362 30.
ROBERTS-THOMSON ET AL.
FRY.L., SEAH.
of skin lesions
-,1uu
1
_I".
31. VLADUTIU, A. 0.and ROSE,N. R (1974): HL-A antigens: associated with disease, lmrnunogenerics I, 305.
VOL.
7,
NO.
4
A,, VAN HOCJFP.J. P and 32. KUENING.J. J., PENA,A. S., VAN LEEUWEN, VANROOD,I. J. (1976): HLA-DW3 associated with coeliac disease. Lancer 1, 506. 33. FERCUSON, A., MACDONALD, T. T.. MCCLURE,J. P. and HOLDEN,R. I. (1975): Cell-mediated immunity to gliadin within the small-intestinal mucosa in coeliac disease, Lancer 1, 895.
Aust. N.Z. J. Med. (1977). 7. vv. 362-367
A Test of the Ventilatory Response to Hypoxia and Hypercapnia for Clinical Use M. J. Hensley" and D. J. C. Read? From the Department of Physiology, University of Sydney
SUInI'nary: A test of the ventilatory response to hypoxia and hypercapnia for clinical use. M. J. Hensley and D. J. C. Read, Aust. N.Z.J. Med., 1977, 7, pp. 362-367.
A new technique is described for testing the ventilatory response to hypoxia and to hypercapnia. The test consists of interposing 15-20 seconds of hypoxia in 3-4 minutes of rebreathing 7% CO,; the hypoxia is induced by taking three to five breaths from a bag containing N,, and CO, at an identical level. When required, hypoxic tests can be performed at several different PCO, levels to define the interaction of hypoxic and hypercapnic stimuli. In eight healthy subjects, 29 hypoxic tests were performed, at an average PCO, of 58 mm Hg (range 53-64). The correlation between ventilatory increments and 0 , desaturation was significant in 27 of the 29 tests (r = 0.87-0.99). A t the minimum 0 , -saturation (average 85%; range 759 I %) there was a statistically significant ventilatory response to hypoxia in all 29 tests (average +60%; range + 14 to -+ 141%). A t 90% 0,-saturation, the average increment of ventilation was +48%. This method has important theoretical and practical advantages for clinical studies: "N.H. and M.R.C. Postgraduate Research Scholar. ?Associate Professor of Physiology. University of Sydney Correspondence: Associate Professor D . J. C. Read, Department of Physiology, University of Sydney, NSW 2006 Accepted for publication: 30 March, 1977
( i ) the test involves only 15-20 seconds of hypoxia; (ii) since the hypoxic drive t o breathing is greatly enhanced by h ypercapnia only a mild degree of hypoxaemia is necessary to obtain a clearly defined response; (iii) the augmented ventilation, produced by rebreathing, allows N , to be rapidly introduced into the lungs without the need for voluntarily imposed deep breathing; (iv) the elevated PCO, increases cerebral blood flow and minimises brain tissue h ypoxia. (v) Since rebreathing 7% CO, greatly reduces mixed venous-arterial and cerebral tissue-arterial PCO, differences, the cerebral tissue PCO, and CO, stimulus are virtually unaffected by both ventilatory and cerebral blood flow responses in this test.
In respiratory failure the severity of hypoxaemia and carbon dioxide retention depends on two opposing factors : (i) the degree of inefficiency of pulmonary gas-exchange ; (ii) any compensatory increase 'of ventilation mediated by chemoreceptors. The response of the brainstem chemoreceptors to COz can be tested by rebreathing an oxygen enriched 7 "/d carbon dioxide mixture.' Such tests reveal major individual differences in the carbon dioxide sensitivity of healthy subjects' and a sequential depression of responses in the course of disease in individual patient^.^ The ventilatory responses to hypoxaemia have not been studied so extensively since the usual tests are not suitable for clinical studies. This is unfortunate since it appears that the
AUGUST
1977
hypoxic ventilatory drive can be depressed by prolonged hypoxaemia4 and other causes, resulting in more severe respiratory failure.’ The present paper reports a new test which simply and rapidly defines the response to both carbon dioxide and to hypoxaemia. A brief report of this study has been presented previously.6 Materials and Methods
The eight subjects, seven males and one female, were members of the medical or laboratory staff of the Department of Physiology. Ages ranged from 22 to 40. All were physically fit, though not in athletic training. No subject had been born or lived at high altitude. One subject was a smoker (10-15 cigarettes per day) and two were ex-smokers. All had normal spirometry (Table 1). The subjects gave informed consent and all were familiar with the rebreathing procedure. Subjects were not provided with any results until the study was completed. The protocol was approved by the Ethical Review Committee of the Faculty of Medicine, University of Sydney. TABLE 1 Physical characteristics of subjects.
Subject
363
VENTILATION IN HYPOXIA AND HYPERCAPNIA
Age (yr)
Sex
31 40 23 31 20 29 30 28
M M M M M F M M
Height Weight FEVl (cm) (kg) (litre) 175 174 173 185 175 165 178 178
74 75 60 85 65 58 70 79
4.2 4.4 4.4 4.5 5.0 3.7 5.2 5.5
VC (litre) 5.5
4.9 5.0 6 .0 5 .1 4.6 6 .2 6.0
Hypoxic Test Procedure The test defines the ventilatory responses to 15-20 seconds of hypoxia, interposed during four minutes of progressive hypercapnia. The desired changes were achieved by breathing from three bags in sequence (Fig. 1). The test was commenced by rebreathing 4-6 litres of a 7 % COz mixture, enriched with O2 (30-35Y0); the end-tidal P C 0 2 was closely followed until it had risen to a predetermined level, identical to bag 2. Inspiration then was switched to the N2/COZmixture of bag 2 to produce 15-20 seconds of progressive hypoxia. To enable rapid exchange of nitrogen for oxygen in the lungs, bag 2 (approximately 20 litres) incorporated a valve-box to prevent re-inspiration of expired oxygen. After taking 3-5 breaths from the second bag, the subject was switched to rebreathe from the third bag containing oxygen, again with C 0 2 at the same level (see typical record Fig. 2). The P C 0 2 values for bags 2 and 3 can be chosen to provide tests at any desired level of hypercapnia. Arterial oxygen saturation was monitored continuously by an ear-oximeter (Waters 0-500).For our studies of normal subjects, this instrument was calibrated by assuming 1000; saturation during oxygen-breathing, and 97 9; during airbreathing at an end-tidal PO, of 100 mmHg (Godart Rapox paramagnetic analyzer). In patients, the ear-oximeter
n
i
%EAR
-.
-FLOWMETER TIDAL VOLUME OXiMETER E.C.G. MONITOR
FlGUR 1 . Respiratory circuit for producing 15-20 seconds of hypoxia during rebreathing of 7% CO,. Arrow represents 4-way tap. Other details discussed in text. can be used to accurately time the events in relation to intermittent blood sampling, since the oximeter has the advantage of providing a virtually instantaneous record when saturation is changing rapidly; in such tests, the oximeter calibration can be obtained from arterial POz measurements. The PCO, was recorded by an infra-red C 0 2 analyzer (Godart Capnograph) which was calibrated with standard gases analyzed by the Haldane technique. The ventilatory responses were obtained from airflow records (Fleisch pneumotachograph, Validyne MP45 pressure-transducer and Hewlett-Packard 8805A carrier preamplifier). For convenience, we used an on-line computer (PDP-11) to derive tidal volume and minute-ventilation, breath-by-breath; these results were presented numerically and as analogue signals for the pen-recorder. For simplicity at the bed-side, the same information can be obtained by enclosing the bags in a box and using a spirometer. In the course of developing this new test, the healthy volunteers were subjected to several tests, on one or more occasions, which involved varying degrees of hypoxia and hypercapnia (see Table 2 and Fig. 3). All tests were performed with the subject seated comfortably in a quiet room listening to music through head-phones. For safety, the electrocardiogram was monitored continuously and facilities were available for resuscitation. No electrocardiogram abnormalities were detected in the subjects tested.
FIGURE 2. Record illustrating a typical response to transient hypoxia during 7% CO, rebreathing in a normal subject. (Subject 1 ) . The details of the traces are discussed in the text.
364
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TABLE 2 Ventilatory responses to hypoxia and hypercapnia Linear approximation of hypoxic response Test Subject
Day
( O 0 )
Control V,t /mi;-' ( +S D)
min S ~ O , Imin-'
Minimum Sa02*
V, at Imin-' 90 SaO,
0, at -
/min-'/",
Imin-'/mmHg
49+5 49+1 4320.1 63k4
3.0 1.4 1.5 3.5
2.3 2.6 3-0 4.1
0.92 0.84
3611 38+2
1 -0 0.8
1-8 1.7
7 7
0.97 0.85 0.91
6812 64+7 7015
2-7 3.4 3.1
5.8 4.3 7.9
1
57 57 57 57
89 77 80 86
24+ 1 2821 31+1 34+ 1
44 64 57 69
7 7 7
'7.
1
58 59
82 78
2911 31+1
44 41
8
57 57 56
90 91 88
5 0 j1 35+1 52+ I
65 55 73
1
(+sD)
AVllAPC02 Bag 1
0.88 0.97 0.99 0.93
1
3
,.**
AVl/ASaO, Slope
I I I
4
1
54 56
86 89
64+ 1 74+1
75 84
5 6
0.69 0.91
74+5 8814
1.1 2-6
5.4 6.2
5
1
59 63 64
83 90 89
37+1 66+1 80+ 1
67 100 111
7 6 7
0.85 0.90 0.91
5914 108+9 11517
2.1 5.2 4.8
2.8 4.3 4.5
6
1 2
55 53 54 53
89 87 86 84
34k0.4 2720.5 30f0.5 26k0.5
48 42 52 57
7 7 7 8
0.95 0.94 0.99 0.99
49+2 40+2 46,l 45+l
1.7 1.7 2.0 2.3
2.9 3.7 3.4 3.4
7
1
60 59 58 60 60 58 59 59
91 89 76 88 75 87 82 90
54+2 48+2 66+2 69+2 65+2 575-3 71 + 3 49+4
64 74 86 87 117 91 126 81
6
6 6 5 6 6 9 7
0.81 0.94 0-88 0.95 0.97 0.99 0.26 0.94
75+8 71 + 4 75+2 84+5 77+3 8121 114+3 79+4
3.6 3.4 1.0 3.6 3.0 3.8 0.3 3.7
5.2 3.6 6.7 5.9 5.2 5.1 6.6 3.3
61 61 62
91 83 82
44+2 49&3 32+2
59 75 77
6 6 7
0.90 0.99 0.98
6323 63+ 1 61 + 2
1.8
2.0 2.6
5.0 4.3 4.1
2 3
8
1 7
&
*Sa02 = Arterial oxygen saturation. t V , = Minute ventilation; calculated from linear regression of PCO, and ventilation for first bag. (Documenta Geigy 1970). I n = Number of breaths. **r = Correlation coefficient for linear regression of SaOz and 0,. Results
The pen-recording of a typical response to transient hypoxia during 7 % C 0 2 rebreathing is presented in Figure 2 for a normal subject. The PCOz showed a step from the resting end-expiratory value of 41 mmHg to 49 mmHg at the onset of 7 % rebreathing (upper trace on left); subsequently the PC02 rose steadily to a final value of about 62 mmHg. The oxygen saturation, recorded by ear-oximeter, showed a transient fall from 99% to a minimum value of 88% over ten seconds (middle section of second trace); the mark below the trace indi-
cates the period of hypoxic breathing. The augmented responses of tidal volume and ventilation during the hypoxic stimulus were clearly separated from the control responses to COz alone (mid section of third and fourth traces); the CO, trace showed that the hypoxic transient occurred without any significant change of PC02. The oxygen saturation rose rapidly to lOOo/o after the period of hypoxia with an associated reduction in the tidal volume and ventilation records. This clearly established that the augmented ventilatory responses could not be attributed to any C 0 2 rise during the
AUGUST
1977
VENTILATION IN HYPOXIA AND HYPERCAPNIA
period of hypoxia. Only after some 90 seconds of continued rebreathing, and a further rise of 7 mmHg in the PCO, did the ventilatory response to C 0 2 per se attain levels comparable to that seen in the hypoxic period. Although all subjects showed a clearly defined increment of ventilation in response to hypoxia, a number of subjects continued ventilation in the posthypoxic period at levels higher than expected for hyperoxic C0,-rebreathing. This phenomenon is the subject of current investigation in our laboratory and appears consistent with the delayed return to control ventilation when carotid sinus nerve stimulation is suddenly withdrawn in anaesthetized cats7, ; this poststimulation hyperpnea has been attributed to a central neural process involving reverberating neural circuits in the reticular activating system. Although a significant response to hypoxaemia can be discerned directly from the records, it is useful to plot the breath-bybreath ventilation in response to the falling 0,-saturation (Fig. 3). This relationship between ventilation and 0,-saturation in general appeared linear, although some degree of curvilinearity sometimes was apparent due to smaller ventilatory increments per unit change of saturation later in the test. The results are summarized in Table 2 by reporting the control ventilation and ventilation at the minimum
Subwd 6
c
I
I
I
I
100
95
90
85
80
ARTERIAL OXYGEN SATURATION(%)
FIGURE 3. Replicate testing of hypoxic ventilatory responses showing high degree of reproducibility (Sub, replicate tests at ject 6). 0 August 1975; @ A the same session, August 1976.
=
365
0,-saturation ; in addition, the correlation coefficient and the least squares regression were computed for each hypoxic response. A high degree of correlation was found in most cases (Table 2; P < 0.05 in 27/29 tests). The reproducibility of replicate tests can be examined in Table 2, for both the response to CO, and to hypoxia. In some of the present subjects the ventilatory responses to CO, prior to hypoxia varied considerably between replicates. The basis for this variability is not known but the brief period over which this response was analysed and subject anxiety may be factors. In practice if the CO, response needs to be quantitated accurately one would obtain replicates with a full four minutes of CO, rebreathing in the absence of hypoxia. The possibility of attaining highly reproducible results under good conditions is shown in Figure 3. This subject, a nurse, not only showed highly reproducible responses to CO, and to hypoxia at a single session on repeated testing, but also showed a virtually identical response to that obtained at a session some 12 months previously. Discussion
Our new test of the hypoxic drive to breathing has- important advantages for clinical studies : (i) the test involves only 15 to 20 seconds of hypoxia ; (ii) since the ventilatory response to hypoxaemia is greatly enhanced by hypercapniag, it is only necessary to produce a mild degree of hypoxaemia to obtain a clearly defined ventilatory response ; (iii)by rebreathing CO, and augmenting ventilation, a method is provided which can rapidly replace the oxygen in the lungs k ith nitrogen ; this avoids the disturbance produced in previous tests" when nitrogen is introduced by voluntarily imposed deep breathing. These various advantages, which might be expected from a theoretical examination of the method, were borne out by our results : averaged data showed that a reduction of arterial saturation to only 8 5 % (PO, about 55 mmHg) increased ventilation 60%, an increment which was easily observed and clearly separated statistically from the control. In previously reported tests4- the practice has been to reduce arterial oxygen tension to
366
HENSLEY AND READ
about 40 mmHg (saturation about 757;) over 5-10 minutes. In such tests the arterial PCO, usually has been kept at its resting value or slightly above, which may be appropriate in physiological research. In clinical practice, not only is a test improved by concurrently increasing the PC02, but this also has the advantage that it focuses attention on the reflex defenses against combined hypoxaemia and hypercapnia, i.e., the defense against acute exacerbations of respiratory failure. More subtle physiological advantages arise under the conditions of the present test. The elevation of PCO, prior to the introduction of hypoxia would be expected to greatly increase cerebralI2 and coronary blood flow.I3 These blood flow increments would minimize the reduction of tissue oxygen tension. This expectation is supported by a recent report showing that the presence of hypercapnia enabled the oxygen saturation to be reduced to a lower level before hypoxic changes occurred in the electroencephalogram.’4 Another technical problem of testing is circumvented. In most procedures, it is very difficult, if not impossible, to establish levels of brain tissue PCO, and C0,-stimulus under clearly defined conditions which are undisturbed by secondary factors, such as the increase of cerebral blood flow which occurs in response to both hypercapnia and hypoxia. During rebreathing of 7 % CO, there is a sudden step of arterial PCO, at the onset of the test and subsequent linear PCO, rise; these changes would be expected to greatly reduce the cerebral tissue-arterial blood PCO, difference and hold this difference relatively constant and independent of cerebral blood flow.” With these conditions and a brief episode of hypoxia, it follows that the hypoxic ventilatory response is measured under conditions in which brain tissue P C 0 2 cannot be disturbed by ill-defined variations in cerebral blood flow. In most of the previously published tests these technical difficulties have been either accepted or ignored. The most common approach has been to add varying amounts of CO, to the inspired gas mixture,’to offset the secondary disturbances of arterial PCO, which would otherwise result from the ventilatory
VOL.
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response to the h y p ~ x i a . This ~ procedure presumably is better than that used in the earlier tests, in which the PCOz was allowed to fall and to secondarily inhibit the hypoxic response. However the workers who stabilize arterial PCO, still ignore the problem of increasing cerebral blood flow in hypoxia and the resultant alteration of brain tissue PCO, and C0,stimulus. In addition patients with lung disease and ventilation/perfusion mismatching are likely to have varying end-tidal-arterial PCO, relationships during hypoxic ventilatory disturbances. A recently proposed’6 and widely advocated “isocapnic” hypoxic test” has been claimed to produce “open loop” conditions in which the stimuli to breathing are independent of the ventilatory responses. The terms “isocapnic” and “open loop” when applied to the hypoxic are mistest developed by Rebuck et leading : when the arterial PCO, is suddenly increased to the mixed venous value and subsequently held constant, the brain tissue PCO, and C0,-stimulus cannot be assumed steady, since a slow rise of brain tissue PCO, to some new steady value will occur’*; under such circumstances the C0,-stimulus not only changes with time, but depends on the degree and time-course of the hypoxia and the responses of the cerebral circulation. The term “open-loop’’ is valid when applied to rebreathing 70,; CO, since the arterial PCO, rise cannot be modified by different responses of ventilation, when an equilibrium is established and maintained between the mixed venous and arterial PC02.1s An “openloop” for oxygen can only exist when a similar equilibrium exisfs between oxygen tensions of mixed venous and arterial blood. Unfortunately these conditions are not maintained for either CO, or 0, in the previously reported tests.”. l6 With the brief period of hypoxia in our test and the unusually small “cerebral tissue-arterial blood PCO, differences’ 5 , these serious difficulties are largely circumvented as discussed previously. At the present time, our new test is being put forward as a clinical procedure to provide information on a patient’s ability to augment ventilation when hypoxia is superimposed on hypercapnia in an acute exacerbation of respir-
AUGUST
1977
VENTILATION IN HYPOXIA AND HYPERCAPNIA
atory failure. The measurement of ventilation rather than indices of effort is appropriate in such clinical circumstances, since an adequate increase in ventilation is required to avoid lifethreatening hypoxia. However, when the question is focused on “drive” or “effort” our test could be modified very simply to measure such indices as work of breathing or pressure developed by respiratory muscles during tracheal occlusion. We wish to emphasize that our test should be regarded as a clinical diagnostic procedure, at the present stage of our investigations. Before our test is advocated for general use in physiological research, the quantitative indices of response should be related to specific physiological events such as the speeds of action and the interactions between different chemoreceptors and stimuli. The carotid bodies are generally thought to react to hypoxia within 1-2 secondslg, and to be the principal receptors mediating the ventilatory response to hypoxia. The brief exposure and rapid onset of hypoxia in our test is thus appropriate in a general sense. However it seems likely that the overall response to hypoxia does involve some slower components” which may be underestimated in a test lasting only 15-20 seconds. On the basis of our current experience, we suggest that evaluation of ventilatory responsiveness to hypoxia can now be undertaken in clinical practice. When arterial oxygen tension is markedly reduced, a test producing further hypoxia is not required since information can be obtained simply and safely by measuring the immediate ventilatory response to one or more breaths of oxygen. When arterial oxygen tension is normal or only moderately reduced, this new hypoxic test can provide useful information about the integrity of the reflex defenses against an acute exacerbation of respiratory
367
failure. Initially it is expected that such tests would be performed in larger hospitals by appropriately experienced staff. For safety, the procedure should incorporate electrocardiographic monitoring and facilities for resuscitation. Acknowledgements
This work was supported by a grant from the National Health and Medical Research Council of Australia. Equipment was provided by the Asthma Foundation of New South Wales and the Coppleson Postgraduate Medical Foundation of the University of Sydney. References I. READ, D. I. C. (1967). A clinical method for assessing the ventilatory response to carbon dioxide, Aust. Ann. Med. 16, 20. 2. BERAL,V. and READ,D. J. C. (1971): Insensitivity of respiratory centre to carbon dioxide in the Enga People of New Guinea, Lancer 2, 1290. 3. READ,D. J. C. 11970): The clinical investigation of the regulation of breathing. M.D. Thesis, University of Sydney, 1970. 4. WEIL, J . V., BYRNE-QUINN, E., SODAL,I. E., FILLEY, G. F. and GROVER, R. F. (1971):Acquired attenuation of chemorecptor function in chronically hypoxic man at high altitude, J. din. Invest. 50, 186. 5 . HUDGEL, D. W. and Well, J. V. (1975): Depression of hypoxic and hypercapnic ventilatory drives in severe asthma, Chest 68, 493. 6 . HENSLEY, M. J. and READ,D. J C. (1975): Testing the hypoxic drive to breathing-a new approach, Ausr. N Z . J. Med. 5, 481. 7. ELDR~DGE. F. L. (1974): Central neural respiratory stimulatory effect of active respiration, J appl. Phy&iol.31, 723. 8. ELDRIDGE, F. L (1976): Central neural stimulation of respiration in unanaesthetized decerebrate cats, J. appl. Physroi. 40, 23. 9. NIELSEN, M. and SMITH,H. (1952): Studies on the regulation of respiration in acute hypoxia, Acfa physrol. scand. 24, 293. 10. KRONENBERG, R , HAMILTON, F. N., GABEL,R., HICKEY, R., READ,D. J. C. and SEVERINGHAUS, J. ( 1972): Comparison of three methods for quantitating respiratory response to hypoxia in man, Resp. Phvsiol. 16, 109. I I . GODPREY,. S.. ED WARDS;^. H. T., COPLAND.G. M. and GROSS,P. L. (I971 ) : Chemosensitivity in normal subjects, athletes, and patients with chronic airways obstruction. J. appl. Pkys,ol 30, 193. 12. BETZ, E. (1972). Cerebral blood flow: Its measurement and regulation, Physrol. Rev. 52, 595. 13. CASE.R. B.. GREENBERG. H. and MosKowlrz. R. 11975): Alterations in coronary sinus PO, and Oi saturation resulting from PCOl changes, Cardiovasc. Res. 9, 167. 14. REBUCK, A. S., DAVIS,C., LONGMIRE, D.. UPTON, A. R. M. and POWLES, A. C. P. (1976): Arterial oxygenation and carbon dioxide tensions in the production of hypoxic electro-encephalographicchanges in man. Clin. Sci. and Mol. Med. SO, 301. 15. READ,D. J. C. and LEIGH. J. (19671: Blood-bram tissue PCO, relationships and ventilation during rebreathing, 1. uppl Physrol. 23, 53. E. J. M. (1974): A clinical method for 16. REBUCK,A. S. and CAMPBELL, assessing the ventilatory response to hypoxia, Amer. Rev. r a p . Dis. 109,345. 17. MILIC-EMILL J. (1975): Clinical methods for assessing the ventilatory response to carbon dioxide and hypoxla, New Engl. J. Med. 293, 864. 18. READ,D. J. C., HENSLEY! M. I. and NICKDLLS,P. M. (1976): Are the brain tissue CO, and C0,-drive constant in “isocapnic” tests of the hypoxic stimulus to breathing, Proc. Australian Physiol. Pharmocol. SOC.7 , 20P. 19. PONTE,J. C. hlr R. and PURVES,M. J (1975): On the speed of response of the chemoreceptors. In: The Peripheral Arterial Chemoreceptors, M. J Purves led.), Cambridge University Press, London, p. 357. Proceedings of an International Workshop. 20. SMITH.E. J and DUTTON.R. E. (1974): Dynamic model of ventilatory response to changes in PO, at the carotid body chemoreceptors. IEEE. Trans. Biomed. Eng. 21, 227.
ROBERTS-THOMSON ET AL.
FRY.L., SEAH.
of skin lesions
-,1uu
1
_I".
31. VLADUTIU, A. 0.and ROSE,N. R (1974): HL-A antigens: associated with disease, lmrnunogenerics I, 305.
VOL.
7,
NO.
4
A,, VAN HOCJFP.J. P and 32. KUENING.J. J., PENA,A. S., VAN LEEUWEN, VANROOD,I. J. (1976): HLA-DW3 associated with coeliac disease. Lancer 1, 506. 33. FERCUSON, A., MACDONALD, T. T.. MCCLURE,J. P. and HOLDEN,R. I. (1975): Cell-mediated immunity to gliadin within the small-intestinal mucosa in coeliac disease, Lancer 1, 895.
Aust. N.Z. J. Med. (1977). 7. vv. 362-367
A Test of the Ventilatory Response to Hypoxia and Hypercapnia for Clinical Use M. J. Hensley" and D. J. C. Read? From the Department of Physiology, University of Sydney
SUInI'nary: A test of the ventilatory response to hypoxia and hypercapnia for clinical use. M. J. Hensley and D. J. C. Read, Aust. N.Z.J. Med., 1977, 7, pp. 362-367.
A new technique is described for testing the ventilatory response to hypoxia and to hypercapnia. The test consists of interposing 15-20 seconds of hypoxia in 3-4 minutes of rebreathing 7% CO,; the hypoxia is induced by taking three to five breaths from a bag containing N,, and CO, at an identical level. When required, hypoxic tests can be performed at several different PCO, levels to define the interaction of hypoxic and hypercapnic stimuli. In eight healthy subjects, 29 hypoxic tests were performed, at an average PCO, of 58 mm Hg (range 53-64). The correlation between ventilatory increments and 0 , desaturation was significant in 27 of the 29 tests (r = 0.87-0.99). A t the minimum 0 , -saturation (average 85%; range 759 I %) there was a statistically significant ventilatory response to hypoxia in all 29 tests (average +60%; range + 14 to -+ 141%). A t 90% 0,-saturation, the average increment of ventilation was +48%. This method has important theoretical and practical advantages for clinical studies: "N.H. and M.R.C. Postgraduate Research Scholar. ?Associate Professor of Physiology. University of Sydney Correspondence: Associate Professor D . J. C. Read, Department of Physiology, University of Sydney, NSW 2006 Accepted for publication: 30 March, 1977
( i ) the test involves only 15-20 seconds of hypoxia; (ii) since the hypoxic drive t o breathing is greatly enhanced by h ypercapnia only a mild degree of hypoxaemia is necessary to obtain a clearly defined response; (iii) the augmented ventilation, produced by rebreathing, allows N , to be rapidly introduced into the lungs without the need for voluntarily imposed deep breathing; (iv) the elevated PCO, increases cerebral blood flow and minimises brain tissue h ypoxia. (v) Since rebreathing 7% CO, greatly reduces mixed venous-arterial and cerebral tissue-arterial PCO, differences, the cerebral tissue PCO, and CO, stimulus are virtually unaffected by both ventilatory and cerebral blood flow responses in this test.
In respiratory failure the severity of hypoxaemia and carbon dioxide retention depends on two opposing factors : (i) the degree of inefficiency of pulmonary gas-exchange ; (ii) any compensatory increase 'of ventilation mediated by chemoreceptors. The response of the brainstem chemoreceptors to COz can be tested by rebreathing an oxygen enriched 7 "/d carbon dioxide mixture.' Such tests reveal major individual differences in the carbon dioxide sensitivity of healthy subjects' and a sequential depression of responses in the course of disease in individual patient^.^ The ventilatory responses to hypoxaemia have not been studied so extensively since the usual tests are not suitable for clinical studies. This is unfortunate since it appears that the
AUGUST
1977
hypoxic ventilatory drive can be depressed by prolonged hypoxaemia4 and other causes, resulting in more severe respiratory failure.’ The present paper reports a new test which simply and rapidly defines the response to both carbon dioxide and to hypoxaemia. A brief report of this study has been presented previously.6 Materials and Methods
The eight subjects, seven males and one female, were members of the medical or laboratory staff of the Department of Physiology. Ages ranged from 22 to 40. All were physically fit, though not in athletic training. No subject had been born or lived at high altitude. One subject was a smoker (10-15 cigarettes per day) and two were ex-smokers. All had normal spirometry (Table 1). The subjects gave informed consent and all were familiar with the rebreathing procedure. Subjects were not provided with any results until the study was completed. The protocol was approved by the Ethical Review Committee of the Faculty of Medicine, University of Sydney. TABLE 1 Physical characteristics of subjects.
Subject
363
VENTILATION IN HYPOXIA AND HYPERCAPNIA
Age (yr)
Sex
31 40 23 31 20 29 30 28
M M M M M F M M
Height Weight FEVl (cm) (kg) (litre) 175 174 173 185 175 165 178 178
74 75 60 85 65 58 70 79
4.2 4.4 4.4 4.5 5.0 3.7 5.2 5.5
VC (litre) 5.5
4.9 5.0 6 .0 5 .1 4.6 6 .2 6.0
Hypoxic Test Procedure The test defines the ventilatory responses to 15-20 seconds of hypoxia, interposed during four minutes of progressive hypercapnia. The desired changes were achieved by breathing from three bags in sequence (Fig. 1). The test was commenced by rebreathing 4-6 litres of a 7 % COz mixture, enriched with O2 (30-35Y0); the end-tidal P C 0 2 was closely followed until it had risen to a predetermined level, identical to bag 2. Inspiration then was switched to the N2/COZmixture of bag 2 to produce 15-20 seconds of progressive hypoxia. To enable rapid exchange of nitrogen for oxygen in the lungs, bag 2 (approximately 20 litres) incorporated a valve-box to prevent re-inspiration of expired oxygen. After taking 3-5 breaths from the second bag, the subject was switched to rebreathe from the third bag containing oxygen, again with C 0 2 at the same level (see typical record Fig. 2). The P C 0 2 values for bags 2 and 3 can be chosen to provide tests at any desired level of hypercapnia. Arterial oxygen saturation was monitored continuously by an ear-oximeter (Waters 0-500).For our studies of normal subjects, this instrument was calibrated by assuming 1000; saturation during oxygen-breathing, and 97 9; during airbreathing at an end-tidal PO, of 100 mmHg (Godart Rapox paramagnetic analyzer). In patients, the ear-oximeter
n
i
%EAR
-.
-FLOWMETER TIDAL VOLUME OXiMETER E.C.G. MONITOR
FlGUR 1 . Respiratory circuit for producing 15-20 seconds of hypoxia during rebreathing of 7% CO,. Arrow represents 4-way tap. Other details discussed in text. can be used to accurately time the events in relation to intermittent blood sampling, since the oximeter has the advantage of providing a virtually instantaneous record when saturation is changing rapidly; in such tests, the oximeter calibration can be obtained from arterial POz measurements. The PCO, was recorded by an infra-red C 0 2 analyzer (Godart Capnograph) which was calibrated with standard gases analyzed by the Haldane technique. The ventilatory responses were obtained from airflow records (Fleisch pneumotachograph, Validyne MP45 pressure-transducer and Hewlett-Packard 8805A carrier preamplifier). For convenience, we used an on-line computer (PDP-11) to derive tidal volume and minute-ventilation, breath-by-breath; these results were presented numerically and as analogue signals for the pen-recorder. For simplicity at the bed-side, the same information can be obtained by enclosing the bags in a box and using a spirometer. In the course of developing this new test, the healthy volunteers were subjected to several tests, on one or more occasions, which involved varying degrees of hypoxia and hypercapnia (see Table 2 and Fig. 3). All tests were performed with the subject seated comfortably in a quiet room listening to music through head-phones. For safety, the electrocardiogram was monitored continuously and facilities were available for resuscitation. No electrocardiogram abnormalities were detected in the subjects tested.
FIGURE 2. Record illustrating a typical response to transient hypoxia during 7% CO, rebreathing in a normal subject. (Subject 1 ) . The details of the traces are discussed in the text.
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TABLE 2 Ventilatory responses to hypoxia and hypercapnia Linear approximation of hypoxic response Test Subject
Day
( O 0 )
Control V,t /mi;-' ( +S D)
min S ~ O , Imin-'
Minimum Sa02*
V, at Imin-' 90 SaO,
0, at -
/min-'/",
Imin-'/mmHg
49+5 49+1 4320.1 63k4
3.0 1.4 1.5 3.5
2.3 2.6 3-0 4.1
0.92 0.84
3611 38+2
1 -0 0.8
1-8 1.7
7 7
0.97 0.85 0.91
6812 64+7 7015
2-7 3.4 3.1
5.8 4.3 7.9
1
57 57 57 57
89 77 80 86
24+ 1 2821 31+1 34+ 1
44 64 57 69
7 7 7
'7.
1
58 59
82 78
2911 31+1
44 41
8
57 57 56
90 91 88
5 0 j1 35+1 52+ I
65 55 73
1
(+sD)
AVllAPC02 Bag 1
0.88 0.97 0.99 0.93
1
3
,.**
AVl/ASaO, Slope
I I I
4
1
54 56
86 89
64+ 1 74+1
75 84
5 6
0.69 0.91
74+5 8814
1.1 2-6
5.4 6.2
5
1
59 63 64
83 90 89
37+1 66+1 80+ 1
67 100 111
7 6 7
0.85 0.90 0.91
5914 108+9 11517
2.1 5.2 4.8
2.8 4.3 4.5
6
1 2
55 53 54 53
89 87 86 84
34k0.4 2720.5 30f0.5 26k0.5
48 42 52 57
7 7 7 8
0.95 0.94 0.99 0.99
49+2 40+2 46,l 45+l
1.7 1.7 2.0 2.3
2.9 3.7 3.4 3.4
7
1
60 59 58 60 60 58 59 59
91 89 76 88 75 87 82 90
54+2 48+2 66+2 69+2 65+2 575-3 71 + 3 49+4
64 74 86 87 117 91 126 81
6
6 6 5 6 6 9 7
0.81 0.94 0-88 0.95 0.97 0.99 0.26 0.94
75+8 71 + 4 75+2 84+5 77+3 8121 114+3 79+4
3.6 3.4 1.0 3.6 3.0 3.8 0.3 3.7
5.2 3.6 6.7 5.9 5.2 5.1 6.6 3.3
61 61 62
91 83 82
44+2 49&3 32+2
59 75 77
6 6 7
0.90 0.99 0.98
6323 63+ 1 61 + 2
1.8
2.0 2.6
5.0 4.3 4.1
2 3
8
1 7
&
*Sa02 = Arterial oxygen saturation. t V , = Minute ventilation; calculated from linear regression of PCO, and ventilation for first bag. (Documenta Geigy 1970). I n = Number of breaths. **r = Correlation coefficient for linear regression of SaOz and 0,. Results
The pen-recording of a typical response to transient hypoxia during 7 % C 0 2 rebreathing is presented in Figure 2 for a normal subject. The PCOz showed a step from the resting end-expiratory value of 41 mmHg to 49 mmHg at the onset of 7 % rebreathing (upper trace on left); subsequently the PC02 rose steadily to a final value of about 62 mmHg. The oxygen saturation, recorded by ear-oximeter, showed a transient fall from 99% to a minimum value of 88% over ten seconds (middle section of second trace); the mark below the trace indi-
cates the period of hypoxic breathing. The augmented responses of tidal volume and ventilation during the hypoxic stimulus were clearly separated from the control responses to COz alone (mid section of third and fourth traces); the CO, trace showed that the hypoxic transient occurred without any significant change of PC02. The oxygen saturation rose rapidly to lOOo/o after the period of hypoxia with an associated reduction in the tidal volume and ventilation records. This clearly established that the augmented ventilatory responses could not be attributed to any C 0 2 rise during the
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VENTILATION IN HYPOXIA AND HYPERCAPNIA
period of hypoxia. Only after some 90 seconds of continued rebreathing, and a further rise of 7 mmHg in the PCO, did the ventilatory response to C 0 2 per se attain levels comparable to that seen in the hypoxic period. Although all subjects showed a clearly defined increment of ventilation in response to hypoxia, a number of subjects continued ventilation in the posthypoxic period at levels higher than expected for hyperoxic C0,-rebreathing. This phenomenon is the subject of current investigation in our laboratory and appears consistent with the delayed return to control ventilation when carotid sinus nerve stimulation is suddenly withdrawn in anaesthetized cats7, ; this poststimulation hyperpnea has been attributed to a central neural process involving reverberating neural circuits in the reticular activating system. Although a significant response to hypoxaemia can be discerned directly from the records, it is useful to plot the breath-bybreath ventilation in response to the falling 0,-saturation (Fig. 3). This relationship between ventilation and 0,-saturation in general appeared linear, although some degree of curvilinearity sometimes was apparent due to smaller ventilatory increments per unit change of saturation later in the test. The results are summarized in Table 2 by reporting the control ventilation and ventilation at the minimum
Subwd 6
c
I
I
I
I
100
95
90
85
80
ARTERIAL OXYGEN SATURATION(%)
FIGURE 3. Replicate testing of hypoxic ventilatory responses showing high degree of reproducibility (Sub, replicate tests at ject 6). 0 August 1975; @ A the same session, August 1976.
=
365
0,-saturation ; in addition, the correlation coefficient and the least squares regression were computed for each hypoxic response. A high degree of correlation was found in most cases (Table 2; P < 0.05 in 27/29 tests). The reproducibility of replicate tests can be examined in Table 2, for both the response to CO, and to hypoxia. In some of the present subjects the ventilatory responses to CO, prior to hypoxia varied considerably between replicates. The basis for this variability is not known but the brief period over which this response was analysed and subject anxiety may be factors. In practice if the CO, response needs to be quantitated accurately one would obtain replicates with a full four minutes of CO, rebreathing in the absence of hypoxia. The possibility of attaining highly reproducible results under good conditions is shown in Figure 3. This subject, a nurse, not only showed highly reproducible responses to CO, and to hypoxia at a single session on repeated testing, but also showed a virtually identical response to that obtained at a session some 12 months previously. Discussion
Our new test of the hypoxic drive to breathing has- important advantages for clinical studies : (i) the test involves only 15 to 20 seconds of hypoxia ; (ii) since the ventilatory response to hypoxaemia is greatly enhanced by hypercapniag, it is only necessary to produce a mild degree of hypoxaemia to obtain a clearly defined ventilatory response ; (iii)by rebreathing CO, and augmenting ventilation, a method is provided which can rapidly replace the oxygen in the lungs k ith nitrogen ; this avoids the disturbance produced in previous tests" when nitrogen is introduced by voluntarily imposed deep breathing. These various advantages, which might be expected from a theoretical examination of the method, were borne out by our results : averaged data showed that a reduction of arterial saturation to only 8 5 % (PO, about 55 mmHg) increased ventilation 60%, an increment which was easily observed and clearly separated statistically from the control. In previously reported tests4- the practice has been to reduce arterial oxygen tension to
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about 40 mmHg (saturation about 757;) over 5-10 minutes. In such tests the arterial PCO, usually has been kept at its resting value or slightly above, which may be appropriate in physiological research. In clinical practice, not only is a test improved by concurrently increasing the PC02, but this also has the advantage that it focuses attention on the reflex defenses against combined hypoxaemia and hypercapnia, i.e., the defense against acute exacerbations of respiratory failure. More subtle physiological advantages arise under the conditions of the present test. The elevation of PCO, prior to the introduction of hypoxia would be expected to greatly increase cerebralI2 and coronary blood flow.I3 These blood flow increments would minimize the reduction of tissue oxygen tension. This expectation is supported by a recent report showing that the presence of hypercapnia enabled the oxygen saturation to be reduced to a lower level before hypoxic changes occurred in the electroencephalogram.’4 Another technical problem of testing is circumvented. In most procedures, it is very difficult, if not impossible, to establish levels of brain tissue PCO, and C0,-stimulus under clearly defined conditions which are undisturbed by secondary factors, such as the increase of cerebral blood flow which occurs in response to both hypercapnia and hypoxia. During rebreathing of 7 % CO, there is a sudden step of arterial PCO, at the onset of the test and subsequent linear PCO, rise; these changes would be expected to greatly reduce the cerebral tissue-arterial blood PCO, difference and hold this difference relatively constant and independent of cerebral blood flow.” With these conditions and a brief episode of hypoxia, it follows that the hypoxic ventilatory response is measured under conditions in which brain tissue P C 0 2 cannot be disturbed by ill-defined variations in cerebral blood flow. In most of the previously published tests these technical difficulties have been either accepted or ignored. The most common approach has been to add varying amounts of CO, to the inspired gas mixture,’to offset the secondary disturbances of arterial PCO, which would otherwise result from the ventilatory
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response to the h y p ~ x i a . This ~ procedure presumably is better than that used in the earlier tests, in which the PCOz was allowed to fall and to secondarily inhibit the hypoxic response. However the workers who stabilize arterial PCO, still ignore the problem of increasing cerebral blood flow in hypoxia and the resultant alteration of brain tissue PCO, and C0,stimulus. In addition patients with lung disease and ventilation/perfusion mismatching are likely to have varying end-tidal-arterial PCO, relationships during hypoxic ventilatory disturbances. A recently proposed’6 and widely advocated “isocapnic” hypoxic test” has been claimed to produce “open loop” conditions in which the stimuli to breathing are independent of the ventilatory responses. The terms “isocapnic” and “open loop” when applied to the hypoxic are mistest developed by Rebuck et leading : when the arterial PCO, is suddenly increased to the mixed venous value and subsequently held constant, the brain tissue PCO, and C0,-stimulus cannot be assumed steady, since a slow rise of brain tissue PCO, to some new steady value will occur’*; under such circumstances the C0,-stimulus not only changes with time, but depends on the degree and time-course of the hypoxia and the responses of the cerebral circulation. The term “open-loop’’ is valid when applied to rebreathing 70,; CO, since the arterial PCO, rise cannot be modified by different responses of ventilation, when an equilibrium is established and maintained between the mixed venous and arterial PC02.1s An “openloop” for oxygen can only exist when a similar equilibrium exisfs between oxygen tensions of mixed venous and arterial blood. Unfortunately these conditions are not maintained for either CO, or 0, in the previously reported tests.”. l6 With the brief period of hypoxia in our test and the unusually small “cerebral tissue-arterial blood PCO, differences’ 5 , these serious difficulties are largely circumvented as discussed previously. At the present time, our new test is being put forward as a clinical procedure to provide information on a patient’s ability to augment ventilation when hypoxia is superimposed on hypercapnia in an acute exacerbation of respir-
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VENTILATION IN HYPOXIA AND HYPERCAPNIA
atory failure. The measurement of ventilation rather than indices of effort is appropriate in such clinical circumstances, since an adequate increase in ventilation is required to avoid lifethreatening hypoxia. However, when the question is focused on “drive” or “effort” our test could be modified very simply to measure such indices as work of breathing or pressure developed by respiratory muscles during tracheal occlusion. We wish to emphasize that our test should be regarded as a clinical diagnostic procedure, at the present stage of our investigations. Before our test is advocated for general use in physiological research, the quantitative indices of response should be related to specific physiological events such as the speeds of action and the interactions between different chemoreceptors and stimuli. The carotid bodies are generally thought to react to hypoxia within 1-2 secondslg, and to be the principal receptors mediating the ventilatory response to hypoxia. The brief exposure and rapid onset of hypoxia in our test is thus appropriate in a general sense. However it seems likely that the overall response to hypoxia does involve some slower components” which may be underestimated in a test lasting only 15-20 seconds. On the basis of our current experience, we suggest that evaluation of ventilatory responsiveness to hypoxia can now be undertaken in clinical practice. When arterial oxygen tension is markedly reduced, a test producing further hypoxia is not required since information can be obtained simply and safely by measuring the immediate ventilatory response to one or more breaths of oxygen. When arterial oxygen tension is normal or only moderately reduced, this new hypoxic test can provide useful information about the integrity of the reflex defenses against an acute exacerbation of respiratory
367
failure. Initially it is expected that such tests would be performed in larger hospitals by appropriately experienced staff. For safety, the procedure should incorporate electrocardiographic monitoring and facilities for resuscitation. Acknowledgements
This work was supported by a grant from the National Health and Medical Research Council of Australia. Equipment was provided by the Asthma Foundation of New South Wales and the Coppleson Postgraduate Medical Foundation of the University of Sydney. References I. READ, D. I. C. (1967). A clinical method for assessing the ventilatory response to carbon dioxide, Aust. Ann. Med. 16, 20. 2. BERAL,V. and READ,D. J. C. (1971): Insensitivity of respiratory centre to carbon dioxide in the Enga People of New Guinea, Lancer 2, 1290. 3. READ,D. J. C. 11970): The clinical investigation of the regulation of breathing. M.D. Thesis, University of Sydney, 1970. 4. WEIL, J . V., BYRNE-QUINN, E., SODAL,I. E., FILLEY, G. F. and GROVER, R. F. (1971):Acquired attenuation of chemorecptor function in chronically hypoxic man at high altitude, J. din. Invest. 50, 186. 5 . HUDGEL, D. W. and Well, J. V. (1975): Depression of hypoxic and hypercapnic ventilatory drives in severe asthma, Chest 68, 493. 6 . HENSLEY, M. J. and READ,D. J C. (1975): Testing the hypoxic drive to breathing-a new approach, Ausr. N Z . J. Med. 5, 481. 7. ELDR~DGE. F. L. (1974): Central neural respiratory stimulatory effect of active respiration, J appl. Phy&iol.31, 723. 8. ELDRIDGE, F. L (1976): Central neural stimulation of respiration in unanaesthetized decerebrate cats, J. appl. Physroi. 40, 23. 9. NIELSEN, M. and SMITH,H. (1952): Studies on the regulation of respiration in acute hypoxia, Acfa physrol. scand. 24, 293. 10. KRONENBERG, R , HAMILTON, F. N., GABEL,R., HICKEY, R., READ,D. J. C. and SEVERINGHAUS, J. ( 1972): Comparison of three methods for quantitating respiratory response to hypoxia in man, Resp. Phvsiol. 16, 109. I I . GODPREY,. S.. ED WARDS;^. H. T., COPLAND.G. M. and GROSS,P. L. (I971 ) : Chemosensitivity in normal subjects, athletes, and patients with chronic airways obstruction. J. appl. Pkys,ol 30, 193. 12. BETZ, E. (1972). Cerebral blood flow: Its measurement and regulation, Physrol. Rev. 52, 595. 13. CASE.R. B.. GREENBERG. H. and MosKowlrz. R. 11975): Alterations in coronary sinus PO, and Oi saturation resulting from PCOl changes, Cardiovasc. Res. 9, 167. 14. REBUCK, A. S., DAVIS,C., LONGMIRE, D.. UPTON, A. R. M. and POWLES, A. C. P. (1976): Arterial oxygenation and carbon dioxide tensions in the production of hypoxic electro-encephalographicchanges in man. Clin. Sci. and Mol. Med. SO, 301. 15. READ,D. J. C. and LEIGH. J. (19671: Blood-bram tissue PCO, relationships and ventilation during rebreathing, 1. uppl Physrol. 23, 53. E. J. M. (1974): A clinical method for 16. REBUCK,A. S. and CAMPBELL, assessing the ventilatory response to hypoxia, Amer. Rev. r a p . Dis. 109,345. 17. MILIC-EMILL J. (1975): Clinical methods for assessing the ventilatory response to carbon dioxide and hypoxla, New Engl. J. Med. 293, 864. 18. READ,D. J. C., HENSLEY! M. I. and NICKDLLS,P. M. (1976): Are the brain tissue CO, and C0,-drive constant in “isocapnic” tests of the hypoxic stimulus to breathing, Proc. Australian Physiol. Pharmocol. SOC.7 , 20P. 19. PONTE,J. C. hlr R. and PURVES,M. J (1975): On the speed of response of the chemoreceptors. In: The Peripheral Arterial Chemoreceptors, M. J Purves led.), Cambridge University Press, London, p. 357. Proceedings of an International Workshop. 20. SMITH.E. J and DUTTON.R. E. (1974): Dynamic model of ventilatory response to changes in PO, at the carotid body chemoreceptors. IEEE. Trans. Biomed. Eng. 21, 227.
