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Drive and Timing Components of Ventilation
recording a pneumotachograph of inspired Bow through a low pass filter (RC 15 sec), but best by computing either as an analog or digital signal, the inspiratory tidal volume divided by the breath period.
=
Notes on Counselling Sub;ects Since ventilation is always a sum of chemical, wakeful and other extraneous stimuli, one may assume that a subject cannot voluntarily continuously hypoventilate. We counsel subjects to wait between breaths until they need to breathe. Subjects should not be told to breathe slowly, which may cause them to prolong the effort of inspiration (and expiration), nor should they be told to breathe less, since shallow breathing may result in increased vagal stimuli and tachypnea.
Minimization of Extraneous Stimuli Ventilation at rest is so easily stimulated that considerable effort and care. are needed to avoid these stimuli. Whereas we assume such stimuli are negligible when ventilation is driven by elevated CO 2 , some of these stimuli may augment hypoxic drive. Full bladder: Note that CO 2 breathing may cause diuresis. Discomfort: Tight nose clip, too large a mouthpiece, awkward head posture as required by apparatus, poor chair, cold drafts. Whispering: More stimulating than conversation, produces anxiety. Anxiety: Produced, not alleviated, by "Everything is all right." A successful trial run is the best cure. Unexpected, threatening or interesting sounds: (eg high heels). Arterial puncture: more the anxiety than the pain. Ingested stimulants: coffee, tea, alcohol, food, drugs. Muscular movement: Even crossing legs stimulates ventilation. Restlessness voids a test. Diurnal variations: Pco, is lowest in the early afternoon, probably indicating degree of activity of reticular activating system. Anticipation of chemical stimuli: A subject may think he has been made severely hypoxic and hyperventilate violently. TECHNICAL COMMENTS
Equation 2 differs from Lloyd's' in that his required a P02 asymptote, and was essentially the hyperbolic method. Rapid blood sampling is acceptable if drawn at constant flow over an integral number of breaths; that is, start and finish must be at the same phase of breathing, such as beginning of inspiration. Dead space need not be minimized since the air breathing values are not used in computation. End tidal gas values should not be considered accurate enough for response analysis. The critical points are those of lowest P0 2 , at which a single arterial sample may be used to define the A-a differences.
CHEST, 70: 1, JULY, 1976 SUPPLEMENT
When one writes the exponential form (equation 2) for the three hypoxic points to solve for 3 unknowns, explicit solutions are not possible. In the hyperbolic form they are, although the solution is rather awkward. Both appear to be more easily handled iteratively. If Ro (or A) is eliminated, one may solve for k (or C) the two remaining equations, equate them and substitute values F - 6/0. of B' beginning with the intercept: B' Ear oximetry offers an important advantage in hypoxic response testing: Immediate monitoring of arterial rather than end tidal oxygenation. The new HP 4720IA oximeter determines saturation without in vivo calibration by using eight wavelengths to compensate for ear thickness, ear blood volume and skin pigmentation.
=
REFERENCES
1 Cunningham DJC: Integrative aspects of the regulation of breathing: A personal view. In Respiratory Physiology (Guyton and Widdicombe, eds). Physiology series I, Vol 2, MTP International Review of Science. London, Butterworths, 1974, p 303-370 2 Rebuck, AS, Campbell EJM: A clinical method for assessing the ventilatory response to hypoxia. Amer Rev Resp Dis 109:345-350, 1973 3 Kronenberg R, Hamilton FN, Gabel R, et al: Comparison of three methods for quantitating respiratory response to hypoxia in man. Resp Physiol 16: 109-125, 1972 4 Weil, JV, Byrne-Quinn E, Sodal ID, et al: Hypoxic ventilatory drive in normal man. J Clin Invest 49:1061-1072, 1970 5 Schmidt-Nielsen K: Energy metablism, body size and the problem of scaling. Fed Proc 29: 1524-1532, 1970 6 Mills E, Jobsis FF: Mitochondrial respiratory chain of carotid body and chemoreceptor response to changes in oxygen tension. J Neurophysiol 35:405, 1972 7 Whitelaw WA, Derenne ]P, Milic-Emili J: Occlusion pressure as a measure of respiratory center output in conscious man. Resp Physiol 23: 181-199, 1975
Drive and Timing Components of Ventilation * t. Milic-Emili M.D., and M. M. Grunstein, Ph.D. most studies of the effects of chemical (eg drugs, I nhormones, arterial Po and physical (body tempera2 )
ture, arterial blood pressure) stimuli on the respiratory response to CO 2 inhalation, the total output of the neural control mechanisms is measured in terms of ventilation. A parallel shift to the left or right of the curve relating to arterial (or alveolar) Pco, is taken ventilation (~E) to indicate an additive effect of the stimulus, while a change in the slope is said to indicate a multiplicative action. Such an analysis is useful for descriptive purposes, but may lead to misleading conclusions, as recently demonstrated by Gru!'stein et al. 1 They studied the effects of °From the Department of Physiology, McGill University, Montreal, Quebec. Reprint requests: Dr. Milic-Emili, McIntyre Medical Building, 3655 Drummond, Montreal, Quebec, Canada
131
given drug has an additive effect on both the VT vs PAC0 2 and the f vs PAC0 2 relations. Since V" VT X f, it follows that the slope of the ventilatory response to CO 2 will also change, unless the changes in the VT vs PAC0 2 and f vs PAC0 2 relations exactly compensate for each other to keep the slope of the V" vs PAC0 2 relation constant. Such precise compensation is, however, unlikely to occur. Let us now continue our analysis by assuming that a subject under control conditions has the V", VT and f responses to CO 2 as shown in Figure 1 (solid lines). He is then given a drug which has no effect on the f vs PAC0 2 relation, but has an additive effect on the VT vs PAC0 2 relation (broken lines). The slope of the VE vs PAC0 2 relation changes. A similar result is also obtained if the drug has no effect on the VT vs PAC0 2 relation, but causes a parallel shift of the f vs PAC0 2 relation. Indeed, even if the respiratory frequency is independent of PAC0 2 , but changes after administration of the drug, there is a change in the slope of the ventilatory response to C02 (Fig 2). As shown in Figure 3, no change in the slope of the ventilatory response curve to C02 is observed only if the effect of the drug on the VT vs PAC02 is additive and the frequency of breathing is (a) independent of PAC0 2 and (b) is not affected by the drug (or vice versa)." These simple mathematical considerations clearly indicate that analysis of VT VS PAC0 2 and f vs PAC0 2 responses provides useful information in determining the type of interaction between PAC0 2 and other respiratory stimuli. An even better analysis can probably be obtained if respiratory responses to CO 2 are analyzed in terms of the mean inspiratory flow, VI VT/Ti, and of the ratio of inspiratory to total respiratory cycle duration, Ti/Ttot. Indeed, since the tidal volume is equal to Vi X Ti and respiratory frequency is given by l/Ttot, it follows that
arterial baroreceptor stimulation on the respiratory response to inhaled CO 2 in anesthetized cats. Increased arterial blood pressure resulted in an immediate decrease in the slope of the ventilatory response to CO 2 , Conventionally, this result would be taken as indicating that arterial blood pressure and Pco, act as multiplicative stimuli in determining the output of the respiratory centers. Ventilation, however, is a rather complex index of respiratory center output, representing the product of tidal volume and respiratory frequency. A more appropriate approach in determining the interaction between arterial Pco, and other respiratory stimuli (such as arterial blood pressure) requires separate assessment of both the tidal volume and respiratory frequency responses to changes in arterial Pco.. Using such an analysis, Grunstein et al found that increased arterial blood pressure caused a parallel shift to the right of the tidal volume (VT) response to CO 2 , indicating that in terms of VT the interaction between arterial blood pressure and Pco, is additive. On the other hand, the changes in tidal volume during baroreceptor stimulation elicited secondary changes in respiratory frequency via the Hering-Breuer inflation reflex. It is these secondarq changes in respiratory frequency which caused a change of the slope of the ventilatory response to CO 2 during baroreceptor stimulation. Indeed, after elimination of the Hering-Breuer reflex by bilateral vagotomy, the V" vs PAC0 2 relationship during baroreceptor stimulation was shifted in a parallel fashion to the right, as that for VT vs PAC0 2 • The latter result provides further evidence that arterial blood pressure and PAC0 2 interact additively on VT. All other changes observed in the vagally intact cat, namely changes in the f vs PAC02 relation and in the slope of the V" vs PAC0 2 relation are secondary effects mediated by the vagus nerves. Clearly, analysis of the V" vs Pco, relationship alone may lead to a misinterpretation of the mode of action of the various respiratory stimuli. Such a conclusion may also be reached by simple algebraic considerations. Assume, for example, that a
3
VT (Ll
,/
,/ ,/
0 30
40
°Since in practice most respiratory stimuli affect directly or indirectly both f and VT, a change in the slope of the VE vs PAC02 relation is commonlyobserved.
'iE (L/mlnJ
f (cpmJ
0----60
30 I
0 30
50
40
PA FIGURE
I
60
20
co2
60
0 30
40
I
i
I
90
40
c50
=
60
,
""
=
I
I
I
I
I
I
I
I
I
50
I
I
I I
I I I I
60
(mmHgJ
1. Respiratory responses to C02 inhalation under control conditions (C) and after
administration of a hypothetical drug (D) which has an additive effect on the VT vs PAC~ response, but no effect on the f vs PAC02 response. The slope of the VE vs PAC02 response increases after drug administration.
132
CHEST, 70: 1, JULY, 1976 SUPPLEMENT
3
Vy (L)
f rcpm) 60
90
40
60
20
30
2
0-----
co
30
40
50
0
60
30
O'----II~_.....L..
40
50
PA
60
30
40
50
_ _....L._
60
(mmHg)
eOa
FIGURE 2. As Figure 1, except that f is independent of PAC02, but changes after drug administration. The slope of the VE vs PAC02 relation increases.
3
f rcpm) 60
60
2 40
c-
0-----
o
30
40
50
.,
20
60
20
0
30
40
O'-_--II:_ _.....L.._ _.L...-_
40
50
PA
60
30
40
50
60
(mmHg)
eOa
FIGURE 3. As Figure 2, except that now the drug has no effect on f. The slope of the VE vs PAC~ relation is now shifted in a parallel fashion to the left, as the VT vs PAC02 relation.
~E
= VT X f = Vi
X Ti/Ttot
The advantage of analyzing respiratory responses in terms of Ti/Ttot and Vi is in that the first parameter is a pure index of "respiratory timing," while the second is an expression of "inspiratory drive" which is essentially independent of the timing element. 0 0 The tidal volume, ~n the contrary, depends on timing since it is equal to ~i X Ti. In this connection it should be noted, however, 00
If the rate of rise of volume during inspiration is linear with respect to time, changes in Ti will have no effect on Vi. If on the contrary, lung volume does not increase lineariy with time, changes in Ti will affect Vi. In man, however, the inspiratory volume-time profile is usually approximately linear, and Vi can be taken as essentially independent of Ti. If curvilinearities in the inspiratory volume-time profile do exist, the inspired volume at a fixed time after the onset of inspiration can be taken as another useful index of "inspiratory drive." The latter index, as well as Vi, however, reflect "inspiratory drive" only if inspiration starts from FRC and the mechanical properties of the respiratory system are fixed.
CHEST, 70: I, JULY, 1976 SUPPLEMENT
that changes in the mechanical properties of the respiratory system will alter Vi for a given neural output of the respiratory centers. Under such conditions, measurements of the rate of rise of mouth occlusion pressure, 2 diaphragmatic EMG3 or phrenic ENG· will provide a more direct measure of inspiratory drive than Vi. REFERENCES
1 Grunstein MM, Derenne J-Ph, Milic-Emili J: Control of depth and frequency of breathing during baroreceptor stimulation in cats. J Appl Physiol 39:395-404, 1975 2 Whitelaw WA, Derenne J-Ph, Milic-Emili J: Occlusion pressure as a measure of respiratory center output in conscious man. Resp PhysioI23:181-199, 1975 3 Lourenco RV, Moranda JM: Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Engl J Med 279:53-59, 1968 4 Eldridge FL: Relationship between respiratory nerve and muscle activity and muscle force output. J Appl Physiol 39: 567-574, 1975
133
=
Notes on Counselling Sub;ects Since ventilation is always a sum of chemical, wakeful and other extraneous stimuli, one may assume that a subject cannot voluntarily continuously hypoventilate. We counsel subjects to wait between breaths until they need to breathe. Subjects should not be told to breathe slowly, which may cause them to prolong the effort of inspiration (and expiration), nor should they be told to breathe less, since shallow breathing may result in increased vagal stimuli and tachypnea.
Minimization of Extraneous Stimuli Ventilation at rest is so easily stimulated that considerable effort and care. are needed to avoid these stimuli. Whereas we assume such stimuli are negligible when ventilation is driven by elevated CO 2 , some of these stimuli may augment hypoxic drive. Full bladder: Note that CO 2 breathing may cause diuresis. Discomfort: Tight nose clip, too large a mouthpiece, awkward head posture as required by apparatus, poor chair, cold drafts. Whispering: More stimulating than conversation, produces anxiety. Anxiety: Produced, not alleviated, by "Everything is all right." A successful trial run is the best cure. Unexpected, threatening or interesting sounds: (eg high heels). Arterial puncture: more the anxiety than the pain. Ingested stimulants: coffee, tea, alcohol, food, drugs. Muscular movement: Even crossing legs stimulates ventilation. Restlessness voids a test. Diurnal variations: Pco, is lowest in the early afternoon, probably indicating degree of activity of reticular activating system. Anticipation of chemical stimuli: A subject may think he has been made severely hypoxic and hyperventilate violently. TECHNICAL COMMENTS
Equation 2 differs from Lloyd's' in that his required a P02 asymptote, and was essentially the hyperbolic method. Rapid blood sampling is acceptable if drawn at constant flow over an integral number of breaths; that is, start and finish must be at the same phase of breathing, such as beginning of inspiration. Dead space need not be minimized since the air breathing values are not used in computation. End tidal gas values should not be considered accurate enough for response analysis. The critical points are those of lowest P0 2 , at which a single arterial sample may be used to define the A-a differences.
CHEST, 70: 1, JULY, 1976 SUPPLEMENT
When one writes the exponential form (equation 2) for the three hypoxic points to solve for 3 unknowns, explicit solutions are not possible. In the hyperbolic form they are, although the solution is rather awkward. Both appear to be more easily handled iteratively. If Ro (or A) is eliminated, one may solve for k (or C) the two remaining equations, equate them and substitute values F - 6/0. of B' beginning with the intercept: B' Ear oximetry offers an important advantage in hypoxic response testing: Immediate monitoring of arterial rather than end tidal oxygenation. The new HP 4720IA oximeter determines saturation without in vivo calibration by using eight wavelengths to compensate for ear thickness, ear blood volume and skin pigmentation.
=
REFERENCES
1 Cunningham DJC: Integrative aspects of the regulation of breathing: A personal view. In Respiratory Physiology (Guyton and Widdicombe, eds). Physiology series I, Vol 2, MTP International Review of Science. London, Butterworths, 1974, p 303-370 2 Rebuck, AS, Campbell EJM: A clinical method for assessing the ventilatory response to hypoxia. Amer Rev Resp Dis 109:345-350, 1973 3 Kronenberg R, Hamilton FN, Gabel R, et al: Comparison of three methods for quantitating respiratory response to hypoxia in man. Resp Physiol 16: 109-125, 1972 4 Weil, JV, Byrne-Quinn E, Sodal ID, et al: Hypoxic ventilatory drive in normal man. J Clin Invest 49:1061-1072, 1970 5 Schmidt-Nielsen K: Energy metablism, body size and the problem of scaling. Fed Proc 29: 1524-1532, 1970 6 Mills E, Jobsis FF: Mitochondrial respiratory chain of carotid body and chemoreceptor response to changes in oxygen tension. J Neurophysiol 35:405, 1972 7 Whitelaw WA, Derenne ]P, Milic-Emili J: Occlusion pressure as a measure of respiratory center output in conscious man. Resp Physiol 23: 181-199, 1975
Drive and Timing Components of Ventilation * t. Milic-Emili M.D., and M. M. Grunstein, Ph.D. most studies of the effects of chemical (eg drugs, I nhormones, arterial Po and physical (body tempera2 )
ture, arterial blood pressure) stimuli on the respiratory response to CO 2 inhalation, the total output of the neural control mechanisms is measured in terms of ventilation. A parallel shift to the left or right of the curve relating to arterial (or alveolar) Pco, is taken ventilation (~E) to indicate an additive effect of the stimulus, while a change in the slope is said to indicate a multiplicative action. Such an analysis is useful for descriptive purposes, but may lead to misleading conclusions, as recently demonstrated by Gru!'stein et al. 1 They studied the effects of °From the Department of Physiology, McGill University, Montreal, Quebec. Reprint requests: Dr. Milic-Emili, McIntyre Medical Building, 3655 Drummond, Montreal, Quebec, Canada
131
given drug has an additive effect on both the VT vs PAC0 2 and the f vs PAC0 2 relations. Since V" VT X f, it follows that the slope of the ventilatory response to CO 2 will also change, unless the changes in the VT vs PAC0 2 and f vs PAC0 2 relations exactly compensate for each other to keep the slope of the V" vs PAC0 2 relation constant. Such precise compensation is, however, unlikely to occur. Let us now continue our analysis by assuming that a subject under control conditions has the V", VT and f responses to CO 2 as shown in Figure 1 (solid lines). He is then given a drug which has no effect on the f vs PAC0 2 relation, but has an additive effect on the VT vs PAC0 2 relation (broken lines). The slope of the VE vs PAC0 2 relation changes. A similar result is also obtained if the drug has no effect on the VT vs PAC0 2 relation, but causes a parallel shift of the f vs PAC0 2 relation. Indeed, even if the respiratory frequency is independent of PAC0 2 , but changes after administration of the drug, there is a change in the slope of the ventilatory response to C02 (Fig 2). As shown in Figure 3, no change in the slope of the ventilatory response curve to C02 is observed only if the effect of the drug on the VT vs PAC02 is additive and the frequency of breathing is (a) independent of PAC0 2 and (b) is not affected by the drug (or vice versa)." These simple mathematical considerations clearly indicate that analysis of VT VS PAC0 2 and f vs PAC0 2 responses provides useful information in determining the type of interaction between PAC0 2 and other respiratory stimuli. An even better analysis can probably be obtained if respiratory responses to CO 2 are analyzed in terms of the mean inspiratory flow, VI VT/Ti, and of the ratio of inspiratory to total respiratory cycle duration, Ti/Ttot. Indeed, since the tidal volume is equal to Vi X Ti and respiratory frequency is given by l/Ttot, it follows that
arterial baroreceptor stimulation on the respiratory response to inhaled CO 2 in anesthetized cats. Increased arterial blood pressure resulted in an immediate decrease in the slope of the ventilatory response to CO 2 , Conventionally, this result would be taken as indicating that arterial blood pressure and Pco, act as multiplicative stimuli in determining the output of the respiratory centers. Ventilation, however, is a rather complex index of respiratory center output, representing the product of tidal volume and respiratory frequency. A more appropriate approach in determining the interaction between arterial Pco, and other respiratory stimuli (such as arterial blood pressure) requires separate assessment of both the tidal volume and respiratory frequency responses to changes in arterial Pco.. Using such an analysis, Grunstein et al found that increased arterial blood pressure caused a parallel shift to the right of the tidal volume (VT) response to CO 2 , indicating that in terms of VT the interaction between arterial blood pressure and Pco, is additive. On the other hand, the changes in tidal volume during baroreceptor stimulation elicited secondary changes in respiratory frequency via the Hering-Breuer inflation reflex. It is these secondarq changes in respiratory frequency which caused a change of the slope of the ventilatory response to CO 2 during baroreceptor stimulation. Indeed, after elimination of the Hering-Breuer reflex by bilateral vagotomy, the V" vs PAC0 2 relationship during baroreceptor stimulation was shifted in a parallel fashion to the right, as that for VT vs PAC0 2 • The latter result provides further evidence that arterial blood pressure and PAC0 2 interact additively on VT. All other changes observed in the vagally intact cat, namely changes in the f vs PAC02 relation and in the slope of the V" vs PAC0 2 relation are secondary effects mediated by the vagus nerves. Clearly, analysis of the V" vs Pco, relationship alone may lead to a misinterpretation of the mode of action of the various respiratory stimuli. Such a conclusion may also be reached by simple algebraic considerations. Assume, for example, that a
3
VT (Ll
,/
,/ ,/
0 30
40
°Since in practice most respiratory stimuli affect directly or indirectly both f and VT, a change in the slope of the VE vs PAC02 relation is commonlyobserved.
'iE (L/mlnJ
f (cpmJ
0----60
30 I
0 30
50
40
PA FIGURE
I
60
20
co2
60
0 30
40
I
i
I
90
40
c50
=
60
,
""
=
I
I
I
I
I
I
I
I
I
50
I
I
I I
I I I I
60
(mmHgJ
1. Respiratory responses to C02 inhalation under control conditions (C) and after
administration of a hypothetical drug (D) which has an additive effect on the VT vs PAC~ response, but no effect on the f vs PAC02 response. The slope of the VE vs PAC02 response increases after drug administration.
132
CHEST, 70: 1, JULY, 1976 SUPPLEMENT
3
Vy (L)
f rcpm) 60
90
40
60
20
30
2
0-----
co
30
40
50
0
60
30
O'----II~_.....L..
40
50
PA
60
30
40
50
_ _....L._
60
(mmHg)
eOa
FIGURE 2. As Figure 1, except that f is independent of PAC02, but changes after drug administration. The slope of the VE vs PAC02 relation increases.
3
f rcpm) 60
60
2 40
c-
0-----
o
30
40
50
.,
20
60
20
0
30
40
O'-_--II:_ _.....L.._ _.L...-_
40
50
PA
60
30
40
50
60
(mmHg)
eOa
FIGURE 3. As Figure 2, except that now the drug has no effect on f. The slope of the VE vs PAC~ relation is now shifted in a parallel fashion to the left, as the VT vs PAC02 relation.
~E
= VT X f = Vi
X Ti/Ttot
The advantage of analyzing respiratory responses in terms of Ti/Ttot and Vi is in that the first parameter is a pure index of "respiratory timing," while the second is an expression of "inspiratory drive" which is essentially independent of the timing element. 0 0 The tidal volume, ~n the contrary, depends on timing since it is equal to ~i X Ti. In this connection it should be noted, however, 00
If the rate of rise of volume during inspiration is linear with respect to time, changes in Ti will have no effect on Vi. If on the contrary, lung volume does not increase lineariy with time, changes in Ti will affect Vi. In man, however, the inspiratory volume-time profile is usually approximately linear, and Vi can be taken as essentially independent of Ti. If curvilinearities in the inspiratory volume-time profile do exist, the inspired volume at a fixed time after the onset of inspiration can be taken as another useful index of "inspiratory drive." The latter index, as well as Vi, however, reflect "inspiratory drive" only if inspiration starts from FRC and the mechanical properties of the respiratory system are fixed.
CHEST, 70: I, JULY, 1976 SUPPLEMENT
that changes in the mechanical properties of the respiratory system will alter Vi for a given neural output of the respiratory centers. Under such conditions, measurements of the rate of rise of mouth occlusion pressure, 2 diaphragmatic EMG3 or phrenic ENG· will provide a more direct measure of inspiratory drive than Vi. REFERENCES
1 Grunstein MM, Derenne J-Ph, Milic-Emili J: Control of depth and frequency of breathing during baroreceptor stimulation in cats. J Appl Physiol 39:395-404, 1975 2 Whitelaw WA, Derenne J-Ph, Milic-Emili J: Occlusion pressure as a measure of respiratory center output in conscious man. Resp PhysioI23:181-199, 1975 3 Lourenco RV, Moranda JM: Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Engl J Med 279:53-59, 1968 4 Eldridge FL: Relationship between respiratory nerve and muscle activity and muscle force output. J Appl Physiol 39: 567-574, 1975
133