3.4 _+0.3 vs. sitesor targetceils. Althoughthereductionin 3.1 _+0.2 days) (P>0.05). Renin-aldostersone EPOproductionrateoccursindependentof the responsiveness following dietary sodium amountof EPOproduced,themagnitudeof the restriction during hyperoxia did not differ from declineappearstobe relatedto thedegreeof the control. These data suggest that the decrease in precedingstimulation. AER during high-altitude exposure is attributable to a decrease in partial pressure of 63. Epstein M and T Saruta. oxygen rather than a reduction in barometric Effects of simulated high altitude on pressure per se and that the hyperoxic renin-aldosterone and Na homeostasis hypobaric atmosphere currently utilized in in normal man. manned space flight does not contribute to the Journal of Applied Physiology 33:204- disturbance in sodium and fluid homeostasis 210, 1972. regularly observed during manned orbital Authors' Abstract missions. The effects of chronic exposure to an environment of a reduced barometric pressure 65. Farber MO, M Heyes, D (258 mm Hg) without concomitant hypoxia Robertshaw, G Robertson and M (hypobaria) on plasma renin activity (PRA), Weinberger. urinary aldosterone excretion (AER), and Renal and endocrine responses to sodium, potassium, and fluid homeostasis hypoxia and hypobaria. were assessed in eight normal male subjects. Clinical Research 28:720A, 1980. Following dietary sodium restriction, sodium (Abstract) balance was attained more rapidly during Authors' Abstract hypobaria than during control (Na tit 2= 0.57 The effect(s) of hypoxia on renal and vs 0.70 days) (P<0.05) with a smaller endocrine function in man have remained ill- decrement in body weight (-1.1% vs -2.6%) defined. 4 groups of normal subjects were (P<0.001). Creatinine clearance decreased studied under conditions of H20 diuresis. Gp I progressively throughout hypobaria, with the (controls) n = 5; Gp II (Hypoxic Hypobaria, decrease approximating 40% by day 8. Renin- barometric pressure (PB = 400 Torr) n = 14; Gp aldosterone responsiveness following dietary III (Hypoxic Normobaria, 10.5% O 2) n = 4; sodium restriction was unimpaired during Gp IV (Normoxic Hypobaria, PB = 400 Ton-, hypobaria. These data suggest that hypobaria 40% 02) n - 4. Experimental exposures were alters sodium homeostasis by establishing a 1 hour. Parameters monitored included: urine new steady state of sodium balance which may volume (Uv), osmolality, sodium; plasma be mediated in part by a decrease in the filtered arginine vasopressin (AVP), cortisol (Cort), load of sodium. renin, aldosterone, prolactin (Prl), osmolality, sodium; blood pressure (MAP); blood gases. 64. Epstein M and T Saruta. Group II showed 2 distinct responses: A, Effects of an hyperoxic hypobaric maintained diuresis and slight drop in MAP; B, environment on renin-aldosterone in marked antidiuresis and much greater drop in normal man. MAP. Pertinent data (hypoxic values, % of Journal of Applied Physiology 34:49- respective controls); 52, 1973. l_0Y.8 Uosm AVP Cort Prl MAP Authors' Abstract HAn=7 97 83 98 131" 90" liB n=7 38' 251" 22044" 220" 236" 82" The effects of chronic exposure to a simulated spacecraft environment of 100% 'p<0.05

24 There was a positive correlation between fail in 67. Fenn CE. MAP and AVP increase. Highest AVP's Energy and nutrient intakes during (>5000%, n = 2) were associated with nausea, high-altitude acclimatization. but significant elevations were observed in the Journal of Wilderness Medicine remaining non-nauseated subjects. In Group 5:318-324, 1994. Ill 2/4, with the greatest fall in MAP, Author's Abstract responded similarly to IIB subjects but Prl did Information on the food intake of free not increase in any. Group IV subjects living individuals during the initial stage of an responded as controls. These data suggest: 1) expedition, when the diet is based on fresh and antidiuresis during hypoxia may be mediated locally available foods, is scarce. A weighed through AVP stimulation caused by either dietary survey was carried out by 10 healthy nausea or large falls in MAP; 2) hypoxic unacclimatized male subjects who walked from hypobaria is a more potent stimulus of Prl an altitude of 2430 m to Everest Base Camp release than a comparable level of hypoxic (5400 m) in 10 days. All food and fluids normobaria; 3) increases in Prl during hypoxia consumed during the study period were exert no measurable effect on H20 diuresis. weighed using dietary scales and recorded in food record books. The mean daily energy 66. Faura J, J Ramos, C Reynafarje, E intake was 10.03 (SE 1.26) MJ. The average English, P Finne and CA Finch. body weight loss was 2.07 (SE 0.6) kg and Effect of altitude on erythropoiesis. there was no change in percentage body fat Blood 33:668-676, 1969. calculated from skinfold thickness Authors' Abstract measurements. The percentage energy from Measurements were made to characterize carbohydrates in the diet was significantly the relationship between erythropoietin output higher (p<0.05) in the final 3 days (59%, SE and erythropoiesis in two groups of subjects, 2.0) compared with the first 3 days of the study one moved from a sea level habitat to high period (51%, SE 3.6). It is likely that the high altitude, and the second moved from a high carbohydrate intake reflected the availability of altitude habitat to sea level. In the first group, foods at this time. With the exception of folic there was a latent period of 6 hours followed acid and vitamin C, the mean daily intakes of B by a rapid increase in erythropoietin, and a vitamins, iron, and zinc exceeded the UK secondary fall to a level of approximately twice Dietary Reference Values. However, these normal. The increased erythropoietin stimulus values refer to healthy populations but not to was also reflected in a shortened marrow those exposed to high altitude when nutrient radioiron transit time. In the second group, requirements may be increased. there was an initial unexplained rise, after which erythropoietin fell within 8 hours to 68. Fletcher RF. undetectable amounts. Birmingham Medical Research Elevated erythropoietin was associated in Expeditionary Society 1977 expedition: Group I with an increased iron uptake within Signs and symptoms. 24 hours of the stimulus, suggesting a direct Postgraduate Medical Journal 55:461- action of erythropoietin on hemoglobin 463, 1979. synthesis by the existing marrow population. Author's Abstract Limitation in erythropoiesis to a rate of less The BMRES group of 17 persons is than twice normal was tentatively explained by described and details are given of the trek to a restricted iron supply. In the second group, 5400 m. The research programme is outlined. marrow activity continued for 3 days despite a Moderately severe acute mountain sickness marked fall in erythropoietin, indicating that (AMS) was observed in 5 subjects. All cells in the maturation phase completed their subjects were rated according to their normal development. symptoms related to AMS by interview, peer review and self-assessment, and the results compared.

25 69. Forsling ML and JS Milledge. 19.5 g/100 ml on the third day. At 17,500 ft Effect of hypoxia on vasopressin renin, aldosterone and cortisol were release in man. significantly elevated on day 3 but had returned Journal of Physiology (London) to control levels by day 5. Sodium and 267:22-23, 1977. potassium excretion was significantly reduced Annotation at both altitudes. Total body water, Purpose extracellular and plasma volumes were reduced To observe vasopressin release during (P<0.05) at 17,500 ft. Subjects pretreated with laboratory induced hypoxia and to investigate acetazolamide and flown directly to 17,500 ft hypoxia induced oliguria leading to pulmonary had significant increases (P<0.001) in plasma oedema. renin, aldosterone, and cortisol levels during Methods the first 4 days at altitude. On day 1 there was a decrease of 45% in sodium and 38% in Five male subjects known to acclimatize well at high altitude were observed during potassium excretion. One day 4 there was a delivery of 10.0-10.5% O 2 via RAF mask. decrease of 63% and 51%, respectively. These Subjects were observed at baseline and after 4 changes are not associated with the hr of O 2 delivery. Blood samples were premedication. The initial changes may reflect collected via a catheter at hourly intervals and at the immediate response to stress and alkalosis 3, 9, and 27 min after staring hypoxia (urine followed by a return to control levels as the was passed every 20 min). Subjects were body adapts to altitude. returned to air breathing via the RAF mask for 90 rain. 71. Fulco CS, A Cymerman, NA Results Pimental, AJ Young and JT Maher. Little change was observed in vasopressin release during hypoxia (0.1 _+0.15 U/ml, n = Anthropometric changes at high altitude. 26) compared to the baseline (0.7 _+0.17 U/ml S.E.M., n = 10). Urine flow was maintained Aviation, Space, and Environmental during hypoxia with the ratio of urine to plasma Medicine 56:220-224, 1985. osmolarity remaining above one for only two Authors' Abstract subjects. Plasma pH showed no significant Eight white males (18-25 yr) were change and urinary pH increased by 0.18 evaluated before, during and after 18-d _+0.06 (n = 4) during the experimental period. residence on the summit of Pikes Peak, CO Conclusion (4300 m; high altitude, HA) to describe the For subjects who acclimatize well at high anthropometric changes associated with weight altitude, hypoxia has little effect on vasopressin loss and to test the accuracy of a number of release. previously published prediction equations in assessing any alteration of the relative fat-to- lean tissue ratio during exposure to HA. Body 70. Frayser R, ID Rennie, GW Gray weight (BW), 10 circumference (C), and 7 and CS Houston. skinfold (SF) measurements were obtained Hormonal and electrolyte response to preprandial at sea level (SL) and on days exposure to 17,500 ft. 2,4,6,9,12,16 and 18 at HA. Body density Journal of Applied Physiology 38:636- was estimated by hydrostatic weighing (HW) 642, 1975. pre- and post-HA. BW differed from SL Authors' Abstract (p<0.01) after day 9 at HA. HW indicated that the pre- to post-HA weight loss was partitioned Hormone, electrolyte, and body fluid into a 2.06 kg loss in fat-free body mass compartment changes were studied in subjects (p<0.001) and an insignificant increase in fat who either spent time at 10,000 ft before flying wt (0.58 kg). Percent body fat (BF) increased to 17,500 ft, or were premedicated with from 16.6 to 17.7 (p<0.02). After day 9 of acetazolamide and flown directly to 17,500 ft. HA, the sum of SF and C measurements In the former group at 10,000 ft, renin and aldosterone were not different from control. increased (p<0.02) and decreased (p<0.05) from SL, respectively. The largest changes Cortisol increased significantly from 9.8 to

26 occurredin thechestandscapulaSF andin the 73. Fusch C, W Gfr6rer, C Koch, A C of thehip, neck,calf, andtwo abdominal Thomas, A Griinert and H sites. Thealterationsin triceps,waist,andtotal Moeller. SFwererelatedto theincreasein fat weight Water turnover and body composition andBF ( r >0.71). Thedecrementsin Cwere during long-term exposure to high relatedonly to thelossin BW (r >0.83). altitude (4,900-7,600 m) Basedon thelack of concurrencewith the Journal of Applied Physiology resultsfrom thehydrostaticweighings,it was 80:1118-1125, 1996. concludedthatSF andC measurementsand/or Authors' Abstract predictionequationsdonotprovideanaccurate Thirteen healthy subjects (11 men and 2 assessmentof thealteredfat-to-leanratio women; 30.2 +5.4 yr; 73.5 +10.3 kg; 178.9 during weightlossathigh altitude. +10.4 cm; body mass index, 22.9 +1.6 kg/m 2) participated at the 62-day expedition to Broad 72. Fulco CS, RW Hoyt, CJ Baker- Peak (8,047 m), Pakistan. Weight, body Fulco, J Gonzalez and A water, and water turnover (deuterium dilution Cymerman. and elimination) were measured eight times to Use of bioelectrical impedance to assess assess long-term changes. Body weight fell body composition changes at high during the ascent to the base camp [from 73.2 altitude. _+9.8 (baseline) to 71.7 _+9.7 kg; P<0.05] and Journal of Applied Physiology decreased until the end of the base camp stay 72:2181-2187, 1992. (66.7 +7.2 kg; P<0.001). Body compartments Authors' Abstract changed at different rates. Total body water This study determined the feasibility of decreased during the ascent (from 43. i +7.3 to using bioelectrical impedance analysis (BIA) to 41.0 +7.7 liters; P<0.05) and remained assess body composition alterations associated unchanged until the base camp was reached with body weight (BW) loss at high altitude. (41.2 +6.9 liters; P<0.01), but decreased The BIA method was also evaluated relative to further during the base camp stay (40.6 +_5.2 anthropometric assessments. Height, BW, liters). Water content of the body (total body BIA, skinfold (SF, 6 sites), and circumference water-to-body weight ratio) fell during the (CIR, 5 sites) measurements were obtained ascent (from 58.6 +3.4 to 55.8 +4.4%; from 16 males (23-35 yr) before, during, and P<0.01), approached the baseline value during after 16 days of residence at 3,700-4,300 m. the base camp (57.4 +4.0 and 58.3 +5.1%), Hydrostatic weighings (HW) were performed and increased again until the end of the base pre- and post-altitude. Results of 13 camp (60.6 +3.4 and 60.9 +4.3%). The previously derived prediction equations using compartment of the solids increased during the various combinations of height, BW, age, ascent (from 30.2 +3.4 to 32.2 +4.9 kg; BIA, SF, or CIR measurements as independent P<0.01) and approached the baseline value on variables to predict fat-free mass (FFM), fat arrival at the base camp (30.5 +4.7 kg). Until mass (FM), and percent body fat (%Fat) were the end of the base camp, the compartment of compared with I--IW. Mean BW decreased the solids fell (26.9 +_2.6 and 26.1 +4.0 kg), from 84.74 to 78.84 kg (P<0.01). As indicating that weight loss was due to a loss of determined by HW, FFM decreased by 2.44 kg body solids, presumably mostly fat mass. (P<0.01), FM by 3.46 kg (P<0.01), and %Fat Water turnover during the pretest period (sea by 3.02% (P<0.01). The BIA and SF methods level) was 45 +7 ml kg -_ • dayt; it increased overestimated the loss in FFM and during the ascent (56 +11 and 60 +10 ml" kg t underestimated the losses in FM and %Fat day t ) but remained constant during the base (P<0.01). Only the equations utilizing the CIR camp stay (63+_12,58:tg, axt56+10rri" kg _" dayt). measurements did not differ from HW values It increased during the ascent to Broad Peak for changes in FFM, FM and %Fat. It was (73 +_20 ml" kg t ' dayt; P<0.05) and even concluded that the BIA and SF methods were more during the descent to civilization (83 +_17 not acceptable for assessing body composition ml' kg t • dayt; P<0.05). changes at altitude.

27 74. Galster WA and PR Morrison. bicarbonate utilizing a modified Astrup Effects of high altitude exposure on technique were normal. components of blood and urine in Is was concluded that the experimental mountaineers. atmosphere had no adverse effect on renal International Journal of function. Biometeorology 18:23-32, 1974. Authors' Abstract 76. Gotshall RW, DS Miles and WR Physiological correlations with impaired or Sexson. unimpaired performance at high altitude were The combined effects of hypoxemia and sought among 24 blood and urine parameters mechanical ventilation on renal measured in 50 mountaineers and 21 observers function. before (preclimb) and after (postclimb) Aviation, Space, and Environmental expeditions on Mt. McKinley. Values and per Medicine 57:782-786, 1986. cent changes were compared for five degrees of Authors' Abstract impairment at high altitude. Average preclimb The combined effects of hypoxemia and values were all near established normal levels mechanical ventilation on renal function were and no correlations with subsequent investigated in anesthetized dogs. involvement at high altitude were found. Spontaneously breathing dogs (S) and dogs Postclimb samples contained more Hb, PCV, mechanically ventilated with a volume- urea, LDH, and HBD and less bilirubin ventilator (V) were made hypoxemic by (P<0.05). But no association was found breathing hypoxic gas to achieve P_O 2 values of between degrees of altitude impairment and 35 and 22 mmHg. At a PaO2 of 35 mm Hg, preclimb/postclimb changes in any of the 24 urine output and sodium excretion were blood and urine parameters. Additional results increased in both groups. These responses from samples collected at 4300-m showed closely followed the blood pressure response, "weaker" mountaineers excreted 1/4 as much which was greater in the V group. Renal blood Na in urine and had 50% more serum FFA flow (RBF), glomerular filtration rate (GFR), concentration than stronger mountaineers. and fractional sodium excretion (FNA) were unchanged. At a PaO2 of 22 mm Hg, both 75. Glatte HV and CL Giannetta. groups demonstrated a reduction in urine flow, Study of man during a 56-day exposure sodium excretion, FNA, RBF, and GFR. to an oxygen-helium atmosphere at However, the mechanism involved was 258 mmHg total pressure. III. Renal different and ventilator-dependent. At this low response. PaO2 , arterial blood pressure was reduced in the Aerospace Medicine 37: 559-562, S group with no change in renal resistance, 1966. while blood pressure increased in the V group Authors' Abstract with a marked increase in renal resistance as a To assess the effects of helium on renal result of the modification of the cardiovascular function, four healthy Air Force officers lived effects of lung inflation reflexes by mechanical for 56 days in a space cabin simulator with a ventilation. These results indicate that renal partial pressure of oxygen of 175 mmHg and function is well-maintained at low PaO2 values helium of 74 mmHg at a total pressure of 258 (35 mm Hg) and reduced at more severe mmHg. hypoxemia, mainly in response to systemic All renal parameters measured during the hemodynamics. control and experimental periods failed to reveal any deviation from accepted normals. 77. Granberg P-O. Studies performed included renal Effects of acute hypoxia on renal hemodynamics utilizing inulin, PAH, and haemodynamics and water diuresis in endogenous creatinine clearances; concentrating man. and diluting tests; and 24-hour urinary Scandinavian Journal of Clinical and excretion of proteins. In addition, multiple Laboratory Investigation 14:Suppl. determinations of blood pH and standard 63:1-62, 1962.

28 Author's Abstract In the present investigations of the renal Earlier studies in man and animals function on man during water diuresis it was concerning the renal function in hypoxia are found that on acute hypoxia with a fall of highly contradictory. The reason for the arterial oxygen saturation to about 60 per cent: frequently divergent results is probably due to (1) the glomerular filtration rate fell more great differences in the methods and than the renal plasma flow; circumstances of the experiments. (2) the extraction of PAH did not fail; The present work is based on investigations (3) the renal oxygen consumption did not of a total of 53 subjects without evidence of perceptibly change; renal disease. During water diuresis in a (4) the urine flow declined markedly; recumbent position the subjects breathed 9 per (5) the decline in the urine flow was cent oxygen in nitrogen during 20 minutes. probably due partly to an increased The glomerular flitration rate (C_), renal secretion of antidiuretic hormone and plasma flow (CpAH) and urine flow were partly to reduced glomerular fdtration studied before, during and after the hypoxia rate; breathing. The arterial oxygen saturation and (6) the hypoxia and not the simultaneously carbon dioxide tension were determined during appearing hypocapnia was the cause of the experiments. the changes found. Thirty-four of the experiments were carried out in a similar way (basic hypoxia cases). In 78. Greenleaf JE, EM Bernauer, WC these the oxygen saturation fell on average to Adams and L Juhos.

64 per cent during hypoxia breathing, and at Fluid-electrolyte shifts and r_O 2 max in this degree of saturation C_ fell to 67 per cent man at simulated altitude (2,287 m). of the initial value. Cp_ remained largely Journal of Applied Physiology 44:652- unchanged. Urine flow declined markedly in 658, 1978 spite of continued hydration and at the end of Authors' Abstract the hypoxia period was 22 per cent of initial Six trained distance runners were studied value. It declined further after the hypoxia, during an 8-day dietary control (C) period at whereas the gl0merular filtration rate returned sea level (24 m, 758 Ton'), followed by 8 days to the initial value. at 2,287 m (576 Torr) in an altitude chamber In approximately half of the experiments (A), and 4 days recovery (R) at sea level. The the urine osmolality and in some subjects the purpose of the study was to determine whether plasma osmolality were determined. Uos M reduction in maximal oxygen uptake (VO 2max) increased during the hypoxia, but did not exceed the plasma level until after the hypoxia during early exposure to the reduction in Po: at period and on average rose only slightly above altitude is accentuated 1) by reduced plasma 400 mOsrn/kg H20 in spite of markedly volume (PV), or 2) to a more generalized reduced urine flow. In some cases Uos Mrose negative water balance. For 2 mo prior to the above 1000 mOsm/kg H20 whereas in others, study the men ran 15 km/day, and during the including one patient with diabetes insipidus, study ran 16 krn/hr for 1 h each day. Mean there was a marked decline of urine flow with +SE VO 2 max was 4.75 _+0.23 l/rain in C, 4.05 only slight increase of Uos M. _+0.22 l/rain at A (A = -14.7%, P<0.05), and Renal vein catheterization was carried out in 4.68 _+0.22 l/rain during R. Basal blood six subjects. EpAH rose during hypoxia in five volume, PV, and red blood cell (RBC) volume of these and was unchanged in one case. The were essentially constant during C and A, and renal oxygen consumption did not change there was no change in fluid balance at A. notably in these experiments when the arterial During maxkrnal exercise the mean calculated oxygen saturation fell. change (shift) of PV was -6% during C, but Comparisons of renal function at different increased to between -11% and -15% at A and oxygen saturations, and experiments with coincided with the reduction of- 13% to -15% hyperventilation of hypoxic gas and air support in 'VO2max. On the 1stday ofR (R+I) the view that the hypoxia and not the concomitant hypocapnia was the cause of the VO2 max returned to sea-level values, but A PV recorded changes.

29 wasstill -15%. However,thelatterreturnedto exposure, and again after the return to low controllevelson R+2. Theshift of plasmaNa, altitude. C1,andosmoticcontentsfollowedtheshift in There was a significant (35-57%) reduction PV, theK responsewasvariable,andtotal in total caloric intake at high altitude. Body proteinandHb contentshiftswererelatively weight decreased progressively, mainly due to stable(A = +4%). The exaggerated PV and a reduction in body fat. The subjects electrolyte shifts during maximal exercise at apparently remained in water balance, while the altitude perhaps reflect alterations in cellular nitrogen balance was always negative during membrane permeability, but neither amplified high altitude exposure. PV shifts nor negative water balance contribute The significant nutritional alterations were to the reduction in "(/0 2max at altitude. mainly observed above 6,000 m. They are discussed with respect to changes in feeding patterns and in hormonal status of the climbers 79. Grigor'yev A J, VI Korol'kov, GI accompanying hypoxia and other stressors Kozyrevskaya and MA Dotsenko. proper to high altitude. Effect of hypoxia on fluid-electrolyte metabolism and renal function in man 81. Gunga H-C, K Kitsch, F Baartz, H-J Steiner, P Wittels and L as related to different degrees of motor Riicker. activity. Fluid distribution and tissue thickness Kosmicheskaya Biologiya i changes in 29 men during 1 week at Aviakosmicheskaya Meditsina 5:10- moderate altitude (2,315 m). 14, 1979. European Journal of Applied Authors' Abstract Physiology 70:1-5, 1995. It was demonstrated that a prolonged (24 Authors' Abstract days) bed rest at altitudes of 2200 m and 3200 To quantify fluid distribution at a moderate m as well as at sea level was accompained by an increased renal excretion of fluids and altitude (2,315 m), 29 male subjects were studied with respect to tissue thickness changes osmotically active substances, including [front (forehead), sternum, tibia], changes of electrolytes. Exercises done during bed rest induced a smaller increase of the renal excretion total body water, changes of plasma volume, total protein concentrations (TPC), of sodium and potassium. However, as bed rest continued the differences between the osmotic pressure (COP), and electrolytes. Tissue thickness at the forehead showed a groups of test subjects disappeared. The levels significant increase from 4.14 mm to 4.41 mm of hypoxia and exercises used in the study 48 h after ascent to the Rudolfshuette (2,315 proved inefficient to prevent changes in the m) (P<0.05). At 96 h after ascent the tissue fluid-electrolyte metabolism occurring during thickness at the tibia was decreased to 1.33 mm bed rest. compared to the control value of 1.59 mm (P<0.01). Body mass increased from 75.5 kg 80. Guillard JC and J Klepping. (control) to 76.2 kg on the last day (P<0.05) Nutritional alterations at high altitude in and body water from 44.21 to 45.01 during the man. week (P<0.01). The accumulation fluid in the European Journal of Applied upper part of the body was paralleled by a Physiology 54:517-523, 1985. decrease in TPC and COP. At 48 h after the Authors' Abstract ascent COP dropped from 29.5 mmHg to 27.5 During the French 1980 Mount Pabil mmHg (P<0.01). After 96 h at moderate (7,120 m) Expedition, a study was made of altitude COP was still significantly decreased four altitude-acclimatised climbers (age 36.5 compared to the control level. At 1.5 h after _+3.6 years: _'O 2 max 50.5 +_3.1 ml kg_). the retum from the Rudolfshuette in Saalfelden Intake of various nutrients, body weight, (744 m) COP was back to the control values. skinfold thicknesses as indices of body The TPC also showed an initial drop from 7.75 composition, and water and nitrogen balances, g • dl _ to 7.48 g' dl" after 48 h at altitude and were recorded before, and during high altitude remained below the control value during the

30 whole week(P<0.01). It seemsfrom our studythatevenwith exposureto moderate 83. Hackett PH, ML Forsling, J altitude,measurablefluid shiftsto theupper Milledge and D Rennie. partof thebodyoccurredwhichweredetected Release of vasopressin in man at by our ultrasoundmethod. altitude. Hormone Metabolic Research 10:571, 82. Hack D, NW Levin, B Goidberg, 1978. SM Perold and A Rubenstein. Authors' Abstract Serum electrolytes at high altitude. While Forsling and Milledge (1977) found South African Journal of Medical that 4 h exposure to 10.5% oxygen (equivalent Science 29:11-16, 1964. to 5490 m altitude) had little effect on Annotation vasopressin release in man, the result of Purpose prolonged exposure is not clear. Excessive To establish values for some commonly fluid retention and hence possibly vasopressin estimated blood constituents in healthy young could contribute to the various forms of oedema seen at altitude. These include people living in Johannesburg (altitude approximately 5,250 feet above sea level) and pulmonary, cerebral and peripheral oedema as to compare them with those measured in defined previously (Hackett, Rennie and subjects living in Cape Town (sea level). Levine 1976). The purpose of the present Methods study was to investigate the release of The subjects studied were healthy medical vasopressin in the human at altitude with a students, 68 being in the Johannesburg group view to a greater understanding of the and 38 in the Cape Town group. Blood pathophysiology of acute mountain sickness (AMS) and altitude oedema. specimens were obtained at 8 a.m. with the The observations were performed at subjects fasting; the estimations were carried Pheriche, Nepal (altitude, 4243 m) in the out over a period of two weeks to check the Himalayas on 14 subjects. These included 7 effects of storage; some samples were estimated at the beginning and at the end of this control subjects (5 female) who showed no period. No differences were found in the symptoms, 2 subjects with AMS (both female) results obtained. and 4 subjects additionally with high altitude Results pulmonary oedema (2 female). On sampling, the blood was immediately centrifuged, the The mean plasma carbon dioxide content and serum sodium concentrations were plasma separated and maintained in liquid nitrogen until analysed in London. Hormone significantly lower and the haemoglobin and determination was performed on extracted serum chloride concentrations significantly plasma as described by Chard and Forsling higher in the group resident in Johannesburg (1976). compared to the group at sea level. There was The results are summarised in the figure. no significant difference between the serum The plasma vasopressin in the control group potassium and plasma phosphorus concentrations. was 1.1 _+0.15 gU/ml ( +SEM, n = 7) as compared with 0.7 _-+0.17 gU/ml (n = 10) in a Conclusions previous study at sea level and there was no This study confirms other reports that the difference in vasopressin concentration concentration of certain electrolytes in subjects between the ascent and the descent from 5,300 at high altitudes is significantly different from m. Thus altitude alone did not appear to affect those measured in persons living at sea level. the release of vasopressin. The results were The reduction in plasma carbon dioxide content similar to those seen with acute hypoxia, when may be due to increased resting ventilation a value of 1.1 l.tU/ml was recorded (Forsling which occurs at 5,750 feet. The resulting and Milledge 1977). Plasma vasopressin was respiratory alkalosis is then compensated for by significantly elevated in those subjects with a decrease in plasma bicarbonate level. Long AMS to a mean concentration of 2.2 _+0.5 (n = term compensation probably occurs mainly in 7, p<0.01). The results of Singh, Malhotra, the kidney with increased tubular reabsorption Khanna, Nanda, Purshattam, Upadhyay, of chloride in preference for bicarbonate.

31 Radhakrishnan and Brahmachari (1974) gain) manifest as peripheral, pulmonary, and/or suggest a similar trend. It was also noted that cerebral edema. five of the climbers with AMS also suffered with peripheral oedema as indicated in the 85. Itackett PH, D Rennie, SE figure. The present studies do not indicate Hofmeister, RF Grover, EB whether the increased vasopressin secretion Grover and JT Reeves. was a primary change and a major factor in the Fluid retention and relative pathophysiology of AMS or secondary to a hypoventilation in acute mountain shift in fluid from the vascular bed or indeed to sickness. stress. The concentrations recorded would Respiration 43:321-329, 1982. have been sufficient to cause a degree of water Authors' Abstract retention provided that the renal sensitivity to The presence of pulmonary, cerebral, vasopressm was unchanged. and/or peripheral edema in acute mountain sickness (AMS) implies a derangement in the 84. Hackett PH, D Rennie, RF Grover body's handling of water. Previously, we and JT Reeves. demonstrated water retention and increased Acute mountain sickness and the symptoms of AMS when hypocapnia was of high altitude: a common prevented in subjects exposed to simulated high pathogenesis? altitude. This led us to the hypothesis that Respiration Physiology 46:383-390, upon ascent to high altitude, those persons who 1981. fail to increase their ventilation adequately and Authors' Abstract hence do not become hypocapnic will retain Within days of ascent to high altitude when water reflected as weight gain and will develop symptoms of acute mountain sickness (AMS) AMS. To test this hypothesis, we studied in are common, pulmonary and cerebral edema Kathmandu, Nepal (1,377 m) 42 healthy may develop. Although peripheral edema of western tourists; all were restudied in Pheriche the hands, face or feet may also appear, its (4,243 m) within 6 days of exposure to high association with AMS is unclear. In addition, altitude. Symptoms of AMS were highly persons with high altitude pulmonary edema correlated (p<0.001) with weight change, often report an antidiuresis. Hence, altitude suggesting that persons becoming symptomatic sickness appears to result from abnormalities in retained fluid. On going from low to high the handling of body water. To test this altitude, those persons who lost weight and hypothesis, we studied 102 men and women remained well increased their resting who were trekking in the Mount Everest region ventilation, whereas those who gained weight of Nepal. Most were seen both at low (1377 did not (p=0.03). This relative hypoventilation m) and at high (4243 m) altitude. Severity of in the latter group was confirmed by higher AMS was measured by an established values of Pco2 (heated hand vein blood) and Symptom Score derived from a questionnaire lower values of arterial saturation (ear and physical examination. Change in body oximeter) at Pheriche. Vital capacity measured water was inferred from change in body weight in Kathmandu was correlated with arterial in less that 10 days. Peripheral edema was saturation at Pheriche (p=0.02); persons with assessed separately by physical examination. low vital capacity were more hypoxemic with AMS Symptom Score correlated directly with more symptoms of A.MS. We conclude that weight change; those who remained well lost relative hypoventilation and weight gain appear weight, whereas increasing signs and early in the development of AMS suggesting symptoms of AMS occurred in those with links between altitude hypoxia, increasing weight gain. The symptomatic hyperventilation, hypocapnia, and the body's subjects also developed peripheral edema and handling of water. reported decreased urinary output. These findings support the hypothesis that with rapid ascent to high altitude, abnormalities in the handling of body water, with antidiuresis, result in fluid retention (weight

32 86. Hackney AC, JT Coyne, R Pozos, S Feith and J Seale. 87. Hannon JP and KSK Chinn. Validity of urine-blood hydrational Effects of high altitude on body fluid measures to assess total body water volumes. changes during mountaineering in the Federation Proceedings 26:719, sub-Arctic. 1967. (Abstract). Arctic Medical Research 54:69-77, Authors' Abstract 1995. Nine young male subjects were studied Authors' Abstract initially at low altitude (San Antonio, Texas) Mountaineering involves high altitude and and subsequently during 15 days' exposure at cold exposure which are each associated with high altitude (Pikes Peak - 14,110 ft). From a significant levels of dehydration (via altitude- low altitude value of 2.99 1., plasma volume cold diuresis, high energy expenditures, and (Evans Blue) decreased progressively at high poor access to water). The purpose of this altitude, reaching a value of 2.40 1. on the 15 _ study was to identify and validate urine and day of exposure. Calculated blood volume blood indices of dehydration as compared to decreased similarly. During the f'u'st 8 days of changes in total body water (which served as exposure, extracellular volume (NaSCN space) the reference standard). Male subjects (n=lO) was reduced from 17.34 1. to 13.79 1. A slight were studied during a 14 day mountaineering recovery, 15.21 l., was observed on the 15 t_ expedition in the sub-Arctic during which they day. Total body water measurements (4- climbed to an altitude of 5245 _+229 m (mean aminoantipyrine space) indicated a slight +SE). Daily activity consisted of dehydration during the first day; i.e. from approximately 10-15 hours skiing, hiking, and 38.52 I. to 37.67 1., and a slight hydration to performing mountaineering tasks with heavy 39.29 1. on the 15_hday of exposure. loads (>30 kg). Various measurements were Measurements of D20 space yielded unreliable made immediately before ascending (Pre) and data. Calculations of intracellular space after descending (Post) the mountain: body showed a progressive increase from 21.19 1. to weight (Bw) and composition (%Fat), urine 24.17 1, over the first 8 days at altitude. Body specific gravity (USG), urine protein (UP), density measurements showed weight loss at plasma electrolytes (K ÷, CI, Na÷), plasma high altitude was due to a loss of fat. proteins (PP), plasma and urinary osmolality (UOsm), hematocrit (Hct), hemoglobin (Hb), 88. Hannon JP, KSK Chinn and JL blood urea nitrogen (BUN), plasma Shields. aldosterone, and total body water (TBW Effects of acute high-altitude exposure determined via deuterium oxide). Post the on body fluids. expedition significant (p<0.05) decreases were Federation Proceedings 28:1178- observed in Bw, and %Fat, while significant 1184, 1969. increases were found in Na ÷, K ÷, USG, UOsm Annotation and UP. TBW was slightly reduced, however, Purpose changes were non-significant (Pre = 52.9 +1.2 To study the mechanisms affecting L vs Post = 52.6 +_1.3 L). USG is often used hemoconcentration at high altitude. to monitor hydration status in field settings; Methods however, no significant correlations were Nine soldier volunteers age 20 to 24 were found between changes in TBW and USG, nor transported to Pikes Peak (14,100 ft) after between changes in TBW and other typical control base measurements were taken at low urinary indicators of dehydration. The altitude. At Pikes Peak the following strongest correlations with alterations in TBW measurements were taken: total body water were the changes in Na ÷, CI, and Hct content, intra-and extracellular volumes, (p < 0.05). These data suggest that during a plasma volume, interstitial volume, and total mountaineering expedition standard urinary extracellular cation concentration. indices of hydration status may be of little Results benefit in determining the presence or Body water measurements based upon magnitude of changes in TBW content.

33 4-aminoantipyrinedilutionandbodydensity chloride concentration, with minor measurementsshowedlittle orno change contributions from protein anion and inorganic duringthefirst weekataltitude,andasmall phosphate. The serum concentrations of (p<0.05)increaseduringthe2ndweek. Plasma sodium and calcium were unaffected by altitude volume,determinedwith theEvansblue exposure while the concentrations of potassium procedure,decreasedaftertwo weeksby 600 and magnesium were slightly elevated. ml or 20%. After 7 daysover3.5L, or 20% Because of marked reduction in extracellular of extracellularfluid, istransferredto the space, total extraceUular electrolytes principally intracellularspace.Between7 and14days sodium, chloride, and bicarbonate, were exposuretherewasaslightbutsignificant similarly reduced. Total body water (4- recoveryof theinterstitialandextracellularfluid aminoantipyrine space), on the other hand, was volumes,whereastheintracellularfluid volume slightly elevated, hence calculated intracellular remainedincreased.Thisrecovery,attributable space was markedly elevated. It was to theslightincreasein totalbodywaterwhich concluded that this high-altitude transfer of wasnotedabove,occurredin thesametime water from the extra- to the intracellular space period. Finally,totalextracellularcationlevel was caused by the osmotic effects associated declinedduringthefirst weekwith ashift with a transfer of electrolytes from the extra- to (recovery)duringthesecondweek. Thiswas the intraceUular compartment. primarily attributableto lossof sodium,a predominantlyextracellularcation. 90. Hannon JP, JL Shields and CW Conclusions Harris. The cause of these altitude-induced changes Anthropometric changes associated in extra- and intra-cellular fluid volumes has yet with high altitude acclimatization in to be resolved; in fact, most explanations are females. still speculative. One intriguing possibility is American Journal of Physical found in the body electrolyte changes seen Anthropology 31:77-84, 1969. during high altitude exposure. A reduction in Authors' Abstract extracellular cations (and osmotic activity) The anthropometric effects of prolonged would be consistent with a movement of water high altitude exposure were studied in eight from the extra- to the intra-cellular college women who lived on the summit of compartment. The cation as well as the anion Pikes Peak (14,100 ft) for 2.5 months. levels in these two compartments, particularly Acclimatization to altitude was associated with the intracellular, obviously need further a decrease of skinfold thickness and a reduction investigation before this suggested mechanism in limb circumference, but little change in body can be verified. weight. It was concluded that these changes reflected a loss of subcutaneous fat during the 89. Hannon JP, KSK Chinn and JL period of altitude exposure. Altitude exposure Shields. did not produce any alterations in trunk Alterations in serum and extracellular circumference at the umbilicus or buttocks, but electrolytes during high-altitude it did cause an increase in the inspiratory chest exposure. circumference at the axillary level and a Journal of Applied Physiology 31:266- reduction in expiratory chest circumference at 273, 1971. the subscapular level. Authors' Abstract The concentration and total quantity of 91. Hannon JP, CW Harris and JL electrolytes in serum and extracellular Shields. (thiocyanate) space were measured in nine Alterations in the serum electrolyte soldiers, initially in San Antonio, Texas (200 levels of women during high altitude m), and subsequently after 1, 3, 7, and 14 (4,300 m) acclimatization. days' exposure in Pikes Peak (4,300 m). International Journal of Altitude exposure caused a total reduction in Biometeorology 14:201-209, 1970. serum bicarbonate concentration of 7.0 mEq/L. Most of this loss was replaced by an increase in

34 Authors' Abstract measurements revealed a marked oliguria EightUniversityof Missouri(230m) during the entire sojoum. These measurements collegewomenwereexposedfor aperiodof 65 also showed the first 3 days to be associated daysto anelevationof 4,300m on PikesPeak. with a net loss of body nitrogen and sodium. Duringthefh-stweekof altitudeexposure During this time period body potassium and markedincreasesin theserumlevelsof phosphorus were conserved, and probably chloride,phosphate,proteinateandcalciumand increased. The urea fraction of total urinary markeddecreasesin theserumlevelsof nitrogen was not affected by altitude exposure, sodium,potassium,magnesiumandestimated nor was the daily excretion of uric acid and bicarbonatewereobserved.Duringthe creatinine. Ammonia excretion, however, was remainderof thealtitudesojournchloride, reduced to 50% of the low-altitude value and phosphate,potassium,andmagnesiumreverted remained at this level throughout the sojourn. towardtheinitial low altitudevalue. Serum With a few exceptions, the qualitative calciumlevels,however,remainedelevated characteristics of altitude hypophagia in women duringthislatterperiodwhile sodiumlevels were similar to those reported for men. continuedto decreaseandproteinatelevels Quantitatively, however, the responses were continuedto increase.Therewaslitre orno much more transient in women. recoveryof theestimatedbicarbonate decrementastheperiodof exposurewas 93. Hannon JP, JL Shields and CW prolonged.Two weeksafterthesubjects Harris. returnedto Missourisomebutnotall of the Effects of altitude acclimatization on electrolytesreturnedto theirinitial levels. blood composition of women. Thosenotrecoveringcompletelyincluded Journal of Applied Physiology 26: calcium,chloride,proteinateandestimated 540-547, 1969. bicarbonate. Authors' Abstract The effects of altitude acclimatization on 92. Hannon JP, GJ Kiain, DM Sudman blood composition were studied in eight and FJ Sullivan. University of Missouri (elev 700 ft) coeds who Nutritional aspects of high-altitude lived on the summit of Pikes Peak (elev 14,000 exposure in women. ft) for 10 weeks. During the period of altitude American Journal of Clinical exposure the following changes were observed: Nutrition 29:604-613, 1976. a transient increase in heart rate, the maximum Authors' Abstract being reached on the 1st day of exposure; an The nutrient intake and urinary excretion early rapid increase in hematocrit and characteristics of eight young university hemoglobin which later became more gradual; women were studied over a 4-day period at low an early and sustained reduction in plasma altitude (140 m) and subsequently over a 7-day volume; a rapid initial increase and a more sojourn on Pikes Peak (4,300 m). High- gradual later increase in plasma protein altitude exposure was associated with a concentration which was attributable to transient decrease in the consumption of elevations in both the albumin and the globulin protein, carbohydrate, fat, sodium, calcium, fractions; a sustained decrease in the albumin- phosphorus, vitamin A, riboflavin, thiamin, to-globulin ratio; a slight but sustained increase and niacin and a more sustained decrease in the in serum oncotic pressure; a slight but consumption of potassium and ascorbic acid. sustained decrease in blood water content and In most instances minimal values were serum and osmolarity; and finally, an unaltered observed during the first 3 days of exposure. total leukocyte count, but a significant increase The carbohydrate fraction of energy intake was in lymphocytes and significant decrease in increased at the expense of fat during this time monocytes. It is concluded that the period. Individual hypophagic responses hematopoietic response to altitude is markedly appeared to be related to severity of acute less in women than that usually observed in mountain sickness. Altitude had no effect on men. In women at least, dietary iron water consumption but did lead to an average supplementation enhances the rate of hematocrit body weight loss of lkg. Urinary increase at altitude. And finally, the loss of

35 plasmavolumeis felt to berealandnotdueto Urinary excretion of electrolytes, simpledehydration. creatinine, urea, and antidiuretic hormone- measured as arginine vasopressin (AVP) by 94. Hansen JM, NV Olsen, B Feldt- radioimmunoassay-was investigated in eight Rasmussen, I-L Kanstrup, M Himalayan mountaineers during ascent on foot D_chaux, C Dubray and J-P from 1900-5400 m. Specimens were collected Richalet. from each individual whenever urine was Albuminuria and overall capillary voided, preserved with 1% boric acid, and permeability of albumin in acute altitude subsequently pooled to give samples hypoxia. representative of 24-h collections. AVP was Journal of Applied Physiology found to be reasonably stable under simulated 76:1922-1927, 1994. conditions of storage. In all subjects, the Authors' Abstract observed AVP excretion rates were mostly in The mechanism of proteinuria at high the lower region of the normal range and there altitude is unclear. Renal function and urinary was generally no correlation with altitude, urine excretion rate of albumin (Ual0 at rest and osmolality, electrolyte excretion, or occurrence during submaximal exercise, and transcapillary of AMS symptoms-even in a fatal case of escape rate of t25I-labeled albumin (TER_b), cerebral oedema. It is concluded that AVP were investigated in 12 normal volunteers at does not play a primary role in the changes in sea level and after rapid and passive ascent rate fluid balance which accompany either to 4,350 m. The calcium antagonist isradipine acclimatization to high altitude or the onset of (5 mg/day; n=6) or placebo (n=6) was AMS. administered to abolish hypoxia-induced rises in blood pressure. Lithium clearance and 96. Heyes MP, MO Farber, F urinary excretion of 13:microglobulin were Manfredi, D Robertshaw, M used to evaluate renal tubular function. High Weinberger, N Fineberg and G Robertson. altitude increased UaLb from 2.8 to >5.0 l.tg/min in both groups (P<0.05). In the placebo Acute effects of hypoxia on renal and endocrine function in normal humans. group, high altitude significantly increased (P<0.05), but this response American Journal of Physiology was abolished by isradipine. Lithium clearance 243:R265-R270, 1982. Authors' Abstract and urinary excretion of 13:microglobulin remained unchanged by hypoxia in both The effects of hypoxia upon renal and endocrine function are unclear. Normal water groups. Exercise did not reveal any further renal dysfunction. In both groups, high loaded subjects were exposed to hypoxia for 1 altitude increased TERa_ b from 4.8 to >6.7%/h h (inspired PO: = 74 Torr) in a decompression (P<0.05). In conclusion, acute altitude chamber (5,100m, n = 8) or by breathing hypoxia increases U_ b despite unchanged 10.5% oxygen at ambient pressure (n = 4). In tubular function and is independent of effects four of eight subjects exposed to hypobaric of isradipine on filtration fraction. The elevated hypoxia: urine flows (V) decreased (mean = TER,a b suggests an overall increase in capillary 56%), urine osmolality increased (340%), permeability, including the glomemlar plasma arginine vasopressin (AVP) increased endothelium, as the critical factor in high- (2,700%), plasma cortisol increased (256%), altitude induced albuminuria. and mean blood pressure (BP) decreased (18%). _r correlated inversely with AVP 95. Harber M J, JD Williams and JJ (r = -0.71, P<0.01) while AVP increases Morton. correlated with falls in mean BP (r = -0.72. Antidiuretic hormone excretion at high P<0.05). Similar results were observed in the altitude. subjects exposed to normobaric hypoxia. Aviation, Space, and Environmental Plasma aldosterone fell in the four subjects Medicine 52:38-40, 1981. who maintained V on exposure to hypobaric Authors' Abstract hypoxia, but plasma renin activity did not change. In both groups prolactin levels were

36 variableandsoluteandcreatinineexcretion water balance. Test subjects who experienced wereunchanged.No changeswereobserved the most severe symptoms of acute mountain in controlsor in subjectsexposedto hypobaria sickness also showed the greatest decrease in alone.Acutehypoxicexposuremayproduce aldosterone excretion at altitude. Data significanthypotensionwith consequent presented are consistent with the conclusion increasedAVP secretionresultingin that aldosterone secretion at altitude follows diminished_r. usual control mechanisms, contrary to previous reports. It is postulated that the observed 97. Heyes MP and JR Sutton. depression in renin release is secondary to decreased renovascular resistance and increased High altitude ills: a malady of water, renal blood flow. electrolyte and hormone imbalance? Seminars in Respiratory Medicine 5:207-212, 1983. 99. Honig A. Authors' Abstract Salt and water metabolism in acute high altitude hypoxia: Role of peripheral Evidence suggests that water retention arterial chemoreceptors. occurs in individuals who develop AMS on News in Physiological Science 4:109- acute exposure to altitude. The predisposed 111, 1989. person also appears to underventilate. Author's Abstract Although increases in AVP are associated with Mammals acutely exposed to hypobaric AMS, these may be the result of AMS rather than a cause. Extensive studies of the renin- hypoxia establish a lower plasma volume by angiotensin-aldosterone system have not increasing urine excretion or by reducing salt and water intake. These responses are of shown any consistent relationship with AMS. Nevertheless, a decrease in angiotensin- adaptive value, for by concentrating available hemoglobin they increase O2-binding capacity converting enzyme activity may have more of the blood. The reactions of sodium important implications for edema formation. metabolism in arterial hypoxia are controlled by This decrease would result in an impaired ability to degrade bradykinin, a potent edematic peripheral arterial chemoreceptors. agent, that could be important for the already 100. Hoon RS, SC Sharma, V vulnerable hypxic lung and might contribute to Balasubramanian and KS systemic and cerebral edema. Chadha. Urinary catecholamine excretion on 98. Hogan III RP, TA Kotchen, AE induction to high altitude (3,658 m) by Boyd III and LH Hartley. air and road. Effect of altitude on renin-aldosterone system and metabolism of water and Journal of Applied Physiology 42:728- 730, 1977. electrolytes. Authors' Abstract Journal of Applied Physiology 35:385- 390, 1973. In a preliminary pilot study we had Authors' Abstract reported a significant difference in urinary catecholamine excretion between symptomatic Plasma renin activity and urinary aldosterone excretion were studied in 10 and asymptomatic individuals inducted to high normal male volunteer test subjects between the altitude by air. The present study covers slower induction by road; 25 lowlanders ages of 19 and 23 who were exposed to a ascended from 1,800 to 3,658 m in 50 h and simulated altitude of 12,000 ft (483 mm Hg) in 33 similar subjects covered the journey in 6 h. a hypobaric chamber for 72 hr. Subjects consumed a controlled 160 mEq sodium, 60 They were studied according to the protocol used in the initial study. None of the 58 mEq potassium diet throughout the study. Plasma renin activity and urinary aldosterone subjects inducted by road developed symptoms excretion were decreased. Subjects retained of high-altitude illness. Their urinary catecholamine excretion remained normal potassium, lost sodium, and had mild water during the 10 days' stay at high altitude. These and weight losses. Increased insensible loss findings lend support to our earlier contention was primarily responsible for the negative

37 thattheremightbearelationshipbetween of Su-4885 (Methopyrapone) showed that the increasedsympathoadrenalactivityandhigh- pituitary-adrenal cortical system was still altitudeillnesses. capable of response to additional stimulation.

101. Hoon RS, SC Sharma, V 103. Houston CS and RL Riley. Balasubramanian, KS Chadha Respiratory and circulatory changes and OP Mathew. during acclimatization to high altitude. Urinary catecholamine excretion on American Journal of Physiology acute induction to high altitude 149:565-588, 1974. (3,658m). Authors' Abstract Journal of Applied Physiology 41:631- Detailed studies of the respiratory and 633, 1976. circulatory changes which occur during the Authors' Abstract process of acclimatization to oxygen lack were Fifty healthy male volunteers, 21-34 yr of made on four men exposed to gradually age, normally resident at altitudes less than increasing simulated altitude during one month 1,000 m, were airlifted to 3,658 m. Urinary in a low pressure chamber. excretion of catecholamines was measured at The data obtained strengthen the concept sea level (198 m) and on the 1_t,2 *d, 4 _, and that acclimatization consists of a series of 10 _hday of a stay at high altitude. The integrated adaptations which tend to restore the symptoms observed on exposure to high oxygen pressure of the tissues toward normal altitude were assigned arbitrary scores. The sea level values despite the lowered pO 2 of the volunteers could, on this basis, be divided into atmosphere. "symptomatic" and "asymptomatic" groups. The transfer of oxygen from inspired air to The two groups showed a markedly different tissue cells can be conveniently divided into pattern of urinary catecholamines excretion on several stages which together comprise the exposure to high altitude and on return to sea oxygen transport system. A theoretical mean level. Significant increase in the catecholamine value for the capillary oxygen pressure has excretion was observed in the symptomatic been introduced to make possible a more group only. A possible role for enhanced quantitative evaluation of circulatory factors sympathoadrenal activity in the than heretofore possible. etiopathogenesis of high-altitude illnesses is The reduction in the pO 2 gradient between postulated. inspired air and mean capillary blood was due mostly to the shape of the oxyhemoglobin 102. Hornbein TF. dissociation curve and to an increase in Adrenal cortical response to chronic pulmonary ventilation; increase in cardiac hypoxia. output, increase in the diffusion constant of the Journal of Applied Physiology 17:246- lung, and increase in oxyhemoglobin capacity 248, 1962. were less important factors. Author's Abstract The same pulmonary and circulatory Although acute oxygen lack causes changes which caused an increase in pO 2 increased adrenal cortical activity, there is necessarily caused a decrease in pCO 2, and an evidence that continued exposure to hypoxia is initial effect of the decrease in pCO 2 was an accompanied by a return of adrenal cortical increase in the alkalinity of the blood. Further function to its sea level status. To evaluate the changes occurred, as acclimatization adrenal cortical response in men living for 14- progressed, to counteract this respiratory 21 days above 21,000 ft., urinary output of 17- alkalosis. The fall in blood bicarbonate hydroxycorticoids was measured in ten reflected the extent of these changes which members of a Himalayan mountaineering included a net increase in the other negative expedition and compared to values obtained ions and probably a net decrease in the positive subsequently at sea level. No significant ions. These changes comprised secondary difference in 17-hydroxycorticoid output was factors in acclimatization. There was no observed between the two altitudes. The evidence that cellular metabolism decreased as response of four subjects to the administration part of the acclimatization process, since the

38 oxygenconsumptionremainedthesameat were compared with daily measurements of altitudeasat sealevel,bothduringrestand packed cell volume (PCV) and reticulocyte duringstandardwork.Sinceclinicalevidence count. Early fluid retention was matched by a indicatedthatthesubjectsweremoderately fall in PCV. There was a diuresis with anoxic,it appearsthatcellularfunctionwas negative fluid balance towards the end of the impairedby low pO2,eventhoughtheamount ascent and again early in descent. There was a of oxygenusedby thecellsremainednormal. slight trend for fluid retention to occur in those most affected by acute mountain sickness but 104. Houston CS, JR Sutton, A the effect was not marked. Cymerman and JT Reeves. Operation Everest II: man at extreme 106. Hoyt RW, MJ Durkot, GH altitude. Kamimori, DA Schoeller and A Journal of Applied Physiology 63:877- Cymerman. 882, 1987. Chronic altitude exposure (4300 m) Authors' Abstract decreases intracellular total body water Rapid ascent to high altitude may cause in humans. serious problems for climbers, skiers, and In: Hypoxia and Mountain Medicine. aviators. In contrast, gradual ascent enables Proceedings of the 7'h International humans to function where the unacclimatized Hypoxia Symposium, edited by JR cannot. To examine changes in the 02 Sutton, G Coates, and CS Houston. transport system that produce acclimatization, New York: Pergamon Press, 1992. eight men were taken in a decompression p.306. (Abstract). chamber (without other stresses experienced on Authors' Abstract high mountains) to a simulated altitude of There are several reports that chronic 8,840m (29,028 ft, ambient PO 2= 43 Torr) in altitude exposure increases intracellular fluid 40 days. Maximal 02 uptake fell to 1.21 volume (ICF) with no change in total body L/min, and arterial pO 2 and pCO 2 were 30 and water volume (TBW). However, our animal 11 Torr, respectively, with pH of 7.56. Many experiments have not supported this position. sophisticated studies were done: Swan-Ganz To further investigate altitude-induced body catheterization and inert gas diffusion studies at fluid redistribution, nine adult males (23 to 33 three altitudes showed that normal cardiac yr) were studied before and after 10 days at function persisted, pulmonary vascular 4300 m elevation. Apparent extraceUular fluid resistance increased and at extreme altitude was volume (ECF_) and TBW were measured by not lowered by 02 , and pulmonary ventilation- NaBr and H2_ZO dilution, respectively. perfusion mismatch increased, though variably. Bromide space was corrected for tracer This appears to be an important factor limiting distribution outside the ECF. The percent performance at extreme altitude. This paper change in plasma volume (PV) was estimated presents the background, general approach, from changes in hemoglobin concentration and and a summary of major observations reported hematocrit. Apparent ICF was calculated in detail in other papers. (ICF_ = TBW - ECF_). There were significant (p<0.05) decreases in body mass (86.6 +_4.6 105. Howell A and DH Cove. vs. 82.2 +4.3 kg) (mean +SEM), TBW (47.6 Birmingham Medical Research +_2.2 vs. 45.9 +_1.9 1), ICF_ (19.3 _+1.4 vs. Expeditionary Society 1977 Expedition: 16.3 +1.3 1), and PV (-20.0 +-1.4%). The The diuresis and related changes during ECF a did not change (28.2 +-1.0 vs. 29.6 +-1.6 a trek to high altitude. l) (p>0.05). Prolonged altitude exposure in Postgraduate Medical Journal 55: humans resulted in both cellular hypohydration 471-474, 1979. and decreased TBW. Authors' Abstract Continuous 24-hr urine collections were made by 17 subjects during a trek to 5400 m. Fluid intake was recorded by diary. Weight and fat folds were measured daily. The results

39 107. Hoyt RW, TE Jones, CJ Baker- physical and hematologic qualities as well as Fulco, DA Schoeller, RB radio phosphorus blood volumes and radio iron Schoene, RS Schwartz, EW turnover rates. One group of subjects was Askew and A Cymerman. normal medical students of the University of Doubly labeled water measurement of San Marcos who were studied in Lima, and human energy expenditure during were then moved to Morococha where the exercise at high altitude. studies were repeated as a function of time of American Journal of Physiology stay there. The second group was normal 266:R966-R971, 1994. natives of Morococha who were studied there Authors' Abstract and were then taken to Lima where the Estimates of total daily energy expenditure examinations were repeated after various (TDEE) by the doubly labeled water (DLW, intervals of time. The third group was ZHElaO) and intake balance (I-B) abnormal natives of Morococha. The results of methods were compared in six male soldiers all of the usual studies were found to conform studied over 6 days that included 5 days of with previous similar investigations by other strenuous winter exercise at 2,500- to 3,100-m individuals. When the medical students moved elevation. Use of body energy stores [-9.54 to high altitude, there was a definite decrease in +1.54 (SD) MJ/day or -2,280 +368 kcal/day] blood volume, primarily as a result of was estimated from changes in body weight, decreased plasma volume. The possible slight body density (hydrodensitometry), and total increase in red cell mass in the group during the body water (HEraO dilution). The subjects 10-day period of acclimatization was within the wore computerized activity monitors and kept limits of error of the measurements. The iron daily records of ration consumption (9.87 turnover rates increased by a factor of 2 with +_3.60 MJ/day or 2,359 +_860 kcal/day). residence at 14,900 ft. Calculations show that Accuracy of individual DLW and I-B TDEE the measured increases in red cell masses values was estimated from the correlations of appearing after time at altitude are compatible TDEE with fat-free mass (FFM) or total weight with the observed production rate. It is (body wt + load). The DLW and I-B estimates observed that data on increases in red cell mass of TDEE differed by -12.0 to 15.2% but covering longer periods of acclimatization at provided comparable estimates of group mean Morococha fit an increase in production rate of TDEE (DLW = 19.07 +_.2.37 MJ/day or 4,558 a factor of 2. However, the value is too high to +_566 kcal/day; I-B = 19.41 +3.72 MJ/day or give an eventual increase in red cell mass that 4,639 +-889 kcal/day; P>0.05). The DLW would be comparable to that of the natives of TDEE was correlated with both FFM (r2 - Morococha. Therefore, it is suggested that a 0.89, P<0.01, power = 0.95) and total body decrease in this rate probably occurs with weight (r 2 - 0.95, P<0.01, power = 0.99), longer periods of acclimatization, since the ratio whereas I-B TDEE was correlated only with of red cell volume of the native at altitude to the total weight (r 2 = 0.75, P<0.03, power = student at sea level is 1.51. When the natives 0.81). Under adverse field conditions the moved to Lima there was little change in blood DLW method provided individual TDEE volume but approximately a 10 per cent estimates that were probably more accurate than decrease in red cell mass in 10 days of those provided by the I-B method. observation. The iron turnover rates fell linearly with time to approximately 0.1 the 108. Huff RL, JH Lawrence, WE Siri, original value in 10 days-values as low as those LR Wasserman and TG seen in patients with aplastic anemia. Hennessy. Calculations show that about one-half the Effects of changes in altitude on decrease in red cell mass is the result of a hematopoietic activity. decreased production rate and that the other half Medicine 30:197-217, 1951. may be the result of an increased rate of Authors' Abstract destruction. This decrease in production rate is Three different groups of subjects in Lima not compatible with life if extended over a (near sea level) and at Morococha (14,900 ft.), longer period of time. Thus during the period Peru were studied with regard to the usual greater than 10 days the rate must return to more nearly normal for sea level dwellers.

40 Theabnormalnativeswith silicosisat androgensafteranascentfrom 600m to 2,000 Morocochahadveryhighredcell massesand m abovesealevelis compatiblewith anACTH- decreasedplasmavolumes.Theiron tumover mediatedstimulationof the entire adrenal cortex rateswereexcessivelyhigh. Therateconstants and/or a diminished elimination of adrenal wereasgreatasthoseseenin themostsevere steroids: The concomitant fall of FSH, LH, and polycythemiaveracases(6). Thepercentof plasma renin would then be a consequence of a redcell iron renewedperdaywasgreaterthan direct negative feedback inhibition of these in thenormalnativesof Morococha. hormones.

109. Humpeler E, F Skrabal and G 110. Hurtado A. Bartsch. Studies at high altitude: blood Influence of exposure to moderate observations on the Indian Natives of altitude on the plasma concentration of the Peruvian Andes. cortisol, aldosterone, renin, American Journal of Physiology testosterone, and gonadotropins. 100:487-505, 1932. European Journal of Applied Authors' Abstract Physiology 45:167-176, 1980. A number of observations on certain of the Authors' Abstract blood characteristics of the Indian natives of the The influence of 11 days at moderate Peruvian Andes have been presented in this altitude (2,000 m) combined with exercise on work. The investigation has been conducted in plasma concentration of testosterone, FSH the town of Morococha, Peru, at an altitude of (follicle-stimulating hormone), LH (luteinizing 14,890 feet, and with an average barometric hormone), cortisol, aldosterone, and renin pressure of 410 mm Hg. The subjects studied activity was studied in ten healthy subjects. have been carefully selected as normal men, Within 48 h of arrival at moderate altitude a and the results obtained suggest the following significant increase in testosterone was found, conclusions: whereas FSH had decreased significantly and 1. Observations on the erythrocyte count LH showed a tendency to decrease. Cortisol gave an average increase of about a million red increased significantly at the beginning and cells per cubic millimeter over the sea level reached a maximum at the end of altitude normal value, but a considerable percentage of these natives live with a red cell count which exposure. The plasma aldosterone level rose continuously and on the last day of altitude was would be considered normal at sea level. This significantly elevated. Plasma renin activity finding indicates that an increase in the showed a tendency to decrease. On return to erythrocytes of the circulating blood, although low land all measured parameters returned to the common finding, is not an essential base line values within 2 days. adaptation process for normal life at high The findings of increases in plasma levels altitudes. There is no relationship between the of aldosterone and testosterone (and serum T 3 red cell count and age or body measurements. and T 4, as reported by others) are in contrast to 2. The average number of grams of the previously found decrease of urinary hemoglobin per 100 cc. of blood has almost the excretion of all these hormones. This appears same value as the normal average at sea level. to be a distinct dissociation of serum levels of In only 50 per cent of the cases was a higher adrenal (and thyroid) hormones from their result obtained. urinary excretion. Each red cell at high altitude contains less The observed increase in plasma hemoglobin, as compared with the normal aldosterone is probably mediated through erythrocyte at sea level, but the corpuscular ACTH and the rise in plasma potassium, since hemoglobin is not a fixed characteristic: it plasma renin activity showed an opposite trend. varies inversely with the level of the red cell The rise in plasma testosterone is probably of count, that is, the higher the count the less adrenal origin since plasma gonadotropins hemoglobin in each cell and vice versa. declined simultaneously. Oxygen determinations in arterial and The increase of plasma levels of venous blood verify these findings, and glucocorticoids, mineralocorticoids, and indicate that the red cell comes to the tissues

41 with aloweroxygencontentascomparedwith process to balance the increased formation of theerythrocyteatsealevel. red cells. 3. There is a marked increase in the 9. The blood coagulation time has a slight hematocrit (RBC per cent), and it is tendency to be shortened at high altitude. It has proportionally greater than the increase in the some inverse relation to the degree of the blood red cell count, with the result that each viscosity. erythrocyte has a larger volume (as compared 10. The average leucocyte count in these with the normal corpuscle at sea level). Again natives is essentially normal, but with a the corpuscular volume is not a fixed tendency to be low. characteristic: it varies inversely with the level 11. The average leucocytic formula falls of the red cell count. within normal percentages of sea level values, The larger size of the erythrocytes has also with the exception of a decrease in the been confirmed by direct measurement of it's eosinophiles. Not infrequently a relative diameter. polynucleosis and monocytosis is found. 4. The diminished amount of hemoglobin Young polynuclear cells are frequently in a larger corpuscle gives a lower value for the observed. In a considerable number of cases concentration of that substance in relation to the histiocytes are found in the peripheral blood, volume of the cell. Only about one-fourth of indicating perhaps an overactivity of the the erythrocyte is saturated with hemoglobin. reticulo-endothelial system. Equal and parallel changes in cell volume and hemoglobin, under the influence of variations 111. Hurtado A, C Merino and E in the red cell count, keep remarkably constant Delgado. such concentration. Influence of anoxemia on the There is an almost perfect inverse hemopoietic activity. correlation between the hematocrit (RBC per Archives of Internal Medicine cent) and the hemoglobin concentration in each 75:284-323, 1945. red cell. Authors' Abstract 5. The above findings suggest that the Investigations have been made at sea level adaptation processes to the high altitude, from and at high altitudes, in several series of the point of view of blood morphology, are to healthy and diseased male subjects, concerning be found not primarily in red cell count and the influence of temporary, intermittent and hemoglobin increases, as it has often been chronic anoxic anoxia (anoxemia) on the remarked, but rather in a fine and close morphologic and other characteristics of the correlation between cell number, volume and circulating blood. The related literature has hemoglobin, and in the existence of a larger been briefly reviewed. The main observations surface area in a given volume of blood and in lead to the following conclusions: the individual erythrocyte for the hemoglobin 1. Exposure to a low barometric pressure and oxygen content, factors which would environment causes in most cases a favour the proper supply of this gas to the polycythemic response. There are wide tissues, this last process being perhaps the individual variations, but in general the level of basic and fundamental problem at high altitude. polycythemia is directly proportional to the 6. The viscosity of the blood is definitely degree, duration and continuity of the anoxic increased, whereas that of the plasma and stimulus. serum remains strictly normal. 2. There seems to be a limit for the 7. The red cells show a marked increase in hematologic response to the anoxic stimulus. the resistance to hemolysis. This is most likely When this is extremely severe, a decrease related to the presence of young erythrocytes rather than a further increase, is observed in the produced by the overactive bone marrow. resulting polycythemia. An interference with 8. A positive indirect Van den Bergh the formation of hemoglobin may be the reaction was obtained in most cases examined, responsible mechanism. and actual determinations of the plasma 3. The level of hemoglobin in the bilirubin gave results slightly above normal. circulating blood may be considered as one of This finding may be related to an increased rate the many factors which tend to preserve the of cell destruction, perhaps a compensatory

42 internal stability, or homeostasis, against the of polycythemia vera is related to the existence disturbing influence of a constant lowering of of an anoxic stimulus. the oxygen tension in the inspired air. 4. The polycythemia associated with the 112. Hyers TM, CH Scoggin, DH anoxemia of high altitudes is absolute in type. Will, RF Grover and JT Reeves. The elevation in the total blood volume, which Accentuated hypoxemia at high altitude at times reaches high values, is due to an in subjects susceptible to high-altitude increased red cell volume. pulmonary edema. 5. The polycythemia observed on persons' Journal of Applied Physiology 46:41- arrival at high altitudes seems to be due to 45, 1979. factors of release of stored blood and Authors' Abstract hemoconcentration; that corresponding to a To investigate the hypotheses that repeated or constant exposure to a low pressure activated coagulation, catecholamine release, or environment is related to an erythropoietic arginine vasopressin release are involved in the hyperactivity. pathogenesis of high-altitude pulmonary edema 6. The polycythemia associated with a (HAPE), we measured these variables in seven constant or intermittent anoxemia tends to show subjects susceptible to HAPE and in nine a proportional elevation in the circulating control subjects at an alitutde of 1,600 m and reticulocytes and in the serum bilirubin. The after 6 and 12 h at a simulated altitude of 4,150 latter characteristic suggests that an increased m. Each subject was studied twice, once after rate of cellular destruction parallels the 3 days of placebo medication and once after 3 increased formation, but other factors such as days of premedication with aspirin and insufficiency of the liver in excretion of dipyridamole. At high altitude, HAPE- pigment, due to the anoxic condition, may also susceptible subjects showed significantly play an etiologic role in the observed exaggerated hypoxemia and a slightly higher hyperbilirubinemia. end-tidai carbon dioxide partial pressure that 7. The stimulating influence of anoxemia did not account fully for the hypoxemia. on the hemopoietic system is restricted to the Fibrinolytic activity was significantly formation of red blood cells and hemoglobin. accelerated in both groups at high altitude, Leukopoietic activity is not affected, and the whereas other coagulation measurements, moderate and temporary leukocytosis which at catecholamines and arginine vasopressin levels, times is observed on a person's arrival at a high and pulmonary function tests were not altitude is probably related to the release and significantly changed. Similar findings were mobilization of stored blood. obtained after both placebo and platelet 8. Chronic anoxemia does not modify the inhibitor premedication. The results indicate erythropoietic activity permanently. When a that none of the three hypothesized person who has lived since birth at high mechanisms, i.e., activated coagulation, altitudes is brought down to sea level, he excessive catecholamine release, or shows after some time blood characteristics antidiuresis, would account for HAPE similar to those found in persons who have susceptibility. Instead, HAPE-susceptible always lived under the latter environmental subjects exhibited exaggerated hypoxemia conditions. During the early period of associated with relative hypoventilation and a adaptation to the normal pressure environment widened alveolar-arterial gas pressure there frequently occurs an abnormal decrease in difference. the red blood cells and hemoglobin. 9. Comparative study of the polycythemia 113. Jain SC, J Bardhan, YV Swamy, of high altitudes and the polycythemic A Grover and HS Nayar. processes observed at sea level indicates that: Body water metabolism in high altitude (a) in cases of anoxemia at sea level due to natives during and after a stay at sea pulmonary changes, the polycythemic response level. tends to be less than with corresponding International Journal of degrees of arterial oxygen unsaturation at high Biometeorology 25:47-52, 1981. altitudes, except in cases of Ayerza's disease; (b) it is not likely that the causative mechanism

43 Authors' Abstract 115. Jain S, WL Wilke and A Tucker. Body fluid compartments were studied in Age-dependent effects of chronic a group of high altitude natives after a stay of hypoxia on renin-angiotensin and two months at sea level and during 12 days at unnary excretions. an altitude of 3,500 m. Measurements of total Journal of Applied Physiology 69:141- body water and extracellular water were made 146, 1990. on day 3 and 12 of reinduction to altitude, Authors' Abstract while plasma volume was measured on day 12 The mechanisms regulating water, only. The intracellular water, blood volume electrolyte, and blood volume homeostasis and red cell mass were computed from the continue to mature in early postnatal life, and above parameters. Total body water and this maturation may be altered by perturbations intracellular water decreased by 3.3% of volume or cardiovascular status. To (P<0.001) and 5.0% (P<0.001), respectively, evaluate the long-term effects of chronic by the 3_ day at altitude and did not change hypoxia on water balance, urinary electrolyte thereafter. Extracenular water increased excretion, heart weights, systemic arterial progressively at altitude, but the increase was pressure, and components of the renin- not significant. Blood volume and red cell angiotensin system, male Sprague-Dawley rats mass increased significantly while plasma were exposed to periods of simulated altitude volume decreased at altitude. These data were of 10,000 ft up to 90 days of age beginning at compared with those of low landers. This 2 or 30 days of age. Altitude exposure of both study suggested body hypohydration on high neonatal and adult rats was associated with altitude induction in low landers as well as in increases in urine output and water intake after high altitude natives on reinduction. 30 days of exposure, and right ventricular (RV) hypertrophy at all ages was examined. 114. Jain SC, J Bardhan, YV Swamy, However, the percent increase in urine output, B Krishna and HS Nayar. water intake, and RV hypertrophy was Body fluid compartments in humans numerically greater in neonates. Neonates also during acute high-altitude exposure. had increases in urinary sodium and potassium Aviation, Space, and Environmental excretion after 30 days of exposure. Plasma Medicine 51:234-236, 1980. renin activity and serum angiotensin-converting Authors' Abstract enzyme (ACE) activity were not affected, but Body fluid compartments were studied in plasma renin substrate was reduced in both a group of sea level residents at sea level and neonatal and adult altitude-exposed rats. Lung during 12 d of acute exposure to an altitude of ACE activity was also decreased in altitude- 3,500 m. Measurements of total body water exposed neonates. These data indicate that the and extracellular water were done on the third degree and, in some cases, the nature of these and 12 _ days of exposure, while plasma homeostatic responses varies with age during volume was measured on 12 _hday only. The long-term hypoxia. intracellular water, blood volume, and red cell mass were computed from the above 116. Janoski AH, BK Whitten, JL parameters. Total body water and extracellular Shields and JP Hannon. water decreased progressively, the decrease Electrolyte patterns and regulation in being 4.7% (p<0.001) and 6.0% (p<0.05), man during acute exposure to high respectively, on the 12 _ day. Plasma volume altitude. and blood volume decreased significantly with Federation Proceedings 28:1185- a slight increase in red cell mass. Intracellular 1189, 1969. water, computed from total body water and Authors' Abstract extracellular water, decreased by 4.3% on 12_h Ten male volunteers in their early twenties day. This study suggested hypohydration on were maintained on a constant sodium and acute altitude exposures. potassium intake for 14 days at sea level, the day of transition, and 9 days at high altitude (14,100 ft) to determine the effects of prolonged hypoxia on water and electrolyte

44 regulation. Decreased urine volume occurred at Nitrogen and mineral metabolism at high altitude and was correlated with altitude. diminished water intake. Urinary potassium Federation Proceedings 28:1195- retention was observed and serum potassium 1198, 1969. increased. There were no significant changes Authors' Abstract in urinary or serum sodium concentrations. Nitrogen balances of 15 men receiving The findings are discussed in light of reports two different liquid diets were positive at sea demonstrating decreased aldosterone secretion level and negative at altitude but appeared to be at high altitude. partially a reflection of intake of both nitrogen and calories since dietary intake was greatly 117. Jezek V, A Ourednik, S Daum and reduced at altitude. Sodium balances, L Krouzkovfi. exclusive of sweat losses, were positive at sea Effect of short-term hypoxaemia on the level and negative at altitude while potassium potassium and sodium metabolism and was retained at sea level and balances near on cardiac contraction. equilibrium were observed at altitude. Calcium Acta Medica Scandinavica 177:175- losses, attributed to low intakes, were observed 182, 1965. throughout the study and magnesium balances Authors' Abstract were generally positive. Large weight losses In a group of 12 healthy subjects and 11 during the 1s' days on the diet and again at patients with chronic cor pulmonale, a short- altitude indicated body water losses. Weight term reduction in the oxygen saturation of gains upon return to sea level were attributed to arterial blood was induced by inhalation of a water retention. gas mixture with a low oxygen content. Values in the course of cardiac contraction, the plasma 119. Jung RC, DB Dill, R Horton and sodium, plasma potassium and red-cell levels SM Horvath. were investigated as well as the urinary sodium Effects of age on plasma aldosterone and potassium excretions. levels and hemoconcentration at In both examined groups, already during altitude. hyposaturation there develops a marked Journal of Applied Physiology 31:593- increase of the plasma potassium levels and a 597, 1971. reduction of the red-cell potassium content. Authors' Abstract The changes persist for one hour after the Total blood volume, red cell and plasma termination of hyposaturation and initial values volume, and plasma aldosterone levels were are reached within 24 hours. In patients with measured on a group of four young and four chronic cot pulmonale, an increased urinary older subjects at sea level and altitude. Red cell potassium excretion was observed during the volumes were unchanged; however, there was period immedicately after the induced a reduction in plasma volume in both groups hyposaturation. In healthy subjects the with the young subjects showing a slightly potassium excretion does not differ from the greater reduction. Plasma aldosterone levels normal diurnal cycle. In neither of the two were reduced in the older subjects but remained groups were changes found in the plasma at sea-level or higher values in the younger sodium levels or the urinary sodium excretion. subjects upon ascent to altitude. It is concluded In patients with cor pulmonale, that plasma aldosterone levels and, therefore, prolongation of isometric contraction during probably secretion rates may be affected by age hypoxaemia as an index of the loss of and that plasma volume may be similarly contractility of myocardium was found. In affected by age. The changes in these values at healthy subjects these changes did not occur. altitude appear to be delayed in physiologically The mechanism of the described changes older individuals. Possible mechanisms for is discussed. this discrepancy with age are discussed. It is suggested that caution should be used in 118. Johnson HL, CF Consolazio, LO analyses and interpretation of body fluid Matoush and HJ Krzywicki. changes and hormonal secretory values at altitude unless these are age correlated and

45 plasmahormonelevelsanalyzedratherthan hemodynamics in five subjects with a history usingurineexcretoryconcentrations. of high-altitude pulmonary edema (HAPE). Plasma renin activity and plasma levels of 120. Kawashima A, K Kubo, K Hirai, aldosterone, epinephrine and norepinephrine S Yoshikawa, Y Matsuzawa and were also measured. The plasma ANP levels T Kobayashi. in HAPE-susceptible subjects rose significantly Plasma levels of atrial natriuretic in response to 10% O 2 (from 34.8 +_5.4 to 51.4 peptide under acute hypoxia in normal +7.3 pg' ml't; P<0.05), not associated with Respiration Physiology 76:79-92, any increase in either atrial pressure. 1989. Compared with six control subjects, the rise of Authors' Abstract ANP level was greater in HAPE-susceptible To investigate whether the acute hypoxia subjects (16.6 _+4.4 vs 3.9 _+1.2 pg' n'd_; can be a stimulus for atrial natriuretic peptide P<0.05). There was a significant positive (ANP) secretion, plasma levels of ANP were correlation between the rise of ANP level and determined under three different hypoxic the increase of pulmonary arterial pressure. No conditions in six normal subjects. During 15% significant difference was observed in any of 02 breathing for 10 min, no significant change other hormonal responses to acute hypoxia in plasma ANP level was observed. Severe between the two groups. We interpret these hypoxia induced by 10% O 2 breathing results as indicating that the ANP secretory increased the mean pulmonary arterial pressure response to acute hypoxia in HAPE-susceptible (Ppa) by 11.6 mm Hg within 10 min (P<0.01), subjects, which is not mediated by an increase accompanying a slight but significant rise in in arterial pressure, may be greater than that in plasma ANP level of pulmonary artery (PA) nonsusceptible subjects in association with a from 24.3 +5.3 to 28.2 +4.6 pg/ml (P<0.05). greater pressor response of pulmonary There was a tendency for the ANP level of PA circulation. to rise under hypoxic hypobaria at 515 Ton" for 10 min, followed by a decrease of that level 122. Keynes R J, GW Smith, JDH during 100% 02 breathing under hypobaric Slater, MM Brown, SE Brown, conditions. These changes, however, still NN Payne, TP Jowett and CC remained in the normal range. No significant Monge. changes were observed both in right atrial Renin and aldosterone at high altitude in pressure and in pulmonary capillary wedge man. pressure under any of the three hypoxic Journal of Endocrinology 92:131-140, conditions. From these results we conclude 1982. that ANP can be released in response to the Authors' Abstract elevation of Ppa caused by acute hypoxia in Measurements have been made of normal subjects, but the changes in plasma hormonal changes relevant to salt and water ANP level may be too small to play a balance during prolonged exposure to hypoxia significant physiological role in hemodynamic to improve our understanding of the syndrome of acute mountain sickness. We have responses to acute hypoxia. attempted to delineate the detailed inter- 121. Kawashima A, K Kubo, Y relationships between the renin-aldosterone and Matsuzawa, T Kobayashi and M the vasopressin systems by a metabolically Sekiguchi. controlled study, involving an orthostatic stress Hypoxia-induced ANP secretion in (450 head-up tfft) and an injection of a standard subjects susceptible to high-altitude dose of ACTH to test adrenal responsiveness. Three Caucasian medical students underwent a pulmonary edema. Respiration Physiology 89:309-317, 7-day equilibration at 150 m (Lima, Peru), 1992. followed by a 6-day sojourn at 4350 m (Cerro Authors' Abstract de Pasco, Peru) and a final 7 days at 150 m. Measurements were made of sodium and We investigated the effects of acute hypoxia (10% 02) on plasma level of atrial potassium balance, body weight, and the 24-h natriuretic peptide (ANP) and pulmonary renal excretion of vasopressin, cortisol and

46 aldosterone18-glucuronide.Thesevariables cholesterol levels. By way of contrast, showedlittle change,exceptfor thatof phospholipid and FFA levels progressively aldosterone18-glucuronide,whichfell sharply increased during the period of altitude ataltitudeandreboundedevenmoresharplyon exposure. High altitude had no effect on serum returnto sealevel. At altitude,basalplasma glucose concentration, but caused a slight levelsof reninactivityandaldosteronefell, and increase in serum water content. The data theresponseto orthostasiswasattenuated,but indicate that high altitude has a marked effect thefall of plasmareninactivity,ascomparedto on lipid metabolism. plasmaaldosterone,wasdelayed;onreturnto sealevelthisdissociationwasexacerbatedwith 125. Klausen T, T Mohr, U Ghisler thereturnof normalreninresponsiveness and OJ Nielsen. laggingbehindthatof aldosterone.Wesuggest Maximal oxygen uptake and thatunknownfactorswhichdissociatethe erythropoietic responses after training at orthodoxrenin-aldosteronerelationship,other moderate altitude. thantheactivityof theangiotensinI-converting European Journal of Applied enzyme,areoperativeonexposureto hypoxia. Physiology 62:376-379, 1991. Authors' Abstract 123. Kjeldsen K and F Damgaard. Six well-trained male cross-country skiers Influence of prolonged carbon trained for 7 days at 2700 m above sea level, monoxide exposure and high altitude on their accommodation being at 1695 m. Blood the composition of blood and urine in samples for haemoglobin concentration [Hb], man. erythropoietin concentration [EPO] and Scandinavian Journal of Clinical and reticulocyte count were collected before, during Laboratory Investigation 103:20-25, and after altitude exposure. Packed cell volume 1968. (PCV), red blood cell count (RBC), Authors' Abstract transferrin-iron saturation, mean red cell The influence of exposure to carbon volume (MCV), mean corpuscular monoxide (average carboxyhaemoglobin haemoglobin concentration (MCHC), maximal saturation 13 per cent) and high altitude (3,454 oxygen uptake, maximal achieved ventilation m) on a number of compounds in blood and and heart rate were determined pre- and post- urine was investigated in 8 healthy volunteers altitude exposure. The [EPO] increased for 8 and 10 days, respectively. Reticulocyte significantly from pre-altitude (mean 36 counts increased 2-3 fold; moderate increases mU ' ml l, SD 5) to maximal altitude values were seen in the urinary volume, on an average (mean 47 mU" ml _, SD 3). The [Hb] had 400-800 ml/24 hrs. Compared to the increased significantly above pre-altitude values remaining days of the study, significantly (mean 8.8 mmol ' 1-_, SD 0.5) on day 2 (mean higher amounts of sodium, chloride and 9.1 mmol' 1_, SD 0.4) and day 7 (mean 9.4 calcium were excreted on the first day of mmol" 1_, SD 0.4) at altitude and on day 4 exposure to both forms of hypoxia. post-altitude (mean 9.2 mmol" 1"t, SD 0.4). The reticulocyte counts had increased 124. Klain GJ and JP Hannon. significantly above pre-altitude values (mean Effects of high altitude on lipid 6%, SD 3%o) on day 3 at altitude (mean 12%o, components of human serum. SD 8%) and day 4 post-altitude (mean 10%, Proceedings of the Society of SD 5%). The RBC counts had increased on Experimental Biology and Medicine the 4 _hpost-altitude day. The transferrin-iron 129:646-649, 1968. saturation had decreased below pre-altitude Authors' Abstract values (mean 23%, SD 4%) on day 4 post- Serum lipid components were measured in altitude (mean 14%, SD 5%) and had increased eight male subjects exposed to an altitude of on day 11 post-altitude (mean 22%, SD 7%). 14,000 feet for 14 days. Concentrations of There were no significant changes in MCV, total lipids rapidly decreased after the third day MCHC, PCV, maximal oxygen uptake and maximal achieved ventilation, and heart rate of exposure and a similar, although less pronounced, decrease was observed in pre- to post-altitude. These observations

47 demonstratedanerythropoieticresponseto the (6,000 m) were compared in ten acclimatized altitudetrainingwhichwasnotsufficientto recumbent mountaineers a mean of 24 days, increasethepost-altitudemaximaloxygen SD 11, after descending from Himalayan uptake. altitudes of at least 4,000 m, with those found in ten non-acclimatized recumbent volunteers. 126. Klausen K, B Rasmussen, H The results showed that natriuresis and diuresis Gjellerod, H Madsen and E typified the renal responses to altitude exposure Petersen. of both the acclimatized as well as non- Circulation, metabolism and ventilation acclimatized subjects, as long as altitude was during prolonged exposure to carbon well tolerated. It was concluded that the renal monoxide and to high altitude. effects were mediated by atrial natriuretic Scandinavian Journal of Clinical and peptide release and slight suppression of Laboratory Investigation 103:26-38, arginine-vasopressin (AVP) secretion, that the 1968. increased urine flow at altitude offset the Authors' Abstract cardiac (volume) overload resulting from Eight male subjects were investigated at hypoxic stimulation of the arterial rest and work during normal sea level chemorecoptors, and that enhanced AVP conditions (control) and the results were secretion, as found in the non-acclimatized compared with experiments performed during subjects at and above 4,000 m, coincided with prolonged exposure to two different hypoxic subjective and objective distress; i.e., with conditions of the same magnitude: 1) Anemic inadequate altitude adjustment owing to hypoxia (carbon monoxide poisoning) and 2) insufficient chemoreflex effects and central hypoxic hypoxia (3454 m above sea level). hypoxia. Almost no change of circulation, metabolism and ventilation was seen during anemic 128. Koller EA, M Schopen, M Keller, hypoxia. The changes found during hypoxic RE Lang and MB Vallotton. hypoxia confirm previous investigations by Ventilatory, circulatory, endocrine, and others. From the results it was calculated that renal effects of almitrine infusion in the mean oxygen tension in the tissues during man: a contribution to high altitude rest was decreased during anemic hypoxia by physiology. about 15-20 per cent as compared to the control European Journal of Applied values, while it was unchanged during hypoxic Physiology 58:419-425, 1989. hypoxia. It is concluded that the regulatory Authors' Abstract functions of the organism during prolonged Diuresis at altitude was thought to be the exposure to hypoxia respond to a decrease of result of chemoreceptor stimulation leading to a the arterial oxygen tension. reduction of cardiac volume overload. This hypothesis was tested in ten young, healthy 127. Koller EA, A Biihrer, L Felder, subjects by infusion of almitrine (0.5 mg' kg _ M Schopen and MB Vallotton. body mass within 30 rain) assuming analogous Altitude diuresis: endocrine and renal sites of action; i.e., arterial chemoreceptors and responses to acute hypoxia of pulmonary vessels, for almitrine as for hypoxic acclimatized and non-acclimatized hypoxia. The results show that almitrine subjects. increases ventilation, heart rate, systolic blood European Journal of Applied pressure, central venous pressure, and Physiology 62:228-234, 1991. natriuresis, but fails to increase significantly Authors' Abstract atrial natriuretic peptide plasma concentration As a result of our recently published and diuresis. It is concluded: (1) that almitrine studies we have thought that altitude diuresis has similar sites of action as hypoxic hypoxia at resulting from hypoxic stimulation of the about 5000 m, (2) that natriuresis during arterial chemoreceptors reduces the cardiac arterial chemoreceptor stimulation might reduce volume overload. To test this hypothesis, cardiac volume overload, (3) that the volume cardiovascular, endocrine and renal responses excretion hypothesis, in particular the pathways to stepwise acute exposure to simulated altitude from the cardiac volume overload to the water

48 diuresis,need,for anunderstandingof the 92%, respectively. This higher loss may be the hypoxia-induceddiuresis,furtherdirect result of a combination of hypoxia and low air investigationsataltitude. temperature. The rate of excretion of osmotically free water was increased and, at its 129. Korol'kov VI, MA Dotsenko, AI height, the osmolarity of the urine decreased Grigor'ev and GI Kozyrevskaya. from 76 to 54 milliosmols/liter. The osmotic Water and mineral metabolism and index and osmotic concentration of the blood kidney function in man at high were unchanged. There was an increase in altitudes. renal excretion of sodium, but not for Fiziologiya Cheloveka 50:849-854, potassium. Arterial blood pH at 3200 m 1979. increased from 7.40 to 7.43; the true carbonate Annotation was reduced from 24.9 to 22.6, and the total Purpose CO 2 concentration was reduced from 26.2 to To study water and mineral metabolism 23.6, and the Pco2 decreased from 42 to 33 and the state of kidney function during gradual mm Hg. Although there were increases in acclimatization of man to high altitudes. circulating blood volume and hematocrit, there Methods was no change in renal plasma flow. Observations were made on six healthy Conclusions men (aged 18-25 yr) with same standard of In healthy subjects at high altitudes with training and same resistance to hypoxia by no restriction on movements, exposure to working up to their limit of tolerance on a hypoxia and low air temperature leads to bicycle ergometer in a pressure chamber during increased renal excretion of water and decrease "ascent" to an altitude of 5,000 m with a 30- in water intake. The late of excretion of min exposure. After two background osmotically active substances and sodium is observations, subjects were taken to an altitude increased, especially at 3200 m. The rate of of 2200 m for 12 days and then to 3200 m for glomerular filtration and renal plasma flow are 12 days; their motor activity was unrestricted not affected, but there are increases in after descent from mountains when they were circulating blood and packed cell volumes. The monitored for 9 days. Subjects were fed a changes in the osmo-and ion-regulatory standard diet of natural products of 3000 function of the kidneys could probably be kcal/day during the entire investigation. ascribed to changes in the hemodynamics or to Determinations were made of body neuroendocrine mechanisms of regulation of weight, and serum and urine concentrations of water and electrolyte homeostasis. The sodium, potassium and osmolality. On the 9 _h absence of hypohydration may be the result of day at 2200 and 3200 m, arterial gas graded acclimatization which promotes more composition and acid-base balance was adequate adaptive reactions of the body to determined. Hemotocrit, plasma volume, hypoxia. serum and urine creatinine levels, and renal plasma flow were determined on the subjects at 130. Kotchen TA, RP Hogan, AE 3200 m. Blood volume, packed cell volume, Boyd, T-K Li, HC Sing and JW glomerular filtration rate, resistance to blood Mason. flow in the kidneys, osmotic index and osmotic Renin, noradrenaline and adrenaline clearance of water were calculated. responses to simulated altitude. Results Clinical Science 44:243-251, 1973. At 2200 m fluid intake was unchanged, Authors' Abstract but at 3200 m it was at the initial level and 1. Plasma renin activity, plasma adrenaline remained so during the ten days of recovery. and noradrenaline concentrations, and urinary Diuresis at 3200 m averaged 280 ml above its adrenaline and noradrenaline excretion rates initial level. The excess of water intake over were measured in ten subjects during 3 days of volume of urine excreted was reduced by 22% exposure to a simulated altitude of 12,000 ft. at 2200 m and by 82% at 3200 m. Renal loss 2. In both the supine and standing of fluid during the training period was 64%; positions, renin activities were suppressed whereas at 2200 m and 3200 m it was 71% and during all 3 days at altitude.

49 3. Plasmanoradrenalineandadrenaline liquid diet with 48% of the Calories as concentrationsweresignificantlyincreasedby carbohydrate and 40% as fat. The second thethird dayataltitude. group was fed a high carbohydrate-low fat diet 4. Urinaryadrenalineexcretiontendedto (68 and 20% of the Calories, respectively). beincreasedduringtheentire3daysataltitude, Significant body weight change at altitude of with no significantchangebetweenthefirst and 3.54 and 3.96 kg in groups I and II which third day. Noradrenalineexcretionwas were partitioned into significant losses of 1.29 significantlyincreasedon thethird day. and 1.46 kg of fat, 1.77 and 1.85 kg of body 5. Thefinding of decreasedreninlevels water, 0.32 and 0.47 kg of body protein, and suggeststhattheenhancedactivityof the 0.16 and 0.18 kg of mineral, respectively. sympatheticnervoussystemathighaltitude Body weight lost in excess of that attributable doesnotstimulatereninrelease. to the caloric deficit appeared to be due to a loss of body water. Blood and plasma volumes 131. Krzywicki HJ, CF Consolazio, demonstrated significant decreases at altitude, HL Johnson, WC Nielsen Jr and which also seem to indicate hypohydration of RA Barnhart. the body. Water metabolism in humans during acute high-altitude exposure (4,300 m). 133. Lawless JJ and EJ Van Liere. Journal of Applied Physiology 30:806- The effect of various degrees of anoxic 809, 197 I. anoxia on water distribution in the Authors' Abstract body. During 6 days of altitude exposure at American Journal of Physiology 4,300 m, the following changes in body water 149:103-106, 1947. compartments were observed, a) Total body Annotation water was significantly decreased by 2.25 kg Purpose during the 6-day altitude exposure, b) To study the effect of short periods of Extracellular water appeared to increase by various degrees of anoxic anoxia on the water 1.27 kg at altitude, although not significantly. content of different tissues of animals. c) Intracellular water, in turn, was significantly Methods decreased by 3.52 kg at altitude, which is Male Wistar albino rats of 110-150 days contrary to some previous reports. Under the were used. Paired animals were weighed; one conditions of this study, with heavy physical placed in the low-pressure chamber and the activity prior to and during altitude exposure, other (control) kept in an adjacent cage for 3 and with fairly high food intakes (above 3,400 hours. The low-pressure corresponded to kcal/day), it appeared that hypohydration and a altitudes of 8,000, 18,000, and 28,000 ft. No diuresis still occurred during acute altitude food or water was permitted to the animals exposure. This suggested that body water loss during the experiment. At the end of the may have been an adaptive mechanism in acute experiment the animals were weighed and the altitude exposure. water content of the liver, adrenals, cerebellum, abdominis rectus and quadratus, skin from the 132. Krzywicki H J, CF Consolazio, back and abdomen, and kidney was LO Matoush, HL Johnson and determined. RA Barnhart. Results Body composition changes during Animals subjected to various degrees of exposure to altitude. anoxic anoxia for a period of 3 _ hours Federation Proceedings 28:1190- 1194, 1969. showed no significant changes in water content Authors' Abstract of several important tissues. The data for the Body composition was studied in two adrenal glands were inconclusive. The water content of muscles and skin was indeterminate; groups of men fed liquid diets for 8 days at sea in some cases the amount of water was level, 12 days after abrupt exposure to high increased and in others decreased. The altitude (4,300 m), and 7 days of sea level rehabilitation. One group was fed a 3,600 kcal cerebellum, kidney and liver showed no important changes in water content following

50 anoxia.All theanimalslostasignificant 135. Lawrence JH, RL Huff, W Siri, amountof weightfollowing a31/2hour LR Wasserman and TG exposureto anoxicanoxia,evenatthe Hennessy. simulatedaltitudeof 8,000feet. A physiological study in the Peruvian Conclusions Andes. Acta Medica Scandinavica Since all animals exposed to anoxic anoxia lost a significant amount of body weight and CXLII:117-131, 1952. Authors' Abstract the various organs studied did not show a 1. The rise in red cell count and hematocrit significant loss of water, it was concluded that hemoconcentration took place. Thus, the developing in the early periods after ascent to altitude is due to hemoconcentration. body, to maintain its homeostatic state, allowed 2. An increased or decreased rate in the blood (and probably the extracellular spaces) to lose water rather than the tissue plasma iron turnover and subsequent cells. Furthermore, the inconstant results incorporation of iron-59 in red cells measured suggests that there was a threshold duration of with Fe 59is the most sensitive measure yet anoxia. found for detection of change in the rate of hematopoietic activity. 134. Lawrence DL, JB Skatrud and Y 3. A change in the rate of red cell Shenker. production can explain the change in the Effect of hypoxia on atrial natriuretic number and volume of red cells resulting from factor and aldosterone regulation in variation in the oxygen in the inhaled air. It is humans. not necessary to consider a change in the duration of life of the red cell as a mechanism American Journal of Physiology of acclimatization. 258:E243-E248, 1990. Authors' Abstract 4. In agreement with the findings of others, altitude polycythemia does not resemble To evaluate the possible physiological role of atrial natriuretic factor (ANF) on the polycythemia vera in that there is no observed dissociation of aldosterone from the concomitant enlargement of the spleen or thrombocytosis or leukocytosis. renin-angiotensin system during acute hypoxia, 5. There is no evidence for an increased 7 men, ages 18-27 yr, were studied on two incidence of polycythemia vera among the separate days for 1 h under hypoxic (12% 02) Peruvian Indians living at high altitude. and normoxic (room air) conditions. Subjects 6. Ten days after descent from 14,900 feet were on a low-salt diet (urinary sodium 67 +13 to sea level, the iron turnover in the native meq / 24 h) and suppressed with Peruvian Indian decreased to one tenth that dexamethasone. Hemoglobin saturation observed in his native habitat. This approaches decreased during hypoxemia to 68 _+1% (P<0.01), whereas heart rate increased from 65 that seen in aplastic anemia. _+3 to 89 _+5 beats/min (P<0.01). Plasma aldosterone levels decreased 43% from basal 136. Leonard P J, V Blackman and KW Jones. during hypoxemia (P<0.01), whereas ANF Total body water, extracellular fluid, levels increased by 50% (P<0.05). Levels of both were unchanged during normoxemia. plasma volume and red cell mass in healthy East Africans. Plasma renin activity, angiotensin II, blood Clinical Science 29:427-431, 1965. pressure, and pH did not change under either Authors' Abstract condition, and plasma cortisol levels were totally suppressed. These results indicate that Kampala lies 830 miles inland from the east coast of Africa, 20 miles north of the acute hypoxemia is a potent stimulus for ANF release and that ANF is probably a major factor equator at an altitude of 3900 ft above sea level. responsible for the dissociation of aldosterone The air temperature fluctuates between 15°C from the renin-angiotensin system under these (60°F) and 29°C (85°F). Variations in ambient conditions. temperature and altitude are known to affect the distribution of body fluids. Increases and decreases in temperature are associated with

51 corresponding changes in the size of the plasma sustained for 4 d during hypoxia. These volume; and an increase in altitude results in an changes were associated with an immediate, increased blood volume (Conley & Nickerson, but transient, rise in plasma atrial natriuretic 1945; Hurtado, Merino & Delgado, 1945; peptide (ANP) to day 4 of 140% in HDBR and Doupe, Ferguson & Hildes, 1957). 41% in CON (p<0.005), followed by a decline Total body water, extracellular fluid, towards baseline. Differences were less plasma volume and red cell mass were striking between HDBR and CON for plasma measured in healthy medical student volunteers antidiuretic hormone and aldosterone, which so that local reference standards would be were transiently reduced by HDBR. Plasma available. catecholamines showed a similar pattern to 1. Body spaces were measured in healthy ANP (+122%) in both HDBR and CON, male subjects living at an altitude of 3900 ft suggesting that elevated ANP and above sea level and exposed to a moderately catecholamines together accounted for the high ambient temperature (15-29°C; 60-85_ _) enhanced fluid shifts with HDBR during throughout the year. hypoxia. 2. Total body water was estimated using tritiated water, the extracellular fluid volume as 138. Lozano R and C Monge C. the 35SO4 space, and plasma volume by the Renal function in high-altitude natives t3*I-lablled human serum albumin technique in and in natives with chronic mountain some subjects and by the SlCr technique in the sickness. remaining subjects. Journal of Applied Physiology 3. Plasma volume was raised by at least 5 20:1026-1027, 1965. ml/kg in those studied. Authors' Abstract 4. Other results were with.in the usually When compared with sea-level residents, accepted range of normal values. the healthy natives living at an altitude of 4,540 m show a 12% reduction in the glomerular 137. Loeppky JA, RC Roach, MA filtration rate, a 37% reduction in effective renal Selland, P Scotto, FC Luft and plasma flow, a 12% reduction in effective renal UC Luft. blood flow, and an increase of 39% in the Body fluid alterations during head- filtration fraction. The corresponding values in down bed rest in men at moderate patients with chronic mountain sickness living altitude. at 4,300 m above sea level are: glomerular Aviation, Space, and Environmental filtration rate, 32% reduction; effective renal Medicine 64:265-274, 1993. plasma flow, 57% reduction; effective renal Authors' Abstract blood flow, 9% increase; and filtration fraction, To determine the effects of hypoxia on 56% increase. The mean hematocrit values of fluid balance responses to simulated zero- the healthy and sick natives investigated were gravity, measurements were made in six 59 and 79%, respectively. The possible subjects (acclimatized to 5,400 ft; 1,646 m) relationships between cardiac output, before and during -50 continuous head-down hematocrit values, and renal hemodynamics are bed rest (HDBR) over 8 d at 10,678 ft. The discussed. same subjects were studied again at this altitude without HDBR as a control (CON) using a 139. Lyons TP, SR Muza, PB Rock cross-over design. During this time, they and A Cymerman. maintained normal upright day-time activities, The effect of altitude pre-acclimatization sleeping in the horizontal position at night. of acute mountain sickness during Fluid balance changes during HDBR in reexposure. hypoxia were more pronounced than similar Aviation, Space, and Environmental measurements previously reported from HDBR Medicine 66:957-962, 1995. studies at sea level. Plasma volume loss (-19% Authors' Abstract on day 6) was slightly greater and the diuresis Acclimatization to high altitude appears to and natriuresis were doubled in magnitude as prevent acute mountain sickness (AMS), as compared to previous studies in normoxia and evidenced by a decline in AMS symptoms as

52 acclimatization progresses. We hypothesized subsequently increased; pregnanediol and that partial retention of acclimatization would pregnanetriol levels remained unchanged. attenuate the incidence and/or severity of AMS 5. PSIs throughout the day become upon reinduction to altitude. To test this progressively lower as the length of stay at hypothesis 6 male lowlanders returned to sea altitude increased. The response to ACTH at level after acclimatizing for 16 d at 4300 m sea level and high altitude appeared to be (HA). After 8 d at sea level (PA), they were similar, but the response to a self-imposed reexposed to 4300 m in a hypobaric chamber stress was longer in duration at high altitude for 30 h (RA). AMS symptom severity was than at sea level. determined by the AMS--cerebral (AMS-C) scores calculated from the dally administration 141. Maher JT, LG Jones, LH Hartley, of the Environmental Symptoms Questionnaire GH Williams and LI Rose. during HA and RA. The mean AMS-C scores Aldosterone dynamics during graded were reduced from 0.6 on HA day 1 (HA1) to exercise at sea level and high altitude. 0.1 during RA (p<0.05). Four subjects were Journal of Applied Physiology 39:18- "sick" (AMS-C >0.7) during HA1, while only 22, 1975. one was "sick" during RA. The % Authors' Abstract oxyhemoglobin, hemoglobin concentration and Hormonal responses to graded exercise of hematocrit were higher during RA compared to eight low altitude residents were examined at HA1. These results suggest that the retention sea level (SL) and after 1 (acute) and 11 of acclimatization after 8 d at low altitude is (chronic) days at 4,300 m (HA). Caloric, sufficient to attenuate AMS upon reinduction to water, and electrolyte intakes were controlled, high altitude. as were temperature and humidity. Blood was sampled at rest and during light and moderate 140. Mackinnon PCB, ME Monk-Jones upright bicycle exercise (20 min at 40% and and K Fotherby. 75% of maximal O2uptake, respectively). A study of various indices of Mean V O2m,x at HA was 27% lower than at adrenocortical activity during 23 days at SL. Resting plasma levels of aldosterone high altitude. (Aldo), renin, and angiotensin II (AII) were Journal of Endocrinology 26:555-566, significantly lower (P<0.05) on day 1 at HA 1963. compared to SL, but returned to SL values by Authors' Abstract day 11. Plasma cortisol values at rest were 1. Four men and three women ascended similar at SL and HA and were not significantly by trl_pherique and helicopter from 1000 to altered by light or moderate exercise. Renin, 4333 m. where they remained for 23 days. AII, and Aldo rose progressively with 2. Measurements of urinary 17- increasing workload in each environment. hydroxycorticosteroids, 17-oxosteroids, With acute HA, renin and Aldo were lower pregnanediol and pregnanetriol and circulating than at either SLor chronic HA. The chronic eosinophils were made at sea level and at high HA levels tended to approximate SL findings, altitude. implying adaptation. The data suggest that 3. An attempt was also made to measure aldosterone is predominantly under the control changes in emotional activity by means of the of the renin-angiotensin system during graded palmar sweat index (PSI). This index was exercise at sea level; and that the response of assessed at intervals throughout the day at sea this system is altered on acute high-altitude level and at high altitude, and in response to exposure. adrenocorticotrophic hormone (ACTH) and a self-imposed stress. 142. Malhotra MS, HD Brahmachari, 4. Within 24 hr. of acute exposure to high K Sridharan, T Purshottam, K altitude urinary 17-hydroxycorticosteroids Ramachandran and U increased whilst circulating eosinophils Radhakrishnan. decreased; by the 5 thday both were returning to Electrolyte changes at 3500 m in males sea-level values. The output of 17-oxosteroids with and without high-altitude was lower by the 5 _ day at high altitude and pulmonary edema.

53 Aviation, Space, and Environmental at HA, indicating a relative hyperactivity of the Medicine 46:409-412, 1975. sympathetic system. After a stay of 1 week, Authors' Abstract there was a gradual recovery in all the Ten normal healthy male subjects between responses, though sympathetic hyperactivity 20-30 years of age were initially examined at was still maintained throughout the 3 weeks of Delhi (200 m) and thereafter airlifted to an stay. In AL also there was a preponderance of altitude of 3,500 m. Excretion of sodium, sympathetic activity, though of relatively lesser potassium and chloride in urine and their magnitude than that seen in sojourners. In plasma level were determined at sea level (SL) HAN, on the other hand, there was a relative and daily at high altitude (HA) for 4 d. At HA, parasympathetic predomination. It has been four subjects developed high-altitude concluded that in lowlanders it takes more than pulmonary edema (HAPE), four remained a year of stay at altitude for complete recovery normal, and two suffered from acute mountain of autonomic balance. sickness. The results on normals and HAPE are presented. There was increased excretion 144. Mandelbaum IM, P Fondu, Ch of potassium at HA in both groups resulting in Heyder-Bruckner, A Van reduction of plasma level. The sodium and Steirteghem and S Kabeya- chloride excretion was also increased in Mudiay. normals at HA irrespective of urine volume. In Erythrocyte enzymes and altitude. HAPE cases, the sodium and chloride excretion Biomedicine 19:517-520, 1973. was related to urine output. With the retention Authors' Abstract of fluid, the excretion of these ions in urine The activities of erythrocyte glucose-6- was diminished without a parallel change in phosphate dehydrogenase (G6PD), hexokinase plasma levels. (HK) and pyruvate-kinase (PK) are significantly higher in healthy subjects living in 143. Malhotra MS, W Selvamurthy, villages located along the western shore of SS Purkayastha, AK Mukherjee, Lake Kivu (altitude I- 460 to 2000 m) than in L Mathew and GL Dua. healthy subjects living in Brussels (altitude 90 Responses of the autonomic nervous m). This phenomenon is obvious in 2 system during acclimatization to high genetically well different groups (Bashi and altitude in man. Belgians). No difference is found for Aviation, Space, and Environmental 6-phosphogluconate dehydrogenase (6PGD). Medicine 47:1076-1079, 1976. The differences of activity are attributed to the Authors' Abstract effect of altitude. The mechanisms involved A study has been conducted on 20 and the role of these modifications are discussed. sojouners, between the ages of 20-30 years, to evaluate responses of the autonomic nervous system during acclimatization to high altitude. 145. Maresh CH, BJ Noble, KL The responses measured consisted of heart rate Robertson and JS Harvey Jr. (HR), blood pressure (BP), oral temperature Aldosterone, cortisol, and electrolyte (Tot), mean skin temperature (Tsk), cold pressor responses to hypobaric hypoxia in moderate-altitude natives. response (CPR), orthostatic tolerance to tilt, and urinary catecholamines. The subjects were Aviation, Space, and Environmental tested initially at Delhi (altitude 260 m) and, Medicine 56:1078-1084, 1985. thereafter, on acute induction to an altitude of Authors' Abstract 3560 m periodically for 3 weeks. For Serum aldosterone, cortisol, and comparison, the same responses were studied electrolyte concentration; and urinary on 10 acclimatized lowlanders (AL) who had aldosterone and electrolyte excretion responses been staying at the same altitude for more than were examined in seven low-altitude natives a year and on 10 high-altitude natives (HAN). (LAN), (373 m or less, aged 19-25 yr) and The studies showed a rise in HR, BP, Tot, and nine moderate-altitude natives (MAN), (1,830- urinary catecholamines, and a fall in Tsk, CPR, 2,200 m, aged 19-23 yr) for 2 d at their own and orthostatic tolerance immediately on arrival residence (home) altitude (PB 740 or 585 mm

54 Hg,respectively):andlaterfor 2 dduring Thus it appears that high-altitude Aldo decompressionata simulatedaltitudeof 4,270 concentrations are more like resident altitude m (PB447mm Hg). TheLAN group values in MAN than LAN subjects. demonstratedhigher(p<0.05)serumcortisol concentrationsandrespirationrates,andlower 147. McDonald RK and VC Kelley. (p<0.05)serumaldosteroneandpotassium, Effects of altitude anoxia on renal andurinaryaldosterone,sodium,and function. potassiumconcentrationsat certaintimes American Journal of Physiology duringdecompressioncomparedto theirhome 154:193-200, 1948. responses.Moderate-altitudenativeresponses, Authors' Abstract on theotherhand,weregenerallyunchanged. Five dogs were subjected to renal function Manifestationsof acutemountainsicknessatPB studies at ground level and at simulated 447mmHgwerealsosignificantlygreaterin altitudes of 18,000 ft and of 24,000 ft. In all theLAN group. Thus,it appearsthattheMAN cases CpAH determinations were started five subjectswereinfluencedlessby thedropin minutes after reaching the desired altitude. In ambientoxygentensionassociatedwith PB447 the case of the group 2 animals, Tmpx H mmHg. measurements were likewise started five minutes after attaining the desired altitude, 146. Maresh CM, BJ Noble, KL while in the case of the group 1 animals the Robertson and RL Seip. Tmp_ measurements were started Adrenocortical responses to maximal approximately 75 minutes after attaining the exercise in moderate-altitude natives at desired altitude. The glomerular filtration rate 447 Torr. in these animals was either increased, Journal of Applied Physiology 56:482- decreased or unaffected depending upon the 488, 1984. reaction of the individual animal to reduced Authors' Abstract ambient pressure. The effective renal plasma Serum hydrocortisone and aldosterone flow was increased in all dogs at an altitude of (Aldo) responses to maximal exercise were 18,000 feet and was further increased in one examined in six low-altitude natives (LAN), dog, but decreased below the ground level (373 m or less, aged 19-25 yr) and eight values in the remaining dogs at 24,000 feet. moderate-altitude natives (MAN), (1,830- The maximum tubular excretory ability was 2,200 m, aged 19-23 yr) at their residence markedly increased at 18,000 feet in 1 animal (home) altitudes (740 and 587 Tort, and at 24,000 feet in 2 of the 5 animals studied. respectively): and later in a hypobaric chamber at a simulated altitude of 4,270 m (447 Torr). 148. McFarland RA and HT Edwards. After 2 days at their respective residence The effects of prolonged exposures to altitude and in the chamber, each subject altitudes of 8,000 to 12,000 feet during exercised to voluntary exhaustion on the Trans-Pacific flights. bicycle ergometer. Fluid intake was similar in Journal of Aviation Medicine 8:156- both groups at all testing locations. Preexercise 177, 1937. 24-h urinary Aldo was lower in both groups at Authors' Abstract 447 Torr, but only significantly reduced in the This investigation was carried out on a LAN group. In general, the changes in routine flight of the Pan American Clipper Ship maximum exercise cardiorespiratory variables between Alameda, California and Manila, P.I., were twice as large in LAN as in MAN subjects and return in order to analyze the effects of going from residence altitude to 447 Torr. prolonged exposures to altitudes averaging Both serum hydrocortisone and Aldo 9,460 feet on seventeen airmen and eleven concentrations were increased (P<0.01) after passengers. The total flying distance of 14,141 exercise in both groups at residence altitude and nautical miles involved 122 _ hours in the air. 447 Torr. Aldo was lower (P<0.05) A series of physiological, biochemical and postexercise at 447 Torr than at residence psychological studies were made during the altitude in both groups, but this decrease was flights and at the various Island stations. The more pronounced (P<0.01) in the LAN group.

55 following conclusions may be drawn from the a slight decrease in the mean Schneider index data obtained on these airmen and passengers: for the eight airmen. 1. These subjects, both airmen and 5. The index of the minute volume of the passengers, maintained a high degree of circulation (pulse rate x pulse pressure) neurocirculatory efficiency throughout the indicated that the load on the heart was flight as judged by the individual items and consistently greater at high altitude compared composite score of the Schneider index. When with sea level (Table III); and that as the flight the test was given in the basal state; i.e., before progressed, particularly in the tropical climate rising, none of the airmen tested below +7, a of Manila, there was a gradual yet consistent score frequently related to a significant degree increase in this index (not to be taken as a of fatigue or unfitness in aviators. Out of a measure of cardiac output). total number of tests in the basal state of 142, 6. There was a tendency toward polyuria only two subjects tested below +10, the in these airmen, as commonly observed in average being +13, close to the mean of +14.8 athletes previous to competition, particularly in for college athletes (cf. Table VI_. The basal those who shared the greatest responsibility in state (fifty-four tests) was 11.5, only three tests handling the ship. As the flight progressed and falling below +7 throughout the flight. The the airmen became acclimatized, the polyuria mean score for the group at high altitude was diminished. +10.8. Out of a total number of ninety-six 7. The partial pressure of oxygen and tests given at a mean altitude of 9,500 feet carbon dioxide in the alveolar air and arterial (seventeen airmen and eleven passengers), only blood on these airmen was similar to values four fell below +7. considered as normal for acclimatized man at 2. There appeared to be a general tendency similar altitudes, suggesting that the added toward low blood pressure as the flight burden of flying the ship had no impairing progressed, similar to that observed in effect on the respiratory mechanism (cf. Table acclimatized workmen at high altitude in the IV). The mean alveolar pO 2 in the acclimatized Andes. Six of the eight airmen had systolic airmen averaged 4.8 mm higher than in blood pressures below 110 (mean age for unacclimatized passengers during rapid ascents group, thirty-two years). There was a to similar altitudes. consistant increase of 5 mmHg in systolic 8. There was an increase of approximately pressure on standing when taken in the basal 10 per cent in the red blood cells at high altitude state. This was, on the average, not true when (cf. Tables V and VI). After five to six days at taken in the non-basal state and at high altitude sea level, the counts returned to more normal (cf. Table II). The initial response to the values in nine of the eleven airmen. Even after altitude during the flights usually showed an eleven days at sea level, however, two of these increase in pulse rate and an increase in systolic airmen had counts 16 per cent and 18 per cent blood pressure, followed by a well controlled above the usually accepted value of 5.0 million fall to normal values if the subject remained at for man at sea level, suggesting a more stable rest. acclimatization in these individuals. 3. As the flight progressed, there was a 9. The normal non-protein nitrogen, blood tendency for the pulse rate to show a greater sugar and cholesterol values suggest that there increase after exercise and a longer time (in was no serious upset of the protein, seconds) for the pulse to return to the normal carbohydrate or fat metabolism of these airmen standing rate. As might be anticipated, this (cf. Table V). The normal values for blood was also true at high altitude while in flight. sugar suggest that there was no intense 4. There was a consistent decrease in the emotional excitement and increased secretion of Schnieder scores in Manila. This was related adrenalin while in flight. to the increased pulse rate due to the high 10. The alterations in the psychological humidity and temperature of that region. After tests of sensory (primarily vision) and mental resting two days in Manila and sleeping in air- functions (primarily quickness of reaction time conditioned quarters, there was an for meaningful material, close attention, and improvement in the Schneider indices. After a memory), on the average, showed no rest period of one week of Honolulu, there was significant alterations at 10,000 feet to 12,000

56 feetcomparedwith sealevelin theseairmen structure and function as measured by these andin two of thepassengers(cf.TableVII). noninvasive techniques. 11.In general,theconclusionmaybe drawnfrom thisinvestigationthatthe17 150. Meehan RT. airmenstudiedduringtypicaltrans-Pacific Renin, aldosterone, vasopressin, operationsbecameacclimatizedtothehigh cortisol and urine electrolyte responses altitudeandmaintainedahighdegreeof mental to hypoxia during exercise. andphysicalefficiencythroughouttheflight. In: Hypoxia, Exercise, and Altitude. The 11passengersof averageageandfitness Proceedings of the 3 rd Banff studied,althoughnotmanifestingthesame International Hypoxia Symposium, degreeof acclimatizationastheairmen,showed edited by JR Sutton, CS Houston, and noobjectivesignsof fatigueorphysical NL Jones. New York: AR Liss Inc., distress. 1983. p.A465. (Abstract). Author's Abstract 149. McKenzie DC, LS Goodman, C The effect of exercise (treadmill: 0 grade, Nath, B Davidson, GO 1 mph, 1000-1600 hrs) at simulated high Matheson, WS Parkhouse, PW altitude (4,760 m) on mean arterial pressure Hochachka, PS Allen, C Stanley (MAP), endocrine responses and urinary and W Ammann. sodium and potassium excretion (U_ V, U K V ) Cardiovascular adaptations in Andean during normoxia (N; room air) and hypoxia (H; natives after 6 wk of exposure to sea FrO 2 12.5%, PaO 2 42 _+3 mmHg) was tested in level. seven male volunteers. A crossover study was Journal of Applied Physiology performed during steady state conditions of 70:2650-2655, 1991. H20, Na and K balance. After exercise, N vs Authors' Abstract H did not differ in: body weight, hematocrit Six male Quechua Indians (34.0 +_1.1 yr, Posm, Uosm, UNaPt UK V or P vasopressin. 159.5 +_2.1 cm, 60.5 _+1.6 kg), life-long MAP was reduced during H (86 +_2 vs 92 _+4 residents of La Raya, Peru (4,350-m altitude mmHg) despite an increased heart rate (102 +_3 with an average barometric pressure of 460 vs 87 _+3), p<0.05. Torr), were studied using noninvasive methods to determine the structural and functional Normoxia (N) Hypoxia (H) 1000hrs 1600hrs 1000hrs 1600hrs changes in the cardiovascular system in P Cort 5.8_+0.9 5.1+1.3 5.8_+0.9 8.2-+1.3 response to a 6-wk deacclimation period at sea g/dl level. Cardiac output, stroke volume, and left P Aldo6.5-+l.3 2.8_+0.5* 9.3-+1.2 2.3_-2-0.2* ventricular ejection fractions were determined ng/dl using radionuclide angiographic techniques at PRA 3.3_+0.6 2.4_+0.4 4.9-!-_1.0 2.3_+0.6* rest and during exercise on a cycle ergometer at ng/ml/hr 40, 60, and 90% of a previously determined *P<0.05, 1000 vs 1600, mean _+SE maximal 02 consumption. Subjects at rest Both N and H exercise abolished normal were subjected to two-dimensional and M- diurnal variation in P cortisol. Exercise mode echocardiograms and a standard 12-lead resulted in decreases in P aldosterone and P electrocardiogram. Hemoglobin and hematocrit renin activity which were greater during H than were measured on arrival at sea level by use of N. Conclusion: six hours of continuous low a Coulter Stacker S÷ analyzer. After a 6-wk level exercise depresses the renin-angiotensin- deacclimation period, all variables were aldosterone system. Moderate hypoxia remeasured using the identical methodology. enhances this depression and lowers MAP. Hemoglobin values decreased significantly over the deacclimation period (15.7 _+1.1 to 151. Meehan RT. 13.5 _+1.2 g/dl; P<0.01). The results indicate Renin, aldosterone, and vasopressin that the removal of these high-altitude-adapted natives from 4,300 m to sea level for 6 wk responses to hypoxia during 6 hours of mild exercise. results in only minor changes to the cardiac Aviation, Space, and Environmental Medicine 57:960-965, 1986.

57 Author's Abstract brought to sea level where they were observed The effect of hypoxia (H) on plasma renin during five weeks. (PRA), aldosterone (PA), and arginine 3. Subjects, residents of high altitude vasopressin levels (AVP) was evaluated during (Morococha), who had lost their adaptation to 6 h of mild exercise (treadmill: 0 grade, 1 it; i.e., who had developed chronic altitude mph). A crossover study was performed on sickness of Soroche (Monge's malady). seven male volunteers during steady state The observations carried out permit the conditions of H20, Na ÷ and K ÷ balance while following conclusions: breathing 12.5% 02 (PaO 2 42 +_3mmHg) and 1. The polycythemic process of subjects room air (N, 21% 02). After exercise there with anoxia caused by a low pressure were no significant differences in body weight, environment is due to a greater blood formation hematocrit, calculated plasma volumes, serum by the hematopoietic organs. This becomes or urine osmolaltiy, urine Na ÷ or K + excretion manifest after forty-eight hours. The very or AVP. Mean arterial pressure (MAP) while discreet polycythemia frequently found during exercising was reduced during hypoxia (86 +_2 the ftrst hours is probably the result of vs. 92 _+4 mmHg, p<0.05). Normal diurnal hemoconcentration and release of stored blood. variation in serum cortisol was lost during 2. This polycythernic process is not exercise (N and H). Plasma renin and accompanied by quantitative alterations of the aldosterone levels fell with exercise in both leukocytes nor of the platelets; thus, differing groups: PRA N 3.3 to 2.4 vs. H 4.9 to 2.3 from polycythemia vera, in which there is as a ng' ml "_' hl; PA N 6.5 to 2.8 vs. H 9.3 to 2.3 rule an increase in all the hematologic elements. ng" dl 1 (p<0.05). Hypoxia per se did not 3. The increased blood volume of exert influence beyond mild exercise regarding residents at high altitude is due exclusively to serum osmolality, urine osmolality or Na ÷or the increased red cell mass, the plasma volume K ÷ excretion. Sustained hypoxia during 6 h of being more likely to be found diminished. mild exercise despite a lower MAP failed to 4. In normal subjects who are temporarily elevate PRA, aldosterone, or AVP levels when or permanently exposed to an atmosphere of normal hydration is maintained. low barometric pressure, the excretion of fecal urobilinogen does not exceed the limits 152. Merino CF. considered normal at sea level, but increases Studies on blood formation and with relation to the larger circulatory destruction in the polycythemia of high hemoglobin mass, a normal hemolytic index altitude. being maintained. The Journal of Hematology V: 1-31, 5. The hyperbilirubinemia very frequently 1950. found in the natives and in those resident for a Author's Abstract long time at high altitudes appears to be related Studies of blood formation and destruction to a lesser excretion of this pigment by the in the polycythernia of high altitude have been liver, probably on the basis of the anoxic state. carried out. Three different groups of subjects The greater production of bilirubin in subjects were studied: at high altitude is not sufficient to explain, in 1. Healthy adult male subjects from sea and of itself, the pigmentary elevation in the level who, after being studied at this level, blood. were taken to an altitude of 4,540 meters 6. The mechanism of the disappearance of (Morococha) where they developed a marked the polycythemia when the subjects from a high polycythemic process. When these subjects altitude are brought to sea level, appears to be returned to sea level, the mechanisms of as follows: (a) temporary diminution or recuperation of the hematologic equilibrium inhibition of erythropoiesis, and (b) a greater were studied. blood destruction. The latter takes place only 2. Normal adult subjects, natives of high during the first days of stay at sea level, being altitude, chronically polycythemic due to their chiefly responsible for the early rapid decrease permanent residence in Morococha, who were of the degree of polycythemia, while the former first studied in their native town and then acts in a more prolonged form and is principally responsible for the erythropoietic "normalization."

58 7. In twocasesof chronic altitude level of polycythemia found in the peripheral sickness, or chronic Soroche (Monge's blood. disease), the output of fecal urobilinogen 3. Myeloid cells and megakaryocytes were exceeded proportionally the increase of the not increased and the maturation process was circulatory hemoglobin mass. The hemolytic normal in both the erythroid and myeloid index was found abnormally high. series. 8. The above findings indicate that the 4. The foregoing findings seem to confirm polycythemia of the normal individual residing further the opinion, previously expressed and at high altitudes is characterized by a derived from studies on peripheral blood, that proportional and direct accentuation in the anoxia acts as a specific stimulus for an processes of blood formation and destruction. increased activity in the formation of the On the other hand, in those subjects also erythroid cells leaving the myeloid cells residing at high altitudes, who exhibit an unaffected. abnormally high polycythemia (chronic 5. A comparative study of our findings Soroche), the accentuation in the processes of and those obtained in similar investigations blood destruction is proportionally greater than made by several observers in cases of that corresponding to the greater polycythemia vera seems to indicate that, in erythropoiesis. This characteristic constitutes a general, the bone marrow cytology and the possible diagnostic criterion and can perhaps degree and kind of hemopoietic hyperactivity explain in part the etiologic mechanism of this are not similar in the polycythemia of high alteration. altitudes and in polycythemia vera. This fact does not conform with the theory that anoxia is 153. Merino CF and C Reynafarje. the underlying etiologic factor in the latter Bone marrow studies in the disease. polycythemia of high altitudes. Journal of Laboratory and Clinical 154. Miles DS, DR Bransford and SM Medicine 34:637-647, 1949. Horvath. Authors' Abstract Hypoxia effects on plasma volume The bone marrow of sixteen, healthy, shifts at rest, work, and recovery in Indian natives of adult age, permanent residents supine posture. in Cerro de Pasco at an altitude of 4,390 meters Journal of Applied Physiology 51:148- (14,400 feet), was studied. Samples were 153, 1981. obtained by means of sternal aspiration, and Authors' Abstract supravital and Wright stained preparations were The purpose of this study was to used for the qualitative as well as quantitative determine the effects of acute exposure to microscopic examinations. All men showed a hypoxia (<1.5 h; gas mixture 12.6% 02-87.4% definite polycythemia in the peripheral blood. N2) on plasma volume (PV) shifts during rest The results obtained were compared with and exercise. Nine unacclimatized males previous observations made in healthy people performed identical protocols in the supine living at sea level and in patients with posture in both normoxic (N) and hypoxic (H) polycythemia vera. conditions. The protocol was rest 60 rain, 1. The bone marrow of healthy, adult submaximal exercise (PWCt4 o, work rate natives, living permanently at an altitude of eliciting a heart rate of 140 beats/rain) for 30 4,390 meters (14,400 feet), was interpreted as rain, immediately followed by maximal showing hyperplasia (hypercellularity) in 81.2 exercise, and 10 rain of passive recovery. per cent of the subjects examined. There were slight but significant losses of 2.7 2. This hyperplasia was characterized by a and 1.4% PV at rest in H and N conditions, marked increase of the cells of the erythroid respectively. At the same relative intensity of series over the myeloid cells. Normoblasts submaximal exercise (work loads reduced by were the most predominant cellular elements 22% in H conditions), PV losses were nearly (normoblasfic hyperplasia), and a reversed M/E identical (N = 11.2%, H = 11.8%). There was ratio was a constant finding. The degree of a further PV efflux subsequent to maximal hyperplasia was not always proportional to the exercise (N = 7.9%, H = 5.2%). The

59 maximumPV effiux, fromthebeginningof to 4300 m on Mount Kenya. Control restto theendof maximalexercise,was20% measurements were made over 2 days at 1300 for bothconditions. Totalplasmaprotein(PP) m before ascent and for 2 days after amval at contentwasunchangedduringrestor exercise 4300 m. These included body weight, 24 h for eitherN or H conditions.After 10rain of urine volume, 24 h sodium and potassium recovery,restitutionof PV was 10%below excretion, blood haemoglobin, packed cell preexercisevaluesfor bothN andH volume, and symptom score for acute mountain conditions.We concludethatacutehypoxic sickness. In 15 subjects blood samples were exposuredoesnot influencethelossof PV or taken for assay of plasma aldosterone and atrial PPduringsubmaximalor maximalexercise. natriuretic peptide. 2. Altitude and the exercise in ascent 155. Milledge JS. resulted in a marked decrease in 24 h urine Salt and water control at altitude. volume and sodium excretion. Aldosterone International Journal of Sports levels were elevated on the f'u'st day and atrial Medicine 13:$61-$63, 1992. natriuretic peptide levels were higher on both Author's Abstract altitude days compared with control. The physiological effect of altitude 3. Acute mountain sickness symptom hypoxia, in the absence of exercise, is a scores showed a significant negative correlation sodium and water diuresis with decrease in with 24 h urinary sodium excretion on the fu'st plasma and extra-cellular volumes. Plasma altitude day. Aldosterone levels tended to be aldosterone concentrations (PAC) are reduced, lowest in subjects with low symptom scores but plasma atrial natfiuretic peptide (ANP) and higher sodium excretion. No correlation levels are modestly increased. Day-long was found between changes in haemoglobin exercise at low altitude has almost opposite concentration, packed cell volume, 24 h urine effects on fluid balance. There is an anti- volume or body weight and acute mountain diuresis, sodium retention, expansion of the sickness symptom score. plasma and extra-cellular compartments, 4. Atrial natriuretic peptide levels at low elevation of PAC and ANP. Subjects who altitude showed a significant inverse correlation develop acute mountain sickness (AMS) show with acute mountain sickness symptom scores a pathological response to hypoxia even before on ascent. the development of symptoms. There is an anti-diuresis, sodium retention, increased 157. Milledge JS, EI Bryson, DM plasma and extra-cellular volumes and Catley, R Hesp, N Luff, BD increased PAC compared with subjects Minty, MWJ Older, NN Payne, resistant to AMS. Plasma ANP tends to be MP Ward and WR Withey. elevated compared with sea level values, but Sodium balance, fluid homeostasis and the relation of ANP levels to AMS is variable. the renin-aldosterone system during the In general therefore, the pathological response prolonged exercise of hill walking. to altitude hypoxia parallels that of exercise at Clinical Science 62:595-604, 1982. low altitude and is opposite to the physiological Authors' Abstract response. Both exercise and the pathological 1. The effect of 5 consecutive days of hill response predispose the subject to edema and walking on electrolyte balance, fluid are probably important in the genesis of AMS. homeostasis, plasma renin activity and plasma aldosterone concentration was studied in five 156. Milledge JS, JM Beeley, S male subjects. McArthur and AH Morice. 2. The 5-day exercise period was preceded Atrial natriuretic peptide, altitude and by a 4-day control period and followed by a 4- acute mountain sickness. day recovery period. Throughout the 13-day Clinical Science 77:509-514, 1989. study subjects ate a fixed diet. Authors' Abstract 3. After 5 days of exercise subjects had 1. To investigate the mechanisms of acute retained a mean of 264 mmol (SD 85) of mountain sickness, 22 subjects travelled to sodium. Plasma sodium concentration 3100 m by road and the following day walked remained constant at 142.0 mmol/1 (SD 5.4).

60 Thisindicatesanexpansionof theextracellular usual close relationship between PAC and PRA spaceby 1.84litres. by reducing ACE activity. 4. By theendof theexerciseperiodthere wasapositivewaterbalanceof about0.9litre. 159. Miiledge JS and DM Catley. Thustherewasa netmovementof 0.94litre of Angiotensin converting enzyme fluid from theintracellularto theextracellular response to hypoxia in man: its role in space. altitude acclimatization. 5.Packedcell volumedecreasedfrom a Clinical Science 67:453-456, 1984. meanof 43.5%to 37.9%after5 daysof Authors' Abstract exercise,indicatingthatabout0.9liter of the 1. The response of serum angiotensin extracellularfluid enteredthevascular converting enzyme (ACE) activity to three compartment.Theremainingfluid maybe grades of hypoxia was studied in two groups responsiblefor thesignificantincreasein lower of human subjects. Hypoxic gas mixtures legvolume. having oxygen concentrations of 14, 12.6 and 6. During theexerciseperiodplasma 10.4% were breathed successively for a period aldosteroneconcentrationandplasmarenin of 10 min at each concentration. Venous blood activityrose,andtherewasahighly significant was sampled at the end of each of the three correlationbetweenthesevaluesandthe periods and arterial oxygen saturation was sodiumretention. Therewasalsoasignificant recorded throughout the experiment. correlationbetweensodiumretentionandthe 2. The subjects were selected as being increasein leg volume,whichsuggeststhat 'good' or 'poor' acclimatizers according to oedemamaybe theresultof prolongedexercise their history of acute mountain sickness. There of thistype. were five subjects in each group. 3. Hypoxia resulted in a reduction in ACE 158. Milledge JS and DM Catley. activity in both groups, the reduction being Renin, aldosterone, and converting linear with respect to arterial oxygen saturation. enzyme during exercise and acute 4. The reduction in ACE activity was hypoxia in humans. greater in the good acclimatizer group as shown Journal of Applied Physiology 52:320- by a significantly greater slope of the response 323, 1982. line of ACE activity to arterial oxygen Authors' Abstract saturation. The possibility that hypoxia might inhibit 5. The significance of this finding in the secretion of angiotensin-converting enzyme relation to the mechanism underlying acute (ACE) would explain the low concentrations of mountain sickness is discussed. aldosterone reported in humans at high altitude. To observe the effect of such a reduction in 160. Milledge JS and DM Catley. ACE concentration on the plasma aldosterone Angiotensin converting enzyme activity concentration (PAC); four subjects performed and hypoxia. mild exercise throughout a 2-h study so as to Clinical Science 72:149, 1987. elevate their plasma renin activity (PRA). Authors' Abstract After the first 60 rain breathing air, they were Subsequent to the publication of our paper switched to breathing 12.8% O 2 (4,000 m on serum angiotensin converting enzyme altitude equivalent). Venous samples were activity (ACE) and hypoxia, we have further taken at intervals for hormone analysis. investigated this effect in man in one study at Results showed the expected rise of PRA and altitude and five laboratory studies at sea level. PAC both tending toward a plateau after about In the study at altitude (4100 m), in six 45 min. There was no significant change in subjects a total of 12 sea level and 56 altitude ACE activity (F = 0.065). Hypoxia produced a serum samples were taken. In the five further 50% rise in PRA but a fall in PAC and laboratory studies, nine subjects (some studied 30% reduction in ACE activity. Angiotensin I on a number of occasions) breathed low concentrations closely followed PRA oxygen gas mixtures (14-10% O 2 for periods throughout (r = 0.984). These results indicate, up to 30 rain): 26 control and 36 hypoxic that during exercise, acute hypoxia changes the serum samples were collected. Samples were

61 analysedin ourown laboratoryby the on first ascent to altitude, PAC and ACE are Friedland& Silversteinfluorimetricmethod reduced, whereas PRA may be raised or andalsobyDr. R. Bird at theRoyalNorthern reduced. After 2-4 wk at 6,300 m all Hospitalusingthesamemethod.In thelast hormones had returned to within +10% of sea- four laboratorystudies(32 serumsamples),the level values. In seven subjects PRA and PAC samesampleswerealsoanalysedby Mr C. were measured when exercise stopped. PRA Dickensof theClinicalChemistryDepartment and PAC were both elevated, PRA more than here,usingacentrifugalanalysermethod. PAC; i.e., the PAC response to PRA was Theresultsof all thesestudiesshowedthat markedly blunted. Since ACE activity was hypoxia,inducedeitherby goingto altitudeor normal, it is suggested that there may be down bybreathinghypoxicgasmixturesat sealevel, regulation, i.e., reduction in density of hadno effecton serumACE activity. In angiotensin II receptors on the adrenal cortex addition,Dr J.W.Ryanof theDepartmentof and/or induction of enzymes which degrade Medicine,Universityof Miami, re-analysed angiotensin II. This mechanism apparently somearchivedserumsamplesfrom anearlier protects the subjects from very high levels of unpublishedstudyusinghis radioactive PAC and sodium retention when hypoxia and substratemethodandalsofoundno difference exercise raise PRA to very high levels. betweencontrolandhypoxicsamples. We cannotaccountfor ourearlierfindings 162. Milledge JS, DM Catley, MP demonstratinganeffect of hypoxiaon serum Ward, ES Williams and CRA ACE activity. We believethatthetruesituation Clarke. is thathypoxia,acuteor chronic,hasno effect Renin-aldosterone and angiotensin- andwe wishto retractthefindingsthatwe converting enzyme during prolonged publishedpreviously. altitude exposure. Recentlyotherinvestigatorshaveshown Journal of Applied Physiology 55:699- thathypoxiadoesnoteffectACE activity. 702, 1983. Thesesupportthepreviouswork of Pitt & Authors' Abstract Lister andCatravas& Gillis, andthemost The effect of 7 week altitude exposure on recentpaperon thesubjectfoundonly some plasma renin activity (PRA), plasma 20%reductionin transpulmonaryconversion aldosterone concentration (PAC), and of ANG I to ANG II in hypoxia. Onepaper angiotensin-converting enzyme (ACE) activity claiminganeffectin endothelialcellculturehas was studied in 10 male subjects at 4,500 m. beenwithdrawn. There was an initial increase in PRA and a Ourstartingobservation,thathypoxia reduction in PAC and ACE. The reduction in reducesthealdosteroneresponseto arisein ACE was significantly greater in the four plasmareninactivity, hasbeenconfm'ned. subjects who had frequently been exposed to This wouldseemnotto bedueto anyreduction extreme altitudes than in the other six subjects. in ACE activityaswasfirst suggested,andthe These changes had returned to control values mechanismremainsunexplained. between 12 and 20 days. Exercise caused a marked elevation of PRA and PAC, but the 161. Milledge JS, DM Catley, FD PAC response to PRA was blunted compared Blume and JB West. with that at sea level. The ratio PAC/PRA at Renin, angiotensin-converting enzyme, rest was reduced initially but returned to control and aldosterone in humans on Mount values with a similar time course to that of ACE Everest. activity. The results are compatible with the Journal of Applied Physiology hypothesis that ACE activity governs the 55:1109-1112, 1983. adrenal response to PRA. Authors' Abstract Plasma renin activity (PRA), serum 163. Milledge JS, DM Catley, ES angiotensin-converting enzyme (ACE) activity, Williams, MP Ward, CRA and plasma aldosterone concentration (PAC) Clarke, JB West and FD Blume. were measured in 15 subjects at sea level and at The effect of chronic hypoxia on the high altitude. Previous work has shown that, renin-aldosterone system in man.

62 In: Hypoxia, Exercise, and Altitude. 4-day recovery period at low altitude. Daily Proceedings of the 3 rd Banff blood samples were taken for estimation of International Hypoxia plasma renin activity (PRA), plasma aidosterone concentration (PAC), and Symposium, edited by JR Sutton, CS Houston, and NL Jones. New York: angiotensin converting-enzyme (ACE) activity. Results showed a maximal rise in PRA and AR Liss Inc., 1983. p.A465-A466. PAC with exercise at altitude maximal on the (Abstract). Authors' Abstract first 2 days. ACE activity fell by 23% at altitude. Compared with similar exercise at sea Expeditions to Mt. Kongur (7,719m) in China and to Mt. Everest afforded level, the rise in PAC was comparable but the rise in PRA was four times greater, indicating a opportunities to study the effect of chronic marked decrease in PAC response to PRA. It hypoxia on the renin-aldosterone system in is suggested that this loss of sensitivity of PAC man. Plasma and serum samples both at rest to PRA is mediated by the measured reduction and on stopping exercise were collected for the in ACE activity. measurement of plasma renin activity (PRA), plasma aldosterone concentration (PAC) and 165. Milledge JS and PM Cotes. angiotensin converting enzyme (ACE) activity. Serum erythropoietin in humans at high At 4,500m in resting subjects during the initial altitude and its relation to plasma renin. 10 days at altitude, PRA was raised and PAC and ACE activity were reduced. By 20 days all Journal of Applied Physiology 59:360- these hormones had returned to control values. 364, 1985. Authors' Abstract Thereafter, all three tended to rise with ACE being 23% above control after 7 weeks. On Serum immunoreactive erythropoietin Everest after 2-4 weeks at 6,300m, the levels (siEp) was estimated in samples collected from of all three hormones had returned to sea level members of two scientific and mountaineering values. Samples taken on stopping exercise expeditions; to Mount Kongur in Western showed elevated PRA and PAC values, but the China and to Mount Everest in Nepal. SiEp was increased above sea-level control values 1 PAC response to a rise in PRA was blunted. This could be attributed to reduced ACE and 2 days after arrival at 3,500 m and remained high on ascent to 4,500 m. activity in the first 12 days at altitude on Thereafter, while subjects remained at or above Kongur, but on Everest this blunted response was seen with ACE activity slightly above 4,500 m, siEp declined; and by 22 days after the ascent to 4,500 m was at control values, but control values. It is suggested that the rapid reduction of ACE activity with acute hypoxia increased on ascent to higher altitude. Thus provides emergency regulation of the system. siEp was at normal level during the Longer term regulation may be provided by maintenance of secondary polycythemia from down regulation of Angiotensin II receptors or high-altitude exposure. On descent, with enzyme induction. removal of altitude hypoxia, siEp decreased; but despite secondary polycythemia levels, remained measurable and in the range found in 164. Milledge JS, DM Catley, ES Williams, WR Withey and BD subjects normally resident at sea level. On Minty. Mount Everest, siEp was significantly Effect of prolonged exercise at altitude (P<0.01) elevated above preexpedition sea- level controls after 2-4 wk at or above 6,300 on the renin-aldosterone system. m. There was no correlation between estimates Journal of Applied Physiology 55:413- 418, 1983. of siEp and plasma renin activity in samples Authors' Abstract collected before and during both expeditions. The combined effect of exercise and 166. Milles J J, PH Baylis, AR altitude on the renin-aldosterone system was Bradwell and Birmingham studied in six male subjects on a fixed diet. Medical Research Expeditionary After 4 control days at rest and at low altitude, Society. subjects ascended to 3,100 m and took about 7 h exercise daily for 5 days. There followed a

63 VasopressinandH20 excretion at high transitory hyperactivity of the adrenal when sea altitude. level residents are exposed to high altitude. In: Hypoxia, Exercise, and Altitude. Proceedings of the 3 ra Banff 168. Moncloa F, A Carcelen and L Beteta. International Hypoxia Symposium, edited by JR Sutton, CS Houston, and Physical exercise, acid-base balance, NL Jones. New York: AR Liss Inc., and adrenal function in newcomers to 1983. p. A466-A467. (Abstract). high altitude. Authors' Abstract Journal of Applied Physiology 28:151- Plasma vasopressin (pVP) was measured 155, 1970. dally in 17 males during a high-altitude trek to Authors' Abstract 5000m. At the highest altitudes pVP was low Newcomers to high altitude show a (1.7 +1.1 pg/ml) and not elevated in the three significant and inverse correlation between Pao2 subjects most affected by acute mountain and either plasma cortisol, urinary 17-OHCS, sickness (AMS). or urinary 17-KGS. No correlation was In the second study 20 males were water demonstrable between Paco2 or pH and indexes loaded at different altitudes up to 5000 m. Half of adrenal function. These results are took acetazolamide sustained release interpreted as indicative that the adrenal (500 mg/day) and half a placebo. There was a hyperactivity at high altitude is not dependent significant reduction in the percentage of the on alkalosis. During exercise acidosis is more water load excreted at higher altitudes: severe than at sea level; and it is associated with 90.8 +_5.2% (mean +SEM) at 150 m vs 59.3 a significant decrease in plasma cortisol not +7.2% (placebo group) p<0.01, and 65.4 observed at sea level. No variation in glucose +_3.5% (acetazolamide group); but this concentration occurred at high altitude in difference did not significantly correlate with contrast to a decrease at sea level. the severity of AMS (p>0.05). Low urine osmolarities were achieved during water 169. Moncloa F, J Donayre, LA loading at different altitudes and were not Sobrevilla and R Guerra-Garcia. significantly different (p>0.05). Endocrine studies at high altitude II. These results suggest that excess Adrenal cortical function in sea level vasopressin does not contribute to water natives exposed to high altitudes (4300 retention at high altitude or to the development meters) for two weeks. of AMS. Journal of Clinical Endocrinology 25:1640-1642, 1965. 167. Moncloa F, L Beteta, I Velazco Authors' Abstract and C Gofiez. Ten young adult males were exposed to ACTH stimulation and dexamethasone 4300 meters of altitude for 2 weeks. Urinary inhibition in newcomers to high 17-ketogenic steroids (17-KGS), 17- altitude. hydroxycorticosteroids (17-OHCS), and the Proceedings of the Society for cortisol secretion rate were transitorily Experimental Biology and increased. Urinary 17-ketosteroids (17-KS) Medicine 122:1029-1031, 1966. were not significantly modified. The changes Authors' Abstract observed in 17-OHCS with exposure to high Previous work from this laboratory has altitude are similar to those found with an 8-hr shown that sea level residents exposed to high intravenous infusion of 1 U of ACTH. altitude increase their cortisol secretion rate; Possible interpretations of the observed however, the response of the adrenal cortex dissociation between 17-KS and the other was not maximal (1). This may represent: 1) a variables studied are discussed. not intense enough stimulation, or 2) adrenal inability of a greater response. The present investigation was undertaken in an effort to answer this question, and also to study whether dexamethasone was able to prevent the

64 170. Moncloa F, I Velasco and L Beteta. 172. Monge CC, R Lozano, C Plasma cordsol concentration and Marchena, J Whittembury and C disappearance rate of 4-14C-cortisol in Torres. newcomers to high altitude. Kidney function in the high-altitude Journal of Clinical Endocrinology native. 28:379-382, 1968. Federation Proceedings 28:1199- Authors' Abstract 1203, 1969. Cortisol plasma concentration, volume of Annotation distribution, metabolic clearance rate and the Purpose fractional turnover rate constants have been To investigate the structural and studied in young male sea level natives before physiological factors that influence the and during exposure to 4300 m of altitude. circulatory and renal function of humans born The second day of stay at high altitude the and living at high altitude vs. humans born and mean plasma cortisol concentration increased living at sea level. from 9.9 _+0.6 to 15.5 +3.1 g/100 ml Methods (p<0.05). The estimated metabolic clearance Metabolic alkalosis was induced in 17 rate was not significantly altered: 239.5 +_22.7 volunteers: 1/24 hr for sea level control vs. 259.7 +15.8 6 normal at sea level 1/24 hi" during exposure to high altitude. The 6 normal high-altitude natives (4,300 m) cortisol is distributed between 2 compartments; 5 high altitude natives (4,300 m) with the second compartment decreased during chronic mountain sickness exposure to high altitude from 11.7 +1.5 to 7.1 Blood acid-base status and bicarbonate +1.0 L (p<0.02). This decrease may be tubular maximum were assessed. partially explained as a consequence of Metabolic acidosis was induced by contraction in the extracellular space. intravenous infusion of ammonium chloride in 6 normal sea-level residents and in 6 normal 171. Monge CC, R Lozano and A high altitude natives (4,300 m). Ten Carcelrn. parameters related to acid-base equilibrium Renal excretion of bicarbonate in high were studied. altitude natives and in natives with Small amounts of synthetic angiotensin chronic mountain sickness. was infused intravenously to 14 volunteers Journal of Clinical Investigation which included: 6 normal sea-level residents 43:2303-2309, 1964. studied at Lima (sea-level), and 8 normal high- Authors' Abstract altitude natives studied in Morococha (4,500 When compared with sea level controls, m). natives from high altitudes (4,300 m above sea Results When metabolic alkalosis was induced: level) have lower arterial Pco 2 and the same renal maximal reabsorption (Tm) of 1) normal high-altitude natives showed a low bicarbonate. Natives with chronic mountain pCO 2 and also a slightly alkaline pH. 2) chronic mountain sickness, high altitude sickness have a higher arterial PCO 2 than their natives and sea-level volunteers exhibit similar own native control group and a higher pCO 2 status, indicating hypoventilation. bicarbonate Tin. The results are interpreted as After bicarbonate loading the three groups indicating that the normal high altitude native is developed a marked increase in pH. Patients in a new state of acid-base equilibrium. The with chronic mountain sickness exhibited high possible roles of high arterial PCO 2, comparative values of bicarbonate reabsorption hypokalemia, and anoxia in the elevation of to compensate for high arterial pCO 2. bicarbonate Tm of patients with chronic When metabolic acidosis was induced: mountain sickness are discussed. 1) normal sea-level residents and normal high altitude natives (4,300 m) exhibited similar acid-base equilibrium responses. 2) both

65 groups also had a similar decrease in urine the first days at the stated altitude attributed to ammonium excretion. decreases in plasma volume. At the same time, When angiotensin was infused hemoglobin concentration decreased and intravenously: 1) reduction of filtration rate and plasma volume increased in the oldest subject. renal plasma flow was observed in both Red cell volumes were slow to change, and it groups, but it was of much lesser magnitude in was concluded that 3 weeks or more of high-altitude natives; 2) as with reabsorption of exposure to this altitude are required to affect bicarbonate and the secretion of hydrogen ions, significantly the red cell volume in man. the tubular capacity of the high altitude kidney to reabsorb sodium in the presence of 174. Okazaki S, Y Tamura, T Hatano angiotensin was not impaired. and N Matsui. Conclusions Hormonal disturbances of fluid- These findings indicated the great capacity electrolyte metabolism under altitude of the kidney to maintain adequate tubular exposure in man. function in the presence of extreme reduction of Aviation, Space, and Environmental plasma flow, greatly increased blood viscosity, Medicine 55:200-205, 1984. marked hypoxemia, and possible anatomical Authors' Abstract changes to accommodate a larger amount of Early alterations in fluid, electrolytes, and blood. their regulating hormones were investigated in The correlative studies between arterial men exposed to 6,000 m simulated altitude (2 pCO 2 and renal bicarbonate tubular maximum h-ascent, 2 h-sojourn, 2 h-return). Hematocrit (Tin) in steady-state conditions of and serum protein rose with elevated serum hyperventilation and relative hypoventilation osmolality and reduced urine flow upon arrival indicate the need to study the clinical at 6,000 m, suggesting decreased plasma respiratory condition at sea level, which so far volume probably due to a hypotonic fluid shift has not been investigated from this point of to the intracellular space. Serum K ÷ declined view. Finally, the response of angiotensin in reflecting respiratory alkalosis. The exposure the high altitude native could be used in an raised plasma antidiuretic hormone (ADH), attempt to clarify the paradoxical response plasma renin activity (PRA), serum cortisol and (natriuresis) which is produced in aldosterone. Increases both in ADH and hypertensives and cirrhotics when angiotensin aldosterone showed close correlations with that is infused. in cortisol, suggesting that ADH may be The reduced filtration rate and plasma elevated by hypoxic stress in addition to flow, elevated filtration fraction, and lack of elevated serum osmolality and decreased reduction of total blood flow favor the view plasma volume, and that increased secretion of that the natriuresis can be explained more by adrenocorticotropin may be the main cause of renal ischemia than by an elevated filtration increased aldosterone, though PRA fraction. involvement cannot be excluded. These rises in ADH and aldosterone may act to retain body 173. Myhre LG, DB Dill, FG Hall and water, and the latter may exaggerate alkalosis; DK Brown. thus, these hormonal changes may be related to Blood volume changes during three- acute mountain sickness. week residence at high altitude. Clinical Chemistry 16:7-14, 1970. 175. Pace N, RL Griswald and BW Authors' Abstract Grunbaum. Circulating red blood cell volumes were Increase in urinary norepinephrine determined by the carbon monoxide method excretion during 14 days sojourn at and plasma volumes were calculated in four 3,800 meters elevation. men 20, 29, 71, and 75 years old, and two Federation Proceedings 23:521, women 29 years of age before, during, and 1964. (Abstract). after exposure to an altitude of 3800 m. In the Authors' Abstract four youngest subjects there were early Urinary excretion rates of epinephrine increases in hemoglobin concentration during (EP) and norepinephrine (NE) were measured

66 in 6 men. After 3 daysin Berkeley(100 changes during the remainder of an 8-day meters),thesubjectsweretakento theBarcroft exposure period were equivocal. Possible Laboratoryof theWhiteMountainResearch explanations of this phenomenon are changes Station(3,800meters)wheremeasurements in intrarenal vasomotor tone and/or in weremadefor 14days.Little changeoccurred glomerular membrane permeability. in EPexcretionrate,otherthanexpected diurnalvariation. In contrast,NE excretion 177. Pauli HG, B Truniger, JK Larsen rateincreasedsteadily,startingthe2 "dday at and RO Mulhausen. Barcroft, to twice that at sea level by the end of Renal function during prolonged the 14 day sojourn (58.9 g/24 hr compared exposure to hypoxia and carbon with a mean sea level value of 30.8 g/24 hr). monoxide Although the bulk of the increase occurred II. Electrolyte handling. during the day, an increase was also noted in Scandinavian Journal of Clinical and the overnight period. Mean resting heart rate Laboratory Investigation 22:61-67, rose from 69/min at sea level to 92/min by the 1968. 2 "a day at altitude, then gradually fell to 87/min Authors' Abstract by the 14th day. Neither NE excretion rate nor Studies of renal electrolyte handling under heart rate had returned to original sea level conditions of prolonged hypoxia indicate an values by the 4 _hday after the altitude sojourn. increase in sodium and chloride elimination due These data are interpreted as evidence for a to elevated tubular rejection of these substantial and continuing response of the electrolytes, mainly during the first 24 hours sympathetic nervous system during at least the after arrival at altitude; while potassium first 14 days at high altitude. They also elimination appears to be affected in a converse indicate some measure of functional adaptation manner. Renal tubular electrolyte handling to increased NE production. values in the initial phase of prolonged exposure to CO were consistent with a 176. Pauli HG, B Truniger, JK Larsen regulatory response to primary elevation of and RO Mulhausen. GFR. Renal function during prolonged exposure to hypoxia and carbon 178. Pic6n-Refitegui E. monoxide Basal metabolic rate and body I. Glomerular filtration and plasma composition at high altitudes. flow. Journal of Applied Physiology 16:431- Scandinavian Journal of Clinical and 434, 1961. Laboratory Investigation Suppl. Author's Abstract 103:55-60, 1968. Basal metabolic rate (BMR) and body Authors' Abstract composition were determined in 17 healthy Prolonged exposure of normal subjects to adult males living at an altitude of 14,900 ft hypoxia and to carbon monoxide seem to affect above sea level. Using body surface area as a renal function differently. During a I0- day standard of reference and following the sojourn at medium altitude (3454 meters above criterion of Boothby et al. (Am. J. Physiol. sea level), a diminution of effective renal 116:468, 1936), the BMR of the high-altitude plasma flow of borderline significance was resident fell within the limits considered normal observed while glomerular filtration rate for healthy adults at sea level. A comparison remained close to control levels. Changes in with the data obtained by investigators in the glomerular filtration rate and effective renal United States and in India shows that, when plasma flow, leading to the well known pattern either fat-free body mass (FFM), cell mass of fully acclimatized subjects or high altitude (C),or cell solids (S) are the standard of dwellers, seem to follow a slow time course. reference, the BMR is higher in the high- An acute increase of glomemlar filtration rate altitude resident. The higher O 2 consumption and, less consistently, of effective renal plasma per kilogram of FFM, C, or S in the high- flow was observed within the first 36 hours of altitude resident seems to be one of the many prolonged exposure to carbon monoxide, while

67 mechanisms developed by the body in its 181. Porchet M, H Contat, B Waeber, process of adaptation to the low 0 2 tension. J Nussberger and HR Brunner. Response of plasma arginine 179. Pic6n-Redtegui E, R Lozano and J vasopressin levels to rapid changes in Valdivieso. altitude. Body composition at sea level and high Clinical Physiology 4:435-438, 1984. altitudes. Authors' Abstract Journal of Applied Physiology 16:589- Plasma arginine vasopressin levels were 592, 1961. studied in 15 normal working men exposed at Authors' Abstract 4-day intervals to a rapid increase or decrease Simultaneous determinations of total body in altitude of 2000 m. water and extracellular fluid, using the Plasma arginine vasopressin levels were antipyrine and sucrose infusion methods, have significantly lower (P<0.001) at the higher been carded out in 28 adult male residents at altitude though plasma osmolality did not sea level and in 28 residents at an altitude of change. 14,900 ft. Body composition was calculated It is concluded that the important diuresis from these data. The various body spaces known to occur physiologically in response to expressed in percentage of body weight, were high altitude may be related to a decrease in similar in the two groups, with the exception of antidiuretic hormone release. the extracellular fluid which was greater in those in the high altitude group (P<0.01). 182. Pugh LGCE. Neither racial characteristics nor altitude appear Physiological and medical aspects of to be factors generally affecting body the Himalayan Scientific and composition. In individuals having adequate Mountaineering Expedition, 1960-61. caloric intake, body composition seems to be British Medical Journal, September 8, influenced principally by physical activity. In 1962. p. 621-627. fact, physical inactivity appeared to produce a Author's Abstract loss of active tissue and its replacement by fat. The expedition spent eight months at heights of over 15,000 fl (4,570 m). 180. Pines A, JDH Slater and TP Physiological investigations were conducted Jowett. over a period of five months in a prefabricated The kidney and aldosterone in laboratory situated at 19,000 ft (5,790 m) (bar. acclimatization at altitude. 380 mmHg) during an attempted ascent of Mt. British Journal of Chest Disease Makalu (27,790 ft; 8,470 m). 71:203-207, 1977. Data are reported on basal metabolism, Authors' Abstract muscular exercise, respiratory regulation, Five climbers were studied during an blood volume, haemoglobin and erythrocytes, ascent of a 7,500 m mountain in the Hindu electrocardiographic changes, nutrition, and Kush. Representative samples from 24-hour endocrine and renal function. The exercise were preserved from five subjects at results include data on lung diffusion, cardiac 5,400 m and 6,600 m, and from two at 7,000 output, and arterial 02 saturation at 19,000 ft m. Sodium and cortisol excretion was normal, (5,790 m); and on O 2 intake, ventilation, and but that of potassium and especially aldosterone heart rate at heights up to 24,400 ft (7,430 m) was low, especially in two climbers who had (bar. 300 mmHg). At 24,400 ft (7,430 m) the episodes of peripheral oedema. maximum O 2 intake was found to be 1.4 l/min, Hypoaldosteronism is a feature of high altitude ventilation B.T.P.S. 119 l/min, and heart rate acclimatization, but its cause and significance 135 beats/min. Haldane end-expiratory gas have still to be elucidated. samples taken at rest at 25,700 ft (7,830 m) (bar. 288 mmHg) had an average O 2 tension of 33 mmHg and CO 2tension of 14 mmHg. Arterial O 2 saturations of less that 50% were observed during periods of two to three

68 minutes'maximumexerciseat 19,000ft (5,790 haemoglobin concentrations in plainsmen living m), theaveragerestingvaluebeing67%. at 18,000 ft (5500 m) and above do not reach Thepartyappearedto acclimatizewellto the values (22.9 g/100 ml.) reported in Andean 19,000ft (5,790m), andcard-sortingand natives living at 17,500 ft (5340 m). The mean other psychological tests revealed no evidence value for eight parties was 20.19 g/100 rnl (SD of mental impairment. However, all members +0.69). It was concluded that change of of the party continued to lose weight, and this plasma volume is a major factor in the makes it doubtful if they could have stayed regulation of haemoglobin concentration under there indefinitely. Newcomers on Mt. Makalu, these conditions. after four to six weeks' acclimatization, were, if anything, fitter and more active than men 184. Pugh LGC and MP Ward. who had wintered at 19,000 ft. (5,790 m.). Some effects of high altitude on man. Medical aspects of the expedition are The Lancet 2:1115-1121, 1956. described. On Mt. Makalu cases occurred of Authors' Abstract cerebral thrombosis, pulmonary infarction, The effects of altitude experienced on three acute pulmonary oedema, pneumonia, and Himalayan expeditions are described. frostbite. The ascent was made without Symptoms varied with individual oxygen equipment, but oxygen was available susceptibility, previous experience, the stages for medical treatment. of the ascent, and time spent at a given altitude. Lassitude, weakness, breathlessness, and 183. Pugh LGCE. retardation of thought and action are the Blood volume and haemoglobin principle effects and were always present over concentration at altitudes above 18,000 18,000 ft. Acute mountain sickness was not ft. (5500 m). seen, although isolated acute symptoms, such Journal of Physiology (London) as headache and vomiting, were noted. 170:344-354, 1964. The physical findings from examination of Author's Abstract men coming down from great heights were 1. Blood volume, haematocrit and essentially normal, except that 3 men suffering haemoglobin concentration were followed in from exhaustion had abnormally low blood- six subjects during prolonged acclimatization at pressure (85-80/70-60 mmHg). varying altitudes up to 19,000 ft (5800 m). Physical deterioration eventually sets in 2. After 18 weeks at heights ranging from above 20,000 ft and is the more rapid and 13,000 ft (4000 m) to 19,000 ft blood volume severe the greater the altitude. Partial was lower than at sea level in four out of six adaptation, however, occurs initially at least up subjects; the mean reduction being 9%. During to 23,000 ft. In previous expeditions further periods of 3-6 weeks and 9-14 weeks at dehydration and lack of food have been (or above) 19,000 ft, blood volume rose important contributory factors in deterioration. slowly; the final mean value being 9% above The mental effects of great altitude and the sea-level control value. their possible sequelae are described in the light 3. The fall in blood volume was associated of previous Everest expeditions from 1922 with a reduction in plasma volume which onwards. amounted to 27%. Plasma volume The problem of how to achieve subsequently rose slowly, but the final mean acclimatisation as quickly as possible is value was still 19% below the sea-level control discussed. value. 4. Red cell volume and total haemoglobin 185. Purshottam T, ML Pahwa and HD rose progressively, reaching mean values 49% Brahmachari. above the sea-level control values. Effects of 6 hours hypoxic and cold 5. Haemoglobin concentration rose by exposure on urinary electrolyte and 30% in the first 18 weeks, and by 8% during catecholamine excretion. the following 9-14 weeks. Aviation, Space, and Environmental 6. According to data collected on eight Medicine 49:62-65, 1978. expeditions to the Himalaya and Karakoram,

69 Authors' Abstract involved acute or chronic normobaric or Eleven young male Indian volunteers hypobaric hypoxia. Regardless of these fasted overnight and were exposed to 6 h of factors, the results were fairly consistent and cold at 8°C (I), hypoxia at 4267 m at 28°C (II), suggested that a factor (or factors) was and cold plus hypoxia of 4267 m at 8°C (III), selectively inhibiting aldosteronogenesis during in a waLk-in climatic chamber; excretion of hypoxia. some urinary constituents was measured. Decreased aldosterone secretion during Urine output was significantly decreased in (II) hypoxia may be due to (1) increased ANP, (2) and increased in (I) and (III). Urine pH a change in potassium balance across the zona significantly increased only in (]I). glomerulosa cell, and/or (3) to a direct effect of Catecholamine excretion significantly increased low 02 on the adrenal. only in (I). Ca _ excretion was significantly Conclusions raised in (I) and (III) and lowered in (II). Na ÷ Curran-Everett et al. summarized the excretion was significantly decreased and K ÷ teleogical reasons for reduced aldosterone as a excretion remained unchanged in all three stress normal homeostatic adaptation to hypoxia. conditions. Cold seemed to be a greater Decreases in aldosterone may help maintain stressor than hypoxia under these stated potassium balance in the face of respiratory experimental conditions. alkalosis due to hypoxia-induced hyperventilation. Decreases in aldosterone 186. Raft H. might also help to maintain sodium excretion, The renin-angiotensin-aldosterone thereby minimizing the formation of edema. system during hypoxia. Curran-Everett et al. proposed that the In: Response and Adaptation to decreased aldosterone may help to maintain a Hypoxia: Organ and OrganeUe, edited normal systemic transmembrane potassium by S Lahiri, NS Chemiach, and RS distribution, a concept supported by studies in Fitzerland. New York: Oxford anephric humans. University Press, 1991. p.211-222. It is interesting that converting enzyme Annotation inkibitors may be beneficial for treating patients Purpose with advanced COPD in whom the hypoxic A discussion of historic and mechanistic inhibition of aldosterone has been overridden approaches for the control of aldosterone by the stimulatory effects of CO 2 retention. It secretion during acute and chronic hypoxia in is also of interest that captopril or ANP healthy humans, sheep, cats, and rats. decreases normocapnic hypoxic pulmonary Methods vasoconstriction. Future therapies for altitude- To begin to analyze the mechanisms, induced pulmonary hypertension or chronic subsequent studies were brought into the lung disease should consider these treatments. laboratory. The studies described are a mixture The suppression of aldosterone during of acute and chronic hypoxia and of hypoxia may be an important homeostatic normobaric and hypobaric hypoxia in the component of an overall adaptation to hypoxia. laboratory or the field. This section is A direct and specific inhibitory effect on the organized as follows: studies on hypoxia per se zona glomemlosa of the adrenal cortex may lead to a decrease in aldosterone secretion are presented first; then studies using various stimulation tests (exercise, ACTH, etc.); and without a decrease in ACTH and cortisol, finally evidence for and against endogenous necessary for adaptation to hypoxia. inhibitors of aldosterone release are described. Furthermore, this would allow a decrease in Results aldosterone without a decrease in plasma The aldosterone response to exercise and angiotensin II concentration, which may be necessary for the maintenance of peripheral physiological increases in ACTH may be vascular resistance in hypoxic states. inhibited during hypoxia. Studies in rats found hypokalemia and this confounded interpretation of the data. The lack of hypokalemia in humans and sheep, however, suggested that this is not a unifying hypothesis. The studies

7O 187. Raft H, J Shinsako and MF while breathing room air (mean O 2 saturation, Dallman. 97 _+0.9%) and again while breathing hypoxic Renin and ACTH responses to gas to lower the O 2 saturation to 90%. A hypercapnia and hypoxia after chronic population of subjects matched for age and sex carotid chemodenervation. adapted to 3000 meters above sea level living in American Journal of Physiology Columbia, South America, was also studied 247:R412-R417, 1984. (mean O 2 saturation, 94 _+0.7%). Hypoxemia, Authors' Abstract either induced at sea level or as a consequence We studied the effect of chronic carotid of high altitude living, resulted in significant body denervation on renin (plasma renin inhibition of aldosterone secretion after acitivity, PRA), adrenocorticotropin (ACTH), progressive administration of increasing doses blood pressure, and hematocrit responses to of ACTH, but did not affect the cortisol acute normocapnic (arterial CO 2 partial response to ACTH. In addition, it was pressure, PaCO 2, 35 Ton.) and hypercapnic associated with higher plasma atrial natriuretic (PaCO 2, 65 Ton') hypoxia (arterial O 2 partial hormone levels. PRA declined only during pressure, PaO 2, 31 Torr) in five anesthetized, acute hypoxemia induced at sea level and did artificially ventilated dogs. Animals were not change during sea level normoxemia or studied at least 3 days before and again at least high altitude living. Plasma sodium and 10 days after carotid body denervation (bilateral potassium concentrations were no different in carotid sinus nerve resection). Increases in the three experimental conditions. We PRA during hypercapnic normoxia [21.8 _+6.4 conclude that hypoxemia inhibits ACTH- ng angiotensin I (ANG I) ml _ • 3 h l] and stimulated aldosterone secretion and speculate normocapnic hypoxia (13.3 +_4.2 ng ANG I that atrial natriuretic hormone may have ml _ ° 3 h 1) were not attenuated by carotid body mediated this effect. denervation. Increases in ACTH during normocapnic hypoxia (117 +34 pg/ml) were 189. Ramirez G, M Hammond, SJ attenuated but not eliminated by carotid body Agosti, PA Bittle, JR Dietz and denervation; the increase in ACTH during GL Colice. hypercapnic hypoxia (295 +_93 pg/ml) was not Effects of hypoxemia at sea level and accentuated by carotid body denervation. high altitude on sodium excretion and Both the blood pressure and hematocrit hormonal levels. responses to normocapnic and hypercapnic Aviation, Space, and Environmental hypoxia were attenuated by carotid body Medicine 63:891-898, 1992. denervation. We concluded that 1) the renin Authors' Abstract response to hypercapnia and hypoxia is not a Acute hypoxemia at sea level is associated carotid chemoreflex, 2) the ACTH response to with decreased aldosterone secretion. This hypoxia is partially a carotid chemoreflex, and inhibition is thought to be mediated through 3) blood pressure and hematocrit responses to secretion of atrial natriuretic factor (ANF). The hypoxia are primarily carotid chemoreflexes. interaction of these two hormones should result in enhanced renal salt excretion during 188. Ramirez G, PA Bittle, M hypoxemic conditions. This hypothesis was Hammond, CW Ayers, JR Dietz tested by administration of a standardized salt and GL Colice. load to seven normal subjects during Regulation of aldosterone secretion normoxemia at sea level (SL), acute hypoxemia during hypoxemia at sea level and (AH) at sea level, and high altitude (HA) moderately high altitude. (3,000 m). Urine and venous blood samples Journal of Clinical Endocrinology and were collected and analyzed. A natriuresis and Metabolism 67:1162-1165, 1988. diuresis was observed only under AH Authors' Abstract conditions. It was accompanied by a decrease The aldosterone and cortisol responses to in plasma aldosterone levels, but did not small doses of ACTH (0.125, 0.25, 0.5, and correlate with changes in plasma aldosterone 1.25 g) after dexamethasone administration levels, ANF, or other hormones. Increased were measured in normal subjects at sea level plasma renin activity (PRA) and increased

71 norepinephrine levels were encountered at HA 191. Reinhart WH, B Kayser, A suggesting sympathetic nervous system Singh, U Waber, O Oelz and P activation. No change in anti- hormone B_irtsch. (ADH) levels with increased plasma osmolality Blood theology in acute mountain was seen at HA. We conclude that excretion of sickness and high-altitude pulmonary a salt load during normobaric hypoxemia is edema. enhanced by a decrease in plasma aldosterone Journal of Applied Physiology 71:934- levels, unrelated to changes in ANF or other 938, 1991. hormones. The differences observed in Authors' Abstract norepinephrine, PRA, and ADH levels during The role of blood rheology in the HA versus AH conditions suggest that pathogenesis of acute mountain sickness and hypobaria or chronic hypoxemia may influence high-altitude pulmonary edema was these hormonal responses. investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, 190. Ramirez G, DO Pineda, PA Bittle, were studied at low altitude (490 m) and at 2 h SJ Agosti, HA Rabb and JR and 18 h after arrival at 4,559 m. Eight Dietz. subjects remained healthy, seven developed Salt excretory capacity in natives acute mountain sickness, and eight developed adapted to moderate high altitude living high-altitude pulmonary edema. Hematocrit, after acute mobilization to sea level. whole blood viscosity, plasma viscosity, Aviation, Space, and Environmental erythrocyte aggregation, and erythrocyte Medicine 66:1063-1070, 1995. deformability (filtration) were measured. Authors' Abstract Plasma viscosity and erythrocyte deformability The sodium excretory capacity of six remained unaffected. The hematocrit level was normal subjects born and raised at moderately lower 2 h after the arrival at high altitude and high altitude (2600 m) was evaluated at high higher after 18 h, compared with low altitude. altitude (HA), and after acute mobilization to The whole blood viscosity changed sea level (SL). The ability of these individuals accordingly. The erythrocyte aggregation was to respond to an acute salt load was evaluated about doubled 18 h after the arrival compared by infusing a volume of 100 ml • m -z body with low-altitude values, which reflects the surface area (BSA) of 5% sodium chloride acute phase reaction. There were, however, no over a 30-min time period in both significant differences in any rheological experimental conditions. HA natives were able parameters between healthy individuals and to excrete a significantly greater salt load at HA subjects with acute mountain sickness or high- than at SL (41.8% vs. 31.6%, respectively, altitude pulmonary edema, either before or p<0.05) in 3 h. No changes in plasma atrial during the illness. We conclude that natriuretic factor (ANF) concentration were rheological abnormalities can be excluded as an found in either experimental condition. Despite initiating event in the development of acute an increase in serum osmolality, no mountain sickness and high-altitude pulmonary vasopressin (AVP) response was noted either edema. at HA or SL. No correlation between serum AVP levels and urine c-AMP concentrations 192. Rennie D, R Frayser, G Gray and was found. The enhanced excretory response C Houston. to a salt load at HA was not explained by the Urine and plasma proteins in men at measured hormonal changes. The lack of AVP 5,400 m. response to increased serum osmolality, both at Journal of Applied Physiology 32:369- HA and SL, in high altitude adapted subjects is 373, 1972. presently unexplainable. Authors' Abstract Urine and plasma proteins were measured before, during and after ascent from 800 to 5,400 m altitude on Mount Logan in completely unacclimatized men who had made the ascent by plane in 40 rain, and in acclimatized

72 individualswhohadclimbedupandhadlived 194. Rennie IDB and BI Joseph. at5,400m for 6 weeks. Proteinexcretionrates Urinary protein excretion in climbers at wereincreased,andcreatinineexcretionand high altitudes. clearanceratesdecreased,with increasesin The Lancet i:1247-1251, 1970. plasmacreatinine levels, in both groups at Authors' Abstract 5,400 m. These changes were similar and Early-morning specimens of urine were therefore independent of acclimatization and of collected about 14 hours after the cessation of polycythemia. There was no evidence, from exercise from thirteen climbers on a month- clearances of proteins and of long trek in the central Himalayas. All had polyvinylpyrrolidone, of any change in normal 24-hour creatinine clearance rates and glomerular sieving, and the character of the exercising protein excretion rates at the start of proteinuria was qualitatively normal. Increases the trek, which took the expedition to just over in plasma protein occurred only in those in 18,000 ft (5,550 m). It was found that the whom there was evidence of dehydration. In mean protein concentration in the urine the unacclimatized, after abrupt ascent, correlated with the altitude at which the samples transferrin levels were decreased, possibly as a were taken. This correlation was increased means of enhancing iron supply to the when the effect of osmolar changes was developing red cells; but after acclimatization removed or the protein concentration expressed tranferrin levels rose to above normal levels. as the protein/osmolar (P/O) ratio. The correlation was further increased both 193. Rennie D, E Marticorena, C individually and collectively when the altitude Monge and L Sirotzky. 24 hours before sampling was considered, Urinary protein excretion in high- despite considerable individual variation both in altitude residents. urine concentrations and the correlations of Journal of Applied Physiology 31:25% altitude with P/O ratios. There was a time-lag 259, 1971. before P/O ratio reflected altitude changes, this Authors' Abstract lag being greater when ascending than when Two-hour urine collections and venous descending, and being similar to the lag in blood samples were taken from three groups of onset of symptoms and signs described by healthy young adult males of Quechua descent, other workers in acute mountain sickness. The bom in the high Andes and studied in their alterations in P/O ratio with changes in altitude places of permanent residence. Seventeen lived was not caused by variations in exercise. in Yauricocha (4,640 m) and twenty-six in San Moderate though not "critical" hypoxia, Cristobal (4,710 m). Thirty, who had moved affecting the kidney indirectly, was a likelier down to Lima (160 m) and had lived there for cause. more than 2 years, were studied there. Urinary protein excretion rates were increased in both 195. Reynafarje C, J Ramos, J Faura groups living at high altitude, compared with and D Villavicencio. the Lima group. The cause was unknown. Humoral control of erythropoietic The San Cristobal group showed relatively activity in man during and after altitude lower creatinine clearances. The similar exposure. hypoxia and dissimilar polycythemia in the two Proceeding of the Society for high-altitude groups suggested that the Experimental Biology and Medicine polycythemia rather than the hypoxia was 116:649-650, 1964. associated with the diminished creatinine Authors' Abstract clearances in the San Cristobal men. Six other The erythropoietic stimulating factor was high-altitude dwellers were found to have low studied in natives and newcomers to high serum total protein and raised serum creatinine altitude (14,900 feet). An increase was found levels and were therefore not included in group only in the group of newcomers after 24 hours comparisons. of exposure. The possibility of the existence of an erythropoietic depressing factor is suggested from the investigation of a group of high

73 altitude polycythemic subjects brought down to erythropoietin (EPO) concentrations, some sea level, where they were followed 72 hours, subjects showed a stable or even a decreasing 10 days, and 20 days after arrival. Plasma hemoglobin concentration, partly because of obtained from them at these time periods, when depressed iron stores, especially in women. injected into rats, had a depressing EPO secretion seemed to be closely linked to erythropoietic action. the intensity of proximal tubular metabolic activity. Subjects showing a high AMS score 196. Richalet J-P, A-M Antezana, had high EPO values. The intense activation of A Bienvenu, M Marchal, J-C the adrenergic system, as shown by increased Souberbiel, E Cauchy, J-L Le plasma norepinephrine, was probably Trong, M D6chaux, R Kacimi, responsible for the renal vasoconstriction. A V Bonaldi, K Westerterp, B blunted cardiac chronotropic response to Kayser and C Dubray. adrenergic activation (exercise or isoproterenol Physiological factors in survival at infusion) was found, as well as a 41% decrease extreme altitude. in the density of lymphocyte beta- Hypoxia and Molecular Medicine. adrenoreceptors, but these phenomena were not Proceedings of the 8 'h International exaggerated when compared with previous Hypoxia Symposium, edited by JR results obtained at 4,350 and 4,800 m. Sutton, CS Houston, and G Coates. Periodic breathing was observed in all subjects Burlington, VT: Queen City Printers, (from 1 to 80% of total sleep time), which may Chapt. 22, 1993. p.235-251. aggravate the hypoxic stimulus. Time spent in Authors' Abstract periodic breathing was related to the hypoxic During a scientific expedition to Mount ventilatory response to hypoxia. In Sajama (Bolivia), a group of ten adult subjects conclusion, exposure to an altitude of 6,542 m (4 female, 6 male) remained for 3 weeks at the induced profound modifications of some altitude of 6,542 m. No severe medical physiological functions. This limitation problem occurred during the stay, persisted during the 3-week stay at high demonstrating the possibility of acclimatization altitude, without further degradation. Renal to a prolonged hypoxic environment (mean function might be important to take into account resting arterial O: saturation was about 69%). when evaluating the altitude-induced variations Aerobic performance decreased by 44% during of water balance and EPO production. Food hypoxia, without further modification during intake deficit is a crucial factor which impairs the stay. Anaerobic performance, evaluated by energy balance. All data show a great a 30s Wingate test, decreased by 11%. When variability of individual tolerance to hypoxic expressed per kg of body weight (BW), stress. aerobic power was decreased but anaerobic power was maintained at high altitude. Mean 197. Richalet J-P, M D6chaux, A BW loss was 9% of initial BW (1 to 10.5 kg). Bienvenu, J-C Souberbielle, A- During the stay at 6,542 m, no further M Antezana and E Cauchy. modification of BW was observed. BW loss Erythropoiesis and renal function at the was predominant in lower limbs, and was altitude of 6,542 m. probably due to a 46% decrease in caloric Japanese Journal of Mountain intake during the 10-day ascent period. A 25 to Medicine 15:135-150, 1995. 27% decrease in renal blood flow, glomerular Authors' Abstract filtration rate, and proximal tubular Erythropoiesis, renal function and related reabsorption, evaluated by clearance methods, hormones were studied in 10 subjects ( 4 was observed in most subjects. In one subject women, 6 men) exposed for 3 weeks at 6,542 suffering from severe acute mountain sickness m. Blood was withdrawn in normoxia (N), (AMS), a large increase in glomerular filtration after one (HI), two (H2) and three (H3) weeks rate and tubular reabsorption was evidenced, at 6,542 m for the measurement of serum probably responsible for marked water erythropoietin (EPO), blood hemoglobin (Hb), retention. After a sharp initial increase in plasma ferritin (FER), renin activity (PRA), erythropoiesis, linked to high serum norepinephrine (NE), dopamine (DA),

74 aldosterone (PAC), atrial natriuretic peptide levels. Prolonged exposure to 6,542m induced (ANP), endothelin (ET), cortisol, profound modifications in renal flows and parathormone (PTH), 25 OH-D 3 and 1.25 related hormones, where key O2-dependent (OH)E-D 3 concentrations. Effective renal enzymes may play an important role, leading to plasma flow (ERPF), glomerular filtration rate a new steady state compatible with (GFR), absolute proximal reabsorption (APR) homeostasis. However, the physiological and distal sodium reabsorption (ADRNa) rates impact is severe and may not be tolerated by were measured by clearance methods, in N and some individuals. H2. After an initial sharp increase, EPO decreased at H2 and H3. Hb increased from N 198. Richalet J-P, C Rathat, A to H 1 and H2 and decreased from H2 to H3. Keromes, J-P Herry, P Increase in EPO at H 1 varied from 3- to 134- Larmignat, M Garnier and P fold among individuals. Two women showed Pilardeau. a large increase in EPO without increase in Hb. Plasma volume, body weight, and acute FER showed a marked decrease in H 1 and H3 mountain sickness. as compared to N. Hb was positively related to The Lancet i:525, 1983. FER in hypoxia. Iron intake in food was Authors' Abstract markedly decreased during the 2 weeks of During the French medical expedition to ascent, before arriving at 6,542 m. EPO was the Himalayas (Exp6dition M6dicale Francaise inversely related to CaO 2 and positively related en Himalaya Numbur 81) in the autumn of to APR. The decrease in Hb from H2 to H3, 1981, we measured plasma volumes on nine in spite of high EPO, may be due to a men aged 24-45 who normally lived at sea- chronically reduced iron availability as level. One of them presented with signs of suggested by the decrease in FER favored by a severe acute mountain sickness (AMS), low iron intake. Factors modulating the without pulmonary oedema. erythropoietic response to EPO in hypoxia Plasma volume was measured by dye- include nutritional and sex differences, iron dilution technique (Evans blue) at sea-level stores, and tubular function that determines 0 2 (SL), at 4,950 m after 1 week of activity supply to renal sensors responsible for EPO between 4,000 and 5000 m (BC1), and at secretion. PRA and PAC were low in H 1 and 4,950 m after 4 weeks' activity between 4000 H3, particularly in women, in spite of high and 7000 m (BC2). The man with AMS did NE. There was no hypoxia-induced not climb higher than 4,950 m (base camp dissociation between PRA and PAC during altitude). Body weight was measured with a exercise. DA was high in H1 and returned to 10 g precision scale. normal in H3. ANP was elevated in some Plasma volume and body weight in the subjects in H1 and was low in H3. ET, eight men who remained free of AMS, apart cortisol and PTH increased with altitude from a slight headache relieved by 1 g aspirin, exposure. 25 OH-D 3 was high and 1.25(OH) 2- •are shown in the figure. The man with AMS D 3 was low at high altitude. ERPF, GFR, was 45 years old and had a severe headache APR, and ADRr_ decreased in H2, except for (resistant to 1 g aspirin), insomnia, anorexia, one subject who suffered from severe acute and slight facial oedema, but no dyspnoea at mountian sickness and showed high intrarenal rest or crepitant rb.les. Signs of right flows and low urine output. The decreased ventricular overload were noticed on an renal flow and increased filtration fraction were electrocardiogram. The development of AMS probably mediated by combined effects of was certainly due to a too rapid ascent from adrenergic drive and ET release. Tubular 3,500 to 4,950 m, 2 days before the function was not altered. Low PRA was measurements at BC 1. This man did not climb attributed to increased blood pressure, any higher and all signs of AMS disappeared downregulation of I_-receptors, or ET release. after 3 days of bed rest. Suppression of PAC was related to decreased As noted by others, plasma volume PRA and increased DA. Calcium and decreased at high altitude in sea-level natives. phosphorus homeostasis was maintained, in We found a 7% decrease at BC1 (p<0.05) and spite of low 1.25(OH)2-D 3, by elevated PTH 10% decrease at BC2 (p<0.05); body weight

75 falling by 3% (p<0.001)and5% (p<0.001), plasma renin activity (PRA), and aldosterone respectively(Student'st testfor paireddata; (ALDO). ANP showed a progressive increase n = 8). In contrast,in themanwith AMS, from rest to postexercise [7.49 +1.63 to 11.32 plasmavolumerosebuthadreturnedto a value +1.80 (SE) pmol/ml and 6.05 +2.55 to 10.38 within the range of the others for BC2; and he +7.20 pmol/ml; P = 0.049, exercise] at SL and was the only man whose body weight rose at AA, respectively, but not at CA (P = 0.039, BC 1. These findings are consistent with a altitude). Similarly, PRA and ALDO rose from water overload in AMS demonstrated here by rest to postexercise (P<0.001, exercise), but plasma volume measurement. the rise in ALDO with exercise was less during If dye escapes from the vascular bed, this AA than during SL and CA (P = 0.002, might artificially increase the dilution volume, phase). The decreased ANP levels during but previous workers have not mentioned this exercise after altitude acclimatization, with no problem, even in peripheral oedema. change in PRA and ALDO, suggest that ANP The pathophysiology of this water balance has little effect on PRA and ALDO under these disturbance is not clear yet, though conditions. modifications in hormonal secretions may play a role. The overload of the circulatory system 200. Rose MS, CS Houston, CS may contribute to the development of Fulco, G Coates, JR Sutton and pulmonary or cerebral oedema, associated with A Cymerman. other factors such as pulmonary hypertension, Operation Everest II: nutrition and body alkalosis, or increase in cerebral blood flow. composition. The normal reaction of the human body to Journal of Applied Physiology a high altitude environment is loss of plasma 65:2545-2551, 1988. volume and body weight; abnormal Authors' Abstract acclimatisation may lead to increases in both. Progressive body weight loss occurs Body weight measurements could be an easy during high mountain expeditions, but whether and cheap way to detect those at risk of severe it is due to hypoxia, inadequate diet, AMS during high altitude treks or expeditions. malabsorption, or the multiple stresses of the harsh environment is unknown. To determine 199. Rock PB, WJ Kraemer, CS whether hypoxia due to decompression causes Fulco, LA Trad, MK Malconian, weight loss, six men provided with a palatable MS Rose, PM Young and A ad libitum diet, were studied during Cymerman. progressive decompression to 240 Torr over 40 Effects of altitude acclimatization of days in a hypobaric chamber where hypoxia fluid regulatory hormone response to was the major environmental variable. Caloric submaximal exercise. intake decreased 43.0% from 3,136 to 1,789 Journal of Applied Physiology kcal/day (P<0.001). The percent carbohydrate 75:1208-1215, 1993. in the diet decreased from 62.1 to 53.2% Authors' Abstract (P<0.001). Over the 40 days of the study the To determine the effect of altitude subjects lost 7.4 +_2.2 (SD) kg and 1.6% (2.5 acclimatization on plasma levels of atrial kg) of the total body weight as fat. natriuretic peptide (ANP) during submaximal Computerized tomographic scans indicated that exercise and its relationship with renin and most of the weight loss was derived from fat- aldosterone, seven male volunteers aged 17-23 free weight. The data indicated that prolonged yr exercised to exhaustion on a cycle ergometer exposure to the increasing hypoxia was at 80-85% of their maximum 02 uptake at sea associated with a reduction in carbohydrate level (SL; 50 m), during 1 h in a hypobaric preference and body weight despite access to chamber [acute altitude (AA); 4,300 m], and ample varieties and quantities of food. This after 14 or 16 days of residence on the summit study suggested that hypoxia can be sufficient of Pikes Peak, CO [chronic altitude (CA); cause for the weight loss and decreased food 4,300 m]. Plasma samples taken before consumption reported by mountain expeditions exercise, 10 min after the start of exercise, and at high altitude. 5 min postexercise were analyzed for ANP,

76 201. Sdnchez C, C Merino and M under normoxic and hypoxic Figallo. conditions. Simultaneous measurement of plasma European Journal of Applied volume and cell mass in polycythemia Physiology 61:398-407, 1990. of high altitude. Authors' Abstract Journal of Applied Physiology 28:775- The present study was designed to 778, 1970. investigate the influence of exercise intensity Authors' Abstract and duration as well as of inspiratory oxygen In 13 native residents of Cerro de Pasco content on plasma atrial natriuretic peptide (4,330 m above sea level) simultaneous concentration ([ANP]) and furthermore to measurement of the red cell and plasma compare ANP with the effect on aldosterone volumes was performed using the 51Cr and the concentration ([Aldo]). Ten untrained male Evans' blue dye techniques, respectively. A subjects performed a maximal exercise test mean value of 51.7 +16.63 ml/kg body wt for (ME) on a cycle ergometer and a submaximal the red cell volume and a mean value of 33.4 + test of 60-min duration at 60% of maximal 9.44 ml/kg body wt for plasma volume were performance (SE) under normoxia (N) and found. The fall in plasma volume in the normobaric hypoxia (H) (partial pressure of majority of the cases had an inverse oxygen: 12.3 kPa). Five subjects were relationship with the hematocrit value, exposed to hypoxia at rest for 90 rain. The resembling the polycythemia seen in congenital [ANP] was mostly affected by exercise heart disease. intensity (5 min after ME-N, +298.1%, SEM 39.1%) and less by exercise duration (at the 202. Scaro JL. end of SE-N: +229.5%, SEM 33.2%). Actividad eritropoyetica del extracto Hypoxia had no effect at rest and reduced the urinario de sujetos residentes en la exercise response (ME-H, +184.3%, SEM altura. 27.2%; SE-H, +172.4%, SEM 15.7%). In Revista de la Sociedad Argentina de contrast to ANP, the Aldo response was Biologia 36:1-8, 1960. affected more by duration at submaximal level Authors' Abstract (+290.1%, SEM 34.0%) than by short The urine alcohol extracts of permanent maximal exercise (+235.7%, SEM 22.2%). residents in Jujuy at 1,260 m above sea level Exposure to hypoxia rapidly decreased [Aldo] does not show erythropoietic activity when (-28.5%, SEM 3.7% after 30min, P<0.01), injected into the rat. but did not influence the exercise effects (ME- The urine extracts of new comers at high H, +206.2%, SEM 26.4%; SE-H, +321.6%, altitude show an erthyropoietic activity whose SEM 51.6%). The [ANP] increase was faster value is highly significant 48 hours after than that of [Aldo] during the maximal tests and arriving at 3990 m. there was no difference during submaximal The activity of urine alcoholic extracts of exercise. Changes in plasma volume (PV), long time residents at high altitude is markedly sodium concentration, and osmolality (Osm) lower than that of new comers two days after were most pronounced during maximal their arrival, but it is nevertheless markedly exercise (for ME-N: PV -13.1%, SD 3.6%, higher than that of residents at 1260 m. sodium +6.2 mmol ° 1_, SD 2.7, Osm +18.4 The weight of the alcohol extract obtained mosmol ° kg H_O -t, SD 6.5). Regression from 1000 cm 3 of urine in the recently arrived analysis showed high correlations between residents increases proportionally with their changes in [ANP] and in Osm during and after erythropoietic activity. maximal exercise and between changes in [ANP] and heart rate for submaximal exercise. 203. Schmidt W, G Brabant, C It is concluded that, besides other mechanisms, Kriiger, S Strauch and A increased Osm might be involved in the Hilgendorf. exercise-dependent increase of plasma [ANP]. Atrial natriuretic peptide during and after maximal and submaximal exercise

77 204. Schmidt W, KU Eckardt, A exercise on plasma erythropoietin concentration Hilgendorf, S Strauch and C ([EPO]). Eight natives from the Bolivian Bauer. Plateau were investigated at 3,600 m above sea Effects of maximal and submaximal level at rest, as well as during and up to 48 h exercise under normoxic and hypoxic after exhaustive exercise (EE) and 60 min of conditions on serum erythropoietin submaximal (60%) cycle ergometer exercise level. (SE). Ten sea-level subjects were used as a International Journal Sports control group for resting values. The mean Medicine 12:457-461, 1991. resting plasma [EPO] of the high-altitude group Authors' Abstract (19.5 _+0.7 mU/mi) did not differ from that of This study was carried out to investigate the sea-level group (18.1 _+0.4 mU/ml), but the influence of different exercise regimens on was higher than would be expected from the serum immunoreactive erythropoietin relationship between [EPO] and hematocrit at concentration (EPO). The same untrained male sea level. Five hours after both types of subjects performed bouts of maximal and exercise, [EPO] decreased by 2.1 _+0.8 (EE, submaximal exercise (60 min at 60% of P<0.01) and by 1.6 _+0.8 mU/ml (SE, maximal performance) under normoxic (n = P<0.05); 48 h after SE [EPO] increased by 2.6 10) and normobaric hypoxia (PIO 2 92 mmHg, _+0.9 mU/ml (P<0.05). It is concluded that 1) n = 9). Five of them were exposed to hypoxia high-altitude natives need relatively high [EPO] for 90 rain under resting conditions (RTH). to maintain their high hematocrit, and 2) [EPO] was unchanged up to five hours after exercise at low basal arterial PO E does not maximal (MEN) and submaximal (SEN) directly increase plasma [EPO] in high-altitude exercise under normoxia. After RTH, [EPO] residents but seems to exert suppressive increased after 3 hours by 5.0 mU/ml effects. (p<0.01). Submaximal exercise under hypoxia (SEH) led to a similar increase in [EPO] (after 206. Schneider EC and LC Havens. 3 hours: +5.5 mU/ml), which remained The changes in the content of elevated the following days (after 24 h: +6.1 haemoglobin and red corpuscles in the mU/ml, 48 h: +5.3 mU/ml; ANOVA p<0.001). blood of man at high altitudes. Maximal exercise under hypoxia (MEH) had no American Journal of Physiology significant effect. The results indicate that 36:380-397, 1914. exercise has no immediate effect on serum Authors' Abstract [EPO], whereas the higher EPO level one and 1. At low altitudes abdominal massage two days after SEH could result from the increases the number of red corpuscles and occurring hemodilution as is indicated by a percentage of haemoglobin in the peripheral slight negative correlation between [EPO] and capillaries. In men partially or wholly Hct (r = 0.59, p<0.001). The number of acclimatized to a high altitude, abdominal reticulocytes increased after all hypoxic massage lowers the content of haemoglobin experiments and after MEN without any and red corpuscles. Before the subject reacts to correlation to [EPO]. the influence of lowered barometric pressure, abdominal massage may raise the content of 205. Schmidt W, H Spieivogel, KU haemoglobin and red corpuscles. Eckardt, A Quintela and R 2. Physical exertion at low altitudes Pefialoza. concentrates the blood, but during a sojourn of Effects of chronic hypoxia and exercise four days to two weeks at a high altitude this on plasma erythropoietin in high- reaction occurs only in the period before the altitude residents. number of red corpuscles and percentages of Journal of Applied Physiology haemoglobin have increased. In a subject who 74:1874-1878, 1993. had lived five and a half months at 14,109 feet Authors' Abstract a given exercise caused a slight concentration of the blood but not as much as it did at the The present study was performed to evaluate the effects of chronic inspiratory altitude of Colorado Springs. hypoxia and its combination with physical

78 3. While thereis areservesupplyof possible pathogenetic role of the corpusclesatlow altitudes;thisis lackingfor sympathoadrenal system in the development of sometimeduringresidenceatthehighaltitude. ill effects in response to high-altitude exposure. 4. Thenumberof redcorpusclesand percentageof haemoglobindo notincrease 208. Shigeoka JW, GL Colice and G immediatelyonarrivalat thehighaltitude. Ramirez. Usuallythereoccurswithin twenty-fourhours Effect of normoxemic and hypoxemic amarkedincreasein both. exercise on renin and aldosterone. 5.Therisein haemoglobinandred Journal of Applied Physiology 59:142- corpusclesfor aparticularsubjectduringthe 148, 1985. first three or four days spent at a high altitude is Authors' Abstract not the same for different visits. The increase Five subjects (group 1) performed is most rapid in subjects who have taken progressive treadmill exercise on 2 separate regular exercise before ascending to the high days, once while breathing room air altitude. (normoxemc) and the other time while 6. Fatigue due to walking up a mountain breathing gas with a fractional inspired O 2 of delays the altitude increase in haemoglobin and 17% (hypoxemic). Five other subjects (group red corpuscles. 2) performed two progressive treadmill 7. The rapid increase in the number of red exercise tests on each of 2 separate days in a corpuscles and percentage of haemoglobin the crossover design. On day 1 normoxemic first two or three days spent at a high altitude is exercise was first, followed by hypoxemic due in part to the throwing into the general exercise, and on the other day the pattern was circulation of a large mass of reserve reversed. Plasma renin activity (PRA) corpuscles, and in part to a loss of fluid from increased to a similar extent with hypoxemic the blood. The blood forming centers also exercise as with normoxemic exercise. Plasma become more active and increase the total aldosterone concentrations (PAC) rose to a number of corpuscles and total amount of significantly higher level during normoxemic haemoglobin. exercise than with hypoxemic exercise. Comparing changes in PRA to PAC with 207. Sharma SC, RS Hoon, V progressive exercise revealed dissociation of Balasubramanian and KS PAC from PRA during hypoxemic exercise. Chadha. The PAC response remained depressed when Urinary catecholamine excretion in normoxemic exercise followed hypoxemic temporary residents of high altitude. exercise. These results indicate that hypoxemia Journal of Applied Physiology 44:725- interferes with PRA-mediated aldosterone 727, 1978. secretions. The mechanism of this inhibition is Authors' Abstract unclear. Urinary catecholamine excretion was estimated in 50 lowlanders temporarily staying 209. Sieker HO, OH Gauer and JP at altitudes above 3,000 m. They were divided Henry. in subgroups according to the length of their The effect of continuous negative continuous stay. For comparison, 25 pressure breathing on water and highlanders who were born and brought up at electrolyte excretion by the human high altitude and 50 lowlanders who had never kidney. been to altitudes of more than 1,000m were Journal of Clinical Investigation also studied. High catecholamine excretion 33:572-577, 1954. was noted in temporary residents staying at Authors' Abstract high altitude for up to 30 days, as compared to The effects of decreased intrathoracic that in lowlanders (P<0.01). The excretion rate pressure on arterial blood pressure, venous gradually returned to basal values thereafter. pressure, cardiac output, and pulmonary Catecholamines were essentially similar in pressure and volume have been investigated in lowlanders and highlanders. The significance the past. The present study was prompted by of these finding is discussed regarding the the association of marked diuresis with

79 continuousnegativepressurebreathingin 211. Singh MV, SC Jain, SB Rawal, anesthetizedanimalsandtheobservationthatin HM Divekar, R Parshad, AK unanesthetizedmancontinuouspositive Tyagi and KC Sinha. pressurebreathingleadsto anoliguria. The Comparative study of acetazolamide purposeof thisinvestigationwasto and spironolactone on body fluid demonstratethathumansubjects,like compartments on induction to high anesthetizedanimals,haveanincreasedurine altitude. flow in responseto continuousnegative International Journal of pressurebreathing.Observationsweremade Biometerorology 30:33-41, 1986. on therenalexcretionof water,sodiumand Authors' Abstract potassium,urinary pH,andendogenous Studies were conducted on 29 male creatinineclearancein thehopethatthe healthy subjects having no previous experience mechanismof thediuresismightbe elucidated. of living at high altitude. These subjects were divided into three groups; i.e., subjects treated 210. Siggaard-Andersen J, FB with placebo, acetazolamide, and Petersen, TI Hansen and K spironolactone, These subjects were first Mellemgaard. studied in Delhi. The drug schedule was Plasma volume and vascular started 24 hour prior to the airlift of these permeability during hypoxia and carbon subjects to an altitude of 3,500 m and was monoxide exposure. continued for 48 hour after arrival at high Scandinavian Journal of Clinical and altitude. Total body water, extracellular water, Laboratory Investigation 103:39-48, plasma volume, blood electrolytes, pH, pO 2, 1968. pCO 2 and blood viscosity were determined on Authors' Abstract the 3 rd and 12th days of their stay at high The effect on plasma volume and capillary altitude. Total body water, extracellular water permeability to albumin of high altitude (3,454 intraceUular water and plasma volume m) and of carbon monoxide (CO) was decreased on high altitude exposure. There investigated during acute exposure (12 hours) was a further slight decrease in these and more prolonged exposure (8 days). compartments with acetazolamide and Prolonged exposure to CO resulted in a spironolactone. It was also observed that decrease or no change in plasma volume, while spironolactone drives out more water from the prolonged exposure to hypoxia showed a more extracellular compartment. Loss of plasma marked decrease in plasma volume. Acute water was also confirmed by increased plasma exposure to hypoxia gave no change or a osmolality. Increase in arterial blood pH was decrease in plasma volume. No changes were noticed on hypoxic exposure, but the increase found in plasma volume during acute exposure was found less in acetazolamide and to CO, although the results probably were spironolactone cases. This decrease in pH is overestimated due to an increase in capillary expected to result in better oxygen delivery to permeability. Capillary permeability was the tissues at the low oxygen tension. It was unchanged during exposure to hypoxia. From also confirmed because blood pO 2 increased in the present results it seems justified to conclude both the groups. No significant change in that CO has a more pronounced effect on the plasma electrolytes was observed in subjects of permeability of the capillaries to albumin than various groups. Blood viscosity slightly hypoxia alone, although the explanation for this increased on exposure to high altitude. The finding could be that the tissue hypoxia was degree of rise was found less in the group more severe in the CO experiments than during treated with spironolactone. This study hypoxia. suggests that both the drugs are likely to be beneficial in ameliorating/prevention of the AMS syndrome.

80 212. Singh I, MS Malhotra, PK pH, PaO 2, PaCO 2 and blood viscosity were Khanna, RB Nanda, T determined on exposure at Delhi and on re- Purshottam, TN Upadhyay, U induction to high altitude. Plasma volume was Radhakrishnan and HD increased after the descent from high altitude Brahmachari. and remained high for up to 21 days. This Changes in plasma cortisol, blood increased plasma volume may have some antidiuretic hormone and urinary significance in the pathogenesis of pulmonary catecholamines in high-altitude oedema. Total body water and intracellular pulmonary oedema. fluid content were increased at 260 m elevation, International Journal of while extracellular fluid decreased. On re- Biometeorology 18:211-221, 1974. induction there was a decrease in total body Authors' Abstract water with no change in the extracellular fluid In 10 subjects susceptible to high altitude content. pulmonary oedema (HAPO), plasma cortisol and antidiuretic hormone (ADH) and urinary 214. Singh MV, SB Rawal and AK catecholamines were estimated both at sea level Tyagi. and dally during their stay at 3,500 m (Leh). Body fluid status on induction, At high altitude 4 of the subjects developed reinduction and prolonged stay at high altitude on human volunteers. HAPO, 2 got acute mountain sickness (AMS), and 4 remained unaffected. Plasma cortisol International Journal of showed a sharp rise on the first day at high Biometeorology 34:93-97, 1990. altitude in all the subjects. Thereafter, it Authors' Abstract declined gradually in the unaffected subjects. Studies on adaptation to high altitude (HA) In the HAPO patients there was a sharp fall in of 3,500 m in the Himalayas were conducted in the plasma cortisol level combined with three phases, each including 10 normal and antidiuresis. Changes in plasma ADH and healthy males normally resident at sea-level. urinary catecholamines were not consistent. It Phase I subjects had no previous experience of appears that failure in the normal adrenocortical HA, phase II subjects after 4-6 months at HA response to altitude stress in susceptible were airlifted to sea-level, and phase III subjects is a factor in precipitating HAPO. subjects stayed continuously for 6 months at 3,500 m. Body fluid compartments and blood 213. Singh MV, SB Rawal, AK Tyagi, gases were determined in all three groups. MJK Bhagat, R Parshad and HM Plasma volume was highly elevated in the Divekar. phase II subjects on reinduction to sea-level Changes in body fluid compartments on from HA. In comparison to phase I subjects, re-induction to high altitude and effect the retention of fluid in the extracellular of diuretics. compartment was increased at HA leading to International Journal of increased susceptibility to high altitude illness. Biometeorology 32:36-40, 1988. Phase III subjects were hyperhydrated with Authors' Abstract decreased plasma volume and increased PO 2 in Studies were carried out in 29 healthy comparison to the other two groups. young adults in the Indian Army stationed in the plains and posted at an elevation of 3500 m 215. Siri WE, C Reynafarje, NI Berlin for more than 6 months. After exposure to a and JH Lawrence. low elevation in Delhi (260 m) for 3 weeks, Body water at sea level and at altitude. they were reinduced to a height of 3,500 m. Journal of Applied Physiology 7:333- The subjects were divided into three groups, 334, 1954. each of which was treated with either placebo Annotation or acetazolamide or spironolactone. The drug Purpose treatment was started immediately after their To elucidate changes in body water and fat landing at high altitude and continued for 2 in humans during and after acclimatization to days only. Total body water, extracellular low oxygen tension. fluid, intracellular fluid, plasma volume, blood Methods

81 Two groups of subjects were used. The marked changes in cardiac and pulmonary first group consisted of 15 normal young males function, subsidence of severe hypoxic (medical students), residents of Lima, Peru; symptoms; and increased serum protein bound whereas the second group consisted of 13 iodine, oxygen consumption, urinary excretion normal male Peruvian Indians (mine workers) of adrenocortical steroids, and concentration of living at 16,400 feet or above. Total body all blood cells except erythrocytes in peripheral water was determined by the tritium dilution blood. No significant changes occurred in total method and fat was determined by the formula red cell and plasma volumes nor in the (%fat = 100-1.37 x %water) measured blood and urinary electrolyte and Results enzyme concentrations. The mean body water and body fat for the subjects at sea level was 55.6 and 23.8%, 217. Slater JDH and TP Jowett. respectively. The mean body water and body The kidney and aldosterone in fat for subjects living at 16,400 ft was 60.6% acclimatization at altitude. and 17.0%, respectively. This difference in British Journal of Diseases of the body water of about 5% was not considered as Chest 71:203, 1977. a significant effect of acclimatization, but rather Authors' Abstract suggests a slight difference in gross body Five climbers were studied during an composition, i.e., in the relative amount of fat ascent of a 7,500 m mountain in the Hindu and lean body mass because of the respective Kush. Representative samples from 24-hour occupations of the two groups. urines were preserved from five subjects at Conclusions 5,400 m and 6,600 m, and from two at 7,000 Total body water was determined in two m. Sodium and cortisol excretion was normal, groups of young, normal subjects. One group but that of potassium and especially aldosterone living at sea level and the other acclimatized to was low, especially in two climbers who had 16,400 ft. The mean values of body water for episodes of peripheral oedema. the two groups were normal for their age range Hypoaldosteronism is a feature of high altitude and occupations. acclimatization but its cause and significance have still to be elucidated. 216. Siri WE, DC Van Dyke, HS Winchell, M Pollycove, HG 218. Slater JDH, RE Tuffley, ES Parker and AS Cleveland. Williams, CH Beresford, PH Early erythropoietin, blood, and Siinksen, RHT Edwards, RP physiological responses to severe Ekins and M McLaughlin. hypoxia in man. Control of aldosterone secretion during Journal of Applied Physiology 21:73- acclimatization to hypoxia in man. 80, 1966. Clinical Science 37:327-341, 1969. Authors' Abstract Authors' Abstract Serum and urinary erythropoietin, plasma- 1. Six normal men were studied under iron turnover, and various physiological controlled conditions with a constant diet for 4- parameters were systematically measured in a 5 day periods before, during and after exposure human subject exposed 4 days to 405.6 mm to mild hypoxia produced by an ascent to 3500 Hg (simulated 16,400 ft) following rapid m above sea level. decompression. Serum erythropoietin became 2. Aldosterone secretion fell (P<0.05) to detectable at 12 hr, reached maximum 65% +8 of mean control values on the third day concentration on the 3 rd day, and fell to low at altitude and rose on descent. The rate of levels on the 4 th. Plasma-iron turnover and renal aldosterone excretion also fell. hemoglobin synthesis followed a similar 3. Cortisol secretion rose significantly on pattern, although elevated rates persisted for ascent and fell slightly on descent. some time after return to sea-level pressure. 4. Plasma renin activity also rose slightly The rise and fall in serum erythropoietin on ascent and fell significantly on descent. correlated with other physiological changes occurring during acute acclimatization including

82 5.We concludethatthechangesof residence at high altitude was studied in 6 aldosteronesecretioncannotbeexplainedin human subjects. termsof knowncontrolmechanisms. The red count and hemoglobin rise almost proportionately throughout, reaching in 3 219. Slater JDH, ES Williams, RHT weeks a maximum of 10 to 15 per cent above Edwards, RP Ekins, PH the sea level value. S_inksen, CH Beresford and M The percentage of red blood cells McLaughlin. (hematocrit) rises somewhat less indicating that Potassium retention during the the individual cells are slightly smaller though respiratory alkalosis of mild hypoxia in capable of holding the same amount of man: Its relationship to aldosterone hemoglobin. secretion and other metabolic changes. There is no evidence of abrupt changes in Clinical Science 37:311-326, 1969. red blood cells or blood volume within the first Authors' Abstract day or two spent at high altitude. 1. Six normal men were studied under Blood volume determinations by the dye controlled conditions with a constant diet for 4- and by the carbon monoxide methods indicate 5 day periods before, during and after exposure that the rise in red cells and hemoglobin is due to hypoxia induced by ascending to an altitude to the production of more cells, not to a of 3,500 m above sea level. redistribution. 2. The expected changes of plasma PaCO 2, bicarbonate and chloride were seen 221. Sobrevilla LA and F Salazar. during hypoxia, but the rate of renal potassium High altitude hyperuricemia. excretion decreased to a mean of 39% +10 of Proceedings of the Society for mean control values (minimal excretion second Experimental Biology and Medicine day) with a 5% increase of plasma potassium 129:890-895, 1968. concentration. Sodium excretion fell slightly Authors' Abstract during the first 2 days at altitude but Fifteen normal male and 15 normal female subsequently rose to 159% + 13 (maximal subjects living permanently at a mining town excretion fourth day). These changes were located at an altitude of 14,000 ft HA in the reversed on return to 520 m. Total solute central Andean plateau demonstrated elevation output and free water reabsorption were almost of the values of serum urate, creatinine, and unchanged. hematocrit when compared with equal numbers 3. Aldosterone secretion fell (P<0.05) to of normal subjects living at sea level (SL). Of 65 % +8 of mean control values on the third day the HA male group, three subjects (20%) had at altitude and rose on descent. urate values above 8 mg/100 ml, the level at 4. We suggest that the fall in the rate of which urate deposition in tissues might take renal potassium excretion represents an overall place. There was a high degree of correlation retention of body potassium which is mediated between the serum urate levels and the partly by a direct effect of extracellular alkalosis hematocrit and between the serum creatinine on skeletal muscle ceils, and partly by a and the hematocrit in the series as a whole. reduction in the rate of Na/K exchange in the Although the mean hematocrit values of the HA renal tubule which we attribute to a reduction of females and the SL males were comparable, the aldosterone action. latter had higher urate levels, reflecting the influence of sex on urate levels. 220. Smith HP, AE Belt, HR Arnold and EB Carrier. 222. Stenberg J, B Ekbiom and R Blood volume changes at high altitude. Messin. American Journal of Physiology Hemodynamic response to work at 71:395-412, 1924. simulated altitude of 4,000 m. Authors' Abstract Journal of Applied Physiology The effect on hemoglobin, red blood ceils, 21:1589-1594, 1966. hematocrit and blood volume of four weeks

83 Authors' Abstract excessively in two of them. Since plasma Oxygen uptake, pulmonary ventilation, volume decreased in four subjects, the change cardiac output (dye-dilution technique), blood in total blood volume was less consistent. In pressure (intra-arterial), oxygen content of one climber dehydration led to a decrease in arterial blood, and blood lactic acid total blood volume. While a significant concentration were determined in six men, 19- correlation was found between maximal 36 years of age, during submaximal and oxygen uptake and red cell volume at sea level, maximal work on a bicycle ergometer at sea the hematologic response to altitude seemed level and after 10-60 n'fin exposure to Ps 462 independent of physical fitness. In one climber mmHg in an altitude chamber (simulated the erythropoietic response was so excessive altitude 4,000 m, 13,115 ft). With the arterial (more than 50% increase in red cell volume), oxygen saturation reduced from 96 to 70%, that he had to be hemodiluted. maximal oxygen uptake was reduced to 72% of that at sea level; i.e., 3.46 and 2.50 liters/min, 224. Sundstroem ES. respectively. Maximal values for pulmonary Studies on adaptation of man to high ventilation were 118 and 124 liters/min, cardiac altitudes: V. Effect of high altitudes on output 23.2 and 23.7 liters/rain, heart rate 184 salt metabolism with special reference and 186 beats/rain, stroke volume 126 and 127 to the mechanism of maintaining the fill, (A-V)O 2 diff 108 and 146 ml at simulated acid-base equilibrium of the body. altitude and at sea level, respectively. University of California Publications Integrated mean arterial blood pressure was in Physiology 5:121-132, 1919. lower during work in hypoxia. At submaximal Author's Abstract work the heart rate, cardiac output, and 1. By computing the intake and output of pulmonary ventilation were significantly acids and bases on a uniform diet in terms of elevated during hypoxia. Moderate. acute decinormal in a case of successful hypoxia does not seem to interfere with cardiac acclimatization to an elevation of 3,100 m, an performance or the tissues' capability to extract increase of the base output was found. This oxygen from the blood during exercise. excess elimination of bases was caused by an increased output of fixed alkalies. 223. Stokke KT, K Rootwelt, R 2. In a case of mountain sickness, at an Wergeland and JR Vale. altitude of 4,300 m, the increase of base Changes in plasma and red cell volumes excretion was delayed. during exposure to high altitude. 3. This excessive output of bases cannot Scandinavian Journal of Clinical and be attributed to an excretion of lactates, since Laboratory Investigation 46:113-117, the excretion of lactic acid remained of normal 1986. dimensions. Authors' Abstract 4. It is suggested that the excessive base Training at moderate altitude has been output was partly due to elimination of used by athletes to improve their performance bicarbonates, and partly to salts of strong fatty at sea level. Not all athletes benefit from acids. altitude training, and there also has been some 5. The decrease of ammonia output is doubt as to whether red cell volume increases explained as a corollary to the increase in the in all subjects. Ten members of the Norwegian elimination of fixed alkalies. Everest Expedition 1985 took part in the 6. The increase of base excretion is present study. Plasma volume was determined considered to be the main mechanism in by isotope dilution using _z_I-albumin. By restoring the reaction of the blood, disturbed by simultaneous measurement of hematocrit, the the loss of carbon dioxide. total blood volume and red cell volume were 7. The possibility that decrease of acid calculated. Measurements were done in Oslo output may be an auxiliary mechanism in (sea level) before departure, and in Base Camp maintaining the acid-base equilibrium is (5300 m) four weeks later. The mean altitude considered. during these four weeks was 4100 m. Red cell volume increased in all participants, and

84 8. It is pointed out that the "Zuntz sea level. In spite of an increased intensity of phenomenon" may also participate in bringing thyroxine binding by plasma proteins, the about adaptation to high altitudes. concentration of plasma free thyroxine was increased at altitude. Since the electrophoretic 225. Surks MI. distribution of plasma proteins was unaltered, Metabolism of human serum albumin in plasma dehydration in the initial phase of man during acute exposure to high altitude exposure was concluded to be altitude (14,100 feet). responsible for most of the observed alterations Journal of Clinical Investigation in thyroxine binding. A decrease in mean 45:1442-1451, 1966. binding capacity of thyroxine-binding Author's Abstract prealbumin is interpreted to reflect changes in The metabolism of human serum albumin protein synthesis and/or degradation which was studied by means of albumin-131I in five may also occur in this environment. young males at 5,280 feet, and for 8 days at 14,100 feet altitude. The data were analyzed in 227. Surks MI, HJ Beckwitt and CA a manner that made possible the daily Chidsey. estimation of the rate of albumin degradation Changes in plasma thyroxine and synthesis + net transfer from the concentration and metabolism, extravascular to intravascular compartments. catecholamine excretion and basal Albumin degradation was increased oxygen consumption in man during markedly for 24 to 48 hours within the first 3 acute exposure to high altitude. days at high altitude. A large shift of high Journal of Clinical Endocrinology specific activity albumin from the extravascular 27:789-799, 1967. to intravascular compartments occurred Authors' Abstract towards the end of altitude exposure and was Plasma total and free thyroxine accompanied by a decrease in the rate of concentration, thyroxine turnover, albumin synthesis + net transfer. catecholamine excretion and basal oxygen A decrease in the intake of calories and consumption were measure in 5 young male protein (minimum - 0.90 g per kg per day), as subjects during a control period at 5280 feet well as a negative nitrogen balance, was altitude and for 8 days at 14,100 feet (Pikes observed during the high altitude period. Peak, Colorado). Turnover data were analyzed The data are discussed in relation to in a manner enabling the calculation of daily changes in thyroid and adrenocortical function rates of thyroxine degradation during the that have been observed in this environment. experimental period. Thyroxine degradation was increased during the first 3 days at high 226. Surks, MI. altitude and thereafter remained slightly Elevated PBI, free thyroxine, and elevated. Mean basal oxygen consumption plasma protein concentration in man at increased from 125 to 147 rnl per min per m 2 high altitude. on the first day at high altitude and then Journal of Applied Physiology progressively decreased toward the control 21:1185-1190, 1966. value. Plasma total and free thyroxine Author's Abstract concentration and norepinephrine excretion Various aspects of thyroxine binding by were not altered during the first 2 days at plasma proteins have been studied in eight sea- altitude, but then increased continually for the level residents before, during, and after 28 remainder of altitude exposure. Epinephrine days exposure to 14,100 ft altitude. Mean and total metanephrine excretion were plasma concentration of protein-bound iodine, unchanged, but the increased sympathetic total protein, and the binding capacity of activity was reflected by an increase in the thyroxine-binding globulin were elevated excretion of vanillymandelic acid. The within 3 days, reached a maximum after 9 temporal association between the initial days, and returned toward low-altitude values hypermetabolism and increased thyroxine between 12-15 days at altitude. They reached degradation at altitude suggests that these control levels within 4 days after descending to changes may be causally related. The later

85 alterationsin sympatheticactivityand potassium (K) (from K *° counting). No circulatingthyroxineconcentrationsmayplaya changes were observed in total body water role in theadaptationto moreprolonged (W), lean body mass, protoplasmic mass (M3), exposureto thisenvironment. and bone mineral, all of which were derived from the same measurements. Although M 3 228. Surks MI and JE Canham. was unchanged, calculations based on Albumin metabolism in man at high creatinine excretion and K showed an increase altitude. in nonmuscle protein at the expense of muscle Federation Proceedings 25:399, protein. Attempts to measure W directly, 1966. (Abstract). employing deuterium oxide dilution, were Authors' Abstract unsuccessful possibly due to uneven The turnover of injected I- 131 albumin distribution of this isotope in the body water was studied in 5 young males during a 10-day compartments at high altitude. A highly control period at 5,280 altitude and for 8 days significant decrease (P<0.001) in plasma at the summit of Pikes Peak, Colorado (14,110 volume after 4 and 8 days at altitude provided ft). The control mean fractional degradation direct evidence for altered water distribution in rate of plasma 1-131-albumin (plasma K) was this environment. 0.1182 _+0.0031 per day which resulted in the degradation of 16.07 _+0.80 g albumin per day. 230. Sutton JR, GW Viol, GW Gray, A marked increase in plasma K occurred during M McFadden and PM Keane. the first 3 days of high altitude exposure. Retain, aldosterone, electrolyte, and Thereafter, mean plasma K remained 10-20% cortisol responses to hypoxic higher than the control. The amount of decompression. albumin degraded during altitude exposure, Journal of Applied Physiology 43:421- however, was less than that anticipated by 424, 1977. alterations in plasma K because of a reduction Authors' Abstract in the intravascular (Iv) albumin pool. Responses of plasma renin activity, Analysis of extravascular (Ev) and plasma plasma aldosterone, plasma cortisol, and specific activity curves initially showed no plasma electrolyte concentration, and urinary increase in the rate of synthesis +Ev net to Iv electrolyte and aldosterone excretion, were transfer of albumin. In the last several days of studied in four men during hypoxic altitude exposure albumin synthesis +Ev to Iv decompression to a simulated altitude of 4,760 transfer was reduced. These observations were m in a pressure chamber. Three of the four correlated with a voluntary decrease in caloric subjects developed significant acute mountain and protein intake and a concomitant negative sickness. Plasma sodium and potassium nitrogen balance. concentrations were unchanged. No significant change in plasma renin activity was observed, 229. Surks MI, KSK Chinn and LRO but the values tended to fall. Plasma Matoush. aldosterone concentration was depressed, while Alterations in body composition in man plasma cortisol was elevated and diurnal after acute exposure to high altitude. variation lost. Urinary sodium excretion was Journal of Applied Physiology unchanged, but urinary potassium and 21:1741-1746, 1966. aldosterone excretion were decreased. The Authors' Abstract decrease in plasma and urinary aldosterone and Body composition was measured in five urinary potassium, in the absence of change in young males, residents of Denver, Colorado plasma renin activity or plasma potassium, is of (5,280 ft altitude) before, during, and after 8 uncertain origin. It is unlikely to be due to a days on the summit of Pikes Peak, Colorado decrease in adrenocorticotropin secretion since (14,100 ft altitude). Body weight plasma cortisol rose during the same time. progressively decreased during the altitude None of the changes could be causally period resulting primarily from a decrease in implicated in the development of acute body fat as estimated by measurements of body mountain sickness, although the increase in density, creatinine excretion, and total body plasma cortisol was greatest in the most ill.

86 Proceedings of the Society for 231. Swenson ER, TB Duncan, SV Experimental Biology and Medicine Goldberg, G Ramirez, S Ahmad 106:714-717, 1961. and RB Schoene. Annotation Diuretic effect of acute hypoxia in Purpose humans: relationship to hypoxic To decrease active reabsorption of sodium ventilatory responsiveness and renal and oxygen consumption in the kidney by hormones. means of low arterial oxygen pressure or Journal of Applied Physiology 78:377- administration of hydrochlorothiazide; to 383, 1995. determine the Na/net 02 ratio under these Authors' Abstract conditions when tubular load and renal blood Acute hypoxia causes increased sodium flow were essentially unchanged; and to gain and water excretion. Animal studies suggest information about basal renal oxygen that this renal response is largely driven by consumption under the influence of hypoxia or direct peripheral arterial chemoreceptor hydrochlorothiazide. stimulation, independent of accompanying Methods changes in ventilation and acid-base status. Twelve normal hydrated mongrels were Whether the diuresis and natriuresis observed anesthetized with nembutal (9 dogs) or with in humans made acutely hypoxic are caused by inactin (3 dogs), and renal oxygen peripheral chemoreceptor stimulation is not consumption and sodium reabsorption were known, but if so, we hypothesized that people determined during hypoxia and under the with a high ventilatory response to hypoxia influence of hydrochlorothiazide. (high peripheral chemosensitivity) should have Results greater diuresis and natriuresis than those with In hypoxia (arterial O 2 saturation 35%) a low ventilatory response to hypoxia. The less sodium was reabsorbed and renal O 2 isocapnic hypoxic ventilatory response (HVR) consumption was diminished. Urine volume of 16 subjects on a fixed sodium intake was was increased with a decrease in U/Pos M, measured, as were their urinary volumes and U/Pc_,,, and T_.20. During administration of sodium and bicarbonate losses during 6 h of hydrochlorothiazide both sodium reabsorption breathing air (in a normobaric environmental and O 2 consumption were lowered. Urine chamber) and, on the subsequent day, 12% 02 . volume and Cos Mwere elevated, U/Pos Mand The isocapnic HVR correlated positively with U/P_a _decreased while TCH2oremained hypoxic diuresis (r = 0.87) and natriuresis unchanged. Plotting Na reabsorption ( eq/g (r = 0.76). In contrast, the isocapnic HVR did rain) against O 2 consumption ( mol/g min) not correlate with bicarbonate excretion despite resulted in a straight line which intercepted the the expected respiratory alkalosis of acute O 2 consumption axis at 1 mol/g min. This hypoxia. The magnitude of diuresis and value may be equated with renal basal 0 2 natriuresis with hypoxia did not correlate with consumption; i.e., without Na reabsorption. changes in circulating aldosterone, renin, atrial The O 2 requirement for renal sodium natriuretic peptide, vasopressin, or a digoxin- reabsorption was calculated to be 28.6-33 like immunoreactive substance. These findings eqNa/mol 0 2. are compatible with a role of the peripheral Conclusions arterial chemoreceptors in mediating the renal The data suggest that active sodium response to hypoxia in humans. The efferent reabsorption and net oxygen consumption in pathway remains unknown. the dog kidney can be lowered proportionately during severe hypoxia. Because the alterations 232. Thurau K. caused by hypoxia were abolished 20 minutes after the dogs were again breathing room-air Renal Na-reabsorption and O2-uptake in makes it unlikely that hormonal influences were dogs during hypoxia and involved. Although it cannot be determined hydrochlorothiazide infusion. with certainty, the decrease in 'l'*w,o may be caused by a decrease of active sodium reabsorption in the medulla by hypoxia. The

87 basaloxygenconsumptionof 1mol/gkidney and eight high altitude (4,500 m) natives min is notaffectedby hypoxiaor before, during and after the infusion of small hydrochlorothiazide. amounts of angiotensin (0.32 g/rain). In basal conditions the high altitude group showed a 233. Timiras PS, N Pace and CA mild reduction in the glomerular filtration rate, Hwang. with a higher reduction in the renal plasma flow Plasma and urine 17-hydroxycortico- and a normal or slightly increased renal blood steriod and urine 17-ketosteroid levels flow. During angiotensin infusion, both sea in man during acclimatization to high level and high altitude groups responded with a altitude. marked reduction in urine flow and sodium Federation Proceedings 16:340, excretion. The glomerular filtration rate and 1957. (Abstract). renal plasma flow diminished, with a greater Authors' Abstract fall in the latter. These changes were smaller in Studies were made on 6 healthy adult the high altitude group, except in the sodium to males during the summer of 1955. The inulin clearance ratio, which was similar in subjects went from their residence in Berkeley both groups. Despite a high filtration fraction, (250 ft) to the Barcroft Laboratory (12,470 ft) the kidney of the high altitude native responds of the White Mountain Research Station for 3 to angiotensin like the sea level kidney. These separate sojourns of 5-8 days each with results are discussed in relation to the intervening periods at sea level. All urine was paradoxical renal response to angiotensin collected throughout successive 12-hr periods observed in the hypertensive patient. for 1-3 days in the week preceding each exposure and every day at altitude. Venous 235. Tucker A, JT Reeves, D blood specimens were obtained before Robertshaw and RF Grover. breakfast. After exposure to altitude, urinary Cardiopulmonary response to acute excretion of 17-hydroxycorticosteroids and of altitude exposure: water loading and 17-ketosteroids was increased by as much as denitrogenation. 300% and 50%, respectively, over sea level Respiration Physiology 54:363-380, values. Similarly, plasma levels of 17- 1983. hydroxycorticosteroids were higher at altitude Authors' Abstract than at sea level with a maximum increase of In order to determine if a positive water 115%. On the other hand, the urine and balance would impair cardiovascular and plasma levels of adrenocortical hormones and ventilatory adjustments during acute altitude their metabolites appeared to be related to the exposure, six healthy male subjects were duration of the exposure and the degree of exposed to 4570 m for 2 h with and without acclimatization. They rose during the first 3 water loading. No significant differences in days of each sojourn at altitude and then any of the measured variables were observed returned toward the sea level values. In between normal and overhydrated subjects. In addition, the magnitude of these changes order to determine if rapid ascent to altitude decreased in successive sojourns. The involves the formation of nitrogen bubbles observations suggest that exposure to altitude which could impair gas exchange, 11 subjects stimulates in man adrenocortical activity but were exposed to 4,570 m with and without that the increase in the levels of the denitrogenation (by breathing 100% 02 prior to adrenocortical hormones is only temporary. ascent) and 6 subjects were exposed to normobaric hypoxia (14% 02). Prior 02 234. Torres C, R Lozano, J breathing reduced their hyperventilatory and Whittembury and CC Monge. alkalotic responses to altitude, tachycardia did Effect of angiotensin on the kidney of not develop, and systemic blood pressure fell, the high altitude native. despite the fact that arterial desaturation was Nephron 7:489-498, 1970. similar to that during the untreated altitude Authors' Abstract exposure. Reduced urine flow and increased Renal hemodynamics, sodium and water urine osmolality were observed in two subjects excretion were studied in six sea level residents at 4,570 m, but these changes were not

88 observedin thesamesubjectsafter02 1. Overnight recumbent atrial natriuretic breathing.Breathing14%02 alsoproduced peptide levels were significantly elevated in all thesamedegreeof arterialdesaturation,butthe ten subjects of the Australian Bicentennial hyperventilatoryresponsewassignificantly Mount Everest Expedition during the first week greaterthanin theprior altitudeexposures. at 5,400 m during acclimatization. Heartrate,blood pressure,andurineflow and 2. Twenty-four hour urine volume and osmolalitywerenotalteredandsymptomsof urine sodium increased markedly at altitude. altitudeillnesswereminimal. Thus,neitherof 3. Plasma renin activity and plasma our hypothesesprovedto becorrect;however, aldosterone levels decreased significantly at we did observeaprolongedeffectof 02 altitude. breathingon thehypoxicventilatoryresponse, 4. No significant changes in plasma andapotentialeffectof hypobariaon cortisol, plasma sodium or potassium, body ventilation. temperature, systolic or diastolic blood pressure or heart rate were observed. 236. Tuffley RE, D Rubenstein, JDH 5. Although it was impossible to control Slater and ES Williams. or measure salt and water intake during the Serum renin activity during exposure to study, results suggest that atrial natriuretic hypoxia. peptide may be important for the reduction in Journal of Endocrinology 48:497-510, renin and aldosterone levels and in the diuresis 1970. and natriuresis necessary to adapt to hypoxia at Authors' Abstract altitude. Changes of serum renin activity, heart rate, blood pressure, renal sodium, potassium 238. Ullmann EA. and metadrenaline excretion, and alveolar gas Renal water and cation excretion at tensions were recorded during two 2-3 h moderate altitude. exposures to 446 mmHg barometric pressure Journal of Physiology (London) 58- (simulated altitude of 4,279 m or 14,000 ft). 59, 1953. (Abstract). Serum renin activity rose considerably during Author's Abstract the first exposure and only slightly during the Water and sodium metabolism were second. This effect was positively correlated studied in one healthy subject during 12 days in with the changes of heart rate. There was little London, 29 days on the Jungfraujoch (11,340 change in blood pressure or in the rate of renal ft, B.P. around 500 mmHg), and a further 14 excretion of sodium, potassium or the days in London. No symptoms of altitude metadrenalines. sickness were experienced at any time. It is suggested that the change of serum Voluntary or anoxic hyperventilation of renin activity cannot be explained by a direct short duration at sea-level leads to an immediate effect of hypoxaemia, emotion, posture or the increase in renal sodium, potassium and water diurnal rhythm of renin secretion, but that it output; water diuresis is markedly accelerated; may be correlated with changes of urinary pH rises and ammonia and titratable cardiovascular function. acid excretion fall. By contrast, during the first 2 days on the 237. Tunny T J, J van Gelder, RD Jungfraujoch water sodium and potassium Gordon, SA Klemm, SM excretion were strongly depressed. A positive Hamlet, WL Finn, GM Carney sodium balance of +240 m.equiv and water and C Brand-Maher. retention of 1.5 1. developed in 48 hr. On the Effects of altitude on atrial natriuretic second day a test dose of water produced peptide: the bicentennial Mount Everest almost no diuretic response. Urinary pH Expedition. remained low, but ammonia and titratable acid Clinical and Experimental outputs were below mean London values. The need for fixed base excretion asserted Pharmacology and Physiology 16:287- 291, 1989. itself on the third day when a sodium diuresis Authors' Abstract began which lasted for 3 days. The daily sodium balance became negative (mean 42

89 m.equiv/day)andwaterandweightwaslostin composition of the urine of healthy human spiteof ahighcalorieintake. Relativelymore adults. sodiumthanwaterwaseliminated.Potassium 2. The respired gas mixtures contained 14- excretionrecoveredmoreslowly. 8% oxygen, usually approximately 10%. Fromthe6_to the29_ dayno further Exposure to anoxia lasted one hour. significantdisturbanceof waterbalance 3. The excretion of sodium, potassium, occurred.Titratableacidandammonia bicarbonate and chloride increased, and the excretionremainedlow, andonly roseagain ratio of (H÷+NH4 ÷) ions to (Na÷+K ÷) ions afterreturnto sea-level. decreased if anoxia was accompanied by Meandaily sodiumoutputfor therestof hypocapnia. theperiodataltitudewasslightlybelowthe 4. If during anoxia the development of Londonmean;aslightbut increasingsodium hypocapnia was carefully prevented, only retentiondevelopedfrom the11_dayonwards. trivial alterations in urinary solute output were Serumsodiumremainedunchangedduringthe found. entireperiodof observation. 5. In most experiments anoxia led to Fromthe7_hday on theJungfraujoch polyuria and enhanced the diuresis following onwardrenalpotassiumexcretionincreased ingestion of water. This could only in part be progressively,both absolutely(Londonmean: attributed to a rise in solute excretion, since it 61 m.equiv/day;Jungfraujoch,8th-29thday, occurred equally in the presence and absence of mean89 m.equiv/day),andrelatively,asa hypocapnia; i.e. of large and small changes in fractionof totalcationexcretion.Theincreased solute output. The findings were consistent outputstoppedabruptlyon returntoLondon. with the hypothesis that in acute anoxia the In theabsenceof datashowingpotassium basal rate of secretion of antidiuretic hormone balance,thepossibilitythattheincreasedloss (ADH) may be diminished. reflectsincreasedintakecannotberuledout, 6. If anoxia caused distress the subjects but thisisunlikely. Togetherwith the rapidly became oliguric. This appeared to be observedchangesin sodiummetabolism,the the result of a sudden discharge of ADH from finding suggestsapossibleincreasein the neurohypophysis. adrenocorticalactivityataltitude.Thediuretic 7. Fainting during anoxia was followed by responseto ingestedwaterwasmorerapidon profound oliguria and longlasting, specific theJungfraujochthanat sealevel. Theadrenal depression of sodium excretion. cortexmaybeimplicatedherealso. 8. The changes in renal excretion which Thestimulusfor theinitial inhibitionof were associated with hyperpnoea, hypocapnia, waterandfixed baseexcretioncannotbe distress and the vasovagal syndrome in anoxia attributedto anoxiaor alkalosis,butwas were the same as those which accompany these probablydueto somenon-specificfactor extra-renal disturbances if they arise from connectedwith changeof environment;perhaps causes other than systemic oxygen lack. It actingthroughreleaseof antidiuretichormone appeared therefore that the intrinsic responses from theposteriorpituitary. This issuggested of the nephrons to those agents which modify by thefactthatexactlythesamesequenceof their excretory and regulatory function were not eventsoccurredon returnto sealevel. In this defective in anoxia. case,however,waterandsodiumretention wereprolongedbeyondthe3_ day. 240. van Beaumont W and JE Greenleaf. 239. Ullmann E. Effect of hyperhydration on working Acute anoxia and the excretion of water men at sea level and simulated altitude. and electrolyte. Federation Proceedings 30:427, Journal of Physiology (London) 1991. (Abstract). 155:417-437, 1961. Authors' Abstract Author's Abstract Overhydrated men working in the heat 1. A study was made of the effects of have lower heart rates and rectal temperatures acute anoxic anoxia with and without than normohydrated men (Moroff and Bass, J. concomitant hypocapnia on the volume and Appl. Physiol. 20:267, 1965). Few additional

90 dataontheinfluenceof hyperhydrationon ANP response to maximal exercise of ANP in work performanceareavailable.In thepresent acute hypobaric exposure compared with that in seriesof experiments,3men workedat32%, normobaric conditions, but no significant 64%, and100%of max 402 atsealeveland difference in the NT-proANP responses simulatedaltitude. Whenthemenwerekept between the two conditions. The divergence hyperhydratedwith awaterloadequalto 2%of may be due to stimulation of the elimination their bodyweight;oxygenconsumption, mechanism of ANP. ventilationandrespiratoryratesweresimilarat all work levelsandatmosphericpressures 242. Wang JM, AR Whang and DE comparedto normohydration.Hyperhydration Smith. reducedtheheartratesduring submaximal Preoperative water deficits at 4,945 feet work at3,000meters.During diuresisatsea above sea level. levelandaltitude,urineflow wasnotreduced Rocky Mountain Medical Journal 65:35-39, 1968. duringwork of 32%max V O2. During work Annotation ratesof 64%max 9 02,urineflow was Purpose progressivelyreducedin spiteof expanded To assess the magnitude of water losses bloodvolumesandnormalplasma sustained by the hydroapenic, preoperative osmolarities.Apparentlyexercisegreaterthan patient at 4,945 feet. 35%max 9 02 hasadirecteffectontherenal Methods fluid retentionmechanism. Observations of preoperative water deficits were made on seven afebrile, ambulatory 241. Vuolteenaho O, P Koistinen, V patients and on two afebrile, ambulatory Martikkala, T Takala and J control subjects during the months of October Lepp_iluoto. and November in Albuquerque, New Mexico Effect of physical exercise in hypobaric situated at 4,945 feet above sea level. All conditions on atrial natriuretic peptide subjects were weighed at 9 p.m. the night prior secretion. to surgery (wt. #1). No food or fluid was American Journal of Physiology permitted during the subsequent 10 hours of 263:R647-R652, 1992. sleep. Urine losses were collected and Authors' Abstract measured at the end of the 10 hour study To evaluate the role of atrial natriuretic period. Fecal losses were nil at 7 a.m.; ten peptide (ANP) in exercise-related hours after the initial weighing the subjects cardiovascular and hormonal adjustments in were re-weighed (wt. #2). Water deficits hypobaric conditions, 14 young athletes incurred during the 10 hour study period were performed a maximal ergometer test in a calculated as the difference in weight (wt. #1 hypobaric chamber adjusted to simulate the wt. #2) giving the net loss in weight from altitudes of sea level and 3,000 m. Plasma which was subtracted the urinary volume. immunoreactive ANP levels rose from 5.89 to Results 35.1 pmoFl at sea level and rose significantly Water losses during the 10 hour study less (P<0.05), from 5.36 to 22.3 pmol/l, at period in preoperative patients average 641 simulated 3,000 m. Plasma immunoreactive milliliters and 495 milliliters in the control amino-terminal peptide of proANP (NT- subjects. Based on these measured losses, the proANP) levels increased to the same extent at estimated 24-hour water deficits approximated sea level and at simulated 3,000 m (from 240 to 1,539 ml and 1,188 ml, respectively. Based 481 pmol/1 and from 257 to 539 pmoFl, upon an estimated endogenous production of respectively). Plasma immunoreactive water of 270 ml per day, the final derived aldosterone increased significantly less at estimation of 24-hour insensible water loss was simulated 3,000 m (P<0.05), but the changes 1,269 ml for the preoperative patients and 918 in plasma renin were similar in both conditions. ml for the control subjects. Plasma immunoreactive endothelin-1 and Conclusions serum erythropoietin levels remained Observations of preoperative water deficits unchanged. In conclusion, we found a blunted were made in Albuquerque, New Mexico

91 situated at 4,945 feet above sea level. The venoconstriction is sustained for at least 24 ha" mean preoperative deficits in seven patients following arrival at high altitude and appears to were 641 ml measured over a 10-hour period precede changes in plasma volume. Additional study period. The estimated net 24-hour studies indicate that administration of a low insensible water losses approximate 1,269 ml. oxygen gas, which produces hypoxia of a similar degree to that at Pikes Peak, does not 243. Weil JV, DJ Battock, RF Grover cause venoconstriction if hypocapnia is and CA Chidsey. prevented by addition of CO 2 to inspired gas. Venoconstriction in man upon ascent to However, when hypoxia is associated with high altitude: studies on potential hypocapnia, venoconstriction occurs. Hypoxia mechanisms. of greater intensity than that seen at 4,300 m Federation Proceedings 28:1160- produces venoconstriction in the absence of 1164, 1969. hypocapnia. Hypocapnia appears to enhance Annotation this response. Purpose To make observations of the venous 244. Westendorp RGJ, AN Roos, M circulation together with measurements of Simons, W Wertheim, FH hematocrit and plasma volume following arrival Bosch, M Fr_ilich and AE at high altitude to determine whether changes Meinders. occur which might be expected to raise Effects of hypoxia and atrial natriuretic capillary pressure and hence cause the peptide on aldosterone secretion in decreased plasma volume generally seen under healthy subjects. these circumstances. Journal of Applied Physiology 75:534- Methods 539, 1993. Forearm venous compliance was Authors' Abstract measured in eight normal male residents of To evaluate the inhibitory effect of Denver, Colorado (1,600 m) in May 1967 hypoxia and atrial natriuretic peptide (ANP) on before they were transported by automobile to aldosterone secretion, 11 healthy male subjects the summit of Pikes Peak (4,300 m). Serial were infused with 5 ng' kg 1 ' min 1 ANP or studies of venous compliance beginning within placebo. The subjects were exposed in a 2 hr of arrival were continued over 24 hr at stepwise fashion to incremental hypobaric high altitude in each subject by using a water- hypoxia, which decreased arterial oxygen filled plethysmograph. Hematocrit, plasma saturation to 79 +_2% in the placebo and 84 volume (T1824), and 24-hr urinary +_2% in the ANP condition (P<0.05). In the vartiUymandelic acid (VMA) excretion were placebo condition, the plasma ANP also measured in Denver and on Pikes Peak. concentration increased from 13.8 +1.0 to 19.6 Results +_2.3 pmol/1 (P<0.01) at the lowest barometric Venous compliance during the control pressure. Plasma renin activity did not change, period averaged 2.76 _+0.087 (SEM) ml/100 whereas the plasma aldosterone levels ml. Changes by 9 hr at high altitude were 17.0 increased consequent to the increase of plasma +6.2% reduction in venous compliance adrenocorticotropic hormone (ACTH). Continuous infusion of ANP increased the (P<0.05). Arterial blood gases at that time were: PaCO 2 29.7 +1.2, PaO 2 43.8 +1.4, and plasma levels twofold (P<0.001) and the level pH 7.48 _+0.01. Normal Denver blood gases of guanosine 3',5'-cyclic monophosphate were: PaCO 2 35.6 _+0.57, PaO 2 69 +1.2, pH threefold (P<0.001). However, the plasma 7.42 _+0.004. Venoconstriction was sustained aldosterone concentrations were not different in for the remainder of the 24 hr observation. the two experimental conditions. Hematocrit and plasma volume were not Administration of supplementary oxygen affected significantly during this period and significantly decreased ACTH to baseline urinary VMA excretion was also unchanged. values (P<0.01) together with a decrease in Conclusions aldosterone. Free water clearance (P = 0.05) but not sodium excretion (P = NS) increased Ascent to high altitude (4,300 m) causes a decrease in venous compliance in man. This during continuous ANP infusion. The data

92 indicatethatthealdosteronesecretionin ADMR/RMR, was 2.2 _+0.3 and 2.2 _+0.1, on hypoxiais notinhibitedby the basis of measured and predicted RMR (patho)physiologicalplasmaANP levels.The values, respectively. The results from this inhibitionof aldosteronesecretionmaywellbe study illustrate the problems of maintaining explainedby adirecteffectof hypoxiaon the energy balance while climbing at high altitude. adrenalcells. ACTH is amajorstimulusof EI is low, whereas energy expenditure reaches aldosteronesecretionin hypoxia,which values comparable to those of highly trained overridesthenatriureticeffectof ANP. endurance athletes at sea level.

245. Westerterp KR, B Kayser, F 246. Westerterp KR, B Kayser, L Brouns, JP Herry and WHM Wouters, J-L Le Trong and J-P Saris. Richalet. Energy expenditure climbing Mt. Energy balance at high altitude of Everest. 6,542 m. Journal of Applied Physiology Journal of Applied Physiology 77:862- 73:1815-1819, 1992. 866, 1994. Authors' Abstract Authors' Abstract Weight loss is a well-known phenomenon Weight loss due to malnutrition and at high altitude. It is not clear whether the possibly intestinal malabsorption is a well- negative energy balance is due to anorexia only known phenomenon in high-altitude climbers. or to an increased energy expenditure as well. Up to 5,000 m, energy balance may be The objective of this study was to gain insight attained and intestinal energy digestibility into this matter by measuring simultaneously remains normal. To see whether 1) energy energy intake, energy expenditure, and body balance may also be attained at 6,542 m and, if composition during an expedition to Mt. not, 2) whether decreased energy digestibility Everest. Subjects were two women and three would play a significant role in the energy men between 31 and 42 yr of age. Two deficit, energy intake (EI), energy expenditure, subjects were observed during preparation at body composition, and energy digestibility of high altitude, including a 4-day stay in the Alps 10 subjects (4 women, 6 men; 27-44 yr) were (4,260 m), and subsequently during four assessed during a 21-day sojourn on the daytime stays in a hypobaric chamber (5,600- summit of Mt. Sajama, Bolivia (6,542 m). EI 7,000 m). Observations at high altitude on Mt. was measured during two 3-day intervals: EI1 Everest covered a 7- to 10-day interval just (days 7-9) and EI2 (days 17-19). Total fecal before the summit was reached in three subjects energy loss during EI 1 was calculated from and included the summit (8,872 m) in a fourth. fecal energy measured by bomb calorimetry. Energy intake (EI) was measured with a dietary Average daily metabolic rate (ADMR) at record, average daily metabolic rate (ADMR) altitude was measured in six subjects (2 with doubly labeled water, and resting women, 4 men) using doubly labeled water metabolic rate (RMR) with respiratory gas over a 10-day interval (days 9-19). Basal analysis. Body composition was measured metabolic rate was measured before and after before and after the interval from body mass, the expedition by respiratory gas analysis. skinfold thickness, and total body water. Body composition was estimated from Subjects were in negative energy balance (-5.7 skinfolds and body mass before and during the +1.9 MJ/day) in both situations, during the altitude sojourn. Subjects were in negative preparation in the Alps and on Mt. Everest. energy balance throughout the observation The loss of fat mass over the observation period (EI1 ADMR = -2.9 +1.8 MJ/day and intervals was 1.4 _+0.7 kg, on average two- EI2 ADMR = -2.3 1.8 MJ/day based on a thirds of the weight loss (2.2 +1.5 kg), and gross energy digestibility of 95%). The was significantly correlated with the energy activity level, expressed as ADMR to basal deficit (r=0.84, P<0.05). EI on Mt. Everest metabolic rate, was 1.56-2.39. The loss of fat was 9-13% lower than during the preparation mass (3.7 +1.5 kg) represented 74 +15% of in the Alps. ADMR was at a high level (13.6 the loss of body mass. Energy content of the +1.7 MJ/day). The activity level, expressed as feces was 21 kJ/g dry wt, and gross energy

93 digestibilityamountedto 85%. Theenergy 248. Whitten BK, JP Hannon, GJ deficit increasedto 3.5MJ/dayaftercorrection Klain and KSK Chinn. for thedecreasedenergydigestibility. In Effects of high altitude (14,100 ft) on conclusion,energybalancewasnotattainedat nitrogenous components of human 6,542m. Theresultingenergydeficitappeared serum. to resultmostlyfrom malnutrition,andonlya Metabolism 17:360-365, 1968. limitedpartcouldbe attributedto Authors' Abstract malabsorption. Serum free amino acids and nitrogenous metabolites were measured in 8 male subjects 247. Westerterp KR, P Robach, L exposed to a high altitude of 14,100 feet for 14 Wouters and J-P Richalet. days. The ratio of total essential amino acids to Water balance and acute mountain total nonessential amino acids was decreased at sickness before and after arrival at high altitude. Glutarnic acid increased and leucine, altitude of 4,350 m. lysine, valine, and threonine decreased Journal of Applied Physiology significantly at altitude. The nitrogenous 80:1968-1972, 1996. metabolites taurine and urea were elevated at Authors' Abstract altitude. Serum water content increased The present study is a fhst attempt to slightly; i.e., about 1 per cent, and therefore measure water balance and its components at changes in the nitrogenous components of altitude by using labeled water and bromide serum at altitude cannot be explained by a dilution and relating the results with acute dehydration effect. Alterations in serum free mountain sickness (AMS). Water intake, total amino acid and nitrogenous metabolite water output, and water output in urine and concentrations in serum of subjects at 14,100 feces were measured over a 4-day interval feet closely parallel changes in these serum before and a subsequent 4-day interval after components reported in subjects on protein transport to 4,350 m. Total body water and deficient diets; however, protein intake at extracellular water were measured at the start altitude was well above minimum and at the end of the two intervals. There was requirements. This suggests that the changes a close relationship between energy intake and in nitrogenous components of serum noted in 8 water intake, and the relationship was male subjects exposed to a high altitude of unchanged by the altitude intervention. 14,100 feet are due to alterations in protein Subjects developing AMS reduced energy metabolism which affect protein utilization. intake and water intake correspondingly. The increase in total body water (TBW) in subjects 249. Williams ES. developing AMS was accompanied by a Electrolyte regulation during the reduction in total water loss. They did not adaptation of humans to life at high show the increased urine output, compensating altitude. for the reduced evaporative water loss at Proceedings of the Royal Society of altitude. Subjects showed a significant increase London Series B 165:266-280, 1966. in TBW after 4 days at altitude. Subjects with Author's Abstract AMS showed the biggest shifts in extracellular Studies related to the body's regulation of water relative to TBW. In conclusion, fluid its sodium and potassium content have been retention in relation to AMS is independent of a made on a number of occasions during periods change in water requirements due to altitude spent at high altitude. It is shown that on exposure. Subjects developing AMS were ascent from usual levels of residence the ratio those showing a fluid shift of at least 1 liter of sodium to potassium in the saliva tends to from the intracellular to the extracellular rise above normal and later to fall with compartment or from the extracellular to the continued residence at altitude. The intracellular compartment. implications of this f'mding have been confirmed by subsidiary studies. The urinary aldosterone excreted while resident at altitude has been assayed and it has been shown to fall to very low levels. In

94 contrast to what occurs with 17- increase in interstitial fluid volume of 2.0 litres hydoxycorticosteroids, there appears to be a (17%), and a decrease in intracellular fluid delay in the fall of urinary aldosterone although volume of 1.8 litres (8%). this has still to be confirmed by further studies 7. These changes, together with the which, are in course of preparation. With clinical observation of facial and ankle oedema continued residence at high altitude the urinary during the experiment, suggest that continuous aldosterone level recovers, but complete exercise may cause oedema and thus may be a recovery takes several weeks. factor in the aetiology of high-altitude oedema. Published data are reviewed and it is concluded that these results are due to the 251. Wolfel EE, MA Selland, RS changes in intravascular volume which occur Mazzeo and JT Reeves. on ascent to an environment of reduced pO 2. It Systemic hypertension at 4,300 m is is probable that the significant volume changes related to sympathoadrenal activity. are intrathoracic. Journal of Applied Physiology 76:1643-1650, 1994. 250. Williams ES, MP Ward, JS Authors' Abstract Milledge, WR Withey, MWJ Residence at high altitude has been Older and ML Forsling. associated with elevation in systemic arterial Effect of the exercise of seven blood pressure, but the time course has been consecutive days hill-walking on fluid little studied and the mechanism is unknown. homeostasis. Because plasma epinephrine (E) and Clinical Science 56:305-316, 1979. norepinephrine (NE) also increase at altitude, Authors' Abstract we hypothesized that heightened 1. The effect of 7 consecutive days of sympathoadrenal activity may cause increased strenuous exercise, hill-walking, on water arterial pressure. We measured ambulatory balance and distribution was studied in five blood pressure by cuff monitor in relation to subjects. The exercise was preceded and 24-hour urinary excretion of E and NE at sea followed by 3 control days. The diet was fixed level and during 3 wk of residence at 4,300 m throughout but water was allowed ad libitum. (Pikes Peak, CO) in 11 healthy men. In five 2. Packed cell volume was measured subjects taking placebo, arterial pressure daily. Serum electrolytes and arginine progressively increased at 4,300 m from 82 +1 vasopressin were measured twice daily. Daily (SE) mmHg at sea level to 88 +3 on day 2, water, sodium and potassium balances were 91 +3 on day 8, and 97 +6 on day 17. In six calculated. subjects propranolol (240 rag/day) decreased 3. During exercise there was a fall in pressure from 85 +4 to 77 +1 mmHg at sea packed cell volume, reaching a maximum of level, but did not prevent sustained increase in 11% by day 5, and a retention of sodium pressure at 4,300 m (84 +1, 81 +1, and 85 +3 reaching a cumulative maximum of 358 mmol mmHg on days 2, 8, and 17, respectively). by day 6. During and immediately after Compared with the placebo group, blood exercise there was a retention of potassium, pressure did not increase further over the initial reaching a total of 120 mmol by day 3 after elevation observed on day 2 in the propranolol stopping exercise. group. There was interindividual variability in 4. There was a loss of 650 rnl of water on the blood pressure responses in both groups, day 1 of exercise, followed by a modest with some subjects demonstrating a more retention reaching a cumulative maximum of marked increase in blood pressure. Urinary 650 ml on day 5 of exercise. excretion of NE increased concomitantly with 5. Neither arginine vasopressin nor serum pressure at altitude in both groups, with a electrolyte concentrations were affected by greater rise in the placebo group. Blood exercise. pressures were related to NE excretion in the 6. From the packed cell volume and placebo (r=0.67, P<0.005) and propranolol sodium and water balances, it was calculated groups (r=0.47, P<0.05), and subjects with that by day 5 of exercise there was an increase the highest blood pressures at 4,300 m had the in plasma volume of 0.68 litre (22%), an greatest NE values. Mean urinary E levels did

95 not increase over time in the placebo group and metabolic changes independent of weight loss increased only minimally at day 17 in the and dietary intake. propanolol group. Despite this lack of increase in E at 4,300 m, arterial pressure was related to 253. Zachariah T, SB Rawai, SN urinary E levels in the placebo (r=0.75, Pramanik, MV Singh, S P<0.005) but not the propranolol group. Kishnani, H Bharadwaj and RM Thus, elevation in systemic arterial pressure at Rai. 4,300 m was related to increased sympathetic Variations in skinfold thickness during activity from NE. The possibility that E also de-acclimatisation and re-acclimatisation contributed to the rise in arterial pressure could to high altitude. not be excluded. European Journal of Applied Physiology 56:570-577, 1987. 252. Young PM, MS Rose, JR Sutton, Authors' Abstract HJ Green, A Cymerman and CS Skinfold thickness, body weight, body Houston. water, anthropometric measurements and Operation Everest 11: plasma lipid and segment volumes were determined in 28 young hormonal responses during a simulated and healthy Indian soldiers on return to Delhi ascent of Mt. Everest. (200 m) after staying for more than 24 months Journal of Applied Physiology at high altitude (3500 m). The measurements 66:1430-1435, 1989. were made on the 2"a day and after 3 weeks. Authors' Abstract Ten subjects were then randomly selected from To examine the effect of hypobaric this group and returned by air to the high- hypoxia on plasma lipid prof'des, fasting blood altitude station, and the measurements were samples were collected from six men (21-31 repeated on the 3_ and 12thday of their yr) at 760 Torr and periodically during a 40- reinduction. day exposure to decreasing barometric pressure Though body weight and total body water culminating in a final ambient pressure of 282 increased marginally on transfer to the lower Torr. Preascent plasma total cholesterol altitude, body density remained more or less concentration ([TC]) was decreased by 25% unchanged. There were significant increases in after the 40-day exposure (P<0.01). High- the thickness of skinfolds, even when body density lipoprotein concentrations (HDL-C]) density had increased. During this period hand decreased 32% (P<0.001) with no alteration in and foot volumes decreased significantly. the TC-toHDL-C weight ratio. Plasma Despite significant increases in thoracic triglyceride concentration increased twofold skinfold thickness, the torso volume decreased during this period (P<0.01). There were no slightly. On returning to high altitude the significant differences in fasting plasma free soldiers lost body weight, were hypohydrated fatty acid concentrations or free fatty acid-to- and showed reduced skinfold thickness. Fat albumin molar ratio throughout the study. losses calculated on the basis of reduction in Fasting plasma insulin levels were increased skinfold thickness were far in excess of those approximately twofold with no significant calculated from losses in body weight and in changes in glucagon concentration or the total body water. As the reduced skinfold insulin-to-glucagon molar ratio. Plasma thickness was unrelated to changes in body norepinephrine concentrations were increased water content at high altitude, it seems that such threefold on reaching 282 Torr (P<0.01), with reductions are due to redistribution of blood in no significant changes in plasma epinephrine the skin. concentrations. Mean energy intake (kcal/day) From the results of these investigations it decreased 42%, whereas mean body weights is concluded that variations in skinfold decreased by 8.9 _+0.8% (P<0.01) with thickness during acclimatisation to high altitude exposure. Increased concentrations of insulin do not accurately represent the changes in body may lead to increased hepatic production of fat content. triglyceride-rich lipoproteins, thus eliciting

96 ADDITIONAL SELECTEDBIBLIOGRAPHY -

Albrecht E and H Albrecht. patients. Aviation, Space, and Physiological studies at high altitude. Environmental Medicine 64:512- Journal of the Association for 516, 1993. Physical and Mental Rehabilitation 21:97-99, 1967. Demopoulos HB, B Highman, PD Altland, MA Gerving and G Arnaud J, H Vergnes, D Gourdin and Kaley. N Gutierrez. Effects of high altitude on granular Erythrocyte enzymes and metabolic juxtaglomerular cells and their changes in man living at high altitude. possible role in erythropoietin Sangre 23:817-822, 1978. production. American Journal of Pathology Bangham CRM and PH Hackett. 46:497-509, 1965. Effects of high altitude on endocrine function in the sherpas of Nepal. Dill DB. Journal of Endocrinology 79:147- International high altitude expedition 148, 1978. to Chile, 1935. Hypoxia, Exercise, and Altitude. Barcroft J, CA Binger, AV Bock, JH Proceedings of the 3rd Banff Doggart, HS Forbes, G International Hypoxia Symposium, Harrop, JC Meakins and AC edited by JR Sutton, CS Houston, Redfield. and NL Jones. New York: AR Liss Observations upon the effect of high Inc., 1983. p. 201-204. altitude on the physiological processes of the human body, carried Dill DB. out in the Peruvian Andes, chiefly at Physiological adjustment to altitude Cerro de Pasco. changes. Philosophical Transactions of the Journal of the American Medical Royal Society of London 211:351- Association 205:123, 1968. 480, 1923. Douglas CG, JS Haldane, Y Bruce CG. Henderson and EC Schneider. The assault on Mount Everest 1922. VI. Physiological observations made London: Edward Arnold & Co., on Pike's Peak, Colorado, with 1923. special reference to adaptation to low barometric pressures. Brull L and A Divry. Philosophical Transactions of the Metabolic and secretory activity of the Royal Society Series B 203:185- kidney under anoxemia. 318, 1912. Archives Internationales de Physiologie LVIII: 415-423, 1951. Feigen GA and PK Johnson. Blood volumes and heart weights in Campbell JA. two strains of rats during adaptation Further observations on oxygen to a natural altitude of 12,470 ft. acclimatisation. In: The Physiological Effects of Journal of Applied Physiology High Altitude, edited by WH Weihe. 63:325-342, 1947. New York: Pergamon Press Limited, 1964. p.45. Colice GL, J Lawrason, A Munsef, P Bittle, J Dietz and G Ramirez. Fink GD and JW Fisher. Hormonal response to exercise in high altitude natives and COPD

97 Roleof sympatheticnervoussystem Journal of Physiology (London) in thecontrolof erythropoietin 53:181-206, 1919. production. In: Kidney Hormones, vol. 2, Hall FG, DB Dill and ES Guzman- Erythropoietin, edited by JW Fisher. Barron. New York: Academic Press, 1977. p. Comparative physiology in high 387-413. altitudes. Journal of Cellular and Comparative Physiology 8:301-313, Forsling ML and E Ullmann. 1936. Plasma vasopressin and renal concentrating ability in the Hannon JP. anaesthetized dog. Nutrition at high altitude. Proceedings of the Endocrine In: Environmental Physiology: Society, 1974. p.41-42. (Abstract). Aging, Heat, and Altitude, edited by SM Horvath and M Yousef. Fulco CS and A Cymerman. Amsterdam: Elsevier North Holland Human performance and acute Inc., 1980. p.309-327. hypoxia. In: Human Performance Physiology and Environmental Heath D and DR Williams. Medicine at Terrestrial Extremes, The pathophysiology of edited by KB Pandolf, MN Sawka, acclimatization and adaptation. and RR Gonzales. Indianapolis: In: Man at High Altitude. London: Benchmark Press, Inc., Chapt. 12, Churchill Livingstone, Chapt. 15. 1988. p. 467-495. 1977. p.157-164.

Gippenreyter YeB, MS Belakovshiy Heath D and DR Williams. and SV Chizhov. Life at high altitude. Fluid intake at high altitude. In: The Institute of Biology's Kosmicheskaya Biologiya i Studies in Biology no. 112. London: Aviakosmicheskaya Meditsina 17: Thomson Litho Ltd., 1979.60p. 17-21, 1983. Heath D and DR Williams. Gregg HW, BR Lutz and EC The skin and nails. Schneider. The changes in the In: Man at High Altitude. London: content of hemoglobin and Churchill Livingstone, Chapt. 23, erythrocytes of the blood in man 1981. p.230-235. during short exposures to low oxygen. Hecht HH. American Journal of Physiology Certain vascular adjustments and 50:216-217, 1919. maladjustments at altitudes. In: Exercise at Altitude, edited by R Hack D, NW Levin, BGoldberg, SM Margaria. Amsterdam: Excerpta Perold and A Rubenstein. Medica Foundation, 1967. p. 198- Serum electrolytes at high altitude. 200. South African Journal of Medical

Science 29:11-16, 1964. Honig A. Diuretic effect of acute hypoxia in Haldane JS, AM Kellas and EL humans: relationship to hypoxic Kennaway. ventilatory responsiveness and renal Experiments on acclimatisation to hormones. reduced atmospheric pressure. Journal of Applied Physiology 78:375-376, 1995.

98 ADDITIONAL SELECTEDBIBLIOGRAPHY

Kayser B.

Honig At Nutrition and energetics of exercise at Peripheral arterial chemoreceptors and altitude. reflex control of sodium and water Sports Medicine 17:309-323, 1994. homeostasis. American Journal of Physiology Knapp CF, A Bhattacharya, E 257: R1282-R1302, 1989. McCutcheon Effects of whole-body oscillating

Honig A° acceleration on orthostatic response Role of the arterial chemoreceptors in after head-down bed rest and water the reflex control of renal function immersion. and body fluid volumes in acute Lexington, KY: Wenner-Gren Res. arterial hypoxia. In: Physiology of Lab. Report NSG-2318, 1981.57p. the Peripheral Arterial Chemorecptors, edited by HAcker, Lenfant C and K Sullivan. and RG O'Regan. Amsterdam: Adaptation to high altitude. Elsevier Science Publishers, Chapt. West England Journal of Medicine 14, 1983. p. 395-429. 248:1298-1309, 1971.

Hoyt RW and A Honig. Malm6jac M J, G Chardon and A Environmental influences on body Gross. fluid balance during exercise: altitude. Influence de l'anoxie sur la s6cr_tion In: Body Fluid Balance, Exercise urinaire. and Sport, edited by ER Buskirk and Socidtd de Biologie D'Alger SM Puhl. Boca Raton, FL: CRC 140:1000-1002, 1946. Press, Chapt. 9, 1996. p.183-196. McFarland RA and DB Dill. Hoyt RW and A Honig. A comparative study of the effects of Body fluid and energy metabolism at reduced oxygen pressure on man high altitude. during acclimatization. In: Handbook of Physiology: Journal of Aviation Medicine 9:18- Section 4: Environmental 44, 1938. Physiology V. The Terrestrial Medal LS, HR Moyado, E Quintanar Altitude Environment, edited by MJ de Rodriguez and J Pizzuto. Fregly and CM Blatteis. New York: Influence de l'altitude star le volume Oxford University Press. Vol. 2. Chapt. 55, 1996. p.1277-1289. sanguin et ses compartiments. Sangre 31:311-321, 1960. Jaeger J J, JT Sylvester, A Cymermann, JC Denniston and Montgomery RD. JT Maher. Electrolytes, corned beef and dust. Evidence for increased intrathoracic The Practioner 188:661-668, 1962. fluid volume in man at high altitude. Journal of Applied Physiology Nevison Jr, TO. 47:670-676, 1979. Physical performance, total body water, and monitoring of various Jungmann H. physiological parameters at 15,000 Acclimatization and adaptation to high feet and above. Proceedings of the altitude. International Symposium on Effect In: Progress in Biometerology of Ahitude on Physical Chapt. 6, 1974. p.471-781. Performance. Albuquerque, NM: 1966. p.57-61.

99 Water intake at high altitude. Journal Okin JT, A Treger, HR Overy, JV of Wilderness Medicine 4:224-227, Weil and RF Grover. 1993. Hematologic response to medium altitude. Reynafarje C. Rocky Mountain Medicine Journal The influence of high altitude on 63:44-47, 1966. erythropoietic activity. Brookhaven Symposia in Biology Olsen NV, I-L Kanstrup, J-P 10:132-146, 1957. Richalet, JM Hansen, G Piazen and F-X Galen. Reynafarje C. Effects of acute hypoxia on renal and Hematologic changes during rest and endocrine function at rest and during physical activity in man at high graded exercise in hydrated subjects. altitude. Journal of Applied Physiology In: Physiological Effects of High 73:2036-2043, 1992. Altitude, edited by WH Weihe. New York: Pergamon Press. 1964. p.73- Pigman EC. 85. Acute mountain sickness: effects and implication for exercise at Roy SB, JS Guleria, PK Khanna, JR intermediate altitudes. Talwar, SC Manchanda, JN Sports Medicine 12:71-79, 1991. Pande, VS Kaushik, PS Subba, and JE Wood. LGC. Pugh Immediate circulatory response to Haemoglobin levels on the British high altitude hypoxia in man. Himalayan Expeditions to Cho Oyu in Nature 217:1177-1178, 1968. 1952 and Everest in 1953. Journal of Physiology (London) 38p- Stickney JC and EJ Van Liere. 39p, 1954. (Abstract). Acclimatization to low oxygen tension. LGCE. Pugh Physiological Reviews 33:13-34, Animals in high altitudes: man above 1953. 5,000 meters--mountain exploration. In: Handbook of Physiology: Stock M J, C Chapman, JL Stirling Adaptation to the Environment, and IT Campbell. Section 4 edited by DB Dill, EF Effects of exercise, altitude, and food Adolph, and CG Wilber. on blood hormone and metabolite Washington, DC: American levels. Physiological Society, 1964. p. 861- Journal of Applied Physiology 867. 45:350-354, 1978.

Raft H, RC Brickner and B Sutton JR. Jankowski. Effect of acute hypoxia on the The renin-angiotensin-aldosterone hormonal response to exercise. system during hypoxia: is the adrenal Journal of Applied Physiology an oxygen sensor.'? 42:587-592, 1977. In: Hypoxia and Mountain Medicine, edited by JR Sutton, G Sutton JR and MP Heyes Coates and CS Houston. New York: Endocrine responses to exercise at Pergamon Press, 1992. p.42-49. altitude. In: Exercise Endocrinology, edited Rennie D. by K Fotherby and SB Pal. New

100 ADDITIONAL SELECTEDBIBLIOGRAPHY

York: WalterdeGruyter& Co., Young AJ and PM Young. 1985. p.239-262. Human acclimatization to high terrestrial altitude. Timiras PS. In: Human Performance Physiology Comparison of growth and and Environmental Medicine at development of the rate at high Terrestrial Extremes, edited by KG altitude and at sea level. Pandolf, MN Sawka and RR In: The Physiological Effects of Gonzalez. Indianapolis: Benchmark High Altitude, edited by WH Weihe. Press, Inc., Chapt, 13, 1988. p.497- New York: Pergamon Press Limited, 543. 1964. p.21. Young PM, JR Sutton, HJ Green, JT West JB and L Sukhamay. Reeves, PB Rock, CS Houston High Altitude and Man. Baltimore: and A Cymerman. Waverly Press Inc., 1984. 191p. Operation Everest 1I: metabolic and hormonal responses to incremental Winsiow RM and C Monge C. exercise to exhaustion. Red cells, red cell and plasma Journal of Applied Physiology volumes, and their regulation. 73:2574-2579, 1992. In: Hypoxia, Polycythemia and Chronic Mountain Sickness, edited by RM Winslow and C Monge C. Baltimore: The Johns Hopkins University Press, Chapt. 3, 1987. p.31-54.

Winslow RM and C Monge C. Renal function in high-altitude polycythemia. In: Hypoxia, Polycythemia, and Chronic Mountain Sickness, edited by RM Winslow and C Monge C. Baltimore: The Johns Hopkins University Press, Chapt. 7, 1987. p.119-141.

101

AUTHOR INDEX (The numbers refer to abstract numbers)

Abbrecht PH: 1 Bhatia MR: 31 Adams WC 55, 78 Bhattacharji P: 42 Agosti SJ: 189, 190 Bharadwaj H: 25, 26, 27, 28, 29, 30, 31, Ahmad S: 231 253 Akhtar M: 42 Bienvenu A: 196, 197 Alexander JK: 2 Bircher HP: 32 Allen PS: 149 Birmingham Medical Research Expeditionary Ammann W: 149 Society: 166 Anand IS: 3 Bittle PA: 188, 189, 190 Anderson RJ: 4 Blackman V: 136 Antezana A-M: 5, 196, 197 Blume FD: 33, 36, 161,163 Antezana G: 5 Bonaldi V: 196 Aoki VS: 6 Bopari MS: 3 Arnand J: 7, 8 Bosch FH: 244 Arnold PE: 4 Bouissou P: 34, 35 Arnold HR: 220 Boutellier U: 61 Aschack R: 9 Boyd III AE: 98, 130 Askew EW: 107 Boyer S J: 33, 36 Asmussen E: 10,11 Brabant G: 203 Aud6tat M: 18 Bradwell AR: 166 Ayers CW: 188 Brahmachari HD: 37, 142, 185,212 Ayers PJ: 12 Braithwaite K: 55 Brand-Maher C: 237 Baartz F: 81 Bransford DR: 154 Babini R: 60 Braverman LE: 33 Baertschi AJ: 13 Brisson G: 35 Baker P: 14 Brooks DP: 43 Baker-Fulco CJ: 72, 107 Brooks GA: 40 Balasubramanian V: 100, 101,207 Brouns F: 245 Banchero N: 15 Brown MM: 122 Bardhan J: 113, 114 Brown DK: 173 Barer AS: 16 Brown SE: 122 Barnhart RA: 131,132 Brunner HR: 181 Bartsch G: 109 Bryson EI: 157 B_xtsch P: 17, 18, 19, 20, 32, 191 Btihrer A: 127 Battock DJ: 243 Burrill MW: 38 Bauer C: 61, 62, 204 Buskirk ER: 39 Baylis PH: 21, 166 Butterfield GE: 40 Beard J: 8 Becker EL: 22 Campbell RW: 13 Becker EJ : 53 Canham JE: 228 Beckwitt HJ: 227 Carcel6nA: 168, 171 Beeley JM: 156 Carlson DE: 13 Behm R: 23 Carmena AO: 41 Belt AE: 220 Carney GM: 237 Beresford CH: 218,219 Carrier EB: 220 Berger EY: 24 Catley DM: 157, 158, 159, 160, 161, 162, Berlin NI: 215 163, 164 Bemauer EM: 55, 78 Cauchy E: 196, 197 Berns AS: 4 Chadha KS: 42, 100, 101,207 BetetaL: 167, 168, 170 Chandana J: 3 Bhagat MJK: 213 Chandrashekhar Y: 3

103 AUTHOR INDEX (The numbers refer to abstract numbers)

Chatterji JC: 42 Eichenberger U: 32 Chidsey CA: 227, 243 Ekins RP: 218, 219 Chinn KSK: 87, 88, 89, 229, 248 Ekblom B: 222 Clarke CRA: 162, 163 English E: 66 Claybaugh JR: 43, 44, 45, 46 Epstein M: 63, 64 Cleveland AS: 216 Coates G: 200 Farber MO: 9, 65, 96 Cohen A: 33 Faura J: 66, 195 Colice GL: 47, 48, 188, 189, 208 Feith S: 86 Consolazio CF: 10, 49, 50, 51, 118, 131, Felder L: 127 132 Feldt-Rasmussen B: 94 Consolazio WV: 58 Fenn CE: 67 Contat H: 181 Ferrari R: 3 Cosby RL: 52 Fiet J: 34 Cotes PM: 165 Figallo M: 201 Cove DH: 105 Finch CA: 66 Coyne JT: 86 Fineberg NS: 9, 96 Cruz JC: 15 Finn WL: 237 Cucinell SA: 45, 46 Finne P: 66 Cunningham WL: 53 Fleming S: 40 Cymerman A: 43, 59, 71, 72, 104, 106, Fletcher RF: 68 107, 139, 199, 200, 252 Fondu P: 144 Forsling ML: 69, 83,250 Dahms TE: 57 Fotherby K: 140 Dallman MF: 187 Franciolli M: 19, 20 Damgaard F: 123 Frayser R: 70, 192 Darrirand A: 59 Freeman S: 38 Das BK: 42 Frias FL: 41 Daum S: 117 Fr61ich M: 244 Davidson B: 149 Fulco CS: 71, 72, 199, 200 Daws TA: 49, 51 Fusch C: 73 Dawson C: 56 D6chaux M: 94, 196, 197 Galarza M: 5 Defer G: 34 Galdston M: 24 Delamare JP: 54 Galen F-X: 34, 241 Delgado E: 111 Galster WA: 74 Dietz JR: 188, 189, 190 Gann DS: 13 Dill DB: 55, 56, 57, 58, 119, 173 Garcia de Testa N: 41 Dirkse J: 33 Gamier M: 198 Dittmer J: 62 Gates J: 40 Divekar HM: 211,213 Gauer OH: 209 Donayre J: 169 Gfr6rer W: 73 Dotsenko MA: 79, 129 Ghisler U: 125 du Souich P: 60 Giannetta CL: 75 Dua GL: 143 Girard J: 17 Dubray C: 94, 196 Gjellerod H: 126 Duncan TB: 231 Glatte HV: 75 Durkot MJ: 59, 106 Gn_idinger MP: 19 Durr JA: 52 Goldberg SV: 231 Goldberg B: 82 Eckardt K-U: 61, 62, 204, 205 Gonzalez J: 72 Edwards HT: 148 Gofiez C: 167 Edwards RHT: 218,219 Goodman LS: 149

104 AUTHORINDEX (Thenumbersreferto abstractnumbers)

GordonRD: 237 HoganIII RP: 98, 130 GotshallRW: 76 HonigA: 99 GranbergP-O: 77 HoonRS: 100,101,207 GrayGW: 70, 192,230 HombeinTF: 102 GreenHJ: 252 HortonR: 119 GreenleafJE: 78,240 HorvathSM: 57, 119,154 Grigor'ev AI: 129 Horwitz SA: 24 Grigor'yev AJ: 79 HoustonCS: 70, 103,104, 192,200, 252 GriswaldRL: 175 HowellA: 105 GroverRF: 2, 84, 85, 112,235, 243 Hoyt RW: 59,72, 106,107 GroverEB: 85 HubbardLJ: 59 GroverA: 113 HuffRL: 108,135 GrunbaumBW: 175 HumpelerE: 109 GrunertA: 73 HurtadoA: 110,111 Guerra-GarciaR: 169 HurterRC: 12 GuezennecCY: 34 HwangCA: 233 Guillard JC: 80 HyersTM: 112 GungaH-C: 81 GuptaA: 29 Ivy AC: 38 GutierrezN: 8 JacksonJT:4 HackD: 82 JainSC: 26, 113, 114,115,211 HackettPH: 83,84, 85 JanoskiAH: 116 HackneyAC: 86 JeekV: 117 Hall FG: 56, 173 JiaoJ-H: 13 Hall DK: 56 JohnsonHL: 49, 50, 51, 118, 131, 132 HamletSM: 237 JonesKW: 136 HammondM: 188,189 JonesLG: 141 HannonJP: 87, 88, 89,90, 91,92,93, 116, JonesTE: 107 124,248 JosephBI: 194 HansenJE: 44 JowettTP: 122,180,217 HansenTI: 210 JuhosL: 78 HansenJM: 94, 241 JungRC: 119 HarberMJ: 95 HarrisCW: 90, 91,93 Kabeya-MudiayS: 144 HartemannD: 60 Kacimi R: 196 HartleyLH: 2, 98, 141 KamimoriGH: 59, 106 HarveyJr JS: 145 KanstrupI-L: 94,241 HarveyRB: 22 KawashimaA: 120,121 HatanoT: 174 KayserB: 191,196,245,246 HavensLC: 206 KeanePM: 230 HeathDA: 21 KellerM: 128 HelieR: 35 KelleyVC: 147 HennessyTG: 108,135 KeromesA: 198 HenryJP: 209 KeynesRJ: 122 Herry J-P: 198,245 KhannaPK: 212 HespR: 157 Kirsch K: 81 Heyder-BrucknerCh: 144 KishnaniS: 29,31,253 HeyesMP: 65,96, 97 KjeldsenK: 123 HilgendorfA: 203,204 Klain GJ: 92, 124,248 Hirai K: 120 KlausenK: 126 HochachkaPW: 149 Klausen T: 125 HofmeisterSE: 85 Klemm SA: 237

105 AUTHORINDEX (Thenumbersreferto abstractnumbers)

KleppingJ: 80 Marticorena E: 193 KobayashiT: 120,121 Martikkala V: 241 Koch C: 73 Mason JW: 130 KoistinenP: 241 Matheson GO: 149 Koller EA: 61,127, 128 Mathew L: 143 Korol'kov VI: 79, 129 Mathew OP: 101 KotchenTA: 98, 130 Matoush LO: 49, 51,118, 132, 229 KozyrevskayaGI: 79, 129 Matsui N: 174 KraemerWJ: 199 MatsuzawaY: 120, 121 KreuzerF: 53 Mazzeo RS: 251 KrishnaB: 114 McArthur S: 156 Kr6gerC: 203 McDonald KM: 4 Krou kovaL: 117 McDonald RK: 147 Krzywicki HJ: 50, 118, 131,132 McFadden M: 230 Kubo K: 120, 121 McFarland RA: 148 Kurtz A: 61, 62 McKenzie DC: 149 McLauglin M: 218, 219 Lane JC: 46 Meehan RT: 150, 151 Lang RE: 128 Meinders AE: 244 Larmignat P: 198 Mellemgaard K: 210 Larose P: 60 Mendez J: 39 Larsen JK: 176, 177 Merino C: 111,152, 153, 201 Lawless JJ: 133 Messin R: 222 Lawrence JH: 108, 135, 215 Miles DS: 76, 154 Lawrence DL: 134 Miles JJ: 166 Le Trong J-L: 196, 246 Milledge JS: 69, 83, 155, 156, 157, 158 Ledoux M: 35 159, 160, 161, 162, 163, 164, 165, Leonard PJ: 136 250 Leppaluoto J: 241 Minty BD: 157, 164 Levin NW: 82 Modelski M: 2 Li T-K: 130 Moeller H: 73 Littell JK: 1 Molar T: 125 Loeppky JA: 137 Moncloa F: 167, 168, 169, 170 Lozano R: 138, 171, 172, 179, 234 Monge CC: 122, 138, 171,172, 193, 234 Luff N: 157 Monk-Jones ME: 140 Luft FC: 137 Mordes JP: 33 Luft UC: 137 Morice AH: 156 Lynch JR: 57 Morrison PR: 74 Lyons TP: 139 Morton JJ: 95 Mukherjee AK: 143 Mackinnon PCB: 140 Mulhausen RO: 176, 177 Madsen H: 126 Muza SR: 139 Maggiorini M: 17, 20, 32 Myhre LG: 173 Maher JT: 46, 71,141 Nanda RB: 212 Malcortian MK: 199 Nath C: 149 Malhotra MS: 27, 28, 30, 31, 37, 142, 143, Nayer HS: 26, 113, 114 212 Neumann R: 62 Malhotra RV: 3 Newton JL: 56 Mandelbaum IM: 144 Nielsen M: 11 Manfredi F: 9, 96 Nielsen OJ: 125 Marchal M: 196 Nielsen Jr WC: 131 Marchena C: 172 Noble BJ: 145, 146 Maresh CM: 145, 146 Noriega I: 5

106 AUTHOR INDEX (The numbers refer to abstract numbers)

Nusseberger J: 181 Rasmussen B: 126 Rathat C: 198 Oelz O: 17, 18, 20, 32, 191 RawalSB: 29, 211,213, 214, 253 Ohri VC: 42 Reeves JT: 40, 84, 85, 104, 112, 235, 251 Okazaki S: 174 Reinhart WH: 191 Older MWJ: 157, 250 Rennie D: 18, 83, 84, 85, 192, 193 Olsen NV: 94, Rennie ID: 70 Ong H: 60 Rennie IDB: 194 Ou ednik A: 117 Reynafarje C: 66, 153, 195,215 Richalet J-P: 5, 94, 196, 197, 198, 241, Pace N: 175,233 246, 247 Pahwa ML: 185 Riley RL: 103 Parker RE: 57 Roach RC: 137 Parker HG: 216 Robach P: 247 Parkhouse WS: 149 Roberston KL: 145, 146 Parshad R: 211,213 Roberston GL: 9 Pauli HG: 176, 177 Robertshaw D: 65, 96, 235 Payne NN: 122, 157 Robertson G: 65, 96 Pefialoza R: 205 Robinson SM: 6 Perold SM: 82 Rock PB: 139, 199 Peronnet F: 35 R6cker L: 81 Perrinjaquet CL: 52 Roos AN: 244 Pesquies PC: 34 Rootwelt K: 223 Petersen FB: 210 Rose LI: 141 Petersen E: 126 Rose MS: 199, 200, 252 Pfluger N: 18 Rubenstein A: 82 Pic6n-Re_itegui E: 178, 179 Rubenstein D: 236 Pilardeau P: 198 Pimental NA: 71 Salazar F: 221 Pineda DO: 190 S_chez C: 201 Pines A: 180 Saris HM: 245 Pluss RG: 4 Saruta T: 63, 64 Pollycove M: 216 Sato AK: 46 Porchet M: 181 Saunier C: 60 Pozos R: 86 Sautegeau S: 60 Pramanik SN: 29, 253 Scaro JL: 202 Pugh LGCE: 182, 183, 184 Schilling JA: 22 Purkayastha SS: 143 Schmidt W: 203,204, 205 Purshottam T: 142, 185,212 Schneider EC: 206 Schobersberger W: 17 Quilici JC: 8 Schoeller DA: 106, 107 Quintela A: 205 Schoene RB: 107, 231 Schopen M: 61,127, 128 Rabb HA: 190 Schrier RW: 4, 52 Radhakrishnan U: 37, 142, 212 Schwartz RS: 107 RaffH: 186, 187 Scoggin CH: 112 Rai RM: 29, 253 Scotto P: 137 Ramachandran K: 37, 142 Seale J: 86 Ramesh B: 3 Seip RL: 146 Ramirez G: 47, 48, 188, 189, 190, 208, 231 Sekiguchi M: 121 Ramos J: 66, 195 Selland MA: 137, 251 Rao SK: 3 Selvamurthy W: 143 Rascher W: 17 Sexson WR: 76

107 AUTHOR INDEX (The numbers refer to abstract numbers)

Sharma SC: 100, 101,207 Timiras PS: 233 Shaw S: 17, 18, 19, 20 Torres C: 172, 234 Shenker Y: 134 Trad LA: 199 Shetty KJ: 3 Truniger B: 176, 177 Shidharan K: 142 Tucker A: 115, 235 Shields JL: 88, 89, 90, 91, 93, 116 Tuffley RE: 218, 236 Shigeoka JW: 208 Tunny TJ: 237 Shinsako J: 187 Tyagi AK: 211,213, 214 Sieker HO: 209 Siggaard-Andersen J: 210 Ullmann EA: 238, 239 Simons M: 244 Upadhyay TN: 212 Sing HC: 130 Singh AP: 28, 191 Valdivieso J: 179 Singh I: 212 Vale JR: 223 Singh MV: 29, 211,213,214, 253 Van Liere EJ: 133 Sinha KC: 211 VaUotton MB: 127, 128 Siri WE: 108, 135,215,216 van Beaumont W: 240 Sirotzky L: 193 van Gelder J: 237 Skatrud JB: 134 Van Dyke DC: 216 Skrabal F: 109 Van Steirteghem A: 144 Slater JDH: 122, 180, 217, 218, 219, 236 Velazco I: 170 Smith DE: 242 Vergnes H: 7, 8 Smith GW: 122 Verma SS: 31 Smith HP: 220 Vetter W: 18 Sobrevilla LA: 169, 221 Villavicencio D: 195 S6nksen PH: 218, 219 Viol GW: 230 Sophocles AM: 52 Vock P: 18 Souberbiel J-C: 196, 197 Vuolteenaho O: 241 Spielvogel H: 205 Sridharan T: 142 Waber U: 191 Srivastava KK: 30 Wade CE: 45, 46 Stanley C: 149 Wadhwa A: 42 Steiner HJ: 81 Waeber B: 181 Stenberg J: 222 Wang JM: 242 Stockley RA: 21 Ward MP: 157, 162, 163, 184, 250 Stokke KT: 223 Wasserman LR: 108, 135 Strauch S: 203,204 Weidmann P: 17, 18, 19, 20 Sudman DM: 92 Well JV: 243 Sullivan FJ: 92 Weinberger M: 65, 96 Sundstroem ES: 224 Weinberger MH: 9 Surks MI: 225, 226, 227, 228, 229 Wergeland R: 223 Sutton JR: 40, 97, 104, 200, 230, 252 Wertheim W: 244 Swamy YV: 113, 114 West JB: 161,163 Swenson ER: 231 Westendorp RGJ: 244 Westerterp K: 196, 245,246, 247 Takala T: 241 Whang AR: 242 Talbott JH: 58 Whittembury J: 172, 234 Tamura Y: 174 Whitten BK: 116, 248 Teague WG: 13 Wilke WL: 115 Tellez W: 7 Will DH: 112 Tewari SC: 42 Williams ES: 12, 162, 163, 164, 218,219, Thomas A: 73 236, 249, 250 Thurau K: 232 Williams JD: 95

108 AUTHORINDEX (Thenumbersreferto abstractnumbers)

WilliamsGH: 141 YakovlevaEV: 16 WillsonD: 13 YeeB: 52 Winchell HS: 216 YoshikawaS: 120 Withey WR: 157,164,250 YoungPM: 199,252 WittelsP: 81 YoungAJ: 71 Wolfel EE: 251 WoutersL: 246,247 ZachariahT: 29,31,253 WozniakDB: 44

109

KEYWORDINDEX (Thenumbersreferto abstractnumbers)

Acclimatization: 1,2, 12,18,67, 69,80,92, Blood pressure: 15,23, 60, 76, 96, 115, 93, 103, 104, 105, 108, 137, 143, 120, 121, 128, 143, 148, 150, 154, 148, 159, 196, 199,200, 216, 217, 209, 236, 243,249, 251 218, 233 Bloodrheology:191 Acetazolamide:70, 166,211 Bloodsugar:148 Acutemountainsickness:6, 17,18,19,45, Bloodvolume: 10,55,56, 57, 87, 108, 46, 50, 54, 68, 83, 84, 87, 100, 101, 113, 114, 119, 132, 135, 154, 173, 122, 142, 155, 156, 159, 160, 161, 182, 183,220, 223 184, 191, 196,198, 199,235, 247 Body composition: 26, 27, 28, 30, 36,50, Adaptation:14,56,99, 184 72, 73, 87, 88, 132, 178, 179,200, Adrenalcorticalactivity: 102,109 229,245 Adrenocorticotrophichormone:34,46, 140, Body density:107,229,253 167, 174, 186, 187,244 Body fat content: 25, 29, 30,36, 80, 87, Aerobicwork capacity:223 132, 157,229, 253 Age: 56, 115, 119 Body fluid balance:54, 59,63, 70, 157, Albumin-toglobulinratio: 93 214 Albuminuria:94 Body fluid compartments:3, 18,50,59, 87, Aldosterone: 5, 9, 12,18,20, 34, 35, 88, 89, 113,212, 213, 250 43,44, 47, 48, 54, 63, 64, 65, 70, Body water: 50,59, 70, 73, 81, 84, 87,89, 96, 98, 109, 119, 122, 134, 141, 106, 113, 114, 132, 136, 157, 179, 151, 155, 156, 157, 158, 161, 162, 215, 247,253 163, 164, 174, 180, 186, 188, 196, Body weight: 27,28, 30, 31, 36,49, 55, 199,208, 217, 218, 219, 230, 231, 59, 67, 71, 72, 80, 81, 86, 87, 88, 237, 241,249 90, 91, 98, 107, 122, 132, 156, 173, Alkalinereserve:58 198,200, 201,229, 242, 245, 246 Alkalosis: 70, 148, 172,219 Bonemarrow:153 Almitrine: 128 Bonemineral: 28,29,30, 3I, 229 Anoxia: 24, 88, 111,133, 147,238 Bradykinins: 9, 97 Ammoniaexcretion: 93 Anorexia: 50,92 Calcium: 42, 89,91,118, 123 Adrenalfunction: 168,169, 170 Carbonmonoxide: 123,126, 176, 177,210 Angiotensin-convertingenzyme: 9, 33,47, Cardiacfunction: 104,117, 127, 143,148, 97, 115, 158, 159, 160, 161, 162, 149, 175, 196,222, 235, 236, 241, 163 251 AngiotensinII: 48, 115,134, 141,234 Cardiacoutput: 10, 15,103, 126, 138,148, Anthropometry: 25, 26,27, 28, 29, 30,31, 154,209,222 71, 72, 80, 81,90, 245 Cardiovascularstatus: 115 Appetite:43 Carotidbodies:23 Arterialchemoreceptors:99 Carotidchemodenervation:187 Arterial natriureticpeptide:3, 5, 13,19,20, Catecholamines:34,53, 100,101, 112, 45, 52, 60, 120, 121, 127, 128, 134, 175,227, 251,252 155, 156, 199,203, 231,237, 250 Cell solids: 30 Autonomicnervoussystem: 143 Cell volume: 55,56,74 BarcroftLaboratory:56 Cerebraledema:84,85,95,97 Bed-rest: 142 Chloride: 58,78,89,91 123,148,219 head-down:137 Cholesterol:124,148 Bicarbonate:89, 91,219 Circulation:126,128 Bilirubin: 74, 110 Climate:56 Bioelectricalimpedence:72 Corpulmonale:117 Bloodcoagulation:110,112 Cortisol: 37,47, 65,70, 109, 122, 141, Bloodelectrolytes:50,86 150, 167, 180,212, 241,244 Blood gases: 9, 24, 58, 59,76, 82, 103, Creatinine: 9, 123,221,229 104, 110, 120, 126,219 clearance:63,95,96, 137

111 KEY'WORD INDEX (The numbers refer to abstract numbers)

Glucose: Dehydration: 49, 51 fasting: 50 Denitrogenation: 235 tolerance: 50 Desert: 56 Glucose-6°phosphate dehydrogenase: 144 Dexamethazone: 167 Glutamic-pyruvic transaminase: 123 2,3-Diphosphoglycerate: 7 Gonadotropins: 109 Diuretics: 213 Diuresis: 50, 69, 115, 116, 127, 128, 130, Half-life: 61, 62 209, 213, 231,237 Head-down bedrest: 137 Edema: 59, 97, 249 Heart rate: 93, 125 Electrolyte balance: 45, 58, 70, 78, 79, 81, Hematocrit: 22, 27, 55, 84, 86, 93, 105, 82, 115, 116, 122, 148, 174, 190, 110, 123, 135, 136, 138, 139, 148, 224, 230 149, 150, 156, 183, 201,220, 221, Endocrine function: 96 237, 243 Endothelin: 241 Hemoconcentration: 57, 88 Energy: Hemoglobin: 55, 56, 57, 74, 93, 99, 110, expenditure: 107 111, 125, 139, 149, 152, 156, 173, requirement: 39, 40, 49, 245, 246, 183, 206, 216, 220 247, 248 saturation: 47, 48, 99, 103, 106 Environment: 56 Hepatic blood flow: 47 Erythrocyte metabolism: 7, 8 Hexokinase: 144 Erythrocyte reducing systems: 7, 8 Hydration: 6, 29, 30, 86, 131 Erythropoiesis: 10, 66, 93, 108, 110, 111, Hypercapnia: 187 125, 135, 152, 191, 195, 196, 197, Hyperhemoglobinemia: 7 202 Hyperoxia: 64 Erythropoietin: 41, 61, 62, 66, 125,204, Hyperuricemia: 221 216, 241 Hypohydration: 114, 248 Excretion: 92, 100, 101 Hypothermia: 14, 185 chloride: 38 Hypoxia: 2, 4, 8, 9, 13, 34, 35, 41, 43, 44, potassium: 38, 42 46, 59, 61, 62, 63, 65, 69, 77, 79, sodium: 38, 42 80,94, 96, 99, 102, 115, 116, 120, Exercise: 2, 15, 17, 20, 32, 34, 35, 48, 51, 121, 122, 123, 126, 128, 134, 137, 56, 78, 93, 107, 137, 141, 146, 150, 141, 150, 154, 155, 156, 158, 159, 151, 154, 157, 158, 161, 164, 168, 160, 162, 163, 165, 168, 170, 174, 182, 186, 196, 199, 203, 204, 205, 176, 177, 185, 186, 203, 204, 205, 208, 222, 249 210,216, 217, 219,231,236,237, ExtraceUular: 244, 245, 249, 252 electrolytes: 89 Hypoxemia: 21,43,46,47,48,60, 71, 111, volume: 88, 106, 113, 114, 131, 117, 126, 188, 189, 208, 241 136, 247 Hypoxic decompression:230

Filtration fraction: 22, 94 Interstitial volume: 88, 250 Fitness: 32 Intracellular water: 87, 106, 113, 114, 131, Fluid balance: 49, 51, 63, 78, 79, 85, 105, 250 137, 146, 156, 174, 199 Intravascular pressure: 15 Fluid-electrolyte shift: 35, 79 Iron-turnover: 108 Free fatty acid: 74, 124 Free water clearance: 60 Lactic acid dehydrogenase: 8, 74, 123 Furosemide: 6 Leucocyte count: 93, 110, 135, 153,216 Lipoproteins: 252 Glomerular filtration rate: 9, 22, 54, 76, 77, 138, 147, 234 Magnesium: 42, 91,123,

112 KEYWORD INDEX (The numbers refer to abstract numbers)

Mean corpuscular hemoglobin osmolality: 44, 45, 235, 240 concentration: 125 protein concentration: 11, 56, Messenger RNA: 62 81, 93, 173, 192, 210 Metabolism: 40, 50, 117, 118, 129, 143, renin activity: 47, 48, 60, 63, 178, 182, 245 64, 109, 121, 134, 218, 244 Methemoglobin: 7, 8 salt: 5, 44, 78, 117, 142 Microcytosis: 7 thyroxine: 227 Microswine: 59 volume: 2, 11, 46, 55, 56, Middle-distance runners: 55 78, 81, 89, 93, 99, 106, 107, Mineral balance: 50, 117, 118, 129, 132 113, 114, 119, 132, 136, Mountain sickness: 3, 6, 18, 20, 32, 83, 139, 154, 157, 173, 174, 138, 139, 171 198, 199, 201, 204, 210, 223, 229, 243, 250 Natriuresis: 54 Polycythemia: 5, 7, 111,135, 138, 152, Nicotine adenine dinucleotide: 8 153, 165, 201,223 Nitrogen: 118 Potassium: 12, 16, 42, 43, 44, 63, 70, 82, balance: 49, 50, 51, 80, 92 89, 91, 92, 98, 116, 117, 123, 177, Norephinephrine: 9 180, 219, 229, 244, 249 Nutrition: 39, 40, 49, 66, 67, 80, 92, 118, Propranolol: 251 131, 132, 200, 225, 245, 247, 252 Protein utilization: 51 Pulmonary: Oral temperature: 86 edema: 19, 20, 32, 52, 83, 84, 85, Orthostatic stress: 122, 143 100, 112, 121, 191 Osmolality: 65, 69, 80 hypertension: 13 Osmoregulation: 33 Oxygen-helium atmosphere: 75 Rats: 133 Oxygen: Red cell carrying capacity: 10, 58 count: 125, 135, 148, 182, 206, 222 saturation: 58, 135,222, 244 mass: 108, 113, 114, 119, 136 tension: 126 volume: 56, 110, 125, 173, 223 uptake: 125,227,232 Renal blood flow: 76, 98, 204 Peripheral edema: 83, 84 function: 54, 63, 64, 65, 75, 76, 79, pH: 58, 69, 75, 224, 238 94, 96, 129, 147, 171, 172, Phosphogluconate dehydrogenase 174, 176, 177, 180, 182, (6PGD): 144 196, 197, 217, 232, 234 Phospholipids: 124 plasma flow: 3, 9, 22, 24, 77, 138, Phosphorous: 82, 89, 91, 92, 123 147, 176, 234 Renin: 9, 34, 35, 43, 44, 48, 63, 64, 65, 70, Physical: 98, 109, 115, 122, 130, 141, 151, activity: 50, 131 155, 157, 162, 163, 164, 187, 208, conditioning: 50, 51, 55 218, 230, 231,236, 237, 241 Pituitary gonadotropins: 109 Renin-angiotensin-aldosterone: 47, 97, 122, Platelets: 216 150, 186, 249 Plasma: Respiration: 182, 209, 216 albumin: 228 Reticulocyte count: 105, 123, 125,204, 216 aldosterone: 48, 54, 119, 121,237 Saliva: 16, 250 catecholamines: 53, 121,130, Serum: 241 albumin: 225 cortisol: 47, 212, 230, electrolytes: 89, 90, 145, 174 erythropoietin: 1 iron-turnover: 216 glucose: 124

113 KEYWORD INDEX (The numbers refer to abstract numbers)

lipids: 124, 252 v_r02 max : 78 magnesium: 42 osmolality: 33, 84, 93, 174 Water: potassium: 42, 54, 116, 174 balance: 3, 4, 11, 23, 43, 44, 80, sodium: 42, 174 115, 116, 122, 129, 142, steroids: 145, 146, 174 166, 180, 194 water: 124 excretion: 4, 11, 20, 23, 27, 65, 77, Skinfold thickness: 253 234, 238, 239, 240 Sodium: 16, 23, 42, 43, 44, 52, 63, 65, 70, intake: 43, 99, 115, 235, 240, 247 74, 78, 89, 91, 92, 98, 115, 117, loss: 3, 11, 23, 43, 118, 242, 246, 157, 177, 180, 189, 249 247, 250 Spironolactone: 211 Weight loss: 40, 71, 118 Stroke volume: 2, 15 Women: 90, 91, 92 Sweat: 140, 242 Work performance: 39, 240, 241 Testosterone: 109 Thirst: 45

Thyroxine-binding: globulin: 226 prealbumin: 226 Total body water: 43, 131 Transferrin-iron saturation: 125

Urea: 95 Urinary: catecholamines: 53, 100, 101,130, 143, 185, 208, 212, 227, 236, 243, 251 electrolytes: 86, 95, 142, 150, 185, 239 osmolality: 84, 94, 96, 166, 199, 235, 250 potassium: 54, 116, 117, 130, 156, 217, 236, 238 prostaglandin (E2): 60 proteins: 192, 193, 194 sodium: 74, 76, 116, 117, 123, 130, 156, 217, 236, 237, 238 specific gravity: 49 steroids: 63, 140, 167, 216, 217, 218, 233, 249 volume: 37, 49, 123, 142, 166, 199, 235, 237, 250, 251

Vasopressin: 6, 9, 17, 19, 21, 33, 36, 44, 45, 46, 52, 60, 65, 69, 95, 96, 97, 112, 122, 127, 128, 150, 166, 174, 181,212, 231,250 Venous compliance: 243 Ventilation: 76, 77, 85, 97, 103, 104, 125, 126, 128, 222, 231,235, 246, 251 Vital capacity: 85

114

Form Approved REPORT DOCUMENTATION PAGE oMeNo.o7o4-o18o

Public reporting burden for this collectionof informationis estimated to average I hour per response,includingthe timefor reviewinginstructions,searchingexisting data sources. gatheringand maintaining the data needed, and completingand reviewingthe collectiono1information. Send commentsregardingthis burdenestimateor any other aspect of this collection of information, includingsuggestionsfor reducingthisburden, to WashingtonHeadquartersServices.Directoratefor informationOperations and Reports, 1215 Jefferson Davis Highway.Suite 1204, Arlington,VA 22202-4302. and to the Office of Management and Budget. PaperworkReductionProject(0704-0188), Washington, DC 20503. 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE 3. REPORT TYPE AND DATES COVERED October 1997 Technical Memorandum 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Water Metabolism and Fluid Compartment Volumes in Humans at Altitude A Compendium of Research (1914-1996)

6. AUTHOR(S) 199-97-62-13

J. L. Chou, N. J. Stad, E. Gay, G. I. West, P. R. Barnes, and J. E. Greenleaf

7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Ames Research Center Moffett Field, CA 94035-1000 A-977517

9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSORING/MONITORING AGENCY REPORT NUMBER

National Aeronautics and Space Administration NASATM-112212 Washington, DC 20546-0001

11. SUPPLEMENTARY NOTES Point of Contact: J. E. Greenleaf, Ames Research Center, MS 239-11, Moffett Field, CA 94035-1000; (415) 604-6604

12a. DISTRIBUTION/AVAILABILITY STATEMENT 12b. DISTRIBUTION CODE

Unclassified -- Unlimited Subject Category 52

13. ABSTRACT (Maximum 200 words)

This compendium includes abstracts and synopses of clinical observations and of more basic studies involving physiological mechanisms concerning interaction of water metabolism and fluid compartment volumes in humans during altitude exposure. If the author's abstract or summary was appropriate, it was included. In other cases a more detailed synopsis of the paper was prepared under the subheadings Purpose, Methods, Results, and Conclusions. Author and subject indices are provided, plus an additional selected bibliography of related work of those papers received after the volume was being prepared for publication. This volume includes material published from 1914 through 1995.

14. SUBJECT TERMS 15. NUMBER OF PAGES 117 Water metabolism, Fluid volumes, Altitude 16. PRICE CODE A06

17, SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT OF REPORT OF THIS PAGE OF ABSTRACT Unclassified Unclassified

NSN 7540-01-280-5500 Standard Form 298 (Rev. 2-89) Prescribed by ANSI Std, Z39-1 e 298-102