[see Margaria, 1929]. The quantitative relationship, however, between. is reached, further increments in oxygen pressure are accompanied

Transcription

1 6I2.OI4.464 ADAPTATIONS OF THE ORGANISM TO CHANGES IN OXYGEN PRESSURE. BY D. B. DILL, H. T. EDWARDS, A. FOLLING, S. A. OBERG, A. M. PAPPENHEIMER, JR. AND J. H. TALBOTT. (From the Fatigue Laboratory, Morgan Hall, Harvard University, Boston, and the U.S. Fish Hatchery, Leadville, Colorado.) PART I. PHYSICOCHEMICAL CHANGES IN HUMAN BLOOD AT LOW OXYGEN PRESSURE. WITH increasing partial pressures of oxygen, starting with the lowest value compatible with life, the rate of change of working capacity is at first large but, by the time sea-level or its equivalent oxygen concentration is reached, further increments in oxygen pressure are accompanied by much smaller increases in capacity of the body for oxygen transport [see Margaria, 1929]. The quantitative relationship, however, between oxygen partial pressure and metabolic processes is not well defined in the range of barometric pressures extending (in air) from 5 to 15 mm. Hg. There is little question as to the beneficial effect of oxygen treatment on pneumonia, but it is not certain to what extent the advantage gained is due to better oxygen supply to an overtaxed heart. Still more obscure is the mechanism of benefit (if it exists) of high concentrations of oxygen on pathological conditions which do not necessarily involve the respiration and circulation'. In the case of a normal man we have, on the one hand, the statement of Barcroft [1925] that researches are not worth doing much below 14, ft., and the conclusion of Margari a that, even without acclimatiation, the working capacity at a barometric pressure of 54 mm. is 88-5 p.c. of its value at sea-level. On the other hand, Furusawa, Hill, Long and Lupton [1924] found that a runner can increase his maximum rate of oxygen intake by two-fifths by breathing at sea-level a mixture containing 4 p.c. oxygen. This observation 1 A steel tank has been built for this purpose at the Medical School of Kansas State University. An air pressure of 2 lb. above atmospheric is maintained. Several hours' treatment each day over a period of many weeks has had favourable results in many cases.

2 48 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. is compared in Fig. 1 with the experiments of Margaria. While Margaria's results indicate that the limiting value for oxygen transport capacity is nearly reached at a barometric pressure of 76 mm., the results of Furusawa, Hill, Long and Lupton suggest that the relation between these two variables is nearly linear between barometric pressures of 5 and 145 mm. Li 3 -J -J 1L)U (1) 1 w,s LLi II MARGARIA /A FURUSAWA. HILL. r,go LONG. AND LUPTON w '~~~~~~~~~~I A~~~~~~~~~- C >- 5 w ~ cr Fig BAROMETRIC PRESSURE IN MM HG Oxygen transport as a function of oxygen partial pressure, given as equivalent barometric pressure of air. These considerations led us to undertake an investigation of physiological changes at the moderate altitudes of 1, and 14, ft. While we were principally concerned with a study of muscular activity, certain observations were made upon the properties of the blood of man at rest, particularly the acid-base equilibrium and the form and position of the carbonic acid and oxygen dissociation curves. Observations were made on venous blood, equilibrated at 37.5, on the eight members of our party and on three members of the Leadville hatchery staff. Six experiments were made on blood from F 611 in g, Oberg and Pappenheimer during a 4-day sojourn at 14, ft. Samples were taken on the fourth day, mixed with heparine, packed in

3 ADAPTATION TO OXYGEN PRESSURE. 49 snow and brought to the laboratory. There was no significant formation of lactic acid in these specimens during the 3-hour return journey. A similar series of experiments were made at sea-level, some details of which have been given by Dill, Edwards and Talbott [193]. Table I TABLE I. Position of the oxygen and carbonic acid dissociation curves at sea-level and at high altitudes*. po2 at half saturation and Total CO2 of oxygenated blood Average ph =7-1 when pco2=4 mm. Hg time, _,_ at high Sea-level 1, ft. 14, ft. Sea-level 1, ft. 14, ft. altitude (mm. (mm. (mm. (meq. (meq. (meq. Subject (days) Hg) Hg) Hg) per 1.) per 1.) per 1.) Pappenheimer FMling Oberg Dill Talbott Edwards Bramlett Bowen Average: visiting party Whiteman Johnson Heiliger Average: residents * The sea-level experiments on Dill, Talbott and Edwards were made before going to Leadville, on the other subjects after their retum: Folling, 2 weeks after; Bowen, 4 weeks; Pappenheimer, 7 weeks; Oberg, 9 weeks; Bramlett, 15 weeks. based upon all experiments, gives the position of the oxygen dissociation curve, calculated to a ph1 value of 7.11 in every case. The affinity of blood for oxygen, thus defined, was either unchanged or slightly decreased at Leadville. Even the observation made on Papp enhei m er after 4 days at 14, ft. was within the normal range for sea-level. Neither did a graphical comparison of the curves show any change in form. The inherent properties of heemoglobin were unchanged under the conditions of our experiments, indicating that the only mechanism for altering the affinity for oxygen of blood in vitro was the hydrogen-ion concentration. The position of the carbonic acid dissociation curve of oxygenated blood, shown in the same table, was lower in every subject at Leadville than at sea-level. The average decrease was 2- meq. per litre or about one-tenth. After 4 days at 14, ft. there was a further change in three subjects of - 1-, + -3 and - -5, averaging - -4 meq. per litre. If 1 ph values for cells were calculated by the Henderson-Hasselbalch equation, assuming pk'=5-93. PH. LXXI. 4

4 5 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. changes in alkaline reserve were proportional to changes in barometric pressures, there would have been a change of - -6 meq. A steady state may not have been reached, but, in any case, second-order phenomena complicate the question when such small differences are involved. Observations were made on the blood of Talbott and Dill over a wide range of oxygen and carbon dioxide pressures. The effect of oxygenation on the acidity of haemoglobin was normal. Correspondingly, the effect of acidity upon the affinity of haemoglobin for oxygen was the same as at sea-level. Particular attention was paid to the distribution of bicarbonate and chloride between cells and serum. Hastings, Sendroy, McIntosh and van Slyke [1928] have shown that the ratios (CI)) and (HCOJ) (C1)s n (H-CO- 8)8 conveniently referred to as ra1 and rhco,, have nearly constant values in human blood, not only in health, but also in a wide range of pathological conditions. But B arcro ft and his associates in the C erro d e Pasco expedition [1922] found that the oxygen dissociation curve was displaced much farther to the left than the C2 content of whole blood indicated, implying either a change in the properties of haemoglobin or an unusual distribution of ions between cells and serum. The data obtained, together with some supplementary observations on cell and serum water, have been employed in calculating the values for these ratios seen in Table II. There appears to be little or no change in chloride ratio, TABLE II. Distribution of chloride and bicarbonate in oxygenated blood at ph, = phc3 14, ft. A _ Subject Sea-level 1, ft. (4th day) Sea-level 1, ft. Pappenheimer Foiling Oberg Dill Talbott Edwards Bramlett Bowen Average: visiting party * -63 WVhiteman Johnson -795 Heiliger -796 Average: residents * Average of values for 1 men at sea-level, including Dill, Talbott and Edwards. 1 Thus rc, means concentration of cell chloride in cell water divided by concentration of serum chloride in serum water.

5 ADAPTATION TO OXYGEN PRESSURE. 51 but there is a slight increase in bicarbonate ratio with altitude. It is possible- that the latter change is related to decrease in alkaline reserve, for it is of the same order of magnitude as that observed by Dill, Edwards and Talbott [193] in exercise which caused a similar change in alkaline reserve. In Fig. 2 we have plotted rhco8 for oxygenated Ito a. C)..84~~~~~~~~~ am.92 l e REST. SEA LEVEL X) WORK. SEA LEVEL x * REST IOOOOFEET B REST 14FEET x x~~~ x El x x-~ x.... Fig VOLS % TOTAL C2 OF OXYGENATED BLOOD AT PCO2-4mm Distribution of bicarbonate between cells and serum against carbonic acid capacity, for varying muscular activity and altitude. blood at ph8 = 745 as a function of carbonic acid capacity of oxygenated blood at a carbonic acid pressure of 4 mm. Hg. The straight line indicates the trend of all the observations, but the scatter is too great to prove that the change observed in rhco8 with altitude is related to alkaline reserve. A number of observations were made on other constituents of blood, vi. total base of serum and of cells, serum protein, himoglobin concentration in cells, lactic acid and serum phosphorus. The values found were within normal limits for sea-level. Since total base concentration is seven times as great as bicarbonate concentration, the compensatory effect on the former of a 1 p.c. change in the latter is relatively small. A summary of serum and cell chloride concentrations at sea-level and at 1, ft. is given in Table III. This suggests that one-half of the compensatory change is due to chloride retention. Even so, the values for serum and cell chloride remain within normal limits for sea-level. 4-2

6 52 D. B. DILL, H. T. EDWARDS, A. POLLING, AND OTHERS. TABLE III. Chloride concentration in serum, cells and blood. HbO2 = 1 p.c. and PH89 = men at 9menat sea-level Leadville Serum Cl (meq. per 1.) Av Max Min Cell Cl (meq per 1.) Av Max Min Whole blood (meq. per 1.) Av. 82* Max Min The increase in haemoglobin concentration in blood was about 1 p.c. -somewhat less than that usually observed at the same altitude. We are inclined to attribute this to strenuous exercise on the ergometer and to climbing expeditions. Destruction of red cells in strenuous mountain climbing was noted 2 years ago by Cohnheim, Kreglinger and Kreglinger [199]. Using the information thus acquired regarding properties of blood in vitro, it is possible to proceed to a study of changes in blood during the respiratory cycle. PART II. GAS EXCHANGE IN THE LUNGS AND THE REACTION OF ARTERIAL SERUM. Some possible adaptations by which oxygen supply may be augmented are: (a) increase in breathing; (b) increase in proportion of haemoglobin in blood; (c) secretion of oxygen; (d) change in the oxygen dissociation curve; (e) increase in circulation rate; (f) increase in rate of oxygen intake by the tissues due to modification of the capillary bed, increase in muscle heamoglobin, etc. Of these various possibilities, (a) and (b) may be accepted as facts, while evidence in regard to (e) and (f) is lacking, and in regard to (c) and (d) is conflicting. We have investigated the questions of oxygen secretion and of the position of the oxygen dissociation curve of blood in vivo. The oxygen dissociation curve at a given ph of blood withdrawn at 1, or at 14, ft. is the same as at sea-level: it remains to be seen to what extent the ph of arterial blood changes at high altitudes. For a categorical answer, observations are required on arterial blood. The literature on these subjects has been reviewed recently by Bock and Dill [Bainbridge, 1931] and earlier by Haldane [1927 a, 1927 b], by Y. Henderson [1925], and by Barcroft [1925]. So far as secretion of oxygen is concerned Haldane has stated his affirmative position in

7 ADAPTATION TO OXYGEN PRESSURE. 53 the Silliman lectures [1927a]. Krogh [1915] has found no positive evidence in favour of secretion, and the experiment of Barcroft, Cooke, Hartridge and Parsons [192] has led Haldane to the modified hypothesis that secretion is not a constant phenomenon but only comes about with acclimatiation. Douglas, Haldane, Henderson and Schneider [1913] found that the position of the oxygen dissociation curve of blood equilibrated with alveolar air was unchanged on Pike's Peak, and by an indirect method found that the partial pressure of oxygen in arterial blood might be much higher than in alveolar air. On the other hand, Barcroft and his associates in the Cerro de Pasco expedition [1922] reached quite different conclusions. Arterial blood had an increased affinity for oxygen at that altitude, and the partial pressure of oxygen in arterial blood was not distinctly higher, but usually lower than in alveolar air. With the technique developed by van Slyke and his associates, it is now possible to study these controversial questions directly and with a much higher degree of accuracy than was possible a few years ago. Thus Bock, Dill, Edwards, Henderson and Talbott [1929] found that, when a subject at sea-level breathes a gas mixture with low oxygen content, the oxygen pressure head from lungs to blood remains positive, even when arterial saturation drops to 6 p.c. It remains to be seen what happens after acclimatiation to a low partial pressure of oxygen. Arterial blood has been obtained on nine occasions: (a) on two subjects at Boston during maximum work in a steady state on the ergometer; (b) on three subjects in similar conditions at Leadville, and (c) on four resting subjects at Leadville. The details of the procedure have been described before [Bock, Dill, Edwards, Henderson and Talbott, 1929; Dill, Edwards and Talbott, 193]. Table IV contains a summary of the results. Just as has been found be- TABLE IV. Relation between arterial and alveolar pco2 and po2 in rest and work. Oxygen Oxygen Total con- satura- CO of pco2 P2 Baro- sump- tion of arterial,_i_-, meter tion arterial blood Arterial Alveolar A Arterial Alveolar A (mm. (1. per blood (meq. (mm. (mm. (mm. (mm. (mm. (mm. Subject Hg) min.) (p.c.) per 1.) Hg) Hg) Hg) Hg) Hg) Hg) Talbott Dill * * Talbott * Dill * * Pappenheimer * Talbott * * Dill * Pappenheimer F.leng '

8 54 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. fore under other experimental conditions, the partial pressure of carbonic acid in arterial blood is practically the same as that in alveolar air. The fact that the differences are small in every case lends further support to the methods followed for obtaining gas samples which represent the mean composition of alveolar air. It is less surprising that such samples can be obtained in rest than it is in exercise when the ventilation and the rate of oxygen consumption are increased more than ten times, and when air in the lungs is undergoing rhythmic variations of great amplitude and frequency. 7 a 6 -J co < 5 Cl:,, 4 to 3 2 o SEA LEVEL. REST a A SEA LEVEL. WORK a o LEADVILLE. REST LEADVILLE. WORK AB it 2 -j 1 ~~~~ A (V o a 3-1 L Fig. 3. OXYGEN SATURATION OF ARTERIAL BLOOD Pressure head of oxygen from lungs to blood as a function of the oxygen saturation of arterial blood. Taking the observations on alveolar air as representative of its mean composition, it follows that, after an acclimatiation period of from 1 days to 3 weeks at 1, ft., the pressure head of oxygen from lungs to blood remains positive. The results have been plotted in Fig. 3 together with observations made at sea-level with special gas mixtures by Bock and others [Bock, Dill, Edwards, Henderson, Talbott, 1929]. It appears that the pressure head is slightly less at 1, ft. than when a

9 ADAPTATION TO OXYGEN PRESSURE. corresponding gas mixture is breathed at sea-level, but this may be due to increased breathing after acclimatiation at the higher altitude and to more rapid diffusion of oxygen in the alveoli at a low barometric pressure. It may be that the result would be different at 14, ft. or higher, but, at the time these punctures were made, Talbott, Pappenheimer and Dill were able to climb to 14, ft. with no symptoms of mountain sickness and without obvious cyanosis. Folling, with the highest oxygen saturation at rest at 1, ft., had some headache during his subsequent 4-day stay at 14, ft. This evidence, obtained by direct examination of arterial blood, leaves no doubt that representative samples of alveolar air can be obtained at high altitudes either in rest or work. Under the conditions -of our experiments the carbonic acid dissociation curves of arterial and of venous blood are identical. It follows that the reaction of arterial blood can be calculated by the Henderson-Hasselbalch equation when one knows the carbon dioxide pressure in alveolar air and the position of the carbonic acid dissociation curves of venous blood. Concentration of free carbonic acid can be calculated from the former, and combined carbonic acid can be calculated from the same datum and the carbonic acid dissociation curve of true plasma of venous blood. The composition of alveolar air in rest is shown in Table V. Boston Date Pappenheimer Oct. 8 F6Ming Aug. 29 Oberg Oct. 21 Dill Mar. 11 Talbott,, 23 Edwards Apr. 15 Bramlett Nov. 18 Bowen Oct. 4 TABLE V. pco2 (mm. Hg) * 42* 42-8 Composition of alveolar air at rest. Leadville A _ pco2 p 2 (mm. (mm. Date Hg) Hg.) July ,, 26 32* * *2,, ,, , ft. PCO, P2 (mm. (mm Date Hg) Hg) July 14 23* it ,, 14 26* Since the Ratio Ratio of PCO2 of pco2 at at Lead- 14, ylle ft. to to pco2 PCO2 at at Boston Boston Average: visiting party Whiteman - - Aug Johnson - -,, Heiliger - -,, Average: residents average carbon dioxide pressure for our party at Leadville is identical with the corresponding average for the residents, it appears that acclimatiation must have been nearly complete. Taking the value at sea-level 55

10 56 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. as 1, the values at 1, ft. ranged from -72 to '82 and at 14, ft. from 54 to -69. These changes correspond closely to those found by Fitgerald [1913, ]. The values for alveolar carbon dioxide pressure have been used in conjunction with the carbon dioxide dissociation curves of blood and plasma (discussed in Part I) for calculating ph of arterial serum. Table VI TABLE VI. Values for ph of arterial serum. HApH, ^ Boston to Boston to Boston Leadville 14, ft. Leadville 14, ft. Pappenheimer Folling Oberg Dill Q - Talbott Edwards 7* Bramlett Bowen Average: visiting party Whiteman 7.43 Johnson Heiliger Average: residents is thus derived and shows that, as a first approximation, the reaction of arterial serum is unchanged or nearly so at 1, ft. and is slightly more alkaline at 14, ft. Actually the average changes are + *3 and + -8 respectively. The value + 3 would not be significant were it not for the fact that all the changes are in the same direction. What does this imply with regard to the oxygen dissociation curve? Since it has been shown that the reaction of plasma may be taken as a reliable index to the position of this curve, it follows that there is no change in the affinity of arterial blood for oxygen at 1, ft. While there is a slight alkalosis and, therefore, a slight increase in affinity at 14, ft., even there the change is not great enough to shift the oxygen dissociation curve outside the normal limits1. The results may be taken, therefore, as fully confirming the experimental observations of the Pike's Peak party [Douglas, Haldane, Henderson and Schneider, 1913] in so far as the position of the oxygen dissociation curve is concerned. 1 When rhco, increases 3 and ph. increases -8, oxygen pressure at half saturation decreases 3 mm.

11 ADAPTATION TO OXYGEN PRESSURE. 57 PART III. MUSCULAR ACTIVITY1. Various adaptations during rest have been described above: this part refers to changes during exercise on a bicycle ergometer. The same sort of experiments were carried out as those of B o c k, Van Caulaert, Dill, F6lling and Hurxthal [1928]. It was our aim to study in detail the performance of each individual in all grades of work up to the maximum which could be maintained for 2 minutes. For conciseness the results will be presented, for the most part, graphically. The question of net efficiency has been studied in men and in dogs in high-altitude expeditions. The conflicting literature on this subject has been reviewed by Benedict and Cathcart [1913]. Our results showed on the average about 1 p.c. greater efficiency at Leadville. Nearly all our Leadville experiments were subsequent to sea-level experiments. Some increase in efficiency is expected with training, so that the efficiency with which bicycle riding is performed at 1, ft. is practically the same as at sea-level. The pulse rate in moderate work of a given level was about the same at the two altitudes. With increase in metabolic rate above 1-5 litres of oxygen per minute there was a linear increase in pulse rate until its limiting value was reached at a metabolic rate of about 2x6 litres per minute at sea-level. At Leadville the same limiting rate was reached at a metabolic rate of about 2-1 litres of oxygen per minute. There was not much evidence that the maximum rate was different at the two altitudes except in the case of b er g, who had a lower maximum rate at 1, ft. than at sea-level. The increase in blood-pressure with metabolic rate appeared to be nearly independent of altitude. The increase in pulse pressure was least in the case of Talbott and most in the case of Edwards, but for each individual the values for a given metabolic rate at sea-level and at Leadville were nearly identical. The data for total ventilation, corrected to standard temperature and pressure, are shown graphically in Fig. 4. It will be noted that the ventilation thus reduced to standard conditions is related to metabolic rate in exactly the same fashion at the two altitudes in the case of Dill. The variation in response in the other subjects is evidently a function of 1 A preliminary account has been given by Dill, Talbott, Edwards and Folling [193].

12 58 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. acclimatiation, for the points falling above the sea-level curves represent experiments carried on after the subjects had been in Leadville for O O 8 o LEADVILLE E H1TE. -J > u ac ax: U F<- J J 3! -nj - SA.. S8 so El.( a- 1~~~ - DB.D. ~~~~~~~~~ 5 3 El~~~~ 1~~~~~~~ - ~~~~~~ METABOLIC RATE IN LITRES OF OXYGEN USED PER MINUTE Fig. 4. Total ventilation in work at Boston and at Leadville. All results are reduced to standard conditions. In the case of H. T. E. the number of weeks spent at Leadville is indicated for each point. several weeks. In the case of E d war ds, the number of weeks elapsed between his arrival and the experiment is indicated for each point. These differences in total ventilation naturally were associated with differences in alveolar ventilation and in alveolar carbon dioxide and

13 ADAPTATION TO OXYGEN PRESSURE. 59 oxygen pressures. Since the general tendency was to vary the rate of total ventilation in a reciprocal fashion with barometric pressure it follows that, after taking into account the constantal alveolar watervapour pressure, the decrease in partial pressure of gases in the alveoli should be approximately proportional to the decrease in barometric pressure. This, in fact, was the case. Composite values for partial pres- 11 1uu BOSTON 9 a. a: < 8 < 7 6 LEADVILLE a- BOSTO Id 3 2J 2 LEADVILLE vn U.4 n ^a U.Q 415 I.C1. As Il C.Vvr}.A C r5iā OXYGEN USED-LITRE S PER MIN Fig. 5. Mean values on four subjects for composition of alveolar air as a function of metabolic rate. sures of oxygen and carbon dioxide in alveolar air are shown as a function of metabolic rate in Fig. 5. Approximately, the partial pressure of each gas at Leadville is seven-tenths the sea-level value. Actually the mean value for partial pressure of carbon dioxide in alveolar air in exercise at Leadville is 74 times the sea-level mean value. The corresponding ratio for alveolar oxygen is O65. In maximum work these ratios are x64 and x72 respectively, the change being due to a greater increase in alveolar ventilation in maximum work at high altitudes than at sea-level. Such ~~~~~ --I

14 6 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. a disproportionate increase was shown to take place in experiments on one individual by the Pike's Peak expedition [Douglas, Haldane, Henderson and Schneider, 1913]. The supply of oxygen to the tissues is dependent upon a large number of factors, chief among which are (a) circulation rate, (b) oxygen capacity of the blood, and (c) oxygen saturation of arterial blood. Estimates were made of the circulation rate, but, so far as could be judged, there was no well-defined difference in the rate during exercise of a given intensity at the two altitudes. There were rather large differences in rate in different individuals. These were not related to differences in working capacity, but there did seem to be a reciprocal relation between circulation rate at a determined metabolic rate and oxygen capacity of the blood. The results suggest that the limiting value for cardiac output in exercise might better be expressed in terms of cell flow rather than blood flow, but more experiments must be carried out before this hypothesis can be accepted. The limiting concentration of lactic acid in blood is reached when oxygen transport is at a maximum. Each of three subjects pushed himself to the limit at sea-level and at 1, ft. The high lactic acid concentrations in the most exhausting experiments on Talbott, Dill and Edwards furnished objective evidence that each of these subjects reached the limit of his oxygen intake for this form of exercise. The actual lactic acid concentrations are shown in Fig. 6 as a function of metabolic rate. Talbott and Dill have a uniform response, Oberg' is somewhat irregular, and there are large irregularities, apparently associated with acclimatiation, in the case of Edwards at Leadville. In his case the lactic acid concentration for a given metabolic rate decreased uniformly throughout the summer. While his alveolar ventilation was about twothirds that of D ill and T a lb o tt in sea-level experiments and in the early Leadville experiments, it increased with time and, by the end of the summer, had reached or slightly exceeded their level. His oxygen transport capacity increased simultaneously. A comparison of oxygen transport capacities is made in Table VII. TABLE VII. Oxygen transport capacity on the ergometer. Boston Leadville (1. per min.) (1. per min.) Ratio: LIB Talbott Dill Edwards Oberg was handicapped by a knee which brought him to a stop at a lower lactic acid concentration than that reached by the other subjects.

15 ADAPTATION TO OXYGEN PRESSURE. 61 T aib ott and Dill are in the same class with a capacity for transporting oxygen at Leadville which was about four-fifths their sea-level capacity. Edwards showed about the same figure early in the summer, but, finally, his oxygen transport capacity increased to 92 p.c. of the sea-level value IL5 4 3 Z 2 O RTE BOSTON -4 if4;-7 / 6 LEADVILLE r4 [1X;7_~~~~~~~~~~~~~~~~~AORID9MI.OL SRAIO =~~~~~~~~~~~~~~~~~~~~~~~~~~O T === DX TD i _ S.AQ T~~~~~~~~e o ;;@ttxx~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ JHT _ = = to t2 1A A METABOLIC RATE IN LMrtS OF OXYGEN USED PER MINUTE Fig. 6. Lactic acid concentration in work at Boston and at Leadville. These individual differences cannot be related to the concentration of heemoglobin in the blood, for T al b ott had less at Leadville than at sealevel, while Dill and Edwards had slightly more. Our results on circulation rate are not sufficiently accurate to be useful in interpreting these relatively small differences. We are inclined to seek an interpretation in terms of oxygen saturation of arterial blood. This was actually determined in the case of Talbott and Dill as indicated in Part II. The saturation in maximum work was approximately 91 p.c. at sea-level and

16 62 D. B. DILL, H. T. EDWARDS, A. FOLLING, AND OTHERS. 87 p.c. at Leadville. If one takes the percentage saturation of venous blood in work as 3 p.c., it follows that the utiliation of oxygen drops from (91-3) to (87-3) a decrease of 7 p.c. Since the percentage of haemoglobin in the blood remained nearly constant, it appears quite probable that there was a decreased capacity for cardiac output due to the lowered oxygen saturation of arterial blood. The results on E dwards can be explained similarly. His inferior pulmonary ventilation at sea-level probably results in a lower oxygen saturation of his arterial blood than in the case of T alb ott and Dill, and hence a lessened cardiac output capacity. On the other hand, his pulmonary ventilation at Leadville was the highest by the end of the summer, and as a result his arterial saturation, and hence his cardiac output, nearly reached sea-level values. SUMMARY. The oxygen dissociation curve of human blood after complete acclimatiation at 1, ft. and after 4 days at 14, ft. has about the same position as at sea-level when hydrogen-ion concentration is constant. The carbonic acid dissociation curve of oxygenated blood is lowered one-tenth at 1, ft. and slightly more after 4 days at 14, ft. Chloride concentration in cells and in serum increases slightly, but its distribution between cells and serum is practically unchanged. The ratio, (HC8)c (HC)8' increases about 3 p.c. at 1, ft. and somewhat more at 14, ft. The increase may be related to decrease in alkaline reserve, since a similar change is found when alkaline reserve is decreased in exercise. The pressure head of oxygen from lungs to blood remains positive even after acclimatiation at 1, ft. No evidence of secretion of this gas was found. The carbon dioxide pressure in alveolar air decreases to three-fourths of its sea-level value at 1, ft. and to two-thirds at 14, ft. The calculated reaction of arterial serum shows an average increase in ph value of 3 at 1, ft. and of -8 at 14, ft., but the change is too small to shift the oxygen dissociation curve of arterial blood outside its normal sea-level range. The oxygen transport capacity may be decreased by one-fifth in normal men at an altitude of 1, ft. It is suggested that this large effect is due to an indirect effect of a small change in oxygen saturation of arterial blood upon the limiting value for cardiac output. This explanation is consistent with the experiments of Furusawa, Hill, Long and Lupton [1924], showing that man can increase his oxygen transport capacity by two-fifths at sea-level by breathing 4 p.c. oxygen.

17 ADAPTATION TO OXYGEN PRESSURE. 63 A part of this investigation was carried on during the summer of 1929 at a hatchery of the U.S. Bureau of Fisheries near Leadville, Colorado. We are indebted to Mr Henry O'Malley, Commissioner of the Bureau, for having offered us accommodation. Our workroom, 4 x 5 ft. in dimensions, was equipped with running water, electric power and lights, and a pyrofax gas system. Mr Van Atta, Superintendent of the Leadville Hatchery, and his assistants, were most hospitable and helpful. Mr L. W. T h o mps o n, Principal of the Leadville High School, also rendered assistance. REFERENCES. Bainbridge, F. A. (1931). The Physiology of Muscular Exercise. 3rd ed. by Bock, A. V. and Dill, D. B. Longmans, Green & Co., London. Barcroft, J. (1925). The Respiratory Function of the Blood. Pt. I. Lessons from High Altitudes. Cambridge Univ. Press. Barcroft, J., Binger, Bock, A. V., Doggart, Forbes, Harrop, G. A., Meakins, J. C., and Redfield, A. C. (1922). Phil. Trans. Roy. Soc. B, 211, 351. Barcroft, J., Cooke, A., Hartridge, H. H., Parsons, T. R. and Parsons, W. (192). J. Physiol. 53, 45. Benedict, F. and Cathcart, E. P. (1913). Muscular Work. A Metabolic Study with Special Reference to the Efficiency of the Body as a Machine. Carnegie Institute, Washington. Bock, A. V., Van Caulaert, C., Dill, D. B., Folling, A. and Hurxthal, L. M. (1928). J. Physiol. 66, 136. Bock, A. V., Dill, D. B., Edwards, H. T., Henderson, L. J. and Talbott, J. H. (1929). J. Physiol. 68, 277. Colhnheim, O., Kreglinger and Kreglinger, Jr. (199). Z. Physiol. Chem. 63, 413. Dill, D. B., Edwards, H. T. and Talbott, J. H. (193). J. Physiol. 69, 267. Dill, D. B., Talbott, J. H., Edwards, H. T. and Folling, A. (193). J. Biol. Chem. 87, xxvi. Douglas, C. G., Haldane, J. S., Henderson, L. J. and Schneider, E. C. (1913). Phil. Trans. Roy. Soc. B, 23, 185. Fitgerald, M. P. (1913). Phil. Trans. Roy. Soc. B, 23, 351. Fitgerald, M. P. ( ). Proc. Roy. Soc. B, 88, 248. Furusawa, K., Hill, A. V., Long, C. N. H. and Lupton, H. (1924). Proc. Roy. Soc. B, 97, 155. Haldane, J. S. (1927 a). Respiration. Yale Univ. Press. Haldane, J. S. (1927 b). Physiol. Rev. 7, 363. Hastings, A. B., Sendroy, J., McIntosh, J. F. and van Slyke, D. (1928). J. Biol. Chem. 79, 193. Henderson, Y. (1925). Physiol. Rev. ES, 131. Krogh, M. (1915). J. Physiol. 49, 271. Margaria, R. (1929). Arbeit8physiol. 2, 261.