203
J. Phyjio. (1979), 296, pp. 203-214 WiAt 5 -eztflgtr Printed in Great Britain
THE EFFECTS OF SUDDEN AIRWAY HYPERCAPNIA ON THE INITIATION OF EXERCISE HYPERPNOEA IN MAN
BY SUSAN A. WARD* From the Physiological Laboratory, Liverpool Univer8ity, Liverpool
(Received 3 January 1979) SUMMARY
1. In three healthy individuals, the first breath of cycle ergometer exercise was characterized by increases of minute ventilation (rrE) and pulmonary capillary CO2 output (1co,), with little change of end-tidal Pco,, suggesting a concomitant increase of pulmonary blood flow (Q) and preservation of J'IQ status. Functional residual capacity fell, depleting lung gas stores of 02 and CO2. 2. The following hypothesis purporting to account for the initiation of exercise hyperpnoea was examined (Filley, 1976): (a) assuming pulmonary capillary plasma to remain unexposed to carbonic anhydrase, its slow alkalinization consequent upon CO2 exchange causes a more acid plasma to enter the pulmonary veins if Q increases abruptly, as at exercise onset; (b) the fall of pulmonary venous plasma pH stimulates an intrapulmonary chemoreflex to elicit a proportionate hyperpnoea, so preserving arterial isocapnia; (c) the initial hyperpnoea should therefore be abolished if pulmonary capillary Vcos is suppressed at exercise onset, as the absence of pulmonary capillary plasma alkalinization should sever the postulated intrapulmonary humoral link between Q and VE. 3. In the present study, while abrupt CO2 inhalation ( 6 % in air) at exercise onset abolished pulmonary capillary 1rco, during the first breath of exercise, the initial hyperpnoea was unaffected. This observation argues against the hypothesis that exercise hyperpnoea is initiated by an intrapulmonary chemoreflex which detects perfusion-related changes in pulmonary venous plasma pH. INTRODUCTION
While the cardiorespiratory events occurring at exercise onset have been extensively described, there remains a lack of consensus as to the nature of the mechanism which initiates the hyperpnoea of exercise. Typically, tachycardia and hyperpnoea occur in the first breath of exercise (Krogh & Lindhard, 1913), accompanied by increases in pulmonary 02 uptake and CO2 output, but with little change in the respiratory exchange ratio or in end-tidal PO, and Pco, (Wasserman, Whipp, Casaburi & Beaver, 1977; Pearce & Milhorn, 1977). Implicit in the greater rate of 02 transfer is an increase in pulmonary capillary perfusion, as the mixed venous blood composition should not yet have changed (Krogh & Lindhard, 1913; Edwards, * Present address: Department of Anesthesiology, School of Medicine, University of California at Los Angeles, Los Angeles, California 90024, U.S.A. 0022-3751/79/5640.0925 $01.50 © 1979 The Physiological Society
204 S. A. WARD Denison, Davies & Campbell, 1972; Raynaud, Bernal, Bourdarias, David & Durand, 1973). The isocapnic character of the hyperpnoea suggests a close matching between alveolar ventilation and perfusion, fortuitously or otherwise (Matell, 1963; Wasserman, Whipp & Castagna, 1974). Neurogenic mechanisms have traditionally been invoked to account for the sudden hyperpnoea at exercise onset, there being little likelihood that any circulating humoral agent released from the working muscles could influence the carotid body and medullary chemoreceptors so soon (Dejours, 1964). Proponents of neurogenesis have tended to favour one of two possibilities: either an irradiation of cortical motor activity destined for the exercising muscles into brainstem areas subserving respiratory control (Krogh & Lindhard, 1913; Goodwin, McCloskey & Mitchell, 1972), or a reflex originating in the muscles themselves (Kao, 1963; Dejours, 1964; Senapati, 1966; McCloskey & Mitchell, 1972). More recently, Filley (1976) has given serious consideration to the possibility that the hyperpnoea of exercise is initiated by an intrapulmonary humoral mechanism. The impetus for this proposal arose from observations of Wasserman et al. (1974) and, later, of Ponte & Purves (1978) that abrupt, experimentally induced increases of pulmonary perfusion in laboratory animals may be accompanied by an immediate hyperpnoea with little change in end-tidal Pco,, events which are reminiscent of those at exercise onset. Central to Filley's (1976) hypothesis is the assumption of a negligible carbonic anhydrase activity in pulmonary capillary plasma. In this situation, where the uncatalyzed dehydration of carbonic acid in plasma is considerably slower than the catalysed reaction in the red cells, the loss of CO2 from blood as it traverses the pulmonary capillary bed generates an [H+] disequilibrium between plasma and red cells, the pH of the latter rising towards its more alkaline arterial level at a substantially faster rate than that of the former (Roughton, 1935; Sirs, 1960; Hill, Power & Longo, 1973; Forster & Crandall, 1975). In fact, plasma pH may only attain arterial equilibrium some distance downstream of the lungs (Hill, Power & Gilbert, 1977; Crandall, Bidani & Forster, 1977). The disequilibrium hypothesis postulates that a sudden increase in pulmonary perfusion, as occurs at exercise onset, causes a more acid plasma to enter the pulmonary venous circulation from the pulmonary capillaries, and that a fast-acting chemoreceptor in this vicinity reflexly translates the change in pulmonary venous acidity into an hyperpnoea sufficient to preserve arterial isocapnia in the face of a greater delivery of metabolic CO2 to the lungs (Filley, 1976; Filley, Hale, Kratochvil & Olson, 1978). As a corollary to this hypothesis, abolition of pulmonary capillary CO2 efflux, as may be achieved transiently by brief CO2 inhalation, should prevent, or at least reduce, the development of a plasma-red cell [H+] disequilibrium and any ventilatory responses deriving therefrom (Filley, 1976; Filley et al. 1978). Accordingly, the extent to which the disequilibrium hypothesis may account for the initiation of exercise hyperpnoea has been investigated by assessing the immediate ventilatory effects of abrupt CO2 inhalation coincident with exercise onset in three healthy adults.
INITIATION OF EXERCISE HYPERPNOEA
205
METHODS Three healthy subjects who were ignorant of physiology and uninformed as to the purpose of the experiments were studied. They were thoroughly familiar with exercise testing procedures, including those demanded by the present investigation. Their anthropometric data are given in Table 1.
TABLE 1. Anthropometric data Subject
C.E. M.A. J.B.
Sex M F F
Age (yr) 36 33 17
Height (cm) 182 156 163
Weight (kg) 92 60 60
Apparatus The subjects breathed through a mouthpiece connected by way of a heated pneumotachograph (Fleisch no. 3, P. K. Morgan, Chatham, England) to a Lloyd valve, this arrangement having a dead space of 125 ml. The inspiratory line carried a wide-bore tap through which was inhaled either room air or a C02-air mixture from a suspended Douglas bag. Single inspirates of the mixture could be delivered to the unsuspecting subjects at will, as the tap was hidden from view and only turned when subjects were exhaling. The volume of the inspiratory line between the tap and the breathing valve served to delay the arrival of the C02-air bolus at the subjects by one breath. Instances in which the bolus arrived after the onset of inspiration were excluded from further study. The Poo, and PO, of respiratory gas drawn continuously from the mouthpiece at 0-5 l./min were measured by rapidly-responding analyzers (models LB2 & OMI1, Beckman-R.I.I.C. Ltd., Manchester, England), frequently calibrated with volumetrically-analyzed gas mixtures. Respiratory flow was monitored by the pneumotachograph and a variable reluctance differential manometer (Validyne no. MP45, P. K. Morgan), calibrated with room air using a rotameter tube of known characteristics. Raising the Pco, of the calibrating gas to levels encountered during the brief Co2 inhalation (see below) was without effect. Inspiratory and expiratory volumes were obtained by integration of the flow signal (Resetting Integrator Coupler 9873B, BeckmanR.I.I.C. Ltd.). Calibration was effected with room air by a 11. syringe. Surface recording from the chest provided an e.c.g. signal. Subjects exercised on a mechanically braked cycle ergometer (Monark, Varberg, Sweden). Pedalling frequency was monitored by a photocell attached to the ergometer frame, the light source for which was interrupted once each revolution of the pedal shaft. Monitored variables were displayed on two ink-pen recorders synchronized by linked marker pens: flow, volume, Pco,, PO on a four-channel model (Dynograph 611, BeckmanR.I.I.C. Ltd.), and e.c.g. and photocell output on a two-channel model (Biophysiograph, San-ei Sokki, Instrumentarium, London, England). Protocol The subjects were informed only of those aspects of the protocol which required their active co-operation: that the experiment would comprise short periods of moderate exercise initiated by the command 'Go' and terminated by 'Stop'; that each exercise period should be started with the right leg from a position immediately above the ergometer photocell (to signal the onset
of movement with minimal delay); that pedalling frequency should be maintained as steady as possible at a comfortable level; and that intervening rest periods should be taken seated quietly on the ergometer, while still breathing through the apparatus. Ample opportunity for familiarization with these manouevres was given. To minimize awareness of other events in the protocol, the apparatus was obscured from view, as was the experimenter, and background disturbance was avoided. When the subject was relaxed, with no evidence of persistent sighing or swallowing, the command to start exercise was given, always towards the end of an expiration. Simultaneously, the experimenter activated the event marker linking both recorders. Allowing for the subjects'
206
S. A, WARD
reaction time, exercise was started just before the onset of the following inspiration and was continued for about five breaths (20 see). The work rate during the first breath was considered to be reasonably constant in a given experiment, as the ergometer load (sufficient to elicit a steadystate heart rate of 100-120 beats/min) was usually attained within the first revolution of the pedals, and the mean pedalling frequency for the whole breath varied little (Table 2). At least 3 minutes were allowed between successive exercise periods. Three test procedures were invoked: T1, a rest-exercise transition throughout which room air was inhaled; T., as T,, except that a CO0-air mixture (5-4-6.8% CO ) was substituted in the first inspiration of exercise to prevent the usual increase in pulmonary CO, output from occurring at exercise onset; T.,, random substitution, at rest, of the CO,-air mixture in a single inspiration. Subjects were unaware of the composition of the inhaled gas mixture. Altogether, forty-three T1 tests, forty-six T, tests, and thirty-seven Ta, tests were successfully performed and analyzed. Data analysi8 The initial response to exercise in any variable was estimated as the difference between its value on the first breath of exercise and the mean value for the three resting breaths immediately preceding the breath in which the command to start pedalling was given. At rest, the initial response was measured in the C00-laden breath. For each test procedure the responses were averaged, subject by subject, and their significance assessed by comparison with zero using a standard two-tailed t test. Basic variables comprised inspiratory and expiratory durations (T,, T,), taken as the intervals between successive zero flow points, and tidal volumes (VT.I, VT.E) converted to b.t.p.s.; endtidalP,00 andPo ; e.c.g. R-R interval, giving heart rate. Derived variables were: breath duration (TT); minute ventilation (VB), = VT.B/TT; mean inspiratory and expiratory flows, = VT.I/TI and VT.BITE; change in functional residual capacity (AFRO), = VT. - VTz,; and, for 8eletd tet only, the rate of pulmonary C00 output (1c0),
I exp
=t.
L
Fco
.
insp
VFaos
dt-
TT
where e (s.t.p.d.) and Fco, are instantaneous values of flow and fractional C02 concentration; the sampling interval was 0'1 sec. The contribution to too, from changing pulmonary CO, gas stores was estimated as AFRCOFET co/TT, where FET CO is the fractional end-tidal C00 concentration and is assumed to reasonably reflect alveolar Pco, during exhalation. RESULTS
The immediacy of the hyperpnoea at exercise onset demands that contributing stimuli be detected and acted upon with virtually no delay. Thus, if sudden C02 inhalation coincident with exercise onset were to abolish an intrapulmonary perfusionrelated stimulus (see Introduction), its influence on ventilation (P.E) should be apparent within the first breath of exercise. Indeed, by the next breath, the inhaled C02 bolus may have activated the carotid body chemoreflex (Ward, Drysdale, Cunningham & Petersen, 1979), so complicating the interpretation of ventilatory events beyond the first breath of exercise. Exercise onset
Apart from manipulation of inspired C02 levels, conditions were largely identical between those exercise transitions throughout which room air was breathed (T1) and those which involved abrupt C02 inhalation at exercise onset (T2). In particular, there was similarity with respect to: (i) BXE, heart rate, PET,Co, and PET,O, before exercise (Table 2); (ii) the subjects' state of awareness, as judged by their reaction
INITIATION OF EXERCISE HYPERPNOEA
207
TABLE 2. Resting cardiorespiratory conditions for the three breaths preceding exercise; reaction time to the exercise command; and pedalling frequency over the first breath of exercise, for Tl and T. tests. Data averaged subject by subject (± 1 s.E. of mean) Minute End-tidal End-tidal Reaction Pedalling Heart rate ventilation time P02 frequency Pc02 Subject n (beats/min) (mm Hg) (mm Hg) (I./min) (sec) (rev/min) C.E. T1 13 739 +0-8 14-5 + 0-5 40-2 + 0-3 105-6 0-6 0-40 + 0-02 49-5 +0-8 T2 13 75-4±0-6 41-2+0-2 15-4+0-4 102-9+0-5 0-39±0-02 49-7+0-6 M.A. T1 15 82-6 +1-4 14-0 + 0-3 35-4+ 0-3 111-4 + 0-4 0-54+ 0-03 353 +1-0 T2 20 85-0+ 1-4 14-2+0-4 112-1± 0-4 0-50+0-02 34-9+0-9 34-8+0-2 J.B. T1 15 95-1+2-2 12-2+0-5 107.0+ 1-1 0-54+0-02 49-S-1i1 38-2+0-3 T2 13 96-9 + 2-1 13-7 + 0-7 37-3 + 0-4 107-5 +0-8 0-51 + 0-02 48-7 +1-5
J.B.T,
5 sec_
PAi
Ergometer photocell signal
B
V V-V,
E.c.g. I nsp.
EO
C, (./m in)
v
100 Exp.
+
f
Exp. v
.f-[ X,> NV ,N NA
E1
l.)[0
E
I nsp.
PC02 mmHg [40
P02 mmHg[E00
A
ETXco2
'PETO2
Fig. 1. Experimental record (subject J.B.) of a transition between rest and exercise during air breathing (T1). From above down: time marker (1 sec intervals); ergometer photocell signal; electrocardiogram (e.c.g.); respiratory flow (v); respiratory volume (v); P00, and POX of respiratory gas. VTI and VT.E are inspiratory and expiratory tidal volumes. PET.,O and P]T.O, are end-tidal gas tensions. A, B are the times when the command to pedal was given and when pedalling actually started (at transition of ergometer signal from steady to periodic form), respectively. Due to the delayed response of the gas analyzers, the gas tension records lag the remaining records, as shown by the broken vertical line which is coincident with the start of pedalling.
times to the exercise command (Table 2); (iii) the onset of exercise, which occurred just before the onset of inspiration (Figs 1 and 2); (iv) mean pedalling frequency during the first breath of exercise (Table 2). The levels of JIE and heart rate obtaining just before exercise (see above) were understandably somewhat greater than one would expect from a truly basal state, in view of the frequent, if brief bouts of exercise.
208
S. A. WARD .5-sec--A
J.B.T2 Ergometer photocell signal
y rVV
E.c.g. Insp. 100 Exp. Exp.
E1
0 VA
~
~
~ itx
J. Phyjio. (1979), 296, pp. 203-214 WiAt 5 -eztflgtr Printed in Great Britain
THE EFFECTS OF SUDDEN AIRWAY HYPERCAPNIA ON THE INITIATION OF EXERCISE HYPERPNOEA IN MAN
BY SUSAN A. WARD* From the Physiological Laboratory, Liverpool Univer8ity, Liverpool
(Received 3 January 1979) SUMMARY
1. In three healthy individuals, the first breath of cycle ergometer exercise was characterized by increases of minute ventilation (rrE) and pulmonary capillary CO2 output (1co,), with little change of end-tidal Pco,, suggesting a concomitant increase of pulmonary blood flow (Q) and preservation of J'IQ status. Functional residual capacity fell, depleting lung gas stores of 02 and CO2. 2. The following hypothesis purporting to account for the initiation of exercise hyperpnoea was examined (Filley, 1976): (a) assuming pulmonary capillary plasma to remain unexposed to carbonic anhydrase, its slow alkalinization consequent upon CO2 exchange causes a more acid plasma to enter the pulmonary veins if Q increases abruptly, as at exercise onset; (b) the fall of pulmonary venous plasma pH stimulates an intrapulmonary chemoreflex to elicit a proportionate hyperpnoea, so preserving arterial isocapnia; (c) the initial hyperpnoea should therefore be abolished if pulmonary capillary Vcos is suppressed at exercise onset, as the absence of pulmonary capillary plasma alkalinization should sever the postulated intrapulmonary humoral link between Q and VE. 3. In the present study, while abrupt CO2 inhalation ( 6 % in air) at exercise onset abolished pulmonary capillary 1rco, during the first breath of exercise, the initial hyperpnoea was unaffected. This observation argues against the hypothesis that exercise hyperpnoea is initiated by an intrapulmonary chemoreflex which detects perfusion-related changes in pulmonary venous plasma pH. INTRODUCTION
While the cardiorespiratory events occurring at exercise onset have been extensively described, there remains a lack of consensus as to the nature of the mechanism which initiates the hyperpnoea of exercise. Typically, tachycardia and hyperpnoea occur in the first breath of exercise (Krogh & Lindhard, 1913), accompanied by increases in pulmonary 02 uptake and CO2 output, but with little change in the respiratory exchange ratio or in end-tidal PO, and Pco, (Wasserman, Whipp, Casaburi & Beaver, 1977; Pearce & Milhorn, 1977). Implicit in the greater rate of 02 transfer is an increase in pulmonary capillary perfusion, as the mixed venous blood composition should not yet have changed (Krogh & Lindhard, 1913; Edwards, * Present address: Department of Anesthesiology, School of Medicine, University of California at Los Angeles, Los Angeles, California 90024, U.S.A. 0022-3751/79/5640.0925 $01.50 © 1979 The Physiological Society
204 S. A. WARD Denison, Davies & Campbell, 1972; Raynaud, Bernal, Bourdarias, David & Durand, 1973). The isocapnic character of the hyperpnoea suggests a close matching between alveolar ventilation and perfusion, fortuitously or otherwise (Matell, 1963; Wasserman, Whipp & Castagna, 1974). Neurogenic mechanisms have traditionally been invoked to account for the sudden hyperpnoea at exercise onset, there being little likelihood that any circulating humoral agent released from the working muscles could influence the carotid body and medullary chemoreceptors so soon (Dejours, 1964). Proponents of neurogenesis have tended to favour one of two possibilities: either an irradiation of cortical motor activity destined for the exercising muscles into brainstem areas subserving respiratory control (Krogh & Lindhard, 1913; Goodwin, McCloskey & Mitchell, 1972), or a reflex originating in the muscles themselves (Kao, 1963; Dejours, 1964; Senapati, 1966; McCloskey & Mitchell, 1972). More recently, Filley (1976) has given serious consideration to the possibility that the hyperpnoea of exercise is initiated by an intrapulmonary humoral mechanism. The impetus for this proposal arose from observations of Wasserman et al. (1974) and, later, of Ponte & Purves (1978) that abrupt, experimentally induced increases of pulmonary perfusion in laboratory animals may be accompanied by an immediate hyperpnoea with little change in end-tidal Pco,, events which are reminiscent of those at exercise onset. Central to Filley's (1976) hypothesis is the assumption of a negligible carbonic anhydrase activity in pulmonary capillary plasma. In this situation, where the uncatalyzed dehydration of carbonic acid in plasma is considerably slower than the catalysed reaction in the red cells, the loss of CO2 from blood as it traverses the pulmonary capillary bed generates an [H+] disequilibrium between plasma and red cells, the pH of the latter rising towards its more alkaline arterial level at a substantially faster rate than that of the former (Roughton, 1935; Sirs, 1960; Hill, Power & Longo, 1973; Forster & Crandall, 1975). In fact, plasma pH may only attain arterial equilibrium some distance downstream of the lungs (Hill, Power & Gilbert, 1977; Crandall, Bidani & Forster, 1977). The disequilibrium hypothesis postulates that a sudden increase in pulmonary perfusion, as occurs at exercise onset, causes a more acid plasma to enter the pulmonary venous circulation from the pulmonary capillaries, and that a fast-acting chemoreceptor in this vicinity reflexly translates the change in pulmonary venous acidity into an hyperpnoea sufficient to preserve arterial isocapnia in the face of a greater delivery of metabolic CO2 to the lungs (Filley, 1976; Filley, Hale, Kratochvil & Olson, 1978). As a corollary to this hypothesis, abolition of pulmonary capillary CO2 efflux, as may be achieved transiently by brief CO2 inhalation, should prevent, or at least reduce, the development of a plasma-red cell [H+] disequilibrium and any ventilatory responses deriving therefrom (Filley, 1976; Filley et al. 1978). Accordingly, the extent to which the disequilibrium hypothesis may account for the initiation of exercise hyperpnoea has been investigated by assessing the immediate ventilatory effects of abrupt CO2 inhalation coincident with exercise onset in three healthy adults.
INITIATION OF EXERCISE HYPERPNOEA
205
METHODS Three healthy subjects who were ignorant of physiology and uninformed as to the purpose of the experiments were studied. They were thoroughly familiar with exercise testing procedures, including those demanded by the present investigation. Their anthropometric data are given in Table 1.
TABLE 1. Anthropometric data Subject
C.E. M.A. J.B.
Sex M F F
Age (yr) 36 33 17
Height (cm) 182 156 163
Weight (kg) 92 60 60
Apparatus The subjects breathed through a mouthpiece connected by way of a heated pneumotachograph (Fleisch no. 3, P. K. Morgan, Chatham, England) to a Lloyd valve, this arrangement having a dead space of 125 ml. The inspiratory line carried a wide-bore tap through which was inhaled either room air or a C02-air mixture from a suspended Douglas bag. Single inspirates of the mixture could be delivered to the unsuspecting subjects at will, as the tap was hidden from view and only turned when subjects were exhaling. The volume of the inspiratory line between the tap and the breathing valve served to delay the arrival of the C02-air bolus at the subjects by one breath. Instances in which the bolus arrived after the onset of inspiration were excluded from further study. The Poo, and PO, of respiratory gas drawn continuously from the mouthpiece at 0-5 l./min were measured by rapidly-responding analyzers (models LB2 & OMI1, Beckman-R.I.I.C. Ltd., Manchester, England), frequently calibrated with volumetrically-analyzed gas mixtures. Respiratory flow was monitored by the pneumotachograph and a variable reluctance differential manometer (Validyne no. MP45, P. K. Morgan), calibrated with room air using a rotameter tube of known characteristics. Raising the Pco, of the calibrating gas to levels encountered during the brief Co2 inhalation (see below) was without effect. Inspiratory and expiratory volumes were obtained by integration of the flow signal (Resetting Integrator Coupler 9873B, BeckmanR.I.I.C. Ltd.). Calibration was effected with room air by a 11. syringe. Surface recording from the chest provided an e.c.g. signal. Subjects exercised on a mechanically braked cycle ergometer (Monark, Varberg, Sweden). Pedalling frequency was monitored by a photocell attached to the ergometer frame, the light source for which was interrupted once each revolution of the pedal shaft. Monitored variables were displayed on two ink-pen recorders synchronized by linked marker pens: flow, volume, Pco,, PO on a four-channel model (Dynograph 611, BeckmanR.I.I.C. Ltd.), and e.c.g. and photocell output on a two-channel model (Biophysiograph, San-ei Sokki, Instrumentarium, London, England). Protocol The subjects were informed only of those aspects of the protocol which required their active co-operation: that the experiment would comprise short periods of moderate exercise initiated by the command 'Go' and terminated by 'Stop'; that each exercise period should be started with the right leg from a position immediately above the ergometer photocell (to signal the onset
of movement with minimal delay); that pedalling frequency should be maintained as steady as possible at a comfortable level; and that intervening rest periods should be taken seated quietly on the ergometer, while still breathing through the apparatus. Ample opportunity for familiarization with these manouevres was given. To minimize awareness of other events in the protocol, the apparatus was obscured from view, as was the experimenter, and background disturbance was avoided. When the subject was relaxed, with no evidence of persistent sighing or swallowing, the command to start exercise was given, always towards the end of an expiration. Simultaneously, the experimenter activated the event marker linking both recorders. Allowing for the subjects'
206
S. A, WARD
reaction time, exercise was started just before the onset of the following inspiration and was continued for about five breaths (20 see). The work rate during the first breath was considered to be reasonably constant in a given experiment, as the ergometer load (sufficient to elicit a steadystate heart rate of 100-120 beats/min) was usually attained within the first revolution of the pedals, and the mean pedalling frequency for the whole breath varied little (Table 2). At least 3 minutes were allowed between successive exercise periods. Three test procedures were invoked: T1, a rest-exercise transition throughout which room air was inhaled; T., as T,, except that a CO0-air mixture (5-4-6.8% CO ) was substituted in the first inspiration of exercise to prevent the usual increase in pulmonary CO, output from occurring at exercise onset; T.,, random substitution, at rest, of the CO,-air mixture in a single inspiration. Subjects were unaware of the composition of the inhaled gas mixture. Altogether, forty-three T1 tests, forty-six T, tests, and thirty-seven Ta, tests were successfully performed and analyzed. Data analysi8 The initial response to exercise in any variable was estimated as the difference between its value on the first breath of exercise and the mean value for the three resting breaths immediately preceding the breath in which the command to start pedalling was given. At rest, the initial response was measured in the C00-laden breath. For each test procedure the responses were averaged, subject by subject, and their significance assessed by comparison with zero using a standard two-tailed t test. Basic variables comprised inspiratory and expiratory durations (T,, T,), taken as the intervals between successive zero flow points, and tidal volumes (VT.I, VT.E) converted to b.t.p.s.; endtidalP,00 andPo ; e.c.g. R-R interval, giving heart rate. Derived variables were: breath duration (TT); minute ventilation (VB), = VT.B/TT; mean inspiratory and expiratory flows, = VT.I/TI and VT.BITE; change in functional residual capacity (AFRO), = VT. - VTz,; and, for 8eletd tet only, the rate of pulmonary C00 output (1c0),
I exp
=t.
L
Fco
.
insp
VFaos
dt-
TT
where e (s.t.p.d.) and Fco, are instantaneous values of flow and fractional C02 concentration; the sampling interval was 0'1 sec. The contribution to too, from changing pulmonary CO, gas stores was estimated as AFRCOFET co/TT, where FET CO is the fractional end-tidal C00 concentration and is assumed to reasonably reflect alveolar Pco, during exhalation. RESULTS
The immediacy of the hyperpnoea at exercise onset demands that contributing stimuli be detected and acted upon with virtually no delay. Thus, if sudden C02 inhalation coincident with exercise onset were to abolish an intrapulmonary perfusionrelated stimulus (see Introduction), its influence on ventilation (P.E) should be apparent within the first breath of exercise. Indeed, by the next breath, the inhaled C02 bolus may have activated the carotid body chemoreflex (Ward, Drysdale, Cunningham & Petersen, 1979), so complicating the interpretation of ventilatory events beyond the first breath of exercise. Exercise onset
Apart from manipulation of inspired C02 levels, conditions were largely identical between those exercise transitions throughout which room air was breathed (T1) and those which involved abrupt C02 inhalation at exercise onset (T2). In particular, there was similarity with respect to: (i) BXE, heart rate, PET,Co, and PET,O, before exercise (Table 2); (ii) the subjects' state of awareness, as judged by their reaction
INITIATION OF EXERCISE HYPERPNOEA
207
TABLE 2. Resting cardiorespiratory conditions for the three breaths preceding exercise; reaction time to the exercise command; and pedalling frequency over the first breath of exercise, for Tl and T. tests. Data averaged subject by subject (± 1 s.E. of mean) Minute End-tidal End-tidal Reaction Pedalling Heart rate ventilation time P02 frequency Pc02 Subject n (beats/min) (mm Hg) (mm Hg) (I./min) (sec) (rev/min) C.E. T1 13 739 +0-8 14-5 + 0-5 40-2 + 0-3 105-6 0-6 0-40 + 0-02 49-5 +0-8 T2 13 75-4±0-6 41-2+0-2 15-4+0-4 102-9+0-5 0-39±0-02 49-7+0-6 M.A. T1 15 82-6 +1-4 14-0 + 0-3 35-4+ 0-3 111-4 + 0-4 0-54+ 0-03 353 +1-0 T2 20 85-0+ 1-4 14-2+0-4 112-1± 0-4 0-50+0-02 34-9+0-9 34-8+0-2 J.B. T1 15 95-1+2-2 12-2+0-5 107.0+ 1-1 0-54+0-02 49-S-1i1 38-2+0-3 T2 13 96-9 + 2-1 13-7 + 0-7 37-3 + 0-4 107-5 +0-8 0-51 + 0-02 48-7 +1-5
J.B.T,
5 sec_
PAi
Ergometer photocell signal
B
V V-V,
E.c.g. I nsp.
EO
C, (./m in)
v
100 Exp.
+
f
Exp. v
.f-[ X,> NV ,N NA
E1
l.)[0
E
I nsp.
PC02 mmHg [40
P02 mmHg[E00
A
ETXco2
'PETO2
Fig. 1. Experimental record (subject J.B.) of a transition between rest and exercise during air breathing (T1). From above down: time marker (1 sec intervals); ergometer photocell signal; electrocardiogram (e.c.g.); respiratory flow (v); respiratory volume (v); P00, and POX of respiratory gas. VTI and VT.E are inspiratory and expiratory tidal volumes. PET.,O and P]T.O, are end-tidal gas tensions. A, B are the times when the command to pedal was given and when pedalling actually started (at transition of ergometer signal from steady to periodic form), respectively. Due to the delayed response of the gas analyzers, the gas tension records lag the remaining records, as shown by the broken vertical line which is coincident with the start of pedalling.
times to the exercise command (Table 2); (iii) the onset of exercise, which occurred just before the onset of inspiration (Figs 1 and 2); (iv) mean pedalling frequency during the first breath of exercise (Table 2). The levels of JIE and heart rate obtaining just before exercise (see above) were understandably somewhat greater than one would expect from a truly basal state, in view of the frequent, if brief bouts of exercise.
208
S. A. WARD .5-sec--A
J.B.T2 Ergometer photocell signal
y rVV
E.c.g. Insp. 100 Exp. Exp.
E1
0 VA
~
~
~ itx
