(PCO2 -B). (3) V, pco2 relation. Smyth, Semple and Gelfand, 1958; Lerche, Katsaros, Lerche and Loeschcke,

Transcription

1 THE EFFECT OF MAINTAINED AMMONIUM CHLORIDE ACIDOSIS ON THE RELATION BETWEEN PULMONARY VENTILATION AND ALVEOLAR OXYGEN AND CARBON DIOXIDE IN MAN. By D. J. C. CUNNINGHAM, D. G. SHAW, S. LAHIRI and B. B. LLOYD. From the University Laboratory of Physiology, Oxford. (Received for publication 2nd June 1961) Five men ingested about 12 g. NH4C1 daily for about a week. Acidaemia was assessed by measuring plasma (HCO3) and alveolar pco,. Before, during and after the period of ingestion the subjects were given various gas mixtures to breathe, and pulmonary ventilation (V) and the alveolar gas pressures (pco,, PO2) were measured in the steady state. The effect of acidaemia on the parameters of the equation V =D(1 +o C)(PCo2 - B) was examined. Only B, which is related to the "CO,-threshold", was consistently changed, being reduced in acidcemia. THE relation between alveolar carbon dioxide pressure (pco2, mm. Hg) and pulmonary ventilation (V, 1./min., B.T.P.S.) may be expressed, over a certain range, by the equation V=S(pCO2 -B).* (1 ) B, the intercept obtained by producing the V, pco2 line to the pco2 axis, is the pco2 of Nielsen's [1936] "apncea point", and is related to the various "CO2-thresholds " in the literature, while S may be termed the "CO2- sensitivity". Nielsen found that in chronic NH4C1 acidosis B was reduced, while S, measured at approximately normal alveolar oxygen pressure (PO2' mm. Hg), remained substantially unchanged. Later workers [Lambertsen, Smyth, Semple and Gelfand, 1958; Lerche, Katsaros, Lerche and Loeschcke, 1960] have obtained similar results, and Lerche et al. have found no difference between the effects of NH4C1, CaCl2 and acetazolamide ("Diamox") on the V, pco2 relation. Lloyd, Jukes and Cunningham [1958] found that the effect of hypoxia could be described by the equation S =D(1 -A ) (2) B being largely unaffected, and it is convenient to combine equations (1) and (2) to give A V=D(1 (PCO2 -B). (3) 323

2 324 Cunningham, Shaw, Lahiri and Lloyd The physiological significance of A and C is still obscure; D is the value of S when there is no hypoxic stimulus to respiration. We have exposed five subjects to various combinations of hypercapnia and hypoxia before, during and after NH4Cl acidosis maintained for some days, and have obtained values of the parameters B, C, D and A. METHODS The subjects were five healthy males (Table I). Blood was drawn and the respiratory parameters determined on most mornings of an day period on subjects 19, 65 and 66, and on alternate mornings, Sundays excluded, of a similar period on subjects 67 and 68. During the middle 5-8 days the subjects took entericcoated capsules of NH4Cl (10-20 g./24-hr. period) throughout the dav, the exact doses being shown in Table I. Subjects 66, 67 and 68 took placebo tablets of entericcoated NaCl when not taking NH4C1, and subject 65 took them during the recovery period after NH4C1. No subject was told what gas mixture he was receiving, and only subject 19 knew what tablets he was taking. All subjects were asked to lead a quiet and orderly life and to avoid excessive exercise during the period of investigation. They were allowed a cup of tea without sugar on rising but were otherwise fasting when they came to the laboratory for experiments in the morning. The apparatus for supplying the subject with any mixture of 02, CO2 and N2, and for measuring V and the alveolar gas pressures has been described [Cunningham, Cormack, O'Riordan, Jukes and Lloyd, 1957]. Appropriate checks were made on the end-tidal sampling. Estimations of pco2 were made with the flowbridge analyser and, with those of P02, in a development of the Haldane apparatus [Lloyd, 1958]. The approximate composition of the inspired gas mixture for a given ventilation and alveolar gas composition was calculated according to equation (1) of Lloyd et al. [ Determination of Respiratory Responses to C02 and Hypoxia.-In a typical experiment on subject 65, he reclined in an adjustable dental chair, and was given four gas mixtures in succession calculated to keep V constant at 20 1./min. and alveolar P02 at 125, 70, 57 and 47 mm.; alveolar pco2 was not allowed to fall below the resting level. On each mixture several observations of V and pco2 were made to ensure that a steady state had been reached: this took up to 20 min. for the first and about 8 min. for subsequent mixtures. End-tidal samples were then collected for immediate or subsequent analysis. The subject was then given seven gas mixtures calculated to keep V between 50 and 60 1./min. and alveolar P02 at 650, 120, 70, 60, 50, 45 and 40 mm., in that order. The aim was to keep V constant by progressive substitution of one respiratory stimulus (hypoxia) for the other (hypercapnia). The subject was usually unaware of changes in the gas mixture at any one level of V. On changing from low to high V there was a preliminary period on a mixture of CO2 and air during which no end-tidal samples were collected. The experiments on subject 19 were similar, but partly exploratory, and the order of gas mixtures varied from experiment to experiment: the linearity of the V, pco2 line at constant P02 was checked in two experiments (19, 13 and 19, 14 in fig. 1). The results on subject 65 adequately confirmed the validity of equation (3), and so the parameters for subjects 66, 67 and 68 were determined by three measurements of PO2' PCO2 and V at high V, and duplicate measurements of one set of values at low V, in each experiment. Sets of measurements were made in the following sequence: first preliminary period: 20 min., V ca /min., P02 ca. 70 mm.; first measurement period: 20 min., V ca /min., P02 ca. 70 mm.; second, third and fourth measurement periods: 20 min. each, V ca /min., P02 ca. 40, 70 and 650 mm.; then gradual lowering of CO2 and O2 until second preliminary period: 20 min., air breathed; fifth measurement period: a repetition of the first measurement period.

3 Ammonium Chloride and Pulmonary Ventilation The two preliminary periods, at high and low V, were found to reduce the differences between the results from the first and fifth measurement periods at low V. Determinations on Blood.-At the beginning of each experiment except the first three on subject 19 the left hand and wrist were immersed in water at C. for a quarter of an hour. 20 ml. blood was drawn from a superficial forearm vein without stasis into a glass syringe with heparin solution in its dead space while the subject was breathing 2 per cent CO2 in air through valves: end-tidal pco2, measured before and during venepuncture, fluctuated little. Most of the blood was transferred to ice-cold centrifuge tubes under paraffin, while some was used for determination of 02 saturation and capacity. 02 saturation and capacity, and plasma C02 content of the " arterialized " venous samples were measured in a modified Haldane blood-gas apparatus [Shaw, 1959] by the method of Courtice and Douglas [1947], the water bath being as usual at room temperature. The arteriovenous (AV) difference for the C02 content of whole blood, obtained from the AV 02 difference by assuming an arterial saturation of 97-5 per cent and a tissue R.Q. of 0-8, was assumed to be distributed equally between the cells and plasma [Dill, Edwards and Consolazio, 1937], and was subtracted from the venous plasma C02 content to give the arterial plasma C02 content. Van Slyke's value, 0-51, for the Bunsen coefficient for C02 in plasma at 38 C. was assumed for the calculation of the arterial plasma [HCO], the arterial pco2 being taken to equal the measured end-tidal pco2. The arterialized venous saturation was above 90 per cent (this corresponds to an AV [HCO] difference of less than 0-6 m.equiv./l.) for forty-two bloods out of forty-six; for three it lay between 86 and 90 per cent, and for the other (experiment 19, 6) it was 35 per cent. There was venous stasis on this occasion and the R.Q. was assumed to be 0 5. This procedure gave an arterial plasma pco2, [HCO3] point for each experiment. Each experiment also yielded a value of B (equation (1)) and the corresponding value, [HCO3IB, for the arterial plasma at this pco2 was obtained by means of small extrapolations based on the nomogram of Dill et al. [1937] for normal young men. 325 RESULTS The daily dosage of NH4Cl and NaCl, the results on blood, and the values of the parameters B, D, A and C are given in Table I. The respiratory results of all experiments are shown in fig. 1, in which V is plotted against pco2, PO2 being given in the legend. Fig. 2 is an enlarged picture of two typical experiments on subject 65, when normal and acidotic, and the P02's are written in against the V, pco2 points. As was to be expected from our previous work, the points at high V in a single experiment are spread out in the direction of the pco2 axis; the spread is greatest at low P02 and diminishes as normal P02 is approached, but is still apparent above it. The decrease in V and/or rise in pco2 on raising P02 to 650 mm. is a consistent finding at high V (in eighteen out of twenty-two experiments in this series) and shows little tendency to change with time, unlike the short-lived effect of high P02 under resting conditions [cf. Dejours, Labrousse, Raynaud, Girard and Teillac, 1958]. The' spread when V is 20 1./min. is much smaller, and the V, pco2 lines at various po2's form a fan. Acidosis had little effect on the shape of the fan, but displaced it bodily to the left; i.e. all pco2's were lower. B of equation (1) was in the first place determined at each P02 by drawing isoxic" lines based on two points at high and low V. The PO2'S of such a

4 326 Cunningham, Shaw, Lahiri and Lloyd TABLE I.-AGE, WEIGHT, HEIGHT AND MONTH OF EXPERIMENT; DAILY DOSAGE OF NH4C1 OR NaCl; MEASURE- MENTS ON ARTERIALIZED VENOUS BLOOD; DERIVED VALUES FOR ARTERIAL PLASMA; ALVEOLAR pco2 DURING VENEPUNCTURE; RESPIRATORY PARAMETERS B, D, A AND C. Experi. g./day a HbO2 Date ment I 02 capacity per m NaCi NH4C cent Derived arterial mm. 1./min./ Hg plasma m.equiv./l. mm. Hg pco2 mm. Hg P02 PC02 [HCOZ] [HCO, ]B Alveolar B D A C Subject 19, 38 years, 182 cm., 91 kg., December a (41-1) Subject 65, 22 years, 190 cm., 72 kg., January Subject 66, 19 years, 184 cm., 84 kg., March Subject 67, 23 years, 191 cm., 85 kg., April

5 Ammonium Chloride and Pulmonary Ventilation TABLE Experi. g./day ~ HbO2 I.-(continued) Derived arterial 1./min. / mm. Hg Date me0nt m - 02 capacity plasma m.equiv./l. mm. HgpCO2 mm. Hg P02 I enacthc ml./l00 ml. per pco2 -~----- NaCl NH4Cl cent [HCO3] [HCO,]B Alveolar B D A C Subject 68, 23 years, 185 cm., 83 kg., April pair of points seldom agreed exactly and the position of each line 327 was fixed by a standard iterative procedure. In subject 65, B was scarcely affected by hypoxia (figs. 1 and 4), the mnean decrease for all experiments being 0-5 mm. pco2 as P02 fell from 120 to 45 mm.; hypoxia thus exerted its effect almost entirely upon S of equation (1), and it was legitimate in this subject to determine a mean value of B for each experiment and to draw V, pco2 lines at the various PO2'S through it and the points at high V (fig. 1). Values of B for subject 19 showed a positive correlation with P02 (fig. 4), unlike the results on subject 65 and on the eight subjects of Lloyd et al. [1958]. In the twelve satisfactory experiments on subject 19, B fell by 1.6 mm. pco2 as P02 fell from 120 to 50 mm., and this relation was used to obtain for each experiment a smoothed set of B's for the PO2's at high V, and a corresponding set of S's (fig. 1). The values of B given for this subject in Table I and fig. 5 are for a P02 of ca. 120 mm. B for the curtailed experiments on the other three subjects was obtained by joining the high point at about 70 mm. pog to the mean of the two low points at about the same P02 and obtaining the intercept on the pco2 axis. Sometimes the line was drawn slightly to one side of the high point in accordance with the difference between the low and high P02'S, though these differences were less than 5 mm. in all but three experiments. A value of S for each of the high points was then obtained by joining them to the intercept B. S is plotted against P02 in fig. 3 for the experiments shown in fig. 2: A, C and D of equation (3) may be obtained from such plots by graphic iteration [Lloyd et at., 1958] or, as has been done here, by fitting a rectangular hyperbola by the method of Hey and Hey [1960] with the help of a suitably programmed computer (e.g. Mercury, Ferranti Ltd.). The curve shown in fig. 3 is that for the experiment before acidosis, and points of the experiment during acidosis lie close to it. When only three pairs of values of S and P02 are available they yield three simultaneous equations by substitution in equation (2) from which values of A, C and D can be calculated explicitly.

6 328 t I Cunningham, ~Shaw, tt 1 *.* Lahtirl -- :1 an( cl T I Lloydt b5.8,j't /i/ 30 / 2* 4 f/k - 3E 33Q -> 4-7K 50 K II4 30I307 S 1/1/ o 1/11/ W" 8 taax/ u X 30 L " Alveolar pccqmm Hq FIG. 1

7 Ammonium Chloride and Pulmonary Ventilation 329 FIG. 1.-The relation between V, pco2 and po9 in normal and acidotic subjects. Each small rectangle refers to one or two experiments on a subject, experiment numbers being given at top left for closed circles * (usually in acidosis) and bottom right for crosses x. The lines have been drawn (with one or two exceptions) through the points at high V and the appropriate vallue of B on the pco2 axis. The values of P02 at a given ventilation usually increase from left to right, as pco2 increases: for subject 65, experiment 65, 1 they are, from left to right at high V (above 30 l./min.)-41, 49, 54, 61, 116, 643; at low V 47, 67, 59, 122. Subject 65 PO2 P0 2 38, 43, 51, 59, 70, 119, 653; 52, 9 61, 69, , 49, 60, 69, 80, 118, 651; 10 52, 62, 71, , 49, 60, 68, 79, 118, 648; 11 51, 60, 67, , 50, 60, 68, 79, 118, 645; 12 47, 59, 67, , 46, 53, 61, 70, 121, 650; 13 50, 62, 70, , 49, 57, 63, 123, 655; 49, 62, , 46, 53, 62, 73, 119, 650; 49, 62, 70, Subject 19 PO. 44, 50, 55, 60, 67, 83, 117; 53, 9 60, 74, , 50, 54, 58, 64, 80, 118; , 49, 54, 58, 67, 81, 116; 50, 11 59, 73, , 51, 54, 58, 69, 117, 630; 52, 12 60, 73, , 49, 53, 58, 69, 117, 630; 13 51, , 45, 52, 58, 70, 116, 650; 50, 14 58, 73, 123 P02 40, 45, 51, 59, 70, 117, 650; 60, , 45, 52, 59, 70, 119, 648; 60 (V20), 68 (V21), , 45, 52, 60, 69, 118, 648; 60, 69, , 47, 53, 58, 73, 122, 652; 61, 70, , 48, 55, 63, 72, 122, 656; 63, 70, , 44, 52, 59, 68, 117, 645; 68, 60, , 49, 48, 48, 50, 48, PO2 47, 50, 55, 79, 630; 51, 59 46, 57, 69, 116, 630; 50, 58, 71, , 47, 53, 57, 68, 115, 627; 50, 57, 72, , , 66, 109, 625; 53, 48, 60, 74, , 48, 50, 55, 66 (V53), 117 (V35), 630, 123; 109, , 47, 51 (V44), 48 (V51), 56 (V46), 67 (V46), 620 (V47), 121 (V42); 49, 63, 47, , 67, 668; 42, 66, 660; 44, 68, 662; 43, 68, 661; 42, 67, 660; 41, 66, 648; 41, 66, 645; 41, 67, 650; PO2 P02 Subject 66 71, , , (V20), 70 (T22) 9 70 (V21), 71 (V22) 10 Subject 67 P02 67, , , , 68, 665; 44, 70, 667; 42, 68, 665; 44, 67, 657; 46, 69, 657; 40, 69, 665; 40, 68, 660; 40, 68, 660; PO2 74, 72 71, 74 80, 70 73, 71 72, 70 PO. 72, 71 71, 70 72, PO2 44, 69, 650; 69, 72 40, 67, 645; 70, 68 43, 70, 660; 72, 71 Subject Where there is ambiguity the figure for V is given in brackets. PO. 42, 70, 665; 74, 72 41, 68, 650; 79, 71 41, 69, 655; 69, 69

8 330 Cunningham, Shaw, Lahiri and Lloyd B.T. P. S. Expt. b5,10 Expt. 65, b5o 59 X b x X X x *,126)0 6 0\67 Aleoa/mCm.m.Hg AlveolarpCOx mm. Hg. FIG. 2.-The effect of acidosis on the VI PCO2, P02 relation. Enlarged picture of experiments 65, 10 and 65, 4 from fig. 1. Crosses x -xperiment before, closed circles 0-experiment during acidosis. Numbers near points indicate P02. The fan Of 'VI pco2 lines is displaced 7 mm. pco2 to the left during acidosis, but is otherwise very similar (see fig. 3). u20 0- E C 0 E E.1 Expts x :AD: X-, D I D bs b50 Alveola r po2, mm Hq. FIG. 3.-The effect of acidosis on the S, P02 relation (equation 2). The slope S of the V, pco2 lines from fig. 2 is plotted against alveolar P02. Crosses x -experiment before, closed circles *- experiment during acidosis. The hyperbola of equation (2) has been fitted to the crosses x. The proximity of the closed circles * to the hyperbola indicates that acidosis has little effect on parameters A, C and D (cf. Table I).

9 Ammonium Chloride and Pulmonary Ventilation 331 The extent to which the four parameters varied from day to day and the effects of ammonium chloride are shown in Table I. Only B varied consistently with the degree of acidosis, and fig. 5 shows the plots of B against (HCO3)B for the five subjects. The absolute values are of some interest. B was close to the resting pco2. C, the critical PO2 at which S approaches infinity, lay around 40 mm. in subject 19 and usually between 20 and 35 mm. in the other, younger, 2 Subject 19 o B - B; * pco2,mm. -2 Subject 6s ; : %0 40 bo 80 1oo 120 Alveolar poz mm. Hg. FIG. 4.-The effect of hypoxia on B (equation 1) for two subjects. For each experiment the mean B has been subtracted from the individual B at each P02, and the differences, B - B, are plotted against the P02's for all experiments on one subject. Hypoxia is associated with a fall in B in subject 19. subjects. D, the limiting value of S when hypoxic stimulation is absent, was between 2.5 and 7 l./min./mm. pco2. AD is the area constant of the hyperbola relating S to PO2 (fig. 3); A, which like C has the dimensions of P02, was more variable and usually lower than C. DiscUSSION We have avoided the sampling of arterial blood because in general blood gas analysis lacks the precision of gas analysis and because arterial puncture for each experiment over the long experimental period seemed unwarranted. The point of the " arterialized " venous blood sample drawn was to characterize the plasma [HCO-], pco2 relations on any one day, and not to determine a particular set of values for its own sake in relation to V. Our work has been based on alveolar gas pressures and we have given reasons in earlier papers for supposing that these are close to arterial gas pressures for CO2 and that the alveolar-arterial PO2 difference is small and

10 332 Cunningham, Shaw, Lahiri and Lloyd nearly constant in healthy young subjects breathing at /min., with scarcely elevated metabolisms. No doubt if accurate arterial gas pressures were available slightly different values for the parameters would emerge, but it is doubtful if the general form of the relations would change, or if our general conclusions would be affected. These experiments throw no light on the a' r5 0.94,r 66 / 67 r:0.97 E E 00 30, / u 30 r 0:.93,e r: Arterial plasma [HC0f8m-equiv/l. FIG. 5.-The correlation between B (equation 1) and [HCO3]B (arterial plasma bicarbonate when pco2=b) in dietary acidlemia. Closed circles *-before and during ingestion of NH4Cl; open circles o after ingestion. Subject numbers are at top left, correlation coefficients at bottom right. The broken lines in the diagram for subject 68 approximately represent the pco,, [HCO ] dissociation curve for true plasma during and after acidosis. question as to which pco2, arterial or venous (jugular or mixed), is an "effective stimulus ", but it is worth noting that if the interaction between hypoxia and CO2 or acid is peripheral [Joels and Neil, 1961], arterial levels are still of importance. In the plots of B against [HCO3]B (fig. 5) the points obtained during the transitions between the normal and acid states lie on substantially the same lines whatever the direction of change, and this absence of hysteresis is consistent with the view that in our experiments there were no long-term adjustments in the mechanism by which CO2 and acid affect V.

11 Ammonium Chloride and Pulmonary Ventilation The exact determination of B is difficult, but it is critically important for assessing the other parameters. Its value is highly dependent on the low-v determinations which, like the resting V and pco2, are subject to minute-tominute, hour-to-hour and day-to-day fluctuations which are greater than the errors of measurement, and due to causes which are certainly not fully known to us: postural variations in our experiments were small. In the period before acid was taken variations in B appear as scatter mainly across the B, [HCO3]B lines shown in fig. 5 and cannot therefore on our evidence be attributed to day-to-day changes in acid-base balance. The evidence for regarding B as being little affected by hypoxia is provided by the experiments of Lloyd et al. [1958] on eight subjects, of Loescheke and Gertz [1958] on five subjects and by the present data on subject 65. The direct correlation of B and P02 in subject 19 (fig. 4), who was some 15 years older than seven of the eight subjects of Lloyd et al. [1958] is exceptional. The effect varied with the plan of the experinients and may be attributed in part to a phenomenon recently noted in this laboratory by which, contrary to expectations, the inhalation of C02-rich mixtures may give rise to a " metabolic " as well as a respiratory acidaemia. Random effects of this phenomenon were largelv avoided by the standardized form of the experiments on subjects In our early experiments [Lloyd et al., 1958] we determined B at each P02 with greater precision than in the present work and at that time we saw a tendency for it to increase slightly in hypoxia. If the direct effect of hypoxia is, as we think, confined to S in equation (1), we would expect an accompanying small increase in B because of the shift towards alkalinity as heemoglobin becomes progressively less oxygenated at constant pco2. This secondary effect would be equivalent to that of ca. 2 mm. pco2 in the most severe hypoxia we have studied. The related acid-base effect that springs from changes in haemoglobin saturation as pco2 changes at constant P02 in a C02-inhalation experiment is smaller. The respiratory parameters other than B show little response to acid; the observation that the response to hypoxia, expressed by A and C, is largely unchanged in dietary acidosis appears to be a new one. The absence of a material change in D in acidosis is relevant to the problem as to which of the factors in what might be termed the Henderson-Hasselbalch complex (pco2, ph, [HCO-], [OH-] etc.) are "direct" stimuli. This problem can also be attacked by examining the correlations between various pairs of variables selected from B, phb, [HCO3]B, [OH-]B, etc. B and [HCO3]B, which are the pair closest to the original measurements, show a high degree of correlation (fig. 5), but at this stage this cannot be taken to mean that pco2 and arterial plasma [HCO-] are necessarily the "direct " factors affecting respiration. The lines drawn in fig. 5 are the reduced major axes, and are quite distinct from pco2, [HCO3] dissociation curves, the approximate slopes of which for normal and acid bloods are shown by the broken lines in the diagram for subject 68. The shift between these two broken lines represents the metabolic acideemia following the ingestion of NH4C1 by this subject. 333

12 334 Cunningham, Shaw, Lahiri and Lloyd ACKNOWLEDGMENTS D. G. S. and S. L. are grateful to Professor E. G. T. Liddell, F.R.S., for laboratory facilities and, respectively, to the Medical Research Council for a Scholarship and to the Government of West Bengal for an Overseas State Scholarship. We thank Mr. T. J. Meadows, Mr. E. Aldsworth and Mr. J. R. Griffiths for skilled assistance, and subjects 65, 66, 67 and 68 for cheerful participation. REFERENCES COURTICE, F. C. and DOUGLAS, C. G. (1947). "The ferricyanide method of blood-gas analysis", J. Physiol. 105, CUNNINGHAM, D. J. C., CORMACK, R. S., O'RIORDAN, J. L. H., JUKES, M. G. M. and LLOYD, B. B. (1957). "An arrangement for studying the respiratory effects in man of various factors", Quart. J. exp. Physiol. 42, DEJOURS, P., LABROUSSE, Y., RAYNAUD, J., GIRARD, F. and TEILLAC, A. ( 1958). "Stimulus oxygene de la ventilation au repos et au cours de l'exercice musculaire, 'a basse altitude (50 m), chez l'homme", Rev. franc. d'etudes clin. et biol. 3, DILL, D. B., EDWARDS, H. T. and CONSOLAZIO, W. V. (1937). "Blood as a physicochemical system. XI", J. biol. Chem. 118, HEY, E. N. and HEY, M. H. (1960). "The statistical estimation of a rectangular hyperbola", Biometrics 16, JOELS, N. and NEIL, E. (1961). "The influence of anoxia and hypercapnia, separately and in combination, on chemoreceptor impulse discharge", J. Physiol. 155, 45-46P. LAMBERTSEN, C. J., SMYTH, M., SEMPLE, S. J. G. and GELFAND, R. (1958). "Respiratory effects in normal men of blood ph change at 'constant' arterial and internal jugular venous Pco2", Fed. Proc. 17, 92. LERCHE, D., KATSAROS, B., LERCHE, G. and LOESCHCKE, H. H. (1960). 'Vergleich der Wirkung verschiedener Acidosen (NH4C1, CaCl, Acetazolamid) auf die Lungenbeliiftung beim Menschen ", Pflug. Arch. ges. Physiol. 270, LLOYD, B. B. (1958). "A development of Haldane's gas analysis apparatus", J. Physiol. 143, 5-6P. LLOYD, B. B., JUKES, M. G. M. and CUNNINGHAM, D. J. C. (1958). "The relation between alveolar oxygen pressure and the respiratory response to carbon dioxide in man", Quart. J. exp. Physiol. 43, LOESCHCKE, H. H. and GERTZ, K. H. (1958). "Einfluss des 0,-Druckes in der Einatmungsluft auf die Atemtatigkeit des Menschen, gepriift unter Konstanthaltung des alveolaren CO2-Druckes", Pfliig. Arch. ges. Physiol. 267, NIELSEN, M. (1936). "Untersuchungen fiber die Atemregulation beim Menschen", Skand. Arch. Physiol. 74, Suppl. 10, SHAW, D. G. (1959). "Some factors affecting respiration in man", B.Sc. thesis. Oxford University.