studies on the regulation of respiration in acute hypoxia: with an appendix on kespiratory (control...

From the Laboratory of Zoophysiology, University of Copenhagen.

Studies on the Regulation of Respiration in Acute Hypoxia.

With an Appendix on Respiratory flontrol During Prolonged Hypoxia:

BY

MARIUS NIELSEN and HELGE SMITH.

Received 9 Jidy 1951.

The purpose of the present experiments is to study the effect of CO, on the pulmonary ventilation at various degrees of acute hypoxia. Since both CO, and low oxygen act as stimuli for respiration, it is necessary in order t o obtain clearcut results, to keep one of these stimuli constant, while the other is varied. I n the present experiments the alveolar carbon dioxide pressure and the alveolar oxygen pressure are used as indicators for the two stimuli, and for a given degree of hypoxia (with constant alveolar 0, pressure) the alveolar carbon dioxide pressure has been varied. The oxygen pressure in the inspired air has consequently been adjusted in such a way, tha t the alveolar oxygen pressure remained a t the same level in spite of the changes taking place in the pulmonary ventilation due to the variation in alveolar pC0,.

Procedure nnd Methods. The experiments were performed on two normal male subjects

(P. G., 23 years, 178 cm, 78 kg and K. S., 26 years, 173 cm, 72 kg). The subjects selected had a pronounced respiratory response towards low oxygen and both of them had, for a long time previous to these experiments, been trained in respiration experiments. The subjects came to the laboratory in the morning without breakfast and rested for one hour in a comfortable armchair. During the experiments care

294 MARIUS NIELSEN AND HELQE SMITH.

Fig. 1. Schematic diagram of the apparatus for automatic sampling of alveolar air. The Marey tambour M interrupts the current to the electromagnet E during inspiration by closing the mercury contact MC. D diaphragm, which separates the iospiratory and expiratory valves. R regulator of the flow of alveolar air. S steel

spring. For further description, see text.

was taken to avoid all noise in the experimental room. Throughout the entire period of experiments it is furthermore necessary that the subjects lead a regulated life, especially with regard to the duration of sleep. If one cannot rely on the subjects with respect to this, it is not possible to obtain results without too much scattering.

In the experiments the subjects breathed mixtures of oxygen, carbon dioxide and nitrogen from a Douglas bag which was continuously filled from cylinders containing the proper air mixture. When preparing the air mixtures in the cylinder, a sensitive manometer was used, and care was taken that temperature changes of the cylinders, caused by blowing off or admixture of gases, had levelled off before gases or gas mixtures again were added. Before the final adjustment the gas mixture in the cylinders was analysed. In this way the oxygen and the carbon dioxide percentages could be adjusted to values which did not differ more than 0.1 per cent from those desired. The expired air was oollected in Douglas bags and measured by emptying the bags into a carefully calibrated spirometer. By using a constant suction, produced by increasing the counter load on the spirometer, the bags could be emptied to exactly the same degree each time.

The alveolar air was taken as the last part of each normal expira- tion (KROGH and LINDHARD, 1914). The sampling was carried out by means of an automatic device (see fig. 1). A narrow rubber tube was connected a t one end with the space just beyond the expiratory valve and a t the other end with a sampling tube filled with mercury. A constant rate of sampling was secured as follows: The levelling bulb of the sampling tube was suspended from a steel spring, and when during the sampling the mercury ran into the levelling bulb, the increased weight of the bulb was just counterbalanced by the stretching of the

STUDIES ON THE REQULATION OF RESPlRATION IN ACUTE HYPOXIA. 295

steel spring. During the expirations the narrow tube was compressed by means of an electromagnetic device, which was supplied with current from a relay. During the inspirations the circuit to the electromagnet was for a short time broken, which allowed small amounts of alveolar air to be sucked over into the sampling tube. Before the end of the inspirations the circuit to the electromagnet was again closed, so that it was impossible for the sample of alveolar air to be contaminated with dead space air from the first part of the following expirations. The closing and breaking of the circuit were made at a mercury contact by means of a Marey tambour operated by the pressure changes in the chamber between the respiratory valves. - The dead space of the apparatus was reduced to an insignificant value by inserting through the middle of the valve chamber a thin metal diaphragm, which completely separated the inspiratory and the expiratory valves from one another (v. DOBELN 1949). All gas analyses we;q made on the HALDANE apparatus modified by KROGH.

As mentioned in the introduction the alveolar PO, should for a given degree of hypoxia, remain at the same level in spite of the changes in the pulmonary ventilation caused by the breathing of CO,. It was, therefore, necessary on each subject and for each degree of hypoxia to carry out some preliminary experiments with CO, breathing. On the basis of the results from these experiments, the oxygen pressures of the inspired air mixtures could then be adjusted t o the correct values

Results.

Fig. 2 and fig. 3 show the pulmonary ventilation in relation to time in two series of experiments on subject P. G. and subject K. S. The composition of the inspired air mixtures is seen in the text underneath the figures. In the experiments with subject P. G., the alveolar oxygen pressure was maintained a t a value of 36.9 f 1.3 mm and, in the experiments with subject K. S., a t a value of 39.2 &- 2.0 mm. The subjects breathed a t first normal atmospheric air through the mouthpiece and the respiratory valves for about 5 minutes. Collection of the expired air began about one minute after connection to the air mixtures had been made.

In the experiments with subject P. G. (fig. 2) the pulmonary ventilation shows a decrease during the experimental period before a steady state ik reached, and, in the experiments with the higher CO, percentages in the inspired air, this decrease is very large. In the steady state the pulmonary ventilation is nearly independent of the CO, percentage in the inspired air up to a value of about 1.9 per cent, whereas in the experiments with higher CO, percentages the ventilation shows very large increases.

296 MARIUS NIELSEN AND HELGE SMITH.

Fig. 2. Subject P. G. Pulmonary ventilation (37", prevailing bar. pressure, satuwt.) during hypoxia (alveolar PO, 36.9 f 1.3 mm) at various CO, percentages in the inspired air in relation to time in minutes from beginning of breathing

the air mixture. I 0 % GO, and 7.89 96 0, in the inspired air

11 0 yo I) )) 7.92 ?(, I) 1) )) I) 1)

I11 0.75 % I) I) 7.81 :(, 1) o I) 1) ' 1)

IV 1.19 % )) A 7.89 ?(, 1) )) 1) )) 1)

V 1.24 % )) 8 7.84 76 I) I) B n 1)

VI 1.68 % 1) I) 7.88 % I) 1) I) I) I)

VII 1.91 yo o I> 7.90 yo a I) I) 1) D VIII 2.50 % 1) )) 7.25 yo s 1) )) >> ))

IX 2.38 % )) 1) 7.15 76 1) u 1) I) I)

X 3.20 % I) 6.84 % I) 1) o I) s XI 3.15 % I) o 6.61 % b D I) 1) 0

XI1 3.81 % I) )) 6.17 % )) I) a 1) n XI11 4.09 % I) I) 6.1 % I) I) D 1) 1)

In the experiments with subject K. 8. (fig. 3) the pulmonary ventilation is nearly constant throughout the entire experimental period except in the experiments with the highest CO, percentages in which the ventilation, in contradistinction to the ventilation in the experiments with subject P. G., shows a small increase before a steady state is reached. The probable reason for this

STUDIES ON THE REGULATION OF RESPIRATION IN ACUTE HYPOXIA. 297

different reaction of the two subjects will be mentioned later on. I n the steady state the pulmonary ventilation shows principally the same relation to the alveolar pC0, as in the experiments with subject P. G., but the increase in the ventilation a t the higher CO, percentages is essentially smaller.

The sampling of alveolar air was usually made only in the steady state, corresponding to the 3-5 last determinations in fig. 2 and fig. 3. In this period of time the alveolar gas pressures had attained a practically constant value except in the experiments with low oxygen without CO, in the inspired air. In these last mentioned experiments the alveolar CO, pressure was still slightly decreasing during the period of sampling.

298 MARIUS NIELSEN AND HELOE SMIFU.

55 I

Fig. 4. Subject P. G. Pulmonary ventilation (37", prerailing bar. pressure, saturat.) in relation to alveolar pC0,.

0 alveolar PO, 36.9 f 1 . 3 mm Hg + 1) 1) 47.2 & 1.5 1) 1)

0 1) D 110.3 & 1.9 )) 1)

x 1) 1) 168.7 f 2.1 1) 1)

In fig. 4 the steady state values of the pulmonary ventilation from the experiments with subject P. G. are plotted versus the alveolar CO, pressure. The curve to the right represents the experiments with normal alveolar oxygen pressure ( 1 1 0 . 3 5 1.9 mm Hg) together with some experiments with a moderately increased alveolar oxygen pressure (168.7 f 2.1 mm Hg). It is seen that the pulmonary ventilation increases linearly with increasing alveolar CO, pressure and that the effect of the increase in CO,

ETUDIES ON THE REGULATION OF RESPIRATION IN ACUTE HYPOXIA. 299

pressure is the same in the experiments with normal oxygen pressure as in the experiments with increased oxygen pressure.

The curve to the left represents experiments in which the alveolar oxygen pressure is maintained at a value of 36.9 & 1.3 mm Hg.l At this degree of hypoxia the pulmonary ventilation is increased and the alveolar pC0, decreased very considerably (to about 21 mm Hg). At higher alveolar CO, pressures, produced by adding CO, to the inspired air, the pulmonary ventilation, however, remains nearly unchanged until a definite value of pC0, (about 30 mm Hg), the threshold value of CO,, is reached. From this point the curve ascends with an extremely steep grade. An increase in alveolar pC0, of 3 mm produces here an increase in the pulmonary ventilation of nearly 30 liters per minute, whereas in normal conditions the same'fncrease in $0, only produces an increase in the ventilation of about 6 liters per minute. In other words, the sensitivity of the respiratory apparatus towards CO, is greatly increased in the hypoxic state as compared to the sensitivity under normal conditions.

The third (middle) curve represents experiments, in which the alveolar PO, is maintained at a value of 47.2 f- 1.5 mm Hg. It is evident, that here also there is a threshold value of the CO, (about 31.5 mm Hg) and that the sensitivity towards CO, for CO, pressures above this value is higher than under normal conditions although not as high as in experiments with the lower

In fig. 5 the pulmonary ventilation from the experiments with subject K. S. is plotted against the alveolar CO, pressure. The curve to the right represents the experiments with normal alveolar PO, (109.2 f- 2.1 mmHg ) and the curve to the left, experiments in which the alveolar PO, is maintained at a value of 39.2 & 2.0 mm Hg. The experiments with subject K. S. show results similar to those with subject P..G. In the low oxygen experiments in which no CO, is present in the inspired air, the pulmonary ventilation is relatively high (about 21 liters per minute) and the alveolar PCO, as low as 17-20 mm Hg. Probably because of the high degree of alkalosis the subject was not able to relax completely in this condition, and it is a well known fact that increased muscle

PO,.

1 In the experiments represented by the points in parentheses the subject oom- plained of severe resistance againsb the respiration. In all likelihood in these experiments the ventilation was therefore a little smaller than it would otherwise have been.

300 MARIUS NIELSEN AND HELGE SMITE.

u/veo/ar p C 4 /n mm Hg

Fig. 5. Subject K. S. Pulmonary ventilation (37”, prevailing bar. pressure saturat.) in relation to alveolar pC0,. 0 alveolar PO, 39.2 & 2.0 mm Hg x )) D 109.2 f 2.1 D ))

tensions lead to an increase in the ventilation. Adding CO, to the inspired air enabled the subject to relax, and it is seen that within a wide range of alveolar pC0, (from pC0, 21 mm to pC0, 33 mm) the ventilation remains at the same level in spite of the changes in CO, pressure. At a CO, pressure of 33 mm, the threshold value of CO, is reached, and for CO, pressures above this threshold value the sensitivity towards CO, is somewhat, increased as compared to the sensitivity under normal conditions.

The threshold value of CO, under normal conditions can be estimated as the point of intersection between the normal curve and the zero line by extrapolating the curve back to the zero line as done in fig. 4 and fig. 5.

In table 1 are presented the threshold value and the “sensitivity index” which are found in the 4 series of experiments performed on subject P. G. and in the 2 series of experiments performed on subject K. S.

STUDIES ON TIIE REQULATION OF RESPIRATION IN ACUTE EYPOXIA. 301

Tablo 1.

36.6 f 1.3 47.2 f 1.5 110.3 f 1.9 168.7 * 2.1 ...................... P . G

30 I 9.4 3.4

31.5 2.1

39.21 f 2.0 . I 33 ...................... 109.2 & 2.1 I 31.5 1 E:: 1 I K . S 1 I- ’ Increase in ventilation per 1 rnm increase in alveolar pC0,.

It is seen from table 1 that the threshhld value of CO, found under normal conditions (norma1 alveolar PO,) is about the same for both subjects as the threshold value found in the experiments with hypoxia. It is further seen that bcth subjects show about the same sensitivity towards CO, under normal conditions. In the experiments with hypoxia both subjects show an increased sensitivity towards GO,, but the increase is much greater in subject P. G. than in subject K. S.

In the experiments, in which the alveolar PO, is maintained a t a value of 36.9 mm, the sensitivity of subject P. G. (fig. 5) is so high that even with ventilations of about 50 liters per minute the corresponding alveolar pC0, (33-33.5 mm Hg) is smaller than the eupneic value of alveolar pC0, (36-36.5 mm Hg). In this case the CO, pressure in the respiratory center must therefore have been decreasing in the first part of the experimental period, and this decrease in CO, pressure offers a probable explanation of the big fall taking place in ventilation before a steady state is reached (see fig. 2). I n the experiments with no CO, or with the smallest CO, percentages in the inspired air, CO, is more rapidly washed out from the arterial blood and from the tissues, and the pC0, thereby brought down to a level lower than corresponds to the threshold value of CO,. Consequently the fall in ventilation (fig. 2) is relatively smaller than in the experiments with the higher CO, percentages in the inspired air.

I n the experiments on subject K. S. with low 0, and high CO, in the inspired air (fig. 3), the alveolar pC0, is considerably higher than the eupneic value of alveolar pC0,. The CO, pressure in the respiratory center has consequently been increasing during the

20-512482. Aetu p h y s . Seundinav. V o l . 24.


first part of the experimental period; and it is seen from fig. 3 that, instead of a big decrease as in subject P. G., a small increase in ventilation is taking place before a steady state is reached. The changes in ventilation during the experimental period are much smaller in subject K. S. (fig. 3) tthan in subject P. G. (fig. 2). This is no doubt due to the fact, that the sensitivity towards CO, in hypoxia is much smaller in subject K. S. than in subject P. G. (see table 1).

Discussion.

The main results of the present experiments are as follows: 1) I n acute hypoxia with pronounced increase in pulmonary

ventilation and decrease in alveolar pCO,, an increase in the alveolar pC0, produced by CO, breathing has no effect at all, or only a slight effect, on the pulmonary ventilation until a certain value of alveolar pCO,, the threshold value of CO, is reached. 2) When the alveolar pC0, is increased above the threshold value, a given increase in the alveolar pC0, has an effect on the respiration which is even larger than in the normal condition. 3) The threshold value of CO, is about the same for the various degrees of hypoxia studied as i t is in the normal condition. - The conclusions which may be drawn from these results regarding the regulation of respiration in acute hypoxia will be mentioned later on.

Earlier studies of the effect of CO, on the respiration in acute hypoxia were made by LINDHARD 1911, SCHNEIDER, TRUESDELL and CLARKE 1926, DILL and ZAMCHECK 1940, DUMKE, SCHMIDT and CHIODI 1941 and SHOCK and SOLEY 1942. I n some of these studies an increased sensitivity towards CO, was found. Other investigators found a simple addition of the combined effects of the hypoxia and the hypercapnia, whereas others still found that CO, had no, or practically no effect on the respiration even a t pronounced degrees of hypoxia. Several reasons may account for this diversity of the results and among these the following two should be emphasized: 1) The investigations were often made with only one step of CO, breathing. It is easily seen from fig. 4 and fig. 5 in this paper, that any result ranging from no response a t all to an increased sensitivity towards CO, may then be obtained, depending upon what concentration of C 0 2 in the inspired air is used. 2) I n none of the earlier investigations was the low oxygen stimulus kept constant, while the CO, stimulus was

STUDIES ON TEE REGULATION OF RESPIRATION IN ACUTE HYPOXIA. 303

varied, and consequently considerable increases in arterial oxygen saturation due to the CO, breathing were found, i. e., the degree of hypoxia was more pronounced in the pure hypoxic condition than when CO, was added to the inspired air.

Through the fundamental work carried out by HEYMANS and his school it is now a firmly established fact that the increase in pulmonary ventilation in acute hypoxia is due mainly or entirely to reflexes from the peripheral chemoreceptors.

The results from the present experiments harmonize very well with this. Due to the reflexly evoked hyperventilation the alveolar CO, pressure is diminished, and the threshold value of CO, found in these experiments corresponds most probably to the CO, pressure a t which CO, begins to stimulate the respiratory center. The fact that the alveolar CO, pressure in thd pronounced degrees of hypoxia (fig. 4 and fig. 5) is lower than the CO, threshold shows, that not only the increase in ventilation but the entire ventilation in such conditions is maintained from the chemoreceptors. The same conclusion was obtained by GESELL, LAPIDES and LEVIN (1940) and BJURSTEDT (1946), who found that temporary cold blocking of the chemoreceptor nerves in dogs during high grade 0, deficiency might cause apnea.

The stimulus for the increase in ventilation in acute hypoxia is thought by many invesfigators to be an increased acidity in the chemoreceptors, caused by a local increase in acid formation. I n the present experiment with hypoxia, the alveolar pC0, could be increased over a wide range before the threshold value of CO, was reached. I n one subject, for instance, the alveolar pC0, could be increased by 1'2 mm Hg without any effect on the pulmonary ventilation although the increase in the CO, pressure of the arterial blood irrigating the chemoreceptors was of the same magnitude. If the stimulus for the hypoxic hyperventilation is an increased acidity in the chemoreceptors, i t must therefore be a question of very large increases in acidity.

The threshold value of CO, found in the present experiments is most probably the value of pC0, at which CO, begins to stimulate the respiratory center. Much discussion, though, remains regarding the relative effectiveness of CO, on the center and on the chemoreceptors respectively. HEYMLVS and BOUCKAERT 1939 concluded from experiments in which the effect on the pulmonary ventilation of localized hypercapnia was studied that the chemoreceptors are more sensitive to CO, than is the center.

304 MARIUS NIELSEN AND HELQE SMITH

GOLLWITZER-MEIER and LERCRE (1941), comparing the central and reflex influence of CO, on the ventilation, found a considerable sensitivity of the chemoreceptors but a still higher sensitivity of the center. - Studies on action potentials in the sinus nerve have usually shown low CO, thresholds for the carotid body, and v. EULER, LILJESTRAND and ZOTTERMAN (1939) found a linear relation between the increase in frequency of action potentials and the increase in alveolar pC0,. I n experiments on dogs GESELL, LAPIDES and LEVIN (1940) and HESSER (1949) found that temporary cold blockings of the chemoceptive impulses in the sinus nerves (vagi cut) caused a small reduction in the pulmonary ventilation during eupneic breathing and in the beginning of pro- gressive hypercapnia, but the absolute reduction in ventilation diminished with increasing hypercapnic hyperventilation until it completely disappeared a t 5-6 per cent CO, in the inspired air. I n explaining these results GESELL et al. proposed the rather paradoxical hypothesis, that increasing CO, stimulation of the chemoreceptors does not increase the pulmonary ventilation, because the increasing CO, pressure itself produces an increasing central blocking action of the signals which it sets up in the chemoreceptors.

Some investigators claim that both hypercapnia and hypoxia act on the chemoreceptors by increasing their acidity (v. EULER, LILJESTRAND and ZOTTERMAN 1939, GESELL et al. 1941, BERNTHAL 1944, WINTERSTEIN 1949 a. 0.). If the hypercapnic hyperventilation found in the present experiments is to any significant degree due to CO, stimulation of the chemoreceptors, then such an effect of CO, does not agree with the CH hypothesis just mentioned. According to this hypothesis, the C, in the chemoreceptors should already, in the pure hypoxic condition, be above the threshold value. I n all probability it is the same elements within the chemoreceptors which are involved by CO, and by low oxygen excitation (v. EULER, LILJESTRAND and ZOTTERMAN 1939). Therefore on the above mentioned suppositions, it should then be expected that an increase in the CO, pressure augments the pulmonary ventilation. Furthermore, in consequence of the results from the cold blocking experiments of GESELL et al. and also from the hypothesis on central blocking action by CO, proposed by these authors (see above), this effect of CO, should be most pronounced a t the relatively low values of the CO, pressure. The experiments reported in the present paper (fig. 4 and fig. 5),

STUDIES ON THE REGULATION OF RESPIRATION IN ACUTE HYPOXIA. 305

however, showed that the alveolar pC0, in the hypoxic condition could be increased over a wide range without causing any significant increase in the pulnionaIy ventilation and only when it was increased above a certain value did the exceedingly powerful effect of CO, on the ventilation appear.

From the many CO, breathing experiments which show about the same respiratory response towards CO, before and after chemoreceptor denervation, and also from the cold blocking experiments of GESELL et al. and of HESSER, mentioned above, it seems most probable that hyperventilation caused by general hypercapnia is due mainly (in unanesthetized or lightly anesthe- tized animals) to the effect of CO, upon the respiratory center, as concluded by SCHMIDT and COMROE (1,940 and 1941). It therefore also seems most probable that the threshold value of CO, found in the present experiments is the CO, threshold for the respiratory center, and that the increased respiratory response towards CO, found in the hypoxic conditions is due to an increased sensitivity of the respiratory center towards CO,. Whether or not an effect of CO, upon the chemoreceptors contributes to any significant degree to the hypercapnic hyperventilation found in the hypoxic conditions cannot, however, be answered definitely. If CO, does have such an effect, it could bz due to a specific action of CO, on the chemoreceptors, but it could not, as pointed out above, be explained by means of the CH hypothesis.

It might be argued that the hypoxic stimulus for a given degree of hypoxia (fig. 4 and fig. 5) has not been constant, in spite of the constancy of the alveolar (and arterial) PO,, because the increase in arterial pC0, tends to diminish the arterial 0, saturation. I n the most pronounced degree of hypoxia (fig. 4)) in which also the increase in sensitivity towards CO, was the most pronounced, the entire hypercapnic hyperventilation, however, was caused by an increase in the alveolar pC0, above the threshold value of only 3.5 mm Hg. The corresponding decrease in arterial oxygen saturation, therefore, has been only slight. Furthermore, the hypoxic stimulus for the respiration seems to depend much more on the oxygen pressure than on the oxygen content of the arterial blood. This has been concluded (COMROE and SCHMIDT 1938, ASMUSSEN and CHIODI 1941, CHIODI, DILL, CONSOLAZIO and HOR- VATH 1941, and DAHLSTROM, OBRESCHKOW and SJOSTRAND 1947) from experiments, in which the oxygen content of the blood was varied within wide limits by means of admixture of CO without

306 MARIUS NIELSEN AND HELGE SMITH.

causing any significant changes in the ventilation. - It might also be argued - from the point of view that the effect of CO, should be due to its nature as an acid - that the increased sensitivity towards CO, found in the hypoxic conditions is caused by a decrease in the alkali reserve in the respiratory center con- tingent upon a local increase in acid formation. A given increase in pC0, should then produce a greater increase in C, and ventilation in the hypoxic conditions than in normal conditions. The fact that the threshold value of CO, is about the same in both conditions, however, speaks definitely against the correctness of such an explanation.

It has often been claimed that hypoxia acts as a depressant on, or is “devitalizing” for, t,he respiratory center itself. Provided that CO, acts mainly on the center itself (see above) the present experiments, however, show that hypoxia in the normal intact man has no such effect on the respiratory center as far as its response to CO, is concerned. On the contrary, for CO, pressures above the threshold value the respiratory center responds even more powerfully to CO, than in normal conditions.

The increased sensitivity towards CO, plays no part in the development of the hypoxic hyperventilation, because the CO, pressure in the hypoxic state actually is far below the threshold value. The biological importance of this mechanism will appear only in conditions where lack of oxygen is combined with accumulation of carbon dioxide.

How the increased sensitivity towards CO, found in the hypoxic conditions is brought about cannot be said from these experiments. It may be that it is evoked reflexly by the hypoxic stimulation of the chemoreceptors or it may be that it is caused by the effect of lack of oxygen on the respiratory center itself. Experi- ments made by DUMKE, SCHMIDT and CHIODI (1941), thougb, speak against the latter of the above mentioned possibilities. These authors found that chemoreceptor denervated dogs had a smaller pulmonary ventilation when breathing CO, in low 0, than when breathing CO, in pure 0, and concluded that the only direct effect of anoxia on the response of the center to CO, was a depressant one. The “sensitivity index” (i. e. , increase in ventilation per mm increase in arterial pCO,, see page 301), calculated from the data of DUMKE, SCHMIDT and CHIODI for the denervated dogs, is on the other hand of about the same magnitude in both conditions (low 0, and pure 0,).

STUDIES ON THE REQULATION OP RESPIRATION IN ACUTE HYPOYIA. 307

GRAY (1946) presented “The Multiple Factor Theory for the Control of Respiratory Ventilation”, in which is was stated that a number of factors, particularly H-ion, pC0, and PO, (measured in the arterial blood) exert independent effects on respiratory ventilation, and that the actual ventilation is represented by the algebraic sum of the partial effects of these factors. The‘ results from the present experiments agree with GRAY’S theory in so far as PO, can exert effects on the ventilation, which are independent of pC0, (and CH), but they disagree with the theory concerning the algebraic summation of the partial effects as i t is clearly seen from the curves in fig. 4 and fig. 5 : A reduction of the pC0, t o values below the CO, threshold does not inhibit the ventilation as thought by GRAY, and qn increase above the CO, threshold exerts different effects in the hypoxic and in the normal condition.

Appendix. Respiratory Control During and After Acclimatization to

Low Oxygen Pressure. The results from the aforementioned experiments with acute

hypoxia will now be compared with some earlier experiments (NIELBEN, 1936) on the effect of CO, on respiration in prolonged oxygen deficiency. I n these experiments two subjects were exposed for a period of seven days to barometric pressures of 474 mm Hg and 437 mm Hg in a low pressure chamber. The experiments showed that the CO, threshold was lowered to such a degree that the alveolar pC0, actually was above the CO, threshold and the “sensitivity index”, i. e . the slope of the stimulus response curves (ventilation plotted against alveolar pC0,) was considerably increased.l I n long lasting hypoxia, CO, therefore again becomes a factor which participates in the maintenance of the ventilation. RAHN and OTIS (1949) also found an increased sensitivity (“sensitivity index”) of the respiratory system to CO, in prolonged hypoxia and assumed that this was due to the compensatory decrease in alkali reserve of the arterial blood which occurs in order to return the p H of the arterial blood to the normal level. I n long lasting ammonium chloride acidosis with a large decrease in alkali reserve, NIELSEN (1936) found a lowering of the CO, threshold, whereas the slope of the stimulus nesponse curves re-

The alveolar PO, was considerably higher in the CO, breathing experiments than in the experiments with no CO, in the inspired air. With constant alveolar PO, the slope of the curves would probably have been increased even more.

308 MARIUS NIELSEN AKD HELGE SNITH.

mained unchanged in one of the subjects and showed a small increase in the other subject. BROWN et al. (1948 and 1950) found that passive hyperventilation (24 hours) in a DRINKER respirator caused a considerable decrease in the plasma CO, content, which was accompanied by an increased sensitivity to CO, (lowered CO, threshold and increased “sensitivity index”). It is therefore tempting to conclude that the increased sensitivity to CO, found in prolonged hypoxia is due partly to the decrease in alkali reserve. I n the above mentioned experiments by NIELSEN on prolonged hypoxia the largest part of the increase in sensitivity, though, had taken place a t a time, when the compensatory decrease in alkali reserve was only small and the artmial blood therefore still considerably more alkaline than in the normal condition.

BJURSTEDT (1946) studied the effect of cold blockings of thc chemoreceptor nerves in dogs during hypoxic hyperventilation and made the important observa,tion that very little or no effect upon the volume of breathing was obtained by blocking after the animals had been breathing 8-1 1 per cent oxygen for 6-10 hours. The hypoxic hyperventilation must consequently have been maintained mainly or entirely by the chemosensitive cells of the center itself, and this was explained by BJURSTEDT as follows: “the center reacts to changes in the acidity of the arterial blood or within its own cells. That the centrogenic breathing is super- normal can be assumed to depend upon the decrease of the buffering capacity of the blood or of the center’s own intracellular fluids against carbon dioxide of metabolic origin.” RAHN and OTIS (1949) interpreted the results from their acclimatization studies in a similar manner and expressed their view upon the regulation of respiration in prolonged hypoxia as follows: “The chemoreceptors play only a temporary part in the acclimatization process to high altitude in producing enough over-ventilation to lower the alkali reserve. Once this has been accomplished and the arterial pH has returned to normal, the centrogenic drive is able to main- tain this hyperventilation by its greater sensitivity to CO,, this in turn being merely a reflection of the lowered buffering capacity.” RILEY and HOUSTON (1951) concluded that the data from their acclimatization experiments were consistent with these con- cepts of ventilatory control during acclimatization.

Several reasons, however, speak against the possibility of explaining the hyperventilation of men acclimatized to low oxygen as being due simply to the lowered alkali reserve. At normal

STUDIES ON THE REQULATION OF REPPIRATION IN ACUTE HYPOXIA. 309

oxygen pressure long lasting (12-16 days) decreases in alkali reserve produced by ingestion of ammonium chloride had only small effects on the pulmonary ventilation, and the arterial blood therefore remained much more acid than in the normal condition (NIELSEN 1936). On the other hand, in long lasting hypoxia, during which the buffering capacity of the intracellular fluids of the center also must be lowered via the blood stream, the effect on the pulmonary ventilation is relatively much greater, and the arterial blood never turns more acid than in the normal condition. To explain this difference one would have to postulate a local increase in the acid formation of the center in the latter case. (Compare discussion on local increase in acid formation in the center during acute hypoxia, page 306.)

As it is well known the alveolar pCb, after acclimatization decreases almost linearlywith decreasing barometric pressure (FITZ- GERALD 1913 a. o.), and the alkali reserve of the arterial blood decreases nearly proportionally with the diminution of the alveolar pC0,; pH, therefore, changes only slightly (DILL 1938). I n acute exposures the pulmonary ventilation, however, does not increase measurably until an altitude of 10,000 to 12,000 feet is reached (RAHN and OTIS 1949). RAHN and OTIS suggested that the small change in alkaline direction, due to the desaturation of the arterial blood a t this altitude, causes a temporary (approximately one hour) inhibition of the hyperventilation, and that the chemoreceptor drive therefore is not able to exert its effect before the arterial pH has by secondary compensations returned t o normal level. It is difficult, though, to understand how the chemoreceptor drive then could exert its effect a t that time, for, as soon as the ventilation is increased, the arterial blood again turns more alkaline and the chemoreceptor drive would thereby be inhibited by its own action. I n the experiments of NIELSEN (1936) the arterial blood a t a barometric pressure of 474 mm Hg (altitude about 12,500 feet) gradually turned more alkaline and remained so for a considerable period of time; in one of the subjects the arterial pH after 3 days showed a value which was about 0.05 higher than in the normal condition.

After acclimatization to an altitude of 10,000 to 12,000 feet, the alveolar pC0, is decreased to a value which is nearly 30 per cent lower than a t sea level and the alkali reserve of the arterial blood is diminished correspondingly. I n acute exposures to this altitude, there is no measurable increase in the pul-


monary ventilation, i. e . the chemoreceptor drive does not produce any overventilation by which the alkali reserve of the blood can be lowered, and - apart from the small alkaline change due to the desaturation of the arterial blood (see above) - there are no disturbances in the acid-base balance of the blood. It seems therefore to be evident that, during the process of acclimatization, under the influence of the low oxygen pressure the ventilation is primarily increased and the alveolar pC0, decreased; the increase in ventilation during acclimatization is, therefore, not due to the decrease in alkali reserve, which occurs as a compensation for the primary decrease in arterial CO, pressure. Since in acute exposure to such altitudes (10,000 to 12,000 feet), there is no measurable increase in ventilation, it seems, when considering the observations of BJURSTEDT (1946) (see page 308), to be most probable that the increase in ventilation which occurs during the acclimatization is due mainly to an increasing centrogenic drive. As pointed out above, this primary increase in the centrogenic drive cannot be explained as being due to the diminution of the alkali reserve of the blood, but most probably it takes place under the influence of the low oxygen pressure. This effect of the low oxygen pressure may on the other hand eventually be strength- ened by the secondary, compensatory decrease of the alkali reserve.

As mentioned earlier, the CO, threshold is, in prolonged hypoxia, diminished to such a degree that the alveolar pC0, actually is above the threshold value, and the slope of the stimulus response curves ( “sensitivity index”) is considerably increased. It is, therefore, possible that the low oxygen pressure acts on the centrogenic drive by causing a slow increase in the sensitivity of the center to CO,, either by a direct action on the center or reflexly through the chemoreceptors. The mechanism by which such an action might occur is still quite unknown. - The increase in CO, sensitivity develops slowly and it disappears again only slowly when returning to normal oxygen pressure. I n the earlier mentioned experiments by NIELSEN (1936) the alveolar pC0, remained relatively low for several days after normal oxygen pressure had been re-established, and the CO, threshold’ was a t the same time considerably decreased and the slope of the stimulus response curves (“sensitivity index”) increased as compared to values in normal conditions. Contrary to this were the

1 The results on CO, sensitivity during the afterperiod were not published.

STUDIES ON THE REQULATION OP’REBPIRATION IN ACUTE HYPOXIA. 311

findings after long lasting NH,Cl acidosis (NIELSEN 1936 p. 140 and p. 177). I n the afterperiod, during which the alkali reserve was increasing towards its normal level, the alveolar pC0, was higher and the arterial blood considerably more acid than nor- mally. Simultaneously the CO, threshold was increased and the slope of the stimulus response curve slightly decreased as compared to the normal values.

Summary and Conclusions. The effect of CO, upon the pulmonary ventilation was studied

in two normal subjects a t various degrees of acute hypoxia. The alveolar PO, was maintained a t a constant level a t each degree of hypoxia. l h e experiments showed the, following results:

1) I n acute hypoxia with pronounced‘ increase in pulmonary ventilation and decrease in alveolar pCO,, an increase in alveolar pC0, produced by CO, breathing had no effect, or only a slight effect, on the pulmonary ventilation until a certain value of alveolar pCO,, the threshold value of C02, was reached.

2) When the alveolar pC0, in the hypoxic state was increased to values higher than the CO, threshold a given increase in alveolar pC0, had a greater effect on the pulmonary ventilation than it had in normal conhtions (normal alveolar PO,). This increased respiratory response towards CO, was much more pronounced in one of the subjects than in the other.

3) The threshold value of CO, was of about the same magnitude a t the various degrees of hypoxia studied as in the normal condition.

These results, together with other evidence from the literature, are discussed in relation to current theories concerning the effect of carbon dioxide and low oxygen on the respiratory center and on the peripheral chemoreceptors. The following conclusions are drawn:

1) I n acute hypoxia with pronounced increase in pulmonary ventilation as in the present experiments, CO, does not a t all contribute to the maintenance of the ventilation. The entire ventilation (not only the increase) is maintained by the hypoxic stimulus, acting on the chemoreceptors.

2) The threshold value of CO, found in the present experiments is most probably the CO, threshold of the respiratory center.

3) No depressing or “devitalizing” effect of the hypoxia on the respiratory center, as far as its response towards CO, is concerned is present in the normal intact man, not even a t such degrees of hypoxia as studied here. On the contrary, in the hypoxic

3 12 MARIUS NIELPEN AND HELOE SMITH.

condition the center responds still more powerfully to CO, than in the normal conditions. 4) The increased sensitivity of the center to CO, found in

the hypoxic conditions is of no importance for the development of the hypoxic hyperventilation. The importance of this mechanism will appear only in conditions in which lack of oxygen is combined with accumulation of carbon dioxide.

5) The increased sensitivity of the respiratory center to CO, cannot be explained as being due to a local increase in acid formation and a consequently diminished alkali reserve in the chemosensitive cells of the center (see p. 306).

6) Some of the conclusions mentioned in the paragraphs above are based on the supposition that the hypercapnic hyperventilation in the normal intact man is due mainly to the effect of CO, upon the respiratory center, which seems to be most probable (see p. 305). Whether or not an effect of CO, upon the chemoreceptors contributes to any significant degree to the hypercapnic hyperventilation cannot, however, be stated definitely. If CO, does have such an effect, it might be due to a specific action of CO,, but it could not (see p. 304-305) be explained by means the CH theory (i. e. that both CO, and lack of 0, act on the chemoreceptors by increasing their acidity).

The regulation of the respiration during and after acclimatization to low oxygen pressure is discussed, in an appendix, on the basis of earlier investigations by NIELSEN (1936), BJURSTEDT (1946), RAHN and OTIS (1949) a. 0. It is concluded that:

The process of respiratory acclimatization cannot be explained simply by means of the decrease of the buffering capacity of the blood or of the intracellular fluids of the center as thought by several authors. It must be assumed, that the low oxygen pressure during acclimatization causes a primary increase in ventilation, probably by increasing the activity of the center. This primary effect of the low oxygen pressure may eventually be strength- ened by the secondary compensatory decrease of the alkali- reserve. - I n prolonged hypoxia the CO, threshold is diminished to such a degree that the alveolar pC0, actually is above the threshold value, and the slope of the stimulus response curves (“sensitivity index”) is increased considerably. It is, therefore, possible that the low oxygen pressure acts on the centrogenic

STUDIES ON TIlE REGULATION O F RESPIRATION IN ACUTE HYPOYIA. 313

drive by increasing the sensitivity of the center t o GOz, either by a direct action on the center or reflexly through the chemoreceptors. The mechanism b y which such an action might occur is still quite unknown.

References.

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BROWN, E. B., A. HEMINGWAY and M. B. VISSCHER, Ibidem. 1950.

CHIODI, H., D. B. DILL, F. CONSOLAZIO and S. M. HORVATH, Amer. J.

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FITZGERALD, M. P., Phil. Trans. Roy. SOC. London (B). 1913. 203. 351. GESELL, R., J. LAPIDES and M. LEVIK, Amer. J. Physiol. 1940.130.155. GOLLWITZER-MEIER, KL. and E. LERCHE, Arch. ges. Physiol. 1941.

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