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Q. Ji exp. Phy8iol. (1971) 56, 92-100 MECHANICAL AND CHEMICAL CONTROL OF BREATH HOLDING. By G. R. KELMAN and K. T. WANN. From the Department of Physiology, University of Aberdeen, Aberdeen, Scotland.

1 Q. Ji exp. Phy8iol. (1971) 56, MECHANICAL AND CHEMICAL CONTROL OF BREATH HOLDING. By G. R. KELMAN and K. T. WANN. From the Department of Physiology, University of Aberdeen, Aberdeen, Scotland. (Received for publication 9th September 1970) The relationship between the maximum duration of a voluntary breath hold (BHT) and the alveolar Pco2 at the start and finish of the period of apnoea has been investigated in six subjects over a wide range of C02 tensions, for breath holds made at VC, 60 per cent VC, and FRC. Alveolar Po2 was maintained above the level at which hypoxia is a significant factor in stimulating pulmonary ventilation. The results suggest that the relationship between BHT and Pco2 at breaking point may be approximated by two straight line segments: for short breath holds (with a high initial Pco2), BHT and breaking point Pco2 are linearly related; for long breath holds (with a low initial Pco2) final PCo2 is independent of the duration of the breath hold. These results suggest that the mechanical component of the drive to resume breathing saturates during long breath holds, the level of saturation depending on the lung volume at which the breath is held. The drive to resume breathing after a period of voluntary apnoea (breath holding) is generally assumed to have two main components-a chemical and a mechanical component [Douglas and Haldane, 1909; Fowler, 1954; Godfrey and Campbell, 1968]. The former is determined by inter alia the tensions of oxygen and carbon dioxide in the arterial blood; the latter depends (in a largely unknown manner) on the fact that, during the breath hold, the pulmonary ventilatory apparatus is prevented from fulfilling its normal function, which is the movement of air in and out of the lungs. Analysis of the mechanical component of the drive to resume breathing indicates that it is dependent also on the lung volume at which the breath hold is performed [Muxworthy, 1951]. In this paper we describe an investigation into the relative importance of mechanical and chemical factors in terminating the breath hold. Our technique and results are similar to those published in abstract form by Patrick and Reed [1969a and b]; our conclusions are, however, markedly different. METHODS The physical characteristics of the six experimental subjects are shown in Table I. Two of the subjects had a good general knowledge of respiratory physiology, but none had any special knowledge of the particular problems of breath holding. Each subject was initially required to rebreathe via a mouth-piece from a 6 litre spirometer containing either pure oxygen or a mixture of carbon dioxide in oxygen. Equilibrium between the subject's lungs and the spirometer occurred during the first see ofrebreathing; thereafter the carbon dioxide tension of the gas in the subjectspirometer system rose steadily (at about 6 mmhg/min) as the body's metabolicallyproduced carbon dioxide was added to the system (Fig. 1). During the latter part of the rebreathing period, the carbon dioxide concentration in the spirometer-lung system was virtually uniform so that the Pco2 in the arterial blood was virtually the same as the end-tidal Pco2 [Read and Leigh, 1967]. 92

Control of Breath Holding 93 The carbon dioxide tension of the gas passing in and out of the lungs was continuously monitored by withdrawing, via a side arm on the subject's mouth-piece, a sample of

2 Control of Breath Holding 93 The carbon dioxide tension of the gas passing in and out of the lungs was continuously monitored by withdrawing, via a side arm on the subject's mouth-piece, a sample of gas which was passed through a fast-response infra-red C02 analyser. This gas sample was then returned to the system through a second side tube. The C02 analyser was frequently calibrated against mixtures of C02 and 02 which had been analysed with a Lloyd-Haldane apparatus. TABLE I. Details of the six experimental subjects. Vital capacity Subject Age Height (M) (litres) I.D D.E D.B I.H C.C M.G When the subject's end-tidal carbon dioxide tension had reached an appropriate level he exhaled to residual volume, inhaled either to functional residual capacity, 60 per cent vital capacity, or vital capacity, and then held his breath as long as possible, i.e. until the drive to resume breathing became intolerable. At the breaking point of the breath hold the subject exhaled fully to give a measure of his final alveolar (and therefore arterial) Pco2 (Fig. 1) W, 0- sec. FIG. 1. Pco2 at mouth in typical subject during rebreathing and breath holding (between arrows). After a rest period of at least 20 min the breath hold manoeuvre was repeated several times at either a different lung volume or a different initial carbon dioxide tension. This was done over several days until a number of breath holds spanning a wide range of carbon dioxide tensions had been obtained at the 3 lung volumes. The order with regard to lung volume and initial Pco2 was randomized in any given subject. Care was taken to ensure that the subjects received no clue about their intermediate performance until the whole series of breath holds had been completed. The alveolar oxygen tension at the end of the longer breath holds was checked with an AEI MS1O mass spectrometer. The ventilatory response to carbon dioxide of each subject was determined by the technique of Read [1967]. The subject rebreathed from a spirometer containing pure oxygen while the Pco2 in the system was continuously monitored with an infra-red analyser. As carbon dioxide built up in the subject-spirometer system the subject's ventilatory minute volume increased, so that it was possible to determine a series of

3 94 Kelman and Wann paired values of his alveolar (and therefore arterial) Pco2 and ventilatory minute volume. The slope of this line was determined by standard least squares regression analysis. RESULTS The reproducibility of the breath hold time (BHT) in a single subject, at a single lung volume and initial Pco2, had a coefficient of variation of the order of 10 per cent. There was no consistent increase of BHT with practice X PCO2 at breaking poinit 70 X * x X x l*iitial PCo2 60_ * xx x x Pco2. x x x 50_ 40_ 40 30_ 0 FIG. 2. pill'.~~~.,ii 1 1,11., _ Breath Hold Time(sec) Relationship between breath hold time and Pco2 at start and end of breath hold (at VC) in typical subject (I.H.). The general form of the relationship between BHT and the carbon dioxide tensions at the start and end of breath holding in a single, typical subject at a single lung volume was two straight line segments with an inflexion point (Fig. 2). The right hand line of the relationship between BHT and final Pco2 in Fig. 2 is approximately horizontal; this is also the case in Figs 3, 4 and 5, which show the relationship between breaking point Pco2 and BHT in all six subjects at VC (Fig. 3), 60 per cent VC (Fig. 4) and FRC (Fig. 5). The curves in these figures were drawn by eye; they do not assume any particular mathematical relationship between Pco2 and BHT. Figs 2-5 suggest that the relationship between BHT and Pco2 at breaking point may be approximated by two straight line segments-a horizontal line to the right of the inflexion point and a sloping line (upwards) and to the left for breath holds of shorter duration. This relationship may be defined by three

4 Control of Breath Holding 95 so Pco2 %CZ. 40 M.G 30 FIG Breath Hold Time(sec) Relationship between breath hold times at VC and Pco2 at breaking point in six subjects PCO2" =-Xc 50 LD- M.G. _ D ~~~~~~~~~~~~~. B FIG Breath Hold Time(sec) Relationship between breath hold times at 60 per cent VC and Pco2 at breaking point in six subjects. s Pco2 i?ll D.E FIG Breath Hold Time(sec) Relationship between breath hold time at FRC and Pco, at breaking point in six subjects.

5 96 Kelman and Wann OD QRdO X OCOX O. _4 P4v:: 61 onno on i~c 6.o _ 0 co CA A~~~~~L r-eco 0eoM co o0 ed toc E-- ~ ~ ~ ~~0 co 0 c QO io co O (M '-w 000 E$oonXs b~~~cq _ X O r s S O O 04

6 Control of Breath Holding 97 PCO2max \ FIG. 6. BHT inflexion Suggested model relationship between breath hold time and Pco2 at start and end of breath hold (for explanation of symbols see text). parameters (Fig. 6)-the Pco2 corresponding to a BHT of zero (Pco2max), the Pco2 at the end of a very prolonged breath hold (Pco2min), and the duration of apnoea corresponding to the inflexion point of the curve relating Pco2 and BHT (BHT inflexion). The values of these parameters, chosen to minimize the sum of the squared errors between the experimental and the model relationship, were determined by standard curve fitting techniques using a PDP-8/S digital computer (Table II) Ṫhe mean rate of rise of alveolar Pco2 during the period of apnoea (difference between final and initial C02 pressures divided by BHT) was approximately TABLE III. Rate of ri8e (mean ±8.e.m.) of alveolar Pco2 during breath hold for 8ix experimental 8ubject8, each at three lung volume8. mean rate of rise of Pco2 during breath hold (mmhg/min) Subject VC 60% VC FRC I.D. 11.4± ±0.7 83±0-6 D.E. 8.3± ±0.8 11*9±0.8 D.B ± ±1.1 I.H. 8.8± ±0*5 8-2±0*4 C.C. 11*8± ± ±0*8 M.G. 12* ±1*3 10*2±0-8 mean * TABLE IV. Parameter8 of 8ub.ect' ventilation/pco2 re8pon8e curve8. Apnoeic threshold Slope of ventilation/pco2 Subject (mmhg) response curve (litre/mmhg) I.D *77 D.E D.B I.H C.C M.G

7 98 Kelman and Wann 10 mmhg/min (Table III). There was no significant correlation between the rate of rise of Pco2 and the duration of the breath hold. The slope of the ventilation/pco2 curves and the extrapolated apnoeic thresholds of the six experimental subjects are given in Table IV. In no subject was the alveolar Po2 at the end of a breath hold found to be below 200 mmhg. DIscUSSION There is general agreement that the duration of a breath hold (BHT) is influenced by both chemical and mechanical factors; but there is no clear understanding of the way in which these two components combine to produce the total drive to the resumption of ventilation. Some workers [e.g. Godfrey and Campbell, 1968] have assumed that the two components simply sum; others [e.g. Patrick and Reed, 1969a] have suggested that they may be combined in a more complicated manner, and that the total drive depends on, perhaps, the product of the two individual factors. In the experiments described here care was taken to prevent hypoxia from becoming a significant factor in producing the drive to resume breathing. In no subject was the alveolar Po2 at breaking point less than 200 mmhg.,it has been suggested by Cunningham, Patrick and Lloyd [1964] that, at high CO2 tensions, the hypoxic threshold lies 'well above 210 torr', but the results of these workers show that, even at these high CO2 tensions, hypoxia is a much less potent stimulus to breathing than hypercapnia. The chemical component of the drive to resume breathing in our experiments was therefore mainly dependent on the Pco2 in the vicinity of the intracranial chemoreceptors which control pulmonary ventilation, because, as shown by Cunningham, Lloyd, Miller and Young [1965], the peripheral chemoreceptors in the absence of hypoxia are largely unresponsive to CO2. Alveolar Pco2 does not, of course, necessarily reflect the Pco2 in the vicinity of the intracranial chemoreceptors [Lambertsen, Gelfand and Kemp, 1965] but the work of Read and Leigh [1967] predicts that blood-brain tissue Pco2 differences, under the conditions of our experiment, are likely to be minimal. Patrick and Reed's [1969a] analysis of the relative importance of lung volume and arterial Pco2 on BHT concentrated on the relationship between the Pco2 at the start of breath holding and the duration of the period of voluntary apnoea. They suggested that if the total drive to the resumption of breathing was the sum of a chemical and a mechanical component, the inflexion point on the Pco2/BHT curve indicated that, during breath holding, there was a 'threshold for CO2 comparable with the one seen in steady-state ventilation'. This interpretation is incorrect; it may be shown mathematically that, when the total drive to resume breathing equals the sum of two components which both rise linearly with time, the relationship between initial (and final) Pco2 and BHT is linear, even when it is assumed that there is a threshold below which one of the components is inactive. It seems to us more logical to concentrate on the relationship between BHT

Control of Breath Holding 99 andfinal Pco2. It is, after all, the final, not the initial, Pco2 which is responsible for the chemical component of the compulsion to resume breathing.

8 Control of Breath Holding 99 andfinal Pco2. It is, after all, the final, not the initial, Pco2 which is responsible for the chemical component of the compulsion to resume breathing. Initial and final carbon dioxide tensions are, of course, linked by the rate of rise of Pco2 during apnoea-about 10 mmhg/minute in our experiments. Figs 2-5 suggest that the relationship between BHT and Pco2 at breaking point may be approximated by two straight line segments as shown diagrammatically in Fig. 6. The simplest physiological interpretation for this relationship is that the mechanical drive increases linearly with time until it reaches a maximum value, at which it becomes constant. For breath holds longer than this critical time the mechanical component of the drive to resume breathing is already maximal; the chemical component, however, continues to rise (linearly) until the total drive to resume breathing, i.e. the sum of the mechanical and chemical components is sufficient to terminate the breath hold. The model relationship between breaking point Pco2 and BHT used to determine the figures in Table II assumed that, for breath holds longer than BHT inflexion, the line was horizontal, i.e. had a slope of zero. Least squares determination of the actual slopes of these segments indicates that they do, in fact, differ from zero, but that the differences, though statistically significant, are very small ( mmhg/sec at VC; ±0*007 mmhg/sec at 60 per cent VC; ±0*017 mmhg/sec at FRC). This suggests that our hypothesis of a mechanical drive which increases with time until it reaches a certain level at which it becomes constant is probably a reasonable one; other interpretations, such as a mechanical drive which approaches its final value asymptotically, are however clearly possible. If this model of the factors influencing the drive to resume breathing is correct, there should be some relationship between the parameters of the model and physiological reality. This does appear to be the case. If the mechanical component of the drive to resume breathing depends, as suggested by Godfrey and Campbell [1968], on the fact that, during the period of apnoea, the respiratory muscles are prevented from shortening, this component would be expected to be greatest at small lung volumes. This would mean that the additional chemical drive required to terminate prolonged breath holds would be less at FRC than at VC. It is. The height of the horizontal plateau (Pco2min) is 52-6 mmhg at VC and 48-0 mmhg for breath holds performed at FRC. The mean difference between the values of Pco2min at the two lung volumes is 4-6 mmhg (SEM = ±1-7 mmhg), which is significantly different from zero (t = 2-73, P<0*05). The mechanical component might also be expected to rise to its final value more rapidly at small lung volumes. The mean inflexion point (BHT inflexion) occurs at 60x5 sec with a breath hold at VC, but at only 50 5 sec when the breath is held at FRC (Table II). This suggests that the mechanical drive increases faster at low lung volumes. A paired test of the differences between values of BHT inflexion at VC and at FRC differs significantly from zero (mean = 10.0 sec, SEM = ±3*1 sec; t = 3-1, P<0 05). There is general agreement [see, e.g. Mithoefer, 1959] that the body is able to tolerate higher carbon dioxide tensions during breath holds performed at VOL. LVI, NO

9 100 Kelman and Wann larger lung volumes. The value of Pco2max is 70-8 mmhg for breath holds at VC and only 62-4 mmhg for breath holds at FRC. The mean difference between these values differs significantly from zero (mean = 8-4 mmhg, SEM = ±16 mmhg; t = 53, P<0.01). Finally, it might intuitively be expected that the greater the slope of the pulmonary ventilatory minute volume/pco2 curve, the greater would be the compulsion to resume breathing at a given lung volume and carbon dioxide tension, and therefore the lower the value of Pco2 corresponding to a BHT of zero (Pco2max). The correlation coefficients between the values of Pco2max and the slopes of the ventilation/pco2 response curves, as determined by the method of Read [1967], in the six experimental subjects were: at VC, r = -0 59; at 60 per cent vc, r = -0-59; and at FRC, r = -0*84. The last value differs significantly from zero, despite the small number of subjects (t = 3 1, P <0*05). REFERENCES CU:NINGHAM, D. J. C., PATRICK, J. M. and LLOYD, B. B. (1964). 'The respiratory response of man to hypoxia.' In Dickens, F. and Neil, E. Oxygen in the animal organiwm. London, Pergamon, DouGLAs, C. G. and HALDANE, J. S. (1909). 'The regulation of normal breathing.' Journal of Phy8iology 38, FOWLER, W. S. (1954). 'Breaking point of breath holding.' Journal of Applied Phy8iology 6, GODFREY, S. and CAMPBELL, E. J. M. (1968). 'The control of breath holding.' Re8piration Phy8iology 5, LAMBERTSEN, C. J., GELFAND, R. and KEMP, R. A. (1965). Dynamic response characteristics of several C02-reactive components of the respiratory control system. In Brooks, C. McC., Kao, F. F. and Lloyd, B. B. Cerebroapinalfluid and the regulation of ventilation. Oxford, Blackwell, pp MITHOEFER, J. C. (1959). 'Lung volume restriction as a ventilatory stimulus during breath holding.' Journal of Applied Phy8iology 14, MUXWORTHY, J. F. (1951). 1. Breath holding studies: Relationship to lung volume. U.S.A.F. Technical Reports, 6528, Wright-Patterson Air Force Base, Dayton, Ohio. PATRICK, J. M. and REED, J. W. (1969a). 'The interaction of stimuli to breathing during breath-holding.' Joumral of Physiology 203, 76-77P. PATRICE, J. M. and REED, J. W. (1969b). 'The influence of lung volume and CO2 on breath-holding.' Journal of Physiology 204, 91-92P. READ, D. J. C. (1967). 'A clinical method for assessing the ventilatory response to carbon dioxide.' Aw9tralian Annal1 of Medicine 16, READ, D. J. C. and LEIGH, J. (1967). 'Blood-brain tissue Pco2 relationships and ventilation during rebreathing.' Journal of Applied Physiology 23,

By S. GODFREY and E. J. M. CAMPBELL. From the Department of

Q. Jl exp. Physiol. (1969) 54, 117-128 MECHANICAL AND CHEMICAL CONTROL OF BREATH HOLDING. By S. GODFREY and E. J. M. CAMPBELL. From the Department of Medicine, Royal Postgraduate Medical School, DuCane