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Breath-holding and the sensations due to chemical and mechanical stimuli to breathing
Brit. 07. Dis. Chest (1969) 63, I77.
Review Article
Breath-holding and the Sensations due to Chemical and Mechanical Stimuli to Breathing SIMON GODFREY Institute of Diseases of the Chest, London SW3
EVERY medical student and, indeed, every schoolboy knows that it is possible to hold the breath for a longer time with lungs fully inflated than at a smaller lung volume, and that the breath-holding time can also be prolonged by hyperventilation beforehand. This prolongation is possible because the onset of the unpleasant sensations which arise during breath-holding is delayed. Thus both mechanical and chemical factors are able to modify the development of the intolerable sensations which causes the subject to break off the breath-hold. The object of the present paper is to review the experiments which have been performed to study this subject and to show how they can help in understanding the origins of respiratory sensation. Ghemical Factors and Lung Volume Some of the most famous names in physiology have been associated with experiments on breath-holding. In 1908 Hill and Flack showed that the breathholding time was prolonged if the subject previously breathed oxygen; in fact the breath-holding time could be prolonged two- to three-fold and, at breaking point, the alveolar Pco 2 was elevated. In the next year Douglas and Haldane (19o9) amplified these experiments and showed that there was relatively little improvement in breath-holding time with elevation of alveolar Po 2 above 120 m m Hg. They also noted that when the breath-holding time was prolonged on high oxygen the Pco 2 at breaking point was higher. This latter finding suggested to them an interaction between CO 2 and oxygen so that hypoxia limited the tolerance of a high Pco2. An exactly similar conclusion was reached some 4 ° years later by Otis et al. (1948) during their experiments, in which hypoxia was produced by simulating altitude in a special chamber. It was rather surprising that none of these workers attempted to assess the effect of initial elevation of Pco 2 but merely studied the effect of initial lowering of Po 2. In experiments to be described in more detail later, we have shown that elevation of Pco2 before a breath-hold undoubtedly shortens the breath-holding time, just as lowering the Po2 before the breath-hold does (Godfrey & Campbell ~968). VOL. LXIII4
(Receivedfor publication, July 1969)
I
I78
GODFREy
The effect of lung volume, referred to earlier, was finally measured by Muxworthy (I 95 I). He found that there was a linear relationship between the breath-holding time and the lung volume at breaking point. Some of his results are shown in Fig. I. 100 -
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The earlier work on the chemical control of breathing had suggested to the various workers that the stimuli arising during breath-holding were chemical, and could be summated according to mathematical equations such as those proposed by Gray (I 950). The obvious effect of lung volume, however, implied that mechanical as well as chemical factors had to be considered. Mithoefer (I959) thought, as a result of his experiments, that there was an interaction between lung volume, Po2 and Pco2 such that a large lung volume increased the tolerance for hypoxia and hypercapnia. He believed that, in the absence of hypoxia, there is probably a unique relationship between the breakingpoint lung volume and breaking-point Pco2, the sensation causing the break being reached by a summation of a Pco2 and a volume stimulus, i.e. a larger volume would allow a toleration of a higher Pco2 and a smaller lung volume would allow toleration of a lower Pco2. Klocke and Rahn (1959) had clearly shown that hypervenfilation on oxygen greatly prolonged the breath-holding time, and Mithoefer (1959) suggested that the final Pco2 and lung volume, even after such a prolonged breath-hold, was what would be expected from the normal relationship between breaking-point lung volume and breaking-point Pco 2 shown in his experiments. However, the initial period of hyperventilation undoubtedly lowered the Pco 2 profoundly, and a prolonged breath-hold resulted in considerable lung shrinkage (see below) so that it is not surprising
BREATH-HOLDING
AND THE SENSATIONS
I79
that the relatively low Pco2 correlated with the relatively low lung volume.
Dynamic Aspects All the experiments so far discussed were based on a static concept of a threshold for which oxygen, CO 2 and lung volume each interacted and summated tO produce the sensation which caused breaking. However, all the time that these experiments were being performed, there was evidence that such concepts were not tenable. In addition to the experiments of Hill and Flack (19o8) described above they also reported the effect of re-breathing expired air from a bag, showing that this allowed the subject to continue for up to four times his breath-holding time; if the re-breathing bag initially contained oxygen, he could continue up to eight times as long as his breath-holding time, with a correspondingly high Peon. This obviously meant that there could not possibly be a sensation threshold dependent solely on Pco2 or Po~ or both because at the end of the re-breathing period the Pco 2 was much higher than at breaking point of breath-holding, and in the air experiment the Po 2 was also much lower. Had there been such static thresholds the subjects would have broken much earlier after the re-breathing experiments. This type of approach was used by Fowler (I 954) in his highly original and informative experiments on breath-holding. He used untrained subjects, who held their breath as long as they could, and at breaking point re-breathed gas mixtures such that the composition of their alveolar gas was not altered. This relieved the distress they had at the breaking point and allowed them to repeat the breath-hold again, and at the end of the second breath-hold after a further re-breathing period they could breath-hold for a third time. Hc noted that the breath-holding times got progressively shorter. This meant that second and subsequent breath-holds were begun with a degree of asphyxia far worse than that at which the initial breath-hold had broken. He suggested that the distress of breath-holding was relieved by motor activity more appropriate to the prevailing stimuli of the respiratory centre. In a more recent version of this experiment, Godfrey et al. (I 969) have shown that not only can the subsequent breath-holds start with a higher Pco 2 but also that the lung volume can be smaller than that at the breaking point of the initial breath-hold. This means that there cannot possibly be a simple summation of static lung volume and chemical stimuli which results in the sensation causing the breaking point. Thus a search must be made for another factor, and one which is relieved by movement of the lungs.
Breath-holding CO 2 Response Curves One of the problems with experiments on breath-holding is that usually more than one factor is varied at a time and often three of four factors are varied at the same time. This makes the interpretation of the results rather difficult. In order to circumvent this problem we have developed a method for obtaining breath-holding CO2 response curves (Godfrey & Campbell 1969)
180
GODFREY
which is similar in many respects to the method for obtaining ventilation CO~ response curves described by Reid (i967) and Clark (i968). To record a breath-holding CO2 response curve the subject re-breathes a mixture of approximately 7°7o CO~ and 937o oxygen from a 3 to 4- litre bag. The first few breaths mix the gas in the b a g with that in the subject's lungs, which then comes into equilibrium with the PeG2 in his mixed venous blood. After recirculation, the PeG2 oi" the blood-lung-bag system then rises at a uniform rate, depending solely upon the metabolic rate. Even if the subject holds his breath the PeG2 in the blood and lungs will continue to rise at this steady rate; that in the bag will be brought up to the same level as re-breathing is started again (Fig. 2). After the initial mixing has taken place the subject holds his breath at the desired volume for as long as possible and when he breaks he recommences re-breathing, thus performing a series of breath-holds alternating with re-breathing. The breath-holding time is then plotted against the Pco~ in the blood-lung-bag system and gives a very good linear relationship (Fig. 3)The lines for starting-point and breaking-point Pco~ converge together to meet where the breath-holding time becomes zero. After obtaining such curves we are able to study the influence of other factors very accurately without having to worry too much about Pco~ because whatever the experimental Pco~ we can
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re-breathing at zero time and after mixing, the PeG2 in the lung-bag system rises steadily thereafter; no rise is recorded during the breath-holding periods since the PeG2 was being measured at the mouth. Each breath-hold was performed at residual volume. Note the decrease in breath-holding time as PeG2 rises. The apparent progressive rise in residual volume (inspiration downwards) is due to lung shrinkage as 02 is consumed but CO z excretion blocked. (After Campbell & Godfrey 1969)
BREATIff-HOLDING AND TI-IE SENSATIONS
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Fzo. 4. Breath-holding time plotted against initial Pco 2 for experiments on several subjects, holding their breath on oxygen at total lung capacity after normal breathing or hyperventilation. Each point represents a separate discreet breath-hold. An approximately linear relationship exists between breath-holding time and initial Peon. S is the slope of the curve. B is its intercept on the Pco 2 line• (After Klocke & Rahn z959)
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obtain the expected breath-holding time from a control curve such as that shown in Fig. 3. It is not essential to perform the re-breathing breath-holding experiments in order to obtain such a curve by the method we describe, but our method is much less laborious than doing the experiment with isolated breath-holds each begun at a different Pco2. Such an experiment was conducted by Klocke and Rahn (1959) and their results have been plotted in Fig. 4. The slope S and the intercept B of their line are very similar to the values obtained in re-breathing breath-holding experiments. This similarity is also shown in Fig. 5 which illustrates an experiment in which a subject performed a serial re-breathing breath-holding experiment and another in which he re-breathed and then performed single breath-holds; the similarity of thc two lines can be appreciated. Using this method, we have attempted to define the nature of the nonchemical stimulus. In the experiments of Fowler (1954) no particular attention was paid to the number of breaths the subjects took at the breaking point of their breath-holds. We used our method to investigate the effects of different numbers of breaths at the breaking point of the breath-hold (Godfrey & Campbell i969) and found that one breath was just as good as five breaths in permitting a subsequent breath-hold (Fig. 6). It therefore seems that whatever the nature of the non-chemical stimulus it can be removed by a single respiratory cycle and presumably then accumulates again during the next breath-hold.
BREATH-HOLDINO AND THE SENSATIONS
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Fzo. 6. The relationship between the number of breaths in a 'cluster of breaths' preceding a breath-hold and the subsequent breath-holding time. An arbitrary time scale is used in which 1007o represents the sum of the mean breath-holding time (BH2) plus cluster time for each subject. The shaded columns represent the duration of the clusters of breaths which obviously increase with cluster size. The differences in the breath-holding times (open columns) are not significant. (From Godfrey & Campbell (I969) Quart. ,7. Exper. Physiol., 54, z I7)
We can think of this in terms of a model (Fig. 7) in which the sensation during breath-holding arises from a chemical stimulus (Pco2 in this case because hypoxia is avoided at all times) to which is added a non-chemical stimulus; the total stimulus, and the sensation due to this stimulus, rises along the lines A, B or C. The lower the initial Pco2 the longer it takes for the total sensation to reach the threshold and the higher the initial Pco 2 the shorter the breath-holding time. The line obtained by plotting the points from this figure are shown as a breath-holding CO2 response curve in Fig. 8. The similarity to the experimental points shown in Figs. 3 and 4 is obvious. The higher absolute values in Figs. 4 and 8 are because the points were based on breath-holding at total lung capacity. The linear relationship between breath-holding time and Pco2 has also been shown using a serial re-breathing breath-holding method to extend well down into the hypocapnic (low Pco2) range (Godfrey & Campbell 1968 ). This experiment emphasized the importance of non-chemical stimuli because in two subjects the initial breath-hold began in the hypocapnic range and terminated at a Pco e which was below their threshold for a ventilatory response to Pco 2.
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TIME (mins) FIG. 7" Model of situation existing during the performance of a breath-holding (202 response curve. The left ordinate represents sensation as a percentage of that which causes the breaking point (threshold). The right ordinate represents the Pco 2 during the breath-hold or rebreathing; the abscissa represents re-breathing and/or breath-holding time; the solid line represents the rising Pco 2 and its sensation, while the dotted lines (A, B and C) represent the sum of chemical and mechanical sensation for three breath-holds begun at a Pco 2 of 25, 45 and 65 m m Hg respectively. The dashed horizontal line represents the breaking-point threshold. The total sensation rises in parallel for the 3 breath-holds but the lower the Pco 2 at the start the longer is the breath-holding time. (From Godfrey & (2ampbell (I968) Respir. Physiol., 5, 385)
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FIo. 8. The breath-holding times in Fig. 7 are plotted against the Pco 2 at the start of the breath-hold and the linear relationship is demonstrated. The slope of the line S depends o n the strengths of the stimuli, and the intercept B is the Pco 2 at which breath-holding was impossible. (From Godfrey & Campbell (i 968) Respir. Physiol, 5, 385)
Lung Shrinkage O n e f a c t o r d u r i n g b r e a t h - h o l d i n g w h i c h p r e s e n t s a t t r a c t i v e l y as t h e n o n c h e m i c a l s t i m u l u s t o b r e a t h i n g is t h e s h r i n k a g e w h i c h o c c u r s i n t h e l u n g s d u r i n g
BREATH-HOLDING AND THE SENSATIONS
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FIO. 9. Breath-holding CO2 response curves for three subjects at sea level (753 mm Hg) and altitude (380 mm Hg). There is no significant difference between the two lines for any one subject. (From Godfrey et al. (1969) Quart. o7. Exper. Physiol., 54, I29) a breath-hold. This shrinkage occurs because of the continued absorption of oxygen while excretion of CO2 is blocked. It was elegantly demonstrated by Stevens et al. (i946) who weighed their subjects under water during breathholding and showed that their buoyancy decreased. I f this shrinkage was the non-chemical stimulus then an increase in shrinkage should shorten the breathholding time. We found that slow voluntary expiration during a breath-hold did not alter the breath-holding CO 2 response curve (Godfrey et al. 1969) but such a breath-hold required voluntary muscular activity. We therefore used an alternative approach to increase the rate of shrinkage by lowering barometric pressure within the lungs. I f the ambient pressure is halved, gas density is halved and therefore for a given number of molecules of oxygen consumed the
I86
GODFREY
volume lost is doubled and the rate of shrinkage is doubled. Despite this great increase in rate of shrinkage there was no significant change in the breathholding CO2 response curve (Fig. 9). This failure of shrinkage to influence breath-holding time means that a simple explanation involving the Herring-Breuer deflation reflex does not explain the source of the non-chemical stimulus. However the experiments of Guz and his colleagues are extremely important here because they show that afferent impulses in the vagus certainly do have a profound effect upon breathholding (Guz et al. I966 ). T h e y found that in normal subjects blocking the vagus and glossopharyngeal nerves greatly prolonged the breath-holding time at all lung volumes and relieved the unpleasant sensation which normally accrues during the breath-hold (Fig. zo). In addition, the ventilatory response to CO2 was also diminished after vagal block, mainly as the result of the failure of the breathing rate to increase. The exact r61e of vagal afferents is difficult to decide at the present time, but it is certainly possible that information about movement of the lungs themselves is important for normal respiratory control. 250.
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FIG. Io. Breath-holding times at different lung volumes for two subjects before and after bilateral block of cervical vagus. Note the considerable prolongation of breath-holding time at any one lung volume in each subject, and the retention of the increase in breath-holding time with increase in lung volume. (After Guz et al. I966) Muscular
Contraction
O n the efferent side Agostoni (I 963) noted that during a breath-hold there was initially a quiescent period and then spasmodic diaphragmatic contractions appeared which became progressively greater and more frequent until breaking point. The onset of diaphragmatic activity was apparently related to Pco2;
]BREATH-HOLDING
AND
THE
z87
SENSATIONS
since the re-breathing of a gas which did not alter the Pco2 at the onset of diaphragmatic activity allowed a subsequent breath-hold the diaphragmatic activity returned almost immediately. Agostoni also noted that the diaphragmatic activity was, surprisingly, little different or if anything rather less at smaller lung volume than at larger lung volume. In a subsequent experiment (Agostoni et al. 1964) it was shown that various central nervous stimulants and depressants could alter the pattern of the onset of diaphragmatic activity. These results suggest that various stimuli might act centrally to produce the diaphragmatic contractions, but that the static lung volume is unlikely to act in this way. If diaphragmatic contraction is such a prominent feature of breath-holding, it seems possible that muscular contraction itself might have something to do with sensation. Thinking on these lines, Campbell and his colleagues decided to try the effect of muscular paralysis during breath-holding. They found that total paralysis by curarization completely relieved the unpleasant sensation associated with apnoea in two conscious normal subjects (Campbell et al. 1967). In this experiment the initial manual ventilation had rather lowered the Pco2 and we therefore repeated the experiment using the re-breathing breath220 -
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FIG. I I. Breath-holding before and after paralysis by d-tubocurarine. Breath-holding times are plotted against the P c o 2 at the start (open symbols) and end (closed symbols) of the breath-hold. The circles represent control experiments and the solid and broken lines are the regression lines of breath-holding time on initial (solid line) and final (broken llne) P c o 2 for these experiments. The shaded bands represent confidence limits of the lines. Square symbols represent breath-holds after atropine alone and triangles represent breath-holds after atropine and tubocurarine. Note the small effect of atropine and the very large effect of tubocurarine. (From Campbell et al. (i969) Clin. Sci., 36, 323)
188
GODFREY
holding method described above (Campbell et al. I969). O n this occasion there was again no sensation whatsoever associated with apnoea, and the breathholding time was grossly prolonged compared with the control values (Fig. i i). Indeed there was no real limit to the breath-holding time since the subject was perfectly prepared to continue as he indicated by finger signals from the arm excluded from the curare by a cuff, but the observers decided that he had been apnoeic long enough. These two experiments showed that muscular paralysis not only removed any sensation which might be due to muscular contractions but also removed the sensation due to the Pco2 which was grossly elevated by the end of the breath-holds in the second experiment. Thus not only mechanical sensation but also chemical sensation must ultimately be mediated through muscular activity, The evidence presented so far suggests that during a breath-hold there arise chemical stimuli due to hypercapnia and hypoxia (unless oxygen has been breathed previously) and a non-chemical stimulus which can be removed by a single breath; it m a y arise from the lungs but is not due to the shrinkage which occurs. All sensation seems to be mediated through a final common pathway in neuro-muscular mechanisms of the diaphragm and chest wall.
Breath-holding and Chemo-sensitivity There are a number of situations in which the external or internal environment of a subject is altered in such a way as to affect his breath-holding time. One of the earliest and most striking observations of this was the effect of altitude on breath-holding (Doughs et al. 1913). In their paper they state: ' W e were all able to hold the breath at sea level for about 4o seconds by a voluntary effort. After the first 43 hours on Pyke's Peak, Henderson, Douglas and Haldane could not hold longer than 15 to I8 s e c o n d s . . . O n our descent to Manitou, Henderson and Haldane found, much to their surprise, that they could stilt hold no longer than on the summit'. We now know a great deal more about the problem of acclimatization to altitude, mainly as the result of the work of R a h n et al. (1953) and more recently of Severinghaus et al. (i963). With simple breath-holding on air the initial shortening of breath-holding time is of course due to hypoxia which occurs at altitude, but with adaptation interesting changes occur in the cerebrospinal fluid in such a way that a given rise in arterial Pco2 causes a much greater acidosis in the CSF, and hence a greater respiratory stimulation. This means that the breath-holding times, even on oxygen, will be greatly reduced. However it is well to think in terms of the model described earlier because after acclimatization to altitude the hypoxiainduced hyperventilation results in a basically lower arterial Pco2. As a result, in the simple type of breath-holding experiment the breath-holds are begun at a lower P~o2 and, by direct comparison with sea-level breath-holding, should give a longer breath-holding time. The fact that despite this the breath-holding times were shorter at altitude means that this shortening has previously been grossly underestimated. It would be very interesting to see the shift that occurs in the breath-holding CO2 response curve with residence at altitude so that the problem of starting from a low Pco2 could be avoided. Similar arguments
BREATH-HOLDING
A N D T H E SENSATIONS
I8 9
apply to experiments on the effect of acid loading on breath-holding time (Stroud I953).
There is fairly general agreement that during muscular exercise the slope of the curve relating ventilatory response to CO2 is shifted to the left, i.e. that there is a greater ventilation for any given level of Pco2 (Asmussen & Nielson I957) : this implies an increase in the sensitivity of the ventilatory response to 120 -
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FIo. I2. The effect of exercise on the ventilation CO2 and breath-holding CO s response curves in one subject. Note the small change in the ventilation curve compared with the notable changes in the breath-holding curve. (From Clark & Godfrey (I969) 07. Physiol. (Lond.), in press)
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FIG. I3. Changes in the ventilation CO 2 and breath-holding CO 2 response curves in one subject before and after the addition of an airways resistance load. Note the obvious flattening of the ventilation curve in the absence of any change in the breath-holding curve. (From Clark & Godfrey (x969) 07 Physiol. (Lond.), in press)
I90
GODFREY
change in Pco2. However, while everybody agrees that the breath-holding time is shortened by exercise, most authors have believed that the higher breaking-point Pco2 after exercise indicates a decrease in CO2 sensitivity (Rodbard 1947; Muxworthy I95Ib; Astrand 196o). In fact this discrepancy between the effect of Pco2 on ventilation during exercise and on breathholding after exercise is more apparent than real. During exercise the rate of production of CO 2 is increased so that during a breath-hold the rate of rise of Pco2 in the closed system of mixed venous blood, alveolar gas and arterial blood is increased; the rate of rise of chemical sensation is thus increased and naturally the breath-holding time is shortened. In an analysis of ventilatory and breath-holding responses to CO 2 during exercise or rest using the re-breathing method, the previous observations were confirmed (Fig. I2), but it was concluded that the change in breath-holding time did not represent a change in CO2 sensitivity per se, differences being due to the alteration in the rate of CO2 production (Clark & Godfrey 1969). A rather similar situation exists with the effect of airways obstruction on CO2 sensitivity. It has been shown experimentally and clinically that airways obstruction reduces the ventilatory response to CO 2 (Milic-Emilic & Tyler 1963; Clark & Read 1966 ). This reduction in the slope of the COa response curve could be due either to a fall in CO 2 sensitivity or could result from the mechanical effects of the resistance preventing an appropriate increase in ventilation. This is of particular importance with regard to patients who have chronic obstructive lung disease and are usually considered to be insensitive to GO2. During breath-holding there is no flow of gas and therefore one would expect that any mechanical effects of the added load of increased resistance would not affect breath-holding time. We therefore studied the ventilatory and breath-holding CO2 response curves in normal subjects with and without the load of all added airway resistance. In the ventilatory response curve experiment, the resistance was present throughout the experiment, but in the breath-holding experiment, the resistance was present during the re-breathing intervals before and between breath-holds. We found that the ventilatory response to CO 2 was grossly flattened but there was no change in the breathholding CO 2 response curve (Fig. 13). We interpret this finding as indicating no change in chemo-sensitivity with an added load to breathing (Clark & Godfrey I969). Conclusions All the evidence from breath-holding experiments discussed indicates that chemical and mechanical factors combine to provide the unpleasant sensation during the breath-hold. The chemical stimuli probably arise from the influence of the Pco2 on the chemoreceptors and respiratory centre (Clarke 1968 ) as the Pco2 influences the pH of cerebrospinal fluid, and from a falling P02 (if the breath-hold is not done under hyperoxic conditions). The origin of the mechanical stimuli remains in doubt. The lungs and afferent impulses travelling along the vagus nerve are obviously very important, and these impulses may signal that the lungs are moving in a normal fashion. During
BREATH-HOLDING AND THE SENSATIONS
I9I
breath-holding vagal information could indicate the absence of lung movement. The loss of this information after vagal block could account for the prolongation of breath-holding time noted. Whatever the origin of this non-chemical stimulus it undoubtedly appears to summate with the chemical stimuli eventually to cause the sensation which results in the break of the breath-hold. In order to produce a sensation it would appear that muscular contraction is necessary, since no sensation whatever was found after curarizafion. The sensation is probably generated in the diaphragm, muscles of the chest wall and muscle or joint receptors, as a result of disproportion between the tension in the respiratory muscles and their length. The tension develops as a result of a motor output from the respiratory centre, but the muscles are prevented from shortening by voluntary inhibition during the breath-hold. If this mis-matching cannot occur because the muscles are paralysed then no sensation would arise. The idea that a mis-match between muscular contraction and the effect it produces in the chest can generate an unpleasant sensation has implications far wider than breath-holding. In patients with chests distorted as a result of chronic lung disease, or of any other condition, it could well be that the pattern of the movement of the chest is not appropriate to the tensions in the muscles used. Some patients with airways obstruction have paradoxical movement of the lower part of their chest (Campbell 1969) , a typical example of inappropriate movement. Bronchodilators which rapidly relieve the distress associated with asthma can simultaneously restore the distorted pattern of chest movement to a more normal pattern (personal observations), which m a y contribute to the relief. I hope that this review has shown that the simple schoolboy trick of breathholding can tell us a lot more about the control of breathing in health and disease than one would have imagined at first.
.~ej~6rgnc6s AGOSTONI, E. (1963) Diaphragm activity during breath-holding: factors related to its onset. 07. Appl. Physiol., I8, 30. AOOSTONI, E., SANT'AMBROGIO,G. & MOGNONI, P. (1964) Effects of central stimulants on onset of diaphragm activity during breath-holding. 07. Appl. Physiol., I9, 408. ASMUSSEN, E. <~: NIELSEN, M. (1957) Ventilatory response to CO 2 during work at normal and at low oxygen tensions. Acta. Physiol. Scand., 39, 27. ASTRAND, P.-O. (196o) Breath-holding during and after muscular exercise. 07. Appl. Physiol., I5, 220. CAMPBELL,E . J . M . (1969) Physical signs of diffusion airways obstruction and lung distension.
Thorax, 24, I. CAMPBELL, E . J . M . , FREEDMAN, S., CLARK, T . J . H . , ROBSON,J. G. & NORMAN,J. (1967) The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding. Clin. Sci., 32, 425 • CAMPBELL, E. J. M. • GODFREY, S. (1969) The interaction of chemical and non-chemical stimuli to breathing by breath-holding. 07. Physiol. (Lond.) (in press). CAMPBELL,E . J . M . , GODFREY, S., CLARK, T . J . H . , FREEDMAN, S. & NORMAN,J. (1969) The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding during hypercapnia. Clin. Sci., 36, 323.
1 92
GODFRE ~"
CLARK,T . J . H . (x968) The measurement ofventilatory response to CO 2. Brit. 37. Dis. Chest, 62, 1 I3.
CLARK, T. J. H. & GODFREY,"S. (I969) The effect of CO2 on ventilation and breathholding during exercise and while breathing through an added resistance. 37. Physiol. (Lond.) (in press). CLARK, T . J . H . & READ, D. J. C. (1966) A re-breathing method for studying ventilatory response to CO 2. .7. Physiol. (Lond.), I84, 4 I. DOUGLAS, C. G. & HALDANE, J. S. (i9o9) The regulation of normal breathing. 37. Physiol. (Lond.), 38, 4~o. DOUGLAS, C. G., HALDANE, J. S., HENDERSON,Y. & SCHNEIDER, E. C. (I913) Physiological observations made on Pyke's Peak, Colorado, with special reference to adaptation to low barometric pressure. Philosoph. Transact., Series B., 203, 185. FOWLER, W. S. (1954) Breaking point of breath-holding. 37. Appl. Physiol., 6, 539. GODFREY, S. • CAMPBELL,E. J. M. (1968) The control of breath-holding. Respir. PhysioL, 5, 385 • GODFREY, S. & CAMPBELL,E. J. M. (I969) Mechanical and chemical control of breathholding. Quart. 37. Exper. Physiol., 54, II7. GODFREY, S., EDWARDS,R. H. T. & WARRELL, D. A. (I969) The influence of lung shrinkage on breath-holding time. Quart. 37. Exper. Physiol., 54, I29. GRAY, J, S. (1946) The multiple factor theory of the control of respiratory ventilation. Science, IO3, 739. Guz, A., NOBLE, M. I. M., WIDDICOMBE,J. G., TRENCHARD, D. I., MUSHIN, W. W. & MAKEY, A. R. (1966) The r61e ofvagal and alonopharyngeal afferent nerves in respiratory sensation, control of breathing and arterial pressure regulation in conscious man. Clin. Sci., 30, 16I.
HILL, L. • FLACK, M. (I908) The effect of excess of carbon dioxide and of want of oxygen upon the respiration and the circulation. 37. Physiol., 37, 77. KLOCKE, F. J. & RAHN, H. (1959) Breath-holding after breathing oxygen. 37. Appl. Physiol., 14, 689. MILIC-EMILIC, J. & TYLER, J. M. (1963) Relationship between PAco2 and respiratory work during external resistance breathing in man. Ann. W. 2". Acad. Sci., lO9, 908. MITHOEPER, J. C. (1959) Lung volume restriction as a ventilatory stimulus during breathholding. 37. Appl. Physiol., I4, 7Ol. MUXWORTHY, J. F., Jr. (I95Ia) I. Breath-holding studies: Relationship to lung volume. A.F. Techn. Rep., no. 6528, pp. 452-456. Wright-Patterson Air Force Base, Dayton, Ohio. MUXWORTHY, J. F., Jr. (I95Ib) 3- Breath-holding studies: Effects of exercise. A.F. Techn. Rep., no. 6528, pp. 479-48I. Wright-Patterson Air Force Base, Dayton, Ohio. OTIs, A. B., RAHN, H. & FENN, W. O. (1948) Alveolar gas changes during breath-holding. Am. 37. Physiol., 152, 674. READ, D. J. c. (1967) A clinical method for assessing the ventilatory response to carbon dioxide. Aus. Ann. Med., x6, 20. RODEARD, S. (I947) The effect of oxygen, altitude and exercise on breath-holding time. Am. 37. Physiol., I5O, I42. SEVERINGHAUS,J. W., MITCHELL, R. A., RICHARDSON, B. W. • SINGER, H. M. (I963) Respiratory control at high altitude suggesting active transport regulation of CSF pH. 37. Appl. Physiol., z8, I155. STEVENS, C. D., FERRIS, ]~. B., WEBE, J. P., ENGEL, G. L. & LOGAN, M. (1946) Voluntary breath-holding. I. Pulmonary gas exchange during breath-holding. 37. Clin. Invest., 25, 723. STROUD, R. C. (I953) Ammonium chloride acidosis and breath-holding. 37. Appl. Physiol.,
6, 15x.
Review Article
Breath-holding and the Sensations due to Chemical and Mechanical Stimuli to Breathing SIMON GODFREY Institute of Diseases of the Chest, London SW3
EVERY medical student and, indeed, every schoolboy knows that it is possible to hold the breath for a longer time with lungs fully inflated than at a smaller lung volume, and that the breath-holding time can also be prolonged by hyperventilation beforehand. This prolongation is possible because the onset of the unpleasant sensations which arise during breath-holding is delayed. Thus both mechanical and chemical factors are able to modify the development of the intolerable sensations which causes the subject to break off the breath-hold. The object of the present paper is to review the experiments which have been performed to study this subject and to show how they can help in understanding the origins of respiratory sensation. Ghemical Factors and Lung Volume Some of the most famous names in physiology have been associated with experiments on breath-holding. In 1908 Hill and Flack showed that the breathholding time was prolonged if the subject previously breathed oxygen; in fact the breath-holding time could be prolonged two- to three-fold and, at breaking point, the alveolar Pco 2 was elevated. In the next year Douglas and Haldane (19o9) amplified these experiments and showed that there was relatively little improvement in breath-holding time with elevation of alveolar Po 2 above 120 m m Hg. They also noted that when the breath-holding time was prolonged on high oxygen the Pco 2 at breaking point was higher. This latter finding suggested to them an interaction between CO 2 and oxygen so that hypoxia limited the tolerance of a high Pco2. An exactly similar conclusion was reached some 4 ° years later by Otis et al. (1948) during their experiments, in which hypoxia was produced by simulating altitude in a special chamber. It was rather surprising that none of these workers attempted to assess the effect of initial elevation of Pco 2 but merely studied the effect of initial lowering of Po 2. In experiments to be described in more detail later, we have shown that elevation of Pco2 before a breath-hold undoubtedly shortens the breath-holding time, just as lowering the Po2 before the breath-hold does (Godfrey & Campbell ~968). VOL. LXIII4
(Receivedfor publication, July 1969)
I
I78
GODFREy
The effect of lung volume, referred to earlier, was finally measured by Muxworthy (I 95 I). He found that there was a linear relationship between the breath-holding time and the lung volume at breaking point. Some of his results are shown in Fig. I. 100 -
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The earlier work on the chemical control of breathing had suggested to the various workers that the stimuli arising during breath-holding were chemical, and could be summated according to mathematical equations such as those proposed by Gray (I 950). The obvious effect of lung volume, however, implied that mechanical as well as chemical factors had to be considered. Mithoefer (I959) thought, as a result of his experiments, that there was an interaction between lung volume, Po2 and Pco2 such that a large lung volume increased the tolerance for hypoxia and hypercapnia. He believed that, in the absence of hypoxia, there is probably a unique relationship between the breakingpoint lung volume and breaking-point Pco2, the sensation causing the break being reached by a summation of a Pco2 and a volume stimulus, i.e. a larger volume would allow a toleration of a higher Pco2 and a smaller lung volume would allow toleration of a lower Pco2. Klocke and Rahn (1959) had clearly shown that hypervenfilation on oxygen greatly prolonged the breath-holding time, and Mithoefer (1959) suggested that the final Pco2 and lung volume, even after such a prolonged breath-hold, was what would be expected from the normal relationship between breaking-point lung volume and breaking-point Pco 2 shown in his experiments. However, the initial period of hyperventilation undoubtedly lowered the Pco 2 profoundly, and a prolonged breath-hold resulted in considerable lung shrinkage (see below) so that it is not surprising
BREATH-HOLDING
AND THE SENSATIONS
I79
that the relatively low Pco2 correlated with the relatively low lung volume.
Dynamic Aspects All the experiments so far discussed were based on a static concept of a threshold for which oxygen, CO 2 and lung volume each interacted and summated tO produce the sensation which caused breaking. However, all the time that these experiments were being performed, there was evidence that such concepts were not tenable. In addition to the experiments of Hill and Flack (19o8) described above they also reported the effect of re-breathing expired air from a bag, showing that this allowed the subject to continue for up to four times his breath-holding time; if the re-breathing bag initially contained oxygen, he could continue up to eight times as long as his breath-holding time, with a correspondingly high Peon. This obviously meant that there could not possibly be a sensation threshold dependent solely on Pco2 or Po~ or both because at the end of the re-breathing period the Pco 2 was much higher than at breaking point of breath-holding, and in the air experiment the Po 2 was also much lower. Had there been such static thresholds the subjects would have broken much earlier after the re-breathing experiments. This type of approach was used by Fowler (I 954) in his highly original and informative experiments on breath-holding. He used untrained subjects, who held their breath as long as they could, and at breaking point re-breathed gas mixtures such that the composition of their alveolar gas was not altered. This relieved the distress they had at the breaking point and allowed them to repeat the breath-hold again, and at the end of the second breath-hold after a further re-breathing period they could breath-hold for a third time. Hc noted that the breath-holding times got progressively shorter. This meant that second and subsequent breath-holds were begun with a degree of asphyxia far worse than that at which the initial breath-hold had broken. He suggested that the distress of breath-holding was relieved by motor activity more appropriate to the prevailing stimuli of the respiratory centre. In a more recent version of this experiment, Godfrey et al. (I 969) have shown that not only can the subsequent breath-holds start with a higher Pco 2 but also that the lung volume can be smaller than that at the breaking point of the initial breath-hold. This means that there cannot possibly be a simple summation of static lung volume and chemical stimuli which results in the sensation causing the breaking point. Thus a search must be made for another factor, and one which is relieved by movement of the lungs.
Breath-holding CO 2 Response Curves One of the problems with experiments on breath-holding is that usually more than one factor is varied at a time and often three of four factors are varied at the same time. This makes the interpretation of the results rather difficult. In order to circumvent this problem we have developed a method for obtaining breath-holding CO2 response curves (Godfrey & Campbell 1969)
180
GODFREY
which is similar in many respects to the method for obtaining ventilation CO~ response curves described by Reid (i967) and Clark (i968). To record a breath-holding CO2 response curve the subject re-breathes a mixture of approximately 7°7o CO~ and 937o oxygen from a 3 to 4- litre bag. The first few breaths mix the gas in the b a g with that in the subject's lungs, which then comes into equilibrium with the PeG2 in his mixed venous blood. After recirculation, the PeG2 oi" the blood-lung-bag system then rises at a uniform rate, depending solely upon the metabolic rate. Even if the subject holds his breath the PeG2 in the blood and lungs will continue to rise at this steady rate; that in the bag will be brought up to the same level as re-breathing is started again (Fig. 2). After the initial mixing has taken place the subject holds his breath at the desired volume for as long as possible and when he breaks he recommences re-breathing, thus performing a series of breath-holds alternating with re-breathing. The breath-holding time is then plotted against the Pco~ in the blood-lung-bag system and gives a very good linear relationship (Fig. 3)The lines for starting-point and breaking-point Pco~ converge together to meet where the breath-holding time becomes zero. After obtaining such curves we are able to study the influence of other factors very accurately without having to worry too much about Pco~ because whatever the experimental Pco~ we can
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re-breathing at zero time and after mixing, the PeG2 in the lung-bag system rises steadily thereafter; no rise is recorded during the breath-holding periods since the PeG2 was being measured at the mouth. Each breath-hold was performed at residual volume. Note the decrease in breath-holding time as PeG2 rises. The apparent progressive rise in residual volume (inspiration downwards) is due to lung shrinkage as 02 is consumed but CO z excretion blocked. (After Campbell & Godfrey 1969)
BREATIff-HOLDING AND TI-IE SENSATIONS
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182
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obtain the expected breath-holding time from a control curve such as that shown in Fig. 3. It is not essential to perform the re-breathing breath-holding experiments in order to obtain such a curve by the method we describe, but our method is much less laborious than doing the experiment with isolated breath-holds each begun at a different Pco2. Such an experiment was conducted by Klocke and Rahn (1959) and their results have been plotted in Fig. 4. The slope S and the intercept B of their line are very similar to the values obtained in re-breathing breath-holding experiments. This similarity is also shown in Fig. 5 which illustrates an experiment in which a subject performed a serial re-breathing breath-holding experiment and another in which he re-breathed and then performed single breath-holds; the similarity of thc two lines can be appreciated. Using this method, we have attempted to define the nature of the nonchemical stimulus. In the experiments of Fowler (1954) no particular attention was paid to the number of breaths the subjects took at the breaking point of their breath-holds. We used our method to investigate the effects of different numbers of breaths at the breaking point of the breath-hold (Godfrey & Campbell i969) and found that one breath was just as good as five breaths in permitting a subsequent breath-hold (Fig. 6). It therefore seems that whatever the nature of the non-chemical stimulus it can be removed by a single respiratory cycle and presumably then accumulates again during the next breath-hold.
BREATH-HOLDINO AND THE SENSATIONS
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Fzo. 6. The relationship between the number of breaths in a 'cluster of breaths' preceding a breath-hold and the subsequent breath-holding time. An arbitrary time scale is used in which 1007o represents the sum of the mean breath-holding time (BH2) plus cluster time for each subject. The shaded columns represent the duration of the clusters of breaths which obviously increase with cluster size. The differences in the breath-holding times (open columns) are not significant. (From Godfrey & Campbell (I969) Quart. ,7. Exper. Physiol., 54, z I7)
We can think of this in terms of a model (Fig. 7) in which the sensation during breath-holding arises from a chemical stimulus (Pco2 in this case because hypoxia is avoided at all times) to which is added a non-chemical stimulus; the total stimulus, and the sensation due to this stimulus, rises along the lines A, B or C. The lower the initial Pco2 the longer it takes for the total sensation to reach the threshold and the higher the initial Pco 2 the shorter the breath-holding time. The line obtained by plotting the points from this figure are shown as a breath-holding CO2 response curve in Fig. 8. The similarity to the experimental points shown in Figs. 3 and 4 is obvious. The higher absolute values in Figs. 4 and 8 are because the points were based on breath-holding at total lung capacity. The linear relationship between breath-holding time and Pco2 has also been shown using a serial re-breathing breath-holding method to extend well down into the hypocapnic (low Pco2) range (Godfrey & Campbell 1968 ). This experiment emphasized the importance of non-chemical stimuli because in two subjects the initial breath-hold began in the hypocapnic range and terminated at a Pco e which was below their threshold for a ventilatory response to Pco 2.
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TIME (mins) FIG. 7" Model of situation existing during the performance of a breath-holding (202 response curve. The left ordinate represents sensation as a percentage of that which causes the breaking point (threshold). The right ordinate represents the Pco 2 during the breath-hold or rebreathing; the abscissa represents re-breathing and/or breath-holding time; the solid line represents the rising Pco 2 and its sensation, while the dotted lines (A, B and C) represent the sum of chemical and mechanical sensation for three breath-holds begun at a Pco 2 of 25, 45 and 65 m m Hg respectively. The dashed horizontal line represents the breaking-point threshold. The total sensation rises in parallel for the 3 breath-holds but the lower the Pco 2 at the start the longer is the breath-holding time. (From Godfrey & (2ampbell (I968) Respir. Physiol., 5, 385)
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FIo. 8. The breath-holding times in Fig. 7 are plotted against the Pco 2 at the start of the breath-hold and the linear relationship is demonstrated. The slope of the line S depends o n the strengths of the stimuli, and the intercept B is the Pco 2 at which breath-holding was impossible. (From Godfrey & Campbell (i 968) Respir. Physiol, 5, 385)
Lung Shrinkage O n e f a c t o r d u r i n g b r e a t h - h o l d i n g w h i c h p r e s e n t s a t t r a c t i v e l y as t h e n o n c h e m i c a l s t i m u l u s t o b r e a t h i n g is t h e s h r i n k a g e w h i c h o c c u r s i n t h e l u n g s d u r i n g
BREATH-HOLDING AND THE SENSATIONS
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FIO. 9. Breath-holding CO2 response curves for three subjects at sea level (753 mm Hg) and altitude (380 mm Hg). There is no significant difference between the two lines for any one subject. (From Godfrey et al. (1969) Quart. o7. Exper. Physiol., 54, I29) a breath-hold. This shrinkage occurs because of the continued absorption of oxygen while excretion of CO2 is blocked. It was elegantly demonstrated by Stevens et al. (i946) who weighed their subjects under water during breathholding and showed that their buoyancy decreased. I f this shrinkage was the non-chemical stimulus then an increase in shrinkage should shorten the breathholding time. We found that slow voluntary expiration during a breath-hold did not alter the breath-holding CO 2 response curve (Godfrey et al. 1969) but such a breath-hold required voluntary muscular activity. We therefore used an alternative approach to increase the rate of shrinkage by lowering barometric pressure within the lungs. I f the ambient pressure is halved, gas density is halved and therefore for a given number of molecules of oxygen consumed the
I86
GODFREY
volume lost is doubled and the rate of shrinkage is doubled. Despite this great increase in rate of shrinkage there was no significant change in the breathholding CO2 response curve (Fig. 9). This failure of shrinkage to influence breath-holding time means that a simple explanation involving the Herring-Breuer deflation reflex does not explain the source of the non-chemical stimulus. However the experiments of Guz and his colleagues are extremely important here because they show that afferent impulses in the vagus certainly do have a profound effect upon breathholding (Guz et al. I966 ). T h e y found that in normal subjects blocking the vagus and glossopharyngeal nerves greatly prolonged the breath-holding time at all lung volumes and relieved the unpleasant sensation which normally accrues during the breath-hold (Fig. zo). In addition, the ventilatory response to CO2 was also diminished after vagal block, mainly as the result of the failure of the breathing rate to increase. The exact r61e of vagal afferents is difficult to decide at the present time, but it is certainly possible that information about movement of the lungs themselves is important for normal respiratory control. 250.
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FIG. Io. Breath-holding times at different lung volumes for two subjects before and after bilateral block of cervical vagus. Note the considerable prolongation of breath-holding time at any one lung volume in each subject, and the retention of the increase in breath-holding time with increase in lung volume. (After Guz et al. I966) Muscular
Contraction
O n the efferent side Agostoni (I 963) noted that during a breath-hold there was initially a quiescent period and then spasmodic diaphragmatic contractions appeared which became progressively greater and more frequent until breaking point. The onset of diaphragmatic activity was apparently related to Pco2;
]BREATH-HOLDING
AND
THE
z87
SENSATIONS
since the re-breathing of a gas which did not alter the Pco2 at the onset of diaphragmatic activity allowed a subsequent breath-hold the diaphragmatic activity returned almost immediately. Agostoni also noted that the diaphragmatic activity was, surprisingly, little different or if anything rather less at smaller lung volume than at larger lung volume. In a subsequent experiment (Agostoni et al. 1964) it was shown that various central nervous stimulants and depressants could alter the pattern of the onset of diaphragmatic activity. These results suggest that various stimuli might act centrally to produce the diaphragmatic contractions, but that the static lung volume is unlikely to act in this way. If diaphragmatic contraction is such a prominent feature of breath-holding, it seems possible that muscular contraction itself might have something to do with sensation. Thinking on these lines, Campbell and his colleagues decided to try the effect of muscular paralysis during breath-holding. They found that total paralysis by curarization completely relieved the unpleasant sensation associated with apnoea in two conscious normal subjects (Campbell et al. 1967). In this experiment the initial manual ventilation had rather lowered the Pco2 and we therefore repeated the experiment using the re-breathing breath220 -
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FIG. I I. Breath-holding before and after paralysis by d-tubocurarine. Breath-holding times are plotted against the P c o 2 at the start (open symbols) and end (closed symbols) of the breath-hold. The circles represent control experiments and the solid and broken lines are the regression lines of breath-holding time on initial (solid line) and final (broken llne) P c o 2 for these experiments. The shaded bands represent confidence limits of the lines. Square symbols represent breath-holds after atropine alone and triangles represent breath-holds after atropine and tubocurarine. Note the small effect of atropine and the very large effect of tubocurarine. (From Campbell et al. (i969) Clin. Sci., 36, 323)
188
GODFREY
holding method described above (Campbell et al. I969). O n this occasion there was again no sensation whatsoever associated with apnoea, and the breathholding time was grossly prolonged compared with the control values (Fig. i i). Indeed there was no real limit to the breath-holding time since the subject was perfectly prepared to continue as he indicated by finger signals from the arm excluded from the curare by a cuff, but the observers decided that he had been apnoeic long enough. These two experiments showed that muscular paralysis not only removed any sensation which might be due to muscular contractions but also removed the sensation due to the Pco2 which was grossly elevated by the end of the breath-holds in the second experiment. Thus not only mechanical sensation but also chemical sensation must ultimately be mediated through muscular activity, The evidence presented so far suggests that during a breath-hold there arise chemical stimuli due to hypercapnia and hypoxia (unless oxygen has been breathed previously) and a non-chemical stimulus which can be removed by a single breath; it m a y arise from the lungs but is not due to the shrinkage which occurs. All sensation seems to be mediated through a final common pathway in neuro-muscular mechanisms of the diaphragm and chest wall.
Breath-holding and Chemo-sensitivity There are a number of situations in which the external or internal environment of a subject is altered in such a way as to affect his breath-holding time. One of the earliest and most striking observations of this was the effect of altitude on breath-holding (Doughs et al. 1913). In their paper they state: ' W e were all able to hold the breath at sea level for about 4o seconds by a voluntary effort. After the first 43 hours on Pyke's Peak, Henderson, Douglas and Haldane could not hold longer than 15 to I8 s e c o n d s . . . O n our descent to Manitou, Henderson and Haldane found, much to their surprise, that they could stilt hold no longer than on the summit'. We now know a great deal more about the problem of acclimatization to altitude, mainly as the result of the work of R a h n et al. (1953) and more recently of Severinghaus et al. (i963). With simple breath-holding on air the initial shortening of breath-holding time is of course due to hypoxia which occurs at altitude, but with adaptation interesting changes occur in the cerebrospinal fluid in such a way that a given rise in arterial Pco2 causes a much greater acidosis in the CSF, and hence a greater respiratory stimulation. This means that the breath-holding times, even on oxygen, will be greatly reduced. However it is well to think in terms of the model described earlier because after acclimatization to altitude the hypoxiainduced hyperventilation results in a basically lower arterial Pco2. As a result, in the simple type of breath-holding experiment the breath-holds are begun at a lower P~o2 and, by direct comparison with sea-level breath-holding, should give a longer breath-holding time. The fact that despite this the breath-holding times were shorter at altitude means that this shortening has previously been grossly underestimated. It would be very interesting to see the shift that occurs in the breath-holding CO2 response curve with residence at altitude so that the problem of starting from a low Pco2 could be avoided. Similar arguments
BREATH-HOLDING
A N D T H E SENSATIONS
I8 9
apply to experiments on the effect of acid loading on breath-holding time (Stroud I953).
There is fairly general agreement that during muscular exercise the slope of the curve relating ventilatory response to CO2 is shifted to the left, i.e. that there is a greater ventilation for any given level of Pco2 (Asmussen & Nielson I957) : this implies an increase in the sensitivity of the ventilatory response to 120 -
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,
80
100
Znit~ial Pcoz (ram Wg)
FIo. I2. The effect of exercise on the ventilation CO2 and breath-holding CO s response curves in one subject. Note the small change in the ventilation curve compared with the notable changes in the breath-holding curve. (From Clark & Godfrey (I969) 07. Physiol. (Lond.), in press)
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I 80
Initial Pco2 ( m m H g )
FIG. I3. Changes in the ventilation CO 2 and breath-holding CO 2 response curves in one subject before and after the addition of an airways resistance load. Note the obvious flattening of the ventilation curve in the absence of any change in the breath-holding curve. (From Clark & Godfrey (x969) 07 Physiol. (Lond.), in press)
I90
GODFREY
change in Pco2. However, while everybody agrees that the breath-holding time is shortened by exercise, most authors have believed that the higher breaking-point Pco2 after exercise indicates a decrease in CO2 sensitivity (Rodbard 1947; Muxworthy I95Ib; Astrand 196o). In fact this discrepancy between the effect of Pco2 on ventilation during exercise and on breathholding after exercise is more apparent than real. During exercise the rate of production of CO 2 is increased so that during a breath-hold the rate of rise of Pco2 in the closed system of mixed venous blood, alveolar gas and arterial blood is increased; the rate of rise of chemical sensation is thus increased and naturally the breath-holding time is shortened. In an analysis of ventilatory and breath-holding responses to CO 2 during exercise or rest using the re-breathing method, the previous observations were confirmed (Fig. I2), but it was concluded that the change in breath-holding time did not represent a change in CO2 sensitivity per se, differences being due to the alteration in the rate of CO2 production (Clark & Godfrey 1969). A rather similar situation exists with the effect of airways obstruction on CO2 sensitivity. It has been shown experimentally and clinically that airways obstruction reduces the ventilatory response to CO 2 (Milic-Emilic & Tyler 1963; Clark & Read 1966 ). This reduction in the slope of the COa response curve could be due either to a fall in CO 2 sensitivity or could result from the mechanical effects of the resistance preventing an appropriate increase in ventilation. This is of particular importance with regard to patients who have chronic obstructive lung disease and are usually considered to be insensitive to GO2. During breath-holding there is no flow of gas and therefore one would expect that any mechanical effects of the added load of increased resistance would not affect breath-holding time. We therefore studied the ventilatory and breath-holding CO2 response curves in normal subjects with and without the load of all added airway resistance. In the ventilatory response curve experiment, the resistance was present throughout the experiment, but in the breath-holding experiment, the resistance was present during the re-breathing intervals before and between breath-holds. We found that the ventilatory response to CO 2 was grossly flattened but there was no change in the breathholding CO 2 response curve (Fig. 13). We interpret this finding as indicating no change in chemo-sensitivity with an added load to breathing (Clark & Godfrey I969). Conclusions All the evidence from breath-holding experiments discussed indicates that chemical and mechanical factors combine to provide the unpleasant sensation during the breath-hold. The chemical stimuli probably arise from the influence of the Pco2 on the chemoreceptors and respiratory centre (Clarke 1968 ) as the Pco2 influences the pH of cerebrospinal fluid, and from a falling P02 (if the breath-hold is not done under hyperoxic conditions). The origin of the mechanical stimuli remains in doubt. The lungs and afferent impulses travelling along the vagus nerve are obviously very important, and these impulses may signal that the lungs are moving in a normal fashion. During
BREATH-HOLDING AND THE SENSATIONS
I9I
breath-holding vagal information could indicate the absence of lung movement. The loss of this information after vagal block could account for the prolongation of breath-holding time noted. Whatever the origin of this non-chemical stimulus it undoubtedly appears to summate with the chemical stimuli eventually to cause the sensation which results in the break of the breath-hold. In order to produce a sensation it would appear that muscular contraction is necessary, since no sensation whatever was found after curarizafion. The sensation is probably generated in the diaphragm, muscles of the chest wall and muscle or joint receptors, as a result of disproportion between the tension in the respiratory muscles and their length. The tension develops as a result of a motor output from the respiratory centre, but the muscles are prevented from shortening by voluntary inhibition during the breath-hold. If this mis-matching cannot occur because the muscles are paralysed then no sensation would arise. The idea that a mis-match between muscular contraction and the effect it produces in the chest can generate an unpleasant sensation has implications far wider than breath-holding. In patients with chests distorted as a result of chronic lung disease, or of any other condition, it could well be that the pattern of the movement of the chest is not appropriate to the tensions in the muscles used. Some patients with airways obstruction have paradoxical movement of the lower part of their chest (Campbell 1969) , a typical example of inappropriate movement. Bronchodilators which rapidly relieve the distress associated with asthma can simultaneously restore the distorted pattern of chest movement to a more normal pattern (personal observations), which m a y contribute to the relief. I hope that this review has shown that the simple schoolboy trick of breathholding can tell us a lot more about the control of breathing in health and disease than one would have imagined at first.
.~ej~6rgnc6s AGOSTONI, E. (1963) Diaphragm activity during breath-holding: factors related to its onset. 07. Appl. Physiol., I8, 30. AOOSTONI, E., SANT'AMBROGIO,G. & MOGNONI, P. (1964) Effects of central stimulants on onset of diaphragm activity during breath-holding. 07. Appl. Physiol., I9, 408. ASMUSSEN, E. <~: NIELSEN, M. (1957) Ventilatory response to CO 2 during work at normal and at low oxygen tensions. Acta. Physiol. Scand., 39, 27. ASTRAND, P.-O. (196o) Breath-holding during and after muscular exercise. 07. Appl. Physiol., I5, 220. CAMPBELL,E . J . M . (1969) Physical signs of diffusion airways obstruction and lung distension.
Thorax, 24, I. CAMPBELL, E . J . M . , FREEDMAN, S., CLARK, T . J . H . , ROBSON,J. G. & NORMAN,J. (1967) The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding. Clin. Sci., 32, 425 • CAMPBELL, E. J. M. • GODFREY, S. (1969) The interaction of chemical and non-chemical stimuli to breathing by breath-holding. 07. Physiol. (Lond.) (in press). CAMPBELL,E . J . M . , GODFREY, S., CLARK, T . J . H . , FREEDMAN, S. & NORMAN,J. (1969) The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding during hypercapnia. Clin. Sci., 36, 323.
1 92
GODFRE ~"
CLARK,T . J . H . (x968) The measurement ofventilatory response to CO 2. Brit. 37. Dis. Chest, 62, 1 I3.
CLARK, T. J. H. & GODFREY,"S. (I969) The effect of CO2 on ventilation and breathholding during exercise and while breathing through an added resistance. 37. Physiol. (Lond.) (in press). CLARK, T . J . H . & READ, D. J. C. (1966) A re-breathing method for studying ventilatory response to CO 2. .7. Physiol. (Lond.), I84, 4 I. DOUGLAS, C. G. & HALDANE, J. S. (i9o9) The regulation of normal breathing. 37. Physiol. (Lond.), 38, 4~o. DOUGLAS, C. G., HALDANE, J. S., HENDERSON,Y. & SCHNEIDER, E. C. (I913) Physiological observations made on Pyke's Peak, Colorado, with special reference to adaptation to low barometric pressure. Philosoph. Transact., Series B., 203, 185. FOWLER, W. S. (1954) Breaking point of breath-holding. 37. Appl. Physiol., 6, 539. GODFREY, S. • CAMPBELL,E. J. M. (1968) The control of breath-holding. Respir. PhysioL, 5, 385 • GODFREY, S. & CAMPBELL,E. J. M. (I969) Mechanical and chemical control of breathholding. Quart. 37. Exper. Physiol., 54, II7. GODFREY, S., EDWARDS,R. H. T. & WARRELL, D. A. (I969) The influence of lung shrinkage on breath-holding time. Quart. 37. Exper. Physiol., 54, I29. GRAY, J, S. (1946) The multiple factor theory of the control of respiratory ventilation. Science, IO3, 739. Guz, A., NOBLE, M. I. M., WIDDICOMBE,J. G., TRENCHARD, D. I., MUSHIN, W. W. & MAKEY, A. R. (1966) The r61e ofvagal and alonopharyngeal afferent nerves in respiratory sensation, control of breathing and arterial pressure regulation in conscious man. Clin. Sci., 30, 16I.
HILL, L. • FLACK, M. (I908) The effect of excess of carbon dioxide and of want of oxygen upon the respiration and the circulation. 37. Physiol., 37, 77. KLOCKE, F. J. & RAHN, H. (1959) Breath-holding after breathing oxygen. 37. Appl. Physiol., 14, 689. MILIC-EMILIC, J. & TYLER, J. M. (1963) Relationship between PAco2 and respiratory work during external resistance breathing in man. Ann. W. 2". Acad. Sci., lO9, 908. MITHOEPER, J. C. (1959) Lung volume restriction as a ventilatory stimulus during breathholding. 37. Appl. Physiol., I4, 7Ol. MUXWORTHY, J. F., Jr. (I95Ia) I. Breath-holding studies: Relationship to lung volume. A.F. Techn. Rep., no. 6528, pp. 452-456. Wright-Patterson Air Force Base, Dayton, Ohio. MUXWORTHY, J. F., Jr. (I95Ib) 3- Breath-holding studies: Effects of exercise. A.F. Techn. Rep., no. 6528, pp. 479-48I. Wright-Patterson Air Force Base, Dayton, Ohio. OTIs, A. B., RAHN, H. & FENN, W. O. (1948) Alveolar gas changes during breath-holding. Am. 37. Physiol., 152, 674. READ, D. J. c. (1967) A clinical method for assessing the ventilatory response to carbon dioxide. Aus. Ann. Med., x6, 20. RODEARD, S. (I947) The effect of oxygen, altitude and exercise on breath-holding time. Am. 37. Physiol., I5O, I42. SEVERINGHAUS,J. W., MITCHELL, R. A., RICHARDSON, B. W. • SINGER, H. M. (I963) Respiratory control at high altitude suggesting active transport regulation of CSF pH. 37. Appl. Physiol., z8, I155. STEVENS, C. D., FERRIS, ]~. B., WEBE, J. P., ENGEL, G. L. & LOGAN, M. (1946) Voluntary breath-holding. I. Pulmonary gas exchange during breath-holding. 37. Clin. Invest., 25, 723. STROUD, R. C. (I953) Ammonium chloride acidosis and breath-holding. 37. Appl. Physiol.,
6, 15x.