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

Transcription

1 Q. Jl exp. Physiol. (1969) 54, 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 Road, London, W. 12., England. (Received for publication 13th June 1968) A method is described for the study of breath holding in which the breath holds are separated by rebreathing to enable accurate control of pco2; its theoretical basis is discussed. At the end of a breath hold, rebreathing a mixture such that the pco2 continues to rise, nevertheless permits the breath hold to be resumed. The number of breaths during the rebreathing is unimportant and a single breath permits as long a resumed breath hold as five breaths. Healthy adult males held their breath at residual volume. The relationship between breath holding time and pco2 at the start or end of a breath hold was found to be linear; the higher the pco2 the shorter the breath holding time. The relationship was unaffected by ten minutes of isocapnic hyperventilation. These findings imply that the duration of breath holding is directly related to PCO2 but is unaffected by the previous mechanical pattern of breathing. MOST of the factors of importance in determining the breaking point of breath holding have been known for many years. Hill and Flack [1908] noted that if oxygen was breathed beforehand rather than air, the breath holding time was longer. They also noted that the alveolar pco2 (hereafter referred to as pco2) was higher at breaking point after breath holding on oxygen; this was presumably due to the longer duration of breath holding. In the same paper they reported that their subjects could rebreathe expired air from a bag for some two to four times as long as their maximum breath holding time on air. They thus demonstrated that ventilation of the lungs allowed the subject to tolerate a greater hypoxia and greater hypercapnia than occurred at the breaking point of breath holding. This finding, now some sixty years old, suggests that some form of interaction of chemicall and mechanical stimuli occurs during breath holding. Subsequent studies defined the roles of oxygen, CO2 and lung volume more clearly [Douglas and Haldane, 1909; Klocke and Rahn, 1959; Muxworthy, 1951] and the whole subject has been reviewed by Mithoefer [1964]. The relationship between rebreathing and breath holding was further explored by Fowler [1954]. He found that after subjects had reached the breaking point of a breath hold, a few breaths of a gas mixture which did not improve their blood gases allowed them to perform a second, shorter breath hold, and subsequently a third. He did not attempt to determine the number of breaths necessary to allow the second (or third) breath hold of the series. VOL. LIV, No

2 118 Godfrey and Campbell Cain [1957] reported that a single gasp of air at the end of a breath hold allowed a second period of breath holding, but of course the blood gases were altered by his procedure. The present series of experiments were designed to investigate the interrelationships of mechanical and chemical factors in breath holding. METHODS Breath-cluster experiments. - All the subjects used in this study were healthy adult males whose physical characteristics are given in Table I. All of them had a good knowledge of respiratory physiology in general but only S.G. had any detailed knowledge of breath holding. The subjects were kept totally unaware of their performances throughout the series of experiments. TABLE 1. DETAILS OF SUTBJECTS. Age Height Weight Subject years cm Kg M.C D.M G.L T.O S.G D.W M.S R.J S.F For the first group of experiments, designed to investigate the effect of the number of breaths on the duration of the second breath hold, the circuit illustrated in fig. 1 was used. The subject rebreathed a gas mixture from a 6 1. rubber bag contained in a bottle. Ventilation was recorded by Bernstein spirometer connected to the bottle, a potentiometer on the spindle of the spirometer being used to obtain a record. End tidal pco2 was recorded from the mouth piece by means of an infra-red CO2 analyser (URAS). The gas was returned to the bag after passing through the cell. The analyser was calibrated with at least three gas mixtures before and after each experiment. Ventilation and pco2 were displayed on a Mingograph recorder. At the start of an experiment the bag was filled with 6 1. of a mixture of approximately 7 per cent CO2 and 93 per cent oxygen. The spirometer was so set that a mark on the bell was placed 2 1. above the water line. The subject expired to residual volume and then switched himself into the circuit and performed a vital capacity manoeuvre. After this he rebreathed from the bag at a rate of 16 breaths/ min set by a metronome, but without any restrictions on his tidal volume. After thirty sec of rebreathing the subject was instructed to hold his breath for as long as possible with the mark on the spirometer at the water level. This meant that he held his breath at approximately 2 1. above residual volume. At breaking point the subject expired to his residual volume. After at least five minutes' rest the procedure was repeated, but the breath hold (B.H.1) was terminated by the operator. During B.H.1 sufficient CO2 was added to the bag by the operator to produce a pco2 close to that anticipated in the lungs of the subject at the end of B.H.1. The operator terminated B.H.1 after 80 per cent of the previously determined maximum breath holding time by giving the command 'breathe'. The value of 80 per cent was selected to ensure a severe stimulus but one which the subject would tolerate without breaking. The subject

3 Control of Breath Holding 119 started to breathe at a rate of 32 breaths/min with an unrestricted tidal volume, and continued to do so until the operator gave the instruction 'hold'. The number of breaths in this 'cluster' taken by the subject was determined from random number tables between one and five. The subject had no prior knowledge of the size of the cluster. At the command 'hold' he again held his breath with the mark on the spirometer at the water level and this time he continued breath holding as long as possible. This period of breath holding is subsequently referred to as B. H.2. Each subject performed the experiment for all of the five cluster sizes and the whole group of experiments was repeated on another day. The experiment was also performed on one subject who held his breath at residual volume on each occasion. Clusters of 1, 3 and 5 breaths were used at random, each cluster size being repeated once during a single session lasting one hour. 3-way Filling port J Subject - CO2 analyser To spirometer Fig. 1. Circuit used for rebreathing and breath holding. Breath holding-co2 Response Curves. - In this group of experiments the subject again rebreathed a gas mixture from a circuit similar to that shown in fig. 1; the composition of the mixture was the same as in the first group of experiments. The subject expired to residual volume and then switched himself into the circuit and rebreathed at will with no fixed rate or tidal volume being imposed. After approximately 30 sec of rebreathing, the subject was instructed to expire to residual volume and then hold his breath for as long as possible. When he reached breaking point he began rebreathing for about sec and again held his breath as long as possible. This procedure was repeated several times so that up to 6 breath holds were interspersed during the period of rebreathing. A graph was constructed relating breath holding time to the pco2 in the lung/bag system. In order to study the effect of hyperventilation on the breath holding-co2 curve, the circuit was modified so that the subject could hyperventilate through the side arm of the three way tap without altering his pco2. This was achieved by connecting the side arm to the partial rebreathing circuit described by Freedman [1966]. The subject was given a target ventilation to follow of 60 1./min and maintained this rate for 10 min. His end tidal pco2 was kept at the control level throughout by adjusting the level of rebreathing. At the end of this period he was switched into the rebreathing bag and performed a residual volume CO2 response experiment exactly as described above, with the one exception that between breath holds he maintained the same rate of ventilation, namely 60 I./min. After the completion of this experiment he rested for at least 10 min and then performed a resting breath holding-co2 response experiment described above. In all these experiments care was taken to ensure that the subjects were hyperoxic throughout. This was achieved by using the high initial bag oxygen mixtures and

4 120 Godfrey and Campbell a check on the PCO2 in the system showed that it never fell below 400 mm Hg at any stage during the breath holding-co2 response curves or during the cluster experiments described earlier. RESULTS Breath-cluster experiments. - During the initial 30 sec of rebreathing, equilibrium was established between the PCO2 in mixed venous blood, alveolar gas and bag gas. Since recirculation occurs in some 15 to 20 sec at rest, the PCO2 of the blood-lung-bag system had already begun to rise, but this rate of rise was very constant at rest (see below). This process ensured that the pco2 at the start of the first breath hold (B.H.1) was very constant for any one subject throughout the various experiments. During the B.H.1 Pco2 Imm.Hg9 C02 added 60 to bag 50, 40 CLUSTER Tidal volume ll) BREATH HOLD 1 BREATH HOLD 2 0 Inspiration + F 62 ~ l ~ ~ ~ ~ ~~~~~~~~~~~ I TIME IN SECS. Fig. 2. Course of a typical experiment. A small amount of C02 was added to the bag during] the first breath hold by the operator and mixed by means of a piston. and the subsequent period of rebreathing for the cluster, the pco2 continued to rise at the same rate. Since the duration of B.H.1 was constant and the clusters differed only a little in duration, the pco2 at the start of the second breath hold (B.H.2) was also very constant (Table II). This second breath hold was continued as long as possible by the subject and was used to judge the effect of clusters of different sizes. Because of the relatively low rate of rise of pco2 (6 mm Hg/min) and the small differences in B.H.2 for any one subject, the calculated pco2 at breaking point of B.H.2 never varied by more than 2-6 mm Hg. The form of a typical experiment for a five breath cluster is shown in fig. 2, and the results for all the experiments are summarized in Table II. For each subject, each of the clusters was repeated on a second occasion and both results are given (A and B in Table II). The time for the first breath hold was 80 per cent of the maximum breath holding time, and therefore varied in any one subject depending upon his maximum breath holding time on the particular day of the experiment.

5 Control of Breath Holding 121 _-4 0 P- rcoo t- 1o00 00x = ON10J to = CZ r- n : rw O co - = =O r- cq C oo '-4N0- _ CO CO CO 10 Ol n CO CO CG1 CO N- s CO: m CO N- 0v) F-4 ce C) CO O 0 CO~LO Ci CO CO CO o 6 (5 cs z U) ce 0 cs co CO a aq10 00a xoo O Xs CO Os X CO CO Ci CO m aq m m COO CO CO ee *n cc X CO 04 cq cs es cq aq ce,d o 1o 10 d4o x W 0- A4 0 eo _ c cq es r t w O~ c: r COX CO D 10 0-r CO l ll Xo a to cn o xo O C) c) H 0 4v c 0 Ce 6l 60 t-: lo o to 10o 100xo o a c; cq e CO C O _ C_ c 100o 10 CS 4 10 r* lao z co O co c) c) Cl1 c;z CO OoO 0o10 0lf o Ca o, 0 oc 4 D10 100o > C i C C1 10 o 00 0o * * o to 14 l o C c O'j 4 10C;O '~- = oIC) 'xo ldq XO 01t 10o o "di 01a o 01 "di 10 ~ ~ ~ ~ c C D 4-n O H m * _, 0H *4-~~~~~~~~~n

6 122 Godfrey and Campbell Because of the considerable variation in breath holding time between individuals, these results have also been calculated on a proportionate scale, so that they could be grouped together. For any individual at any one session the mean duration of all second breath holds plus clusters was taken as 100 per cent. The actual duration of the separate B.H.2 and cluster 120 Cluster 1 25B.H.2 CJ100 ~80 C', J ~ ~ NUMBER OF BREATHS IN CLUSTER Fig. 3. The relationship between cluster size and the duration of the second breath hold. Each open column represents the group mean value for B.H.2±1 S.D. after the cluster of breaths indicated below. An arbitrary scale is used in which the 100 per cent is the duration of the mean B.H.2 plus cluster time for each subject. The shaded columns represents the duration of the cluster, which must obviously increase with its size, but the small differences in B.H.2 are not significant. times were then calculated as fractions of this 100 per cent. The results for breath holds at the larger lung volume expressed in this way are shown in fig. 3. Each column represents the mean percentages for all subjects with one standard deviation for B.H.2. The total height of the columns increases with the number of breaths in the cluster, but it can be seen that this is due to an increase in the duration of the cluster rather than any significant increase in B.H.2. It is obvious that with a fixed rate of breathing, the duration of the cluster had to increase with the number of breaths in the cluster, but it is the lack of change in B.H.2 that is of particular interest. The results contained in fig. 3 were also submitted to an analysis of variance, which confirmed the impression that there was no significant change in

7 Control of Breath Holding 123 the duration of B.H.2 after clusters containing different numbers of breaths; and even between the 1 breath and 5 breath clusters, the difference in mean duration of B.H.2 was not significant (P=0 20). It should be remembered that the duration of B.H.1 was fixed by the design of the experiment and does not therefore come into this analysis. Further experience with breath holding led us to believe that the smaller the lung volume, the more reproducible were the results, and we therefore repeated the cluster experiment in one subject using residual volume (Table II, S.G.). Once again the duration of B.H.2 was very constant irrespective of cluster size, confirming the observations made at the larger lung volume S. G. M.C. 50 _... * Beginning o End <20-10 (o l l l I l l l l l PCO2 (mm.hg.) Fig. 4. The relationship between breath holding time and pco2 at the start (0) and end (0) of a series of breath holds at residual volume, separated by rebreathing, in two subjects. The shaded area represents the rise of pco2 during the breath hold. Note the approximately linear relationship between breath holding time and either value for pco2, and the convergence on a threshold value at which the breath holding time is zero. Breath holding-co2 Response Curves. - Because the rebreathing approach permitted a series of breath holds to be performed at progressively higher levels of pco2, it was possible to construct a graph relating breath holding time to the PCO2 at either the start or end of the breath holds (fig. 4). The curves illustrated were obtained in two subjects for breath holds begun at residual volume. The pco2 at the end of the breath holds (breaking point) was calculated from the known rate of rise of pco2 during breath holding for each subject, since expiration at the end of a residual volume breath hold was impossible. This rate of rise of pco2 was obtained from the end tidal pco2 at the start and end of breath holds performed at larger lung volumes. In fact we have found that the rate of rise of pco2 during breath holding is virtually independent of lung volume and is only slightly higher

8 124 Godfrey and Campbell than during simple rebreathing under the conditions described in these experiments (Table III). It also shows little inter-subject variation. In any one subject, the form of the curve relating breath holding time to the pco2 at the start or end of the breath holds remained relatively TABLE III. RATE OF RISE OF pco2 (mm Hg/min) Mean S.D. n 1. Rebreathing before breath holding at T.L.C. = During breath hold at T.L.C Rebreathing before breath holding at F.R.C. = During breath hold at F.R.C. = 683 1*01 6 The rate of rise of pco2 for rebreathing preceding a breath hold and for the breath hold itself are given for breath holds at two different lung volumes. Differences between them were not significant. constant and could be described by a straight line to a close approximation. The form of such a line can be described by its slope (SBH) and intercept, that is the PCO2 at which the breath holding time is zero (BBH); these terms are comparable with those introduced by Lloyd, Jukes and Cunningham * Before hyperventilation o 10 mins. after hyperventilation x Immediately after hyperventilation 60 M.S. x D.W R.J. - =~~~~~~~~~~~~~~~~~~~ 60 Ec END TIDAL Pco2 AT START OF BREATH HOLDING Fig. 5. The effect of isocapnic hyperventilation on the breath holding-co2 relationship in three subjects. The three curves for each subject do not differ consistently. [1958] to describe the ventilatory response to pco2. Such relationships could equally well be applied to the initial or final pco2, but for the reasons given below we have chosen to use the initial pco2 as our standard reference. We have measured the parameters in many subjects, and found much intersubject but little intra-subject variation, much as has been found for the ventilatory response to pco2. In one subject (D.W.) studied on five separate occasions, SBH varied from 3-6 to 5.4 sec/mm Hg (mean = 4* S.D.) N,

9 Control of Breath Holding 125 and BBE. varied from 62 to 68 mm Hg (mean = S.D.), giving coefficients of variation of 8-6 per cent and 2-8 per cent respectively. Residual volume breath holding-co2 response curves were obtained in three subjects before, immediately after, and ten minutes after hyperventilation at constant pco2 (isocapnic hyperventilation). For any one subject, no difference was found in the relationship between breath holding time and pco2 (fig. 5) as a result of hyperventilation. DIscusSION It is well known that under ordinary circumstances, the breath holding time varies from individual to individual, and that this is due in some degree to the subjects' will power. Other factors known to affect the breath holding time include lung volume and blood gases, acting as interrelated stimuli [Mithoefer, 1959]. Most of the studies on breath holding previously reported, have been complicated by varying more than one of these factors at a time. This has probably resulted in greater variations in breath holding times than need have occurred, and may indeed have masked real changes. In the present study we have attempted to control the various factors by using the rebreathing method. The high initial 02 tension in the bag ensured that the P02 of the subjects never fell to levels low enough to affect breath holding [Otis et al., 1948]. In all our experiments, the lung volume was always the same at the start of the breath hold for any given type of study. The remaining factor, pco2, has been allowed to vary in a controlled manner. It is the control of pco2 which forms the essential part of the rebreathing method we describe (sometimes called an 'open-loop' approach). It is now well established that rebreathing of a gas with a pco2 close to mixed venous pco2 results in rapid equilibrium between mixed venous blood, alveolar gas and bag gas [Campbell and Howell, 1960; Collier, 1956]. After passage through the lungs, the blood enters the systemic circulation with the elevated level of pco2 and then picks up a new load of CO2 from the tissues. This means that after recirculation the pco2 of the blood-lung-bag system will rise. It has been shown that the rate of rise of pco2 is very steady after the first 20 sec of rebreathing [Read, 1967] and moreover, the bag pco2 is a very good index of chemoreceptor pco2 [Read and Liugh, 1967]. It has also been shown that the rate of rise of pco2 during rebreathing is independent of the size of the bag up to about [Fowle and Campbell, 1964]. Once the pco2 of the system has begun to rise, it will not matter if the subject holds his breath, since the situation for gas exchange will be the same, i.e., the excretion of CO2 is prevented. The only difference between breath holding and rebreathing under these circumstances will be due to the volume of the gas phase. The actual quantity of CO2 required to raise the pco2 of the gas phase by the resting rate of 6 mm Hg per min will be only a little greater during rebreathing, which accounts for our observations that the rate of rise of pco2 is virtuallv independent of the

10 126 Godfrey and Campbell volume of gas in the system. All these remarks only apply to rebreathing or breath holding under hyperoxic conditions. Because of these very special relationships, the pco2 in the lungs during our experiments rises at a steady rate whether the subject is rebreathing or breath holding. It is true that during a breath hold the pco2 in the bag ceases to rise, but the small difference between lung and bag pco2 at the end of the breath hold is rapidly removed by the first two or three breaths. The rebreathing 'open-loop' situation implies that: 1. The pco2 at the beginning and end of a breath hold can be accurately known without taking arterial blood. 2. Since the inspired-expired pco2 difference is virtually removed (being only 1-7 mm Hg in our experiments), inspired gas does not dilute alveolar C02, and so the pco2 is independent of lung volume. 3. It is possible to perform serial rebreathing and breath holding in one experiment, with the pco2 rising steadily and predictably. By means of this approach we were able to standardize the first (stressing) breath hold in the cluster experiments, both in terms of duration and of pco2, and to present each subject with a uniform experience at the start of the different sized clusters. The similar duration of B.H.2 whatever the cluster size meant that breaking point pco2 was virtually constant for any subject. The fact that the breath holds (B.H.2) did not differ significantly means that a single breath is as effective as five breaths in allowing the resumption of breath holding. There was a certain degree of variability in the performance of individual subjects. This was probably due in part to the larger lung volumes and less definite end points in the earlier experiments, as well as to lack of experience. However, the results with residual volume breath holding confirmed the earlier findings. We know of no previous work to define the number of breaths required to permit a breath hold. Our subsequent use of the rebreathing 'open-loop' situation was to define the relationship between breath holding time and pco2 so that it could be compared under different conditions. Fowler [1954] first showed that serial breath holding and rebreathing was possible, but his subjects were also hypoxic and he made no attempt to quantitate the relationship. As we have shown (fig. 4), there is an almost linear relationship for either initial or final pco2. This follows from the fact that the rise of pco2 during the breath hold is itself a linear function of the breath holding time. It is clear that no single level of pco2 will exist at the breaking point of a breath hold, the final pco2 depending on the initial pco2. For this reason we have chosen to relate the breath holding time to the initial pco2 rather than the more conventional final pco2. We believe that the pco2 may affect the breath hold right from its beginning; in most sensory experience duration is as important as intensity. The lines relating breath holding time to initial and final pco2 converge as the breath holding time falls and they would meet at a pco2 at which

11 Control of Breath Holding 127 breath holding is impossible (BBH). This pco2, usually about 70 to 80 mm Hg, could reasonably be considered as the true PCO2 threshold; or rather the sensation due to CO2 has now reached the breaking point threshold for total sensation during breath holding [Godfrey and Campbell, 1968]. It is very uncomfortable for the subject at these levels of pco2, but in experiments where this has been achieved the breath holding time falls 25 * Serial breath holds x Single breath holds, x S.F. -= 10_X INITIAL PCO2 (mm.hg.) Fig. 6. Breath holding-co2 response curves in one subject obtained by serial breath holds separated by rebreathing ( * - 0 ), or by entirely separate experiments in which the subject rebreathed up to the desired PCO2 and then held his breath (x-x). The curves are essentially similar. to one or two sec and it is impossible to distinguish between breath holding and rebreathing. It did seem possible that the fall in breath holding time during the experiments might have been partly due to fatigue. We therefore allowed one subject (S.F.) to rebreathe to various levels of pco2 before beginning the breath hold: We found his breath holding time was the same as when there had been a preceding breath hold(s) interspersed with the rebreathing (fig. 6). As the level of pco2 rises during the experiment, so a ventilatory response occurs and the ventilation increases during the rebreathing periods. It has been shown that hyperventilation may cause the central respiratory mechanisms to habituate to a new level of ventilation even when the pco2 is prevented from falling [Smith et al., 1961]. In our experiments, a short period of severe isocapnic hyperventilation did not displace the breath holding-co2 response curve, which suggests that the pattern of breathing has little effect on a subsequent breath hold.

12 128 Godfrey and Campbell The experiments described in this paper imply that there is no breaking point threshold for pco2, the only true threshold being the pco2 at which breath holding becomes impossible. The duration of a breath hold is directly related to pco2 below this true threshold, whether the initial or final value is considered, and it is independent of the size of previous mechanical experience. In the following paper, the relevance of lung shrinkage during breath holding is considered. ACKNOWLEDGEMENT We thank our colleagues who acted as subjects for these experiments. REFERENCES CAIN, S. M. (1957). 'Breaking point of two breath holds separated by a single inspiration', J. appl. Physiol. 11, CAMPBELL, E. J. M. and HowELL, L. B. J. (1960). Simple rapid methods for estimating arterial and mixed venous PCO2', Br. med. J COLLIER, C. R. (1956). 'Determination of mixed venous CO2 tensions by rebreathing', J. appl. Physiol. 9, DOUGLAS, C. G., and HALDANE, J. S. (1909). 'The regulation of normal breathing', J. Physiol. (Lond.), 38, FOWLE, A. S. E., and CAMPBELL, E. J. M. (1964). 'TThe immediate carbon dioxide storage capacity of man', Clin. Sci. 27, FOWLER, W. S. (1954). 'Breaking point of breath holding', J. appl. Physiol. 6, FREEDMAN, S. (1966). 'Prolonged maximum voluntary ventilation', J. Physiol. (Lond.), 184, GODFREY, S., and CAMPBELL, E. J. M. (1968). 'The control of breath holding', Resp. Physiol. 5, HILL, L., and FLACK, M. (1908). 'The effect of excess carbon dioxide and of want of oxygen upon the respiration and the circulation', J. Physiol. (Lond.), 37, KLOCKE, F. J., and RAHN, J. (1959). 'Breath holding after breathing oxygen', J. appl. Physiol. 14, LLOYD, B. B., JUKES, M. G. M., and CUNNINGHAM, D. J. C. (1958). 'The relationship between alveolar oxygen pressure and the respiratory response to carbon dioxide in man', Q. Ji exp. Physiol., 43, MITHOEFER, J. C. (1959). 'Lung volume restriction as a ventilatory stimulus during breath holding', J. appl. Physiol., 14, MITHOEFER, J. C. (1964). Breath holding. In Handbook of Physiology. Section 3: Respiration. Vol.II,pp AmericanPhysiologicalSociety. Washington D.C. MUXWORTHY, J. F. JR. (1951). Breath holding studies: relationship to lung volume. A. F. Tech. Rep. 6528, , Wright-Patterson Air Force Base, Dayton, Ohio. OTIS, A. B., RAHN, H., and FENN, W. 0. (1948). 'Alveolar gas changes during, breath holding', Am. J, Physiol., 152, READ, D. J. C. (1967). 'A clinical method for assessing the ventilatory response to carbon dioxide', Aust. Ann. Med., 16, READ, D. J. C., and LEIGH, J., (1967) 'Blood-brain tissue pco2 relationships and ventilation during rebreathing', J. appl. Physiol., 23, SMITH, A. C., SPALDING, J. M. K., and WATSON, W. E. (1961). 'Ventilation volume as a stimulus to spontaneous ventilation after prolongecl artificial ventilation', J. Physiol. (Lond.), 160,