Control of the respiratory cycle in conscious humans
G. F. RAFFERTY AND W. N. GARDNER
Department of Physiology, Biomedical Sciences Division, King’s College London,
London W8 7AH; and Department of Respiratory Medicine, King’s College School
of Medicine and Dentistry, London SE5 9PJ, United Kingdom
chemical drive; respiratory pattern; carbon dioxide
THE RESPIRATORY CYCLE can be divided into drive [inspired tidal volume (VTI ), mean inspiratory flow (MIF),
or VT/TI] and timing variables [inspiratory time (TI )
and expiratory time (TE )]. These are influenced by
different control mechanisms (7, 12), but few models of
integrated control of breathing indicate the relative
strengths of the mechanisms controlling these individual variables around their resting set points. This
dimension of respiratory control, especially in humans,
appears to have been largely neglected.
In a previous study in normal humans (21), we used a
computerized system of auditory feedback selectively to
impose changes on an individual variable over long
periods of time while keeping constant other aspects of
the respiratory cycle and chemical drive. The study was
designed for other purposes, but coincidentally it also
demonstrated that TI and TE under isocapnic conditions could be changed over a wide range with little
difficulty for up to 1 h. Whereas extreme breathing
patterns can be sustained for a few breaths, the ability
of the respiratory control system to tolerate such large
alterations of every breath over such long periods of
time suggested that mechanisms controlling timing of
the respiratory cycle were very weak.
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In previous unpublished pilot experiments, Gardner,
using himself as a subject breathing various steadystate levels of CO2, noted that the CO2 forced him to
breathe in up a ‘‘ramp’’ that became progressively
steeper (i.e., with a faster rate of inspiration) as the
level of inhaled CO2 increased and that it was almost
impossible to breathe in up a ramp that was shallower
(i.e., with a slower rate of inspiration) than that
dictated by that level of inhaled CO2. It appeared that
this was one of the major, and possibly the only,
controlling influence in the respiratory cycle.
We wished to demonstrate this in a more systematic
way using the technique of auditory feedback described
above. The slope of the ramp of inspiration is given by
MIF. We wished to determine the range and ease over
which MIF and VTI could be increased and decreased
away from their free-breathing resting values at various levels of inhaled CO2 and to compare these responses with equivalent changes of timing variables TI
and TE in a more extended series of experiments than
described above.
METHODS
Subjects
We studied various combinations of 17 healthy young
subjects (10 men and 7 women, age range 18–35 yr) with no
history of pulmonary, cardiovascular, or other diseases. Subjects were naive as to the physiological aims of each experiment. Permission was obtained from the Ethical Committee
of King’s College, London, and informed consent was obtained
in accordance with the guidelines laid down by the committee.
Equipment
An open-circuit system was used (Fig. 1). Warmed humidified air flowed at a constant rate of 80 l/min down a wide-bore
line from which the subject could inspire and expire freely via
a mouthpiece attached to a T piece and heated Fleisch
pneumotachograph. This air was warmed and humidified and
could be enriched with various concentrations of O2 and CO2,
the flow of both gases being measured and controlled by
individual solenoid valves (Chell Instruments, Walsham Norfolk, UK). Respiratory flow from the pneumotachograph was
measured by a Validyne MP45 pressure transducer (P. K.
Morgan, Gillingham, Kent, UK) and was analyzed in real
time by computer with analog-to-digital sampling at 100 Hz
(system from Systematika, London, UK). This system was
responsible for data acquisition and auditory feedback.
Respiratory data acquisition. A computer program written
in FORTRAN 77 extracted key respiratory variables (Fig. 2)
from the respiratory flow signal. Inspired and expired volumes (VTI and VTE, respectively) were derived by integration
of flow. The start of inspiration and expiration, required to
measure TI and TE, respectively, were located from zero flow
(i.e., the point of phase transition, set at zero analog-to-digital
0161-7567/96 $5.00 Copyright r 1996 the American Physiological Society
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Rafferty, G. F., and W. N. Gardner. Control of the
respiratory cycle in conscious humans. J. Appl. Physiol. 81(4):
1744–1753, 1996.—We studied in conscious humans the
relative strength of mechanisms controlling timing and drive
components of the respiratory cycle around their resting set
points. A system of auditory feedback with end-tidal PCO2
held constant in mild hyperoxia via an open circuit was used
to induce subjects independently to change inspiratory time
(TI ) and tidal volume (VTI ) over a wide range above and below
the resting values for every breath for up to 1 h. Four
protocols were studied in various levels of hypercapnia (1–5%
inspired CO2 ). We found that TI (and expiratory time) could
be changed over a wide range (1.17–2.86 s, P , 0.01 for TI )
and VTI increased by $500 ml (P , 0.01) without difficulty.
However, in no protocol was it possible to decrease VTI below
the free-breathing resting value in response to reduction of
auditory feedback thresholds by up to 600 ml. This applied at
all levels of chemical drive studied, with resting VTI values
varying from 1.06 to 1.74 liters. When reduction in VTI was
forced by the more ‘‘programmed’’ procedure of isocapnic
panting, end-expiratory volume was sacrificed to ensure that
peak tidal volume reached a fixed absolute lung volume.
These results suggest that the imperative for control of
resting breathing is to prevent reduction of VTI below the
level dictated by the prevailing chemical drive, presumably to
sustain metabolic requirements of the body, whereas respiratory timing is weakly controlled consistent with the needs for
speech and other nonmetabolic functions of breathing.
RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
1745
units) plus or minus a small threshold (Thr 1 in Fig. 2) to
allow for baseline noise and drift. An inspiratory deflection
was interpreted as the start of a breath when inspiratory flow
crossed a second threshold set before the experiment at about
one-third of average peak inspiratory flow (Thr 2 in Fig. 2).
Fig. 2. Diagrammatic representation of key respiratory variables
extracted by data-acquisition program. Insp, inspiratory; Exp, expiratory; Thr 1 and Thr 2, lower and upper thresholds; VTI, inspired tidal
volume; TE, expiratory time; VTE, expired tidal volume.
PCO2 and PO2 were sampled directly and continuously from
the mouthpiece and measured by a mass spectrometer (model
VG SX200, VG Quadrupoles, Cheshire, UK). The inspired
and expired gases were analyzed in real time by the computer
to provide a breath-by-breath record of inspired PCO2 and
end-tidal PCO2 (PETCO2). Variables were stored in an array and
transferred to disk at the end of the experiment. MIF and
minute ventilation were calculated for each breath off-line.
The program provided a visual display in real time on the
computer visual display unit of VTI, VTE, TI, and TE for each
breath. This gave the experimenter the feedback information
with which to monitor and, if required, keep constant (see
below) each of these variables on a breath-by-breath basis
during the experiment.
Auditory feedback control system. A computerized technique using auditory feedback controlled from within the
data-capture program as described above allowed one or two
variables to be changed over a wide range away from resting
or held constant for every breath over long periods of time at
a constant PETCO2. A ‘‘bleep’’ consisting of a 0.2-s tone of a fixed
pitch generated by an oscillator circuit was triggered in real
time via the digital-to-analog board of the computer when a
threshold value of a variable was reached as measured in real
time by the data-capture program. Auditory feedback could
be imposed on two different variables simultaneously, each
variable generating a tone of different pitch. In the present
experiments, feedback was imposed on VTI and TI simultaneously or on just one of these variables.
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Fig. 1. Diagrammatic representation of apparatus. Top right: open circuit; left: computerized system for data
acquisition and auditory feedback (‘‘bleep’’ box). Thick arrows show direction of gas flow. ADC, analog-to-digital
converter. VT, tidal volume; TI, inspiratory time.
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RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
Protocols
Five different protocols were performed. In protocols in
which a variable was increased and decreased, the increase
and decrease were performed in the same experiment with a
break between each half of the protocol, and the order in
which the two halves of the experiment were performed was
randomized.
In all these protocols, PETCO2 was held constant by manipulation of CO2 in the open circuit at the level achieved by the
subject at the beginning of each run. In protocol 3, PETCO2 was
held constant at each level of chemical drive studied. Thus all
responses were uncoupled from chemical feedback control.
Protocol 1: TI increased and decreased (auditory feedback
on TI alone). This protocol was designed to confirm earlier
findings (21) that the mechanism controlling TI around its
resting set point is very weak. VTI was not held constant as in
these previous experiments to increase the degrees of freedom by which the control system could respond to the
imposed changes of TI. The threshold of the TI auditory
feedback was increased or decreased without the subjects’
knowledge every 3 min by 200-ms steps to a maximum
change in each direction of 1,000 ms. Inspired CO2 was
initially set at 2%.
Protocol 2: VTI increased and decreased and TI constant
(auditory feedback on VTI and TI). This experiment determined the ease with which VTI could be forced to deviate from
its resting set point with TI maintained constant by auditory
feedback to ensure a change of MIF in parallel with the
changes of VTI. The threshold of the VTI auditory feedback
was increased in 100-ml steps to a maximum of 500 ml and
was decreased in 50-ml steps in an attempt to achieve a
maximum decrease of 300 ml. Inspired CO2 was initially set
at 2%.
Protocol 3: VTI increased and decreased (auditory feedback
on VTI alone). This protocol was similar to protocol 2, but no
auditory feedback was imposed on TI to allow the system to
respond with more degrees of freedom. The threshold of the
VTI auditory feedback was increased or decreased in 100-ml
steps to a maximum change in each direction of 500 ml. A
higher starting level of CO2 inhalation (3%) was used to
increase the initial value of VTI and allow a larger reduction of
VTI threshold to be imposed.
Protocol 4: VTI and TI decreased in tandem (auditory
feedback on VTI and TI). This protocol allowed the response to
a change of VTI to be studied in the absence of a parallel
change of MIF. The VTI threshold was reduced in 150-ml steps
to a maximum of 600 ml while the TI threshold was reduced in
parallel to match the VTI reduction and keep MIF constant.
The experiment was repeated at inspired CO2 of 7, 21, and 35
Torr (1, 3, and 5%) to study the influence of chemical drive on
these responses.
Protocol 5: free ‘‘panting.’’ The subject was asked to ‘‘pant’’
by significantly reducing resting tidal volume and increasing
respiratory frequency to a level that could be comfortably
maintained for 6 min. Inspired CO2 was initially set at 3%
and subsequently increased to maintain PETCO2 constant
during the hyperventilation.
Statistical Analysis
All variables were obtained for every breath throughout
each protocol and were averaged over the minute at the end of
each steady state after an intervention. These means were
then averaged for the equivalent stage of each protocol across
all subjects. Significance of change was determined by oneway analysis of variance and paired or unpaired Student’s
t-test comparison of the resting values with the values for
each variable at the extremes of change of the clamped
variables for each steady state.
RESULTS
In the present experiments, no subject had difficulty
in breathing to the auditory feedback when thresholds
were set to match the free-breathing resting values. A
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The subjects were initially coached in the significance of
each tone and were allowed a dummy experiment in which to
practice. After a period of free breathing, the auditory feedback was started, with threshold values initially set to match
the value produced by the subject during free breathing. The
subjects were required to inspire for a sufficient time and/or
to a sufficient tidal volume to activate correctly the auditory
feedback. When two tones were imposed, the subjects were
further instructed to make them coincide by making small
voluntary adjustments of volume or time. Expiration was
initiated as soon as possible after the sounding of the tones,
leaving TE free to be set by the subject. The countdown for the
auditory feedback started only when the subject chose to
begin initiating inspiration as sensed by the computer.
When a sufficient period of resting breathing had been
obtained to ensure stability and compliance with the auditory
feedback, the threshold for one or both tones was changed in
tiny and undetectable steps from the keyboard over 1 min to
reach a new level, which was then maintained for a further 2
min. Values of VTI, TI, TE, MIF, and PETCO2 were stored for
each breath throughout the experiment.
Auditory feedback was imposed on every breath for 45–60
min. Although voluntary effort was required to make the
auditory feedback coincide or to track it initially, only a short
orientation period was required at the start of each experiment to allow the subjects to reduce to a minimum the
concentration required to perform these tasks. The subjects
were easily able to follow the small imposed changes in the
threshold of the variables on which auditory feedback was
imposed and had little conscious awareness that a change
had been imposed.
In all cases, there was a time lapse between the tones
sounding and the subject terminating inspiration because of
the time needed to respond to the auditory signal. For VTI this
was usually ,100–150 ml, and for TI it was ,400–500 ms.
Good control was signified by the constancy of this overshoot.
Failure to comply with the restrictions imposed by the
auditory feedback was signified by persistent failure over
many minutes to make the tones coincide, by failure to
terminate inspiration at the time of the tones with an
increase in the gap between imposed and actual values of VTI
and/or TI, as determined by analysis of the computer data
after the experiment, and by termination of the experiment
with the subject reporting inability to continue. In each
protocol, the way in which control was lost gave insight into
the priorities of the control system for each variable.
In most experiments, changes of end-expired volume (EEV)
were assessed by an uncalibrated respiratory inductive plethysmograph (Respitrace) in direct-current coupled mode.
PETCO2 could be kept constant by subtraction or addition of
CO2 to the open circuit as ventilation changed during the
experiment, with subtraction of CO2 being facilitated by
performing the experiments at varied low and moderate
levels of inspired PCO2, which induced a state of mild respiratory stimulation. All experiments were performed in mild
hyperoxia with the inspired PO2 at ,200 Torr to eliminate any
possible influence of hypoxia on the results and to reduce the
influence of the peripheral chemoreceptors to simplify the
interpretation of the results.
RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
section of experimental trace with breath-by-breath
uncalibrated flow and PCO2 is shown for one experiment
of protocol 2 in Fig. 3. This illustrates the transition
from rest to activation of the auditory feedback on VTI
and TI and subsequent reduction of VTI threshold by
100 and 150 ml, respectively. PETCO2 was maintained
constant by manipulation of the mixture in the open
circuit throughout these transitions. A similar level of
control was maintained in all protocols. The results of
the different protocols are as follows.
Protocol 1
TI. MIF decreased nonsignificantly as TI increased and
increased markedly and significantly as TI fell.
Protocol 2
Twelve subjects (6 men and 6 women) were studied.
Figure 5 shows mean values as in Fig 4. All subjects
increased VTI without difficulty from a mean resting
value of 1.06 liters to a mean of 1.61 liters (P , 0.01) in
response to the imposed change of auditory feedback
threshold of 500 ml while TI and PETCO2 were held
constant. The ease with which VTI increased was shown
subjectively by reports from the subjects at the end of
the experiments and objectively by the stability of
successive values of all variables as VTI increased and
by the constancy of the overshoot (,0.23 liter for VTI
and 600 ms for TI ) in the variables controlled by the
auditory feedback.
By contrast, 10 of 12 subjects were unable to reduce
VTI below the free-breathing resting value, as indicated
by the horizontal dotted line in Fig. 5, and only from the
mean resting value with the auditory feedback activated of 1.06 to 1.00 liter (n 5 12) in response to the
300-ml decrease in auditory feedback threshold. The
failure of breathing to change as the VTI threshold was
reduced is also shown in the example in Fig. 3. EEV did
not change. Failure to change breathing to track the
auditory feedback on VTI was signified at the time of the
experiment by inability to make the tones for TI and VTI
coincide and complaints of difficulty and is indicated in
the analysis by progressive increase in the overshoot
for VTI and by large swings in other variables as VTI fell
(Fig. 5).
MIF increased in parallel with an increase in VTI
(P , 0.001). The attempt to decrease VTI was associated
with a maximum mean decrease in MIF of 2.8 l/min
(9.7%) below the resting value with the auditory feedback activated and 3.6 l/min (12.4%) below the mean
free-breathing resting value.
Fig. 3. Experimental trace of PCO2 and uncalibrated respiratory flow for 1 subject in protocol 2 showing transition
from free breathing to auditory feedback at VTI of 0 ml and subsequent reduction of VTI feedback threshold by 100
and 150 ml, respectively. Note constancy of end-tidal PCO2 throughout and failure of breathing to respond to
decreasing VTI thresholds.
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Nine subjects (5 men and 4 women) were studied.
Mean values averaged for all subjects are shown for
VTI, TI, MIF, and PETCO2 in Fig. 4. The variable influenced by the auditory feedback is also shown. The
auditory feedback target values and the actual values
attained in response to this feedback are shown, with
the difference between the two being the overshoot due
to the time to register and respond to the auditory cue.
Free-breathing resting values are also shown.
The results reflected the findings from our previous
study, in that all subjects were able to comply with the
protocol and track the imposed change of TI throughout
the experiment. From a mean resting value for TI of
1.94 s, there was a highly significant (P , 0.001) change
of TI in both directions (mean range 1.17–2.86 s). The
ease with which subjects were able to comply with the
changes imposed by the auditory feedback was indicated by the constancy of the overshoot of the actual TI
above the threshold value set by the auditory feedback
(Fig. 4) and by the stability of successive values of all
variables and especially PETCO2 as TI increased and
decreased.
VTI, which was freely determined by the subject,
increased significantly (P , 0.01) as TI increased but,
as TI decreased, did not fall below the free-breathing
resting value, except at the most extreme reduction of
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RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
Protocol 3
Protocol 4
Eleven subjects (8 men and 3 women) were studied.
Figure 6 shows the responses averaged across all
subjects. As in protocol 2, in 9 of 11 subjects VTI could
not be forced to decrease below the free-breathing
resting value, despite the absence of restraint on
change of TI and the larger reduction in VTI demanded.
There was an increasingly wide divergence between the
values imposed by the auditory feedback and the
achieved values as the VTI auditory feedback threshold
was decreased, and mean VTI with the auditory feedback activated (averaged across all 11 subjs) only
decreased from 1.24 liters to a minimum of 1.01 liters
(P , 0.01) in response to the 500-ml decrease in
auditory feedback threshold. By contrast, VTI increased
to a mean of 1.71 liters without difficulty when the
threshold was increased by 500 ml. TI increased (P ,
0.05) and decreased (P , 0.001) in parallel with change
of VTI. PETCO2 and EEV did not change significantly in
either direction. MIF significantly increased above the
resting level in both directions.
Seven subjects (4 men and 3 women) were studied.
Figure 7 shows that, at each level of chemical drive, VTI
appeared to approach asymptotically the free-breathing value associated with that level of drive, and
subjects were not able to reduce VTI below that level
(Fig. 7A). However, subjects were able significantly to
reduce TI (Fig. 7B) with relatively constant overshoot
throughout the protocol (500 ms). By contrast, mean TI
changed significantly (P , 0.01) and without difficulty
over a wide range (Fig. 7) as its auditory threshold was
reduced. The responses of individual subjects reflected
these mean responses at the three levels of CO2 inhalation studied. PETCO2 was maintained constant in each
part of the protocol, and EEV did not change. As control
of VTI was lost, MIF (and ventilation) also increased,
but these changes were not significant. In testing the
ability of VTI to reduce at constant or increased MIF,
this protocol confirmed that VTI, rather than MIF, was
the actively limited variable. It also showed that the
limitation on reduction of VTI applied at different levels
of chemical drive at least up to 5% inspired CO2.
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Fig. 4. Results of protocol 1. Response of VTI, TI, MIF, and end-tidal PCO2 (PETCO2) plotted against increase
and decrease from resting value (at 0 ms) of imposed change of TI as imposed by auditory feedback at constant
PETCO2 (means 6 SE; n 5 9). j, Means averaged across all subjects for last minute of each 3-min steady state.
q, Threshold values imposed by auditory feedback for TI; presence of auditory feedback is indicated by bass clef
sign. Dashed lines, free-breathing resting values. Significance of change in each direction from resting values is
shown for each variable. MIF, mean inspiratory flow.
RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
1749
Fig. 5. Results of protocol 2 (means 6
SE; n 5 9) plotted as for Fig. 4 but with
imposed changes of VTI on x-axis. Auditory feedback is imposed on VTI and TI
as shown by treble and bass musical
clef signs. TI and PETCO2 are kept constant.
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Fig. 6. Results of protocol 3 (means 6 SE; n 5 11) plotted as for Fig. 5 but with auditory feedback applied only to VTI.
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RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
Protocol 5
Four subjects (2 men and 2 women) were studied. All
subjects were able to significantly reduce VTI throughout the period of overbreathing, with a mean reduction
to ,50% of resting (Fig. 8) associated with reduction of
TI and TE (73 and 79%, respectively) and increase in
MIF and ventilation. However, the respiratory inductance plethysmograph traces (Fig. 9) showed that all
subjects increased EEV sufficiently during panting to
maintain peak tidal volume at approximately the absolute lung volume attained in resting conditions. PETCO2
was maintained constant via the open circuit throughout the experiment. Questioning the subjects at the end
of each experiment revealed no discomfort during the
panting maneuver.
DISCUSSION
The present results provide a new method of studying the integrated control of breathing in conscious
humans. They support our initial hypothesis in showing that when the feedback loop to chemical drive is
broken, the main priority of the respiratory control
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Fig. 7. Results of protocol 4. Filled symbols, mean responses (n 5 7)
of VTI (A) and TI (B) to parallel step decreases in auditory feedback
thresholds for VTI and TI at constant PETCO2 from starting values of
inspired PCO2 of 1% (7 Torr), 3% (21 Torr), and 5% (35 Torr).
Significance of changes of VTI and TI are shown. Horizontal dashed
lines, free-breathing values at each level of chemical drive. Values
imposed by auditory feedback (treble and bass clef signs) are shown
on line of identity by corresponding open symbols.
mechanisms during normal quiet breathing is to prevent reduction of tidal volume below its resting values,
whereas respiratory cycle timing, as reflected by TI and
TE, is much more weakly controlled (21). VTI can be
increased without difficulty. Contrary to our initial
hypothesis, VTI, rather than MIF, appears to be the
variable that has to be preserved, although VTI and
MIF are clearly closely related. The finding that forced
panting causes preservation of peak tidal volume with
loss of control of EEV was unexpected and has not, to
our knowledge, been described previously.
These findings are logical, in that respiratory timing
needs to be free to change easily to allow the performance of voluntary respiratory motor acts such as
speech and other behavioral respiratory acts, whereas
tidal volume provides the main link with the chemical
feedback system to ensure maintenance of blood gas
homeostasis. It would probably be impossible to perform voluntary respiratory acts if timing were strongly
controlled by the automatic system. These findings
were consistent across all protocols and were still
obtained when the number of potential degrees of
freedom of the system were increased by application of
auditory feedback to one instead of two variables
(protocols 1 and 3). Two of 17 subjects (subjs 1 and 10)
were consistently able to reduce VTI, suggesting some
individual variation of this response.
Further insights into this control mechanism were
provided by protocol 4, which showed that the restriction to reduction of VTI was applicable at all levels of
inspired CO2 studied. It is reasonable to conclude that
VTI cannot be reduced far below the resting level as
dictated by the prevailing chemical drive. This protocol
and the results of the other protocols do not support a
similar restriction on the reduction of MIF.
Protocol 5 showed that, in free voluntary overbreathing, VTI could indeed be reduced for a prolonged period
of time with very little effort and discomfort, but the
EEV increased to ensure that the peak lung volume
was not reduced. One explanation for the difference
between this result and those obtained from the auditory feedback protocols may be that freely determined
voluntary overbreathing was similar to panting, requiring a preprogrammed set of instructions similar to the
complex integration of responses required for maneuvers such as sneezing and laughing. This may have
been a more compelling stimulus to reduce VTI than
was imposed by breathing with auditory feedback, in
which there was a precise control exerted on a breathby-breath basis that was possibly closer to normal
breathing. To our knowledge, these phenomena have
not been previously described and are not featured in
the control model proposed by von Euler (11), but they
are consistent with responses to sustained resistive loading, during which there is also preservation of VTI (2).
Mechanisms responsible for alteration of EEV during
quiet breathing in normal subjects are uncertain. EEV
is fundamentally determined by the balance of elastic
forces in the lung and chest wall. It is altered by posture
and reduced by exercise (18, 28), and there is conflicting
evidence as to whether it is altered by chemical drive (6,
RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
1751
Fig. 8. Results of protocol 5. Responses
of VTI, TI, MIF, and PETCO2 to free
‘‘panting’’ (PANT) at constant PETCO2
plotted against time for each subject.
The 4 subjects are shown individually
by different symbols.
nisms, although the need to attain a fixed peak tidal
volume during the free panting protocol would also
require some afferent feedback about the position of the
lung or chest wall.
The underlying basis of our auditory feedback technique has been discussed previously (21) but is based
on the assumption that a cortically induced pattern can
entrain the underlying automatic respiratory centergenerated rhythm. In humans, many respiratory motor
activities such as speech require higher center voluntary control of breathing, which is a powerful mechanism able to modulate and override underlying auto-
Fig. 9. Results of protocol 5. Uncalibrated
volume trace obtained by respiratory inductive plethysmograph (Respitrace) for 1st
subject showing increase in end-expired
volume with constancy of peak tidal volume during panting.
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17, 24). EEV can cycle in long runs by as much as 600
ml (16). Increasing EEV is energetically unfavorable to
the control mechanism and appears not to take precedence over maintaining VTI unless a very compelling
command is imposed.
In seeking a mechanism to explain these results, it is
difficult to propose a control mechanism that will not
allow VTI to fall far below the resting value as dictated
by the chemical drive, that will allow virtually unlimited increase in VTI, and that is independent of the level
of chemical drive. The best explanation is probably
provided by interaction of central neuronal mecha-
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RESPIRATORY CYCLE CONTROL IN CONSCIOUS HUMANS
These results could not be explained by any prolonged or transient changes of chemical drive. PETCO2
was kept at a constant level within each experiment, as
shown by the mean values presented in RESULTS, and
transient variation of PETCO2 within each experiment
was minimal (Fig. 3). In that the experiments were
performed with enrichment of O2, the contribution of
peripheral chemoreceptors was minimized, and most
chemosensitivity was contributed by the central chemoreceptors, which have a half time of response of 120 s
(13) and would be unlikely to respond to any transient
variation of PETCO2. It is difficult to conceive that the
conclusions in this study would not be equally applicable to the air-breathing situation.
There are a number of implications from these results. First, they simplify any future analysis of respiratory control in humans, in that the chemical control of
tidal volume and the slope of the inspiratory ramp are
by far the most important and significant aspects of
cycle control and are directly related to the level of CO2
(and probably the overall chemical drive when hypoxic
drive is significant). Cycle timing is probably determined by the inherent properties of the brain stem
pacemaker, can easily be overridden by cortical and
other factors, and is of much less importance. Second,
these results may have implications for dyspnea in
patients with respiratory disease, in that dyspnea is
likely to occur when the disease forces a ramp of
inspiration with a lesser slope than dictated by the
prevailing blood gases. Of course, this is unlikely to be
the only mechanism of dyspnea in these patients. The
results are also likely to have an implication for many
situations in which subjects spontaneously breathe at a
low tidal volume or are forced to do so by, for example,
the constraints of panting, speech, and ventilatory
support.
In conclusion, this investigation presents a new way
of studying integrated control of breathing in conscious
humans. The only imperative for respiratory control
seems to be the attainment of a tidal volume that is
appropriate to the prevailing chemical drive, presumably to ensure metabolic homeostasis. The extremely
weak control of respiratory timing is appropriate for
the behavioral and nonmetabolic functions of breathing.
G. F. Rafferty thanks Profs. P. McNaughton and S. Howell for
laboratory facilities. W. N. Gardner thanks the late Dr. Dan Cunningham for long-lasting enthusiasm for, and endorsement of, these
techniques.
The authors thank the Wellcome Trust, and G. F. Rafferty thanks
the Medical Research Council for financial support.
These experiments have been reported in abstract form (22).
Address for reprint requests: G. F. Rafferty, Dept. of Child Health,
4th Fl., Ruskin Wing, King’s College Hospital, Denmark Hill, London
SE5 9RS, UK.
Received 11 July 1995; accepted in final form 23 May 1996.
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