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Departments of 1 Physiology and 2 Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Imperceptible levels of proportional assist ventilation applied throughout inspiration reduced inspiratory time (TI) in awake humans. More recently, the reduction in TI was associated with flow assist, but flow assist also reaches a maximum value early during inspiration. To test the separate effects of flow assist and timing of assist, we applied a pseudorandom binary sequence of flow-assisted breaths during early, late, or throughout inspiration in eight normal subjects. We hypothesized that imperceptible flow assist would shorten TI most effectively when applied during early inspiration. Tidal volume, integrated respiratory muscle pressure per breath, TI, and TE were recorded. All stimuli (early, late, or flow assist applied throughout inspiration) resulted in a significant increase in inspiratory flow; however, only when the flow assist was applied during early inspiration was there a significant reduction in TI and the integrated respiratory muscle pressure per breath. These results provide further evidence that vagal feedback modulates breathing on a breath-by-breath basis in conscious humans within a physiological range of breath sizes.
vagus; control of respiration; mechanical ventilation; Hering-Breuer reflex
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE HERING-BREUER REFLEX, in which passive overinflation of the lungs or prevention of inspiration or expiration alters respiratory timing (11), has been documented in humans by using airway occlusion during anesthesia (19) or passive overinflation of the lungs during sleep (12). The reflex has been more difficult to elicit during wakefulness in humans. However, airway occlusion and overinflation of the lungs are potent stimuli not typically encountered during eupneic breathing, and these stimuli may evoke behavioral responses if applied during wakefulness, which could mask the effects of the Hering-Breuer reflex. In a previous study in adult human subjects (3), our laboratory investigated the effect of unloading the respiratory system by using imperceptible levels of proportional assist ventilation applied in a pseudorandom binary sequence. We found that a small but significant increase in tidal volume (VT) and inspiratory flow rate (VT/TI) resulted in a significant reduction in inspiratory time (TI), consistent with the action of the Hering-Breuer reflex. In a subsequent investigation using a similar technique (4), our laboratory examined the separate effects of imperceptible flow and volume-assist ventilation on respiratory timing. Although flow and volume assist resulted in similar increases in VT and VT/TI, only during flow-assisted breaths was there a significant reduction in TI. Flow-assist ventilation occurs early during inspiration and has a decrementing pressure profile, whereas volume assist has an augmenting pressure profile and reaches a maximum level of assist at the end of the breath. Thus the timing of the respiratory assistance, rather than the type of assist (volume vs. flow assist), may have influenced intrabreath vagal feedback.
In the present study, we investigated the effect of the timing of flow
assistance on respiratory activity during wakefulness. We hypothesized
that if imperceptible flow assistance were administered during early
inspiration, reflex shortening of TI and integrated inspiratory muscle pressure (
Pmus) would occur. As in prior studies (3, 4), we applied assistance in a pseudorandom binary
sequence of breaths at levels below the threshold of conscious
perception. The respiratory response was modeled by using a linear
system estimation procedure based on the prediction-error method
(15). This technique requires an input (the pseudorandom
binary sequence of assisted and unassisted breaths) and an output (the
respiratory variables we measured) to develop a mathematical model of
the respiratory system. The parameters of the mathematical model are selected to minimize the differences between the actual values of the
variables measured and the predicted values of the same variables
derived from model calculations. This technique can be used to model
the first breath response to an impulse (the flow assist) by using data
from every breath of the pseudorandom binary sequence of flow assist
and permits, as a result, the quantification of small responses to
stimuli that would not be evident by using other methods such as
single-breath tests or responses to steady-state changes in a stimulus.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. We recruited eight adult volunteers of either sex without prior or current respiratory disease. The consent form stated that the investigators would measure the mechanical characteristics of each subject's respiratory system, assess each subject's ability to detect when a ventilator was helping the subject breathe, and measure each subject's response to respiratory assistance from a mechanical ventilator. Neither the consent form nor the investigators revealed the objectives of the study to any of the subjects. None of the subjects had significant knowledge of respiratory psychophysics. The local Institutional Review Board approved the study.
Instrumentation and setup. Each subject was studied while sitting semirecumbent in a dental chair, wearing a nose clip, and breathing though a mouthpiece attached to a prototype ventilator (University of Manitoba, Winnipeg, Canada). Each subject listened to white noise through earphones so that he or she was not distracted or given clues about the activity of the ventilator. The dead space of the breathing circuit was ~0.1 liter. We recorded analog signals from the ventilator proportional to airway pressure and flow. We used software written in LabVIEW (National Instruments, Austin, TX) to calculate the instantaneous flow-assist level and to command the ventilator to give the appropriate assist pressure.
For analysis, airway pressure measured at the mouth (Pm) and inspiratory airflow were recorded directly from a calibrated analog output supplied by the ventilator, and flow was integrated with a zero-crossing reset to calculate VT. End-tidal carbon dioxide (ETCO2) was measured at the mouth with a CAPSTAR-100 carbon dioxide analyzer (CWE, Ardmore, PA). During the estimation of respiratory mechanics, airflow at the mouth was occluded with a two-way shutoff valve (9340 series inflatable balloon controlled with an 8230 series automatic controller, Hans Rudolph, Kansas City, MO). Programs written with LabVIEW software controlled the ventilator and balloon valves and displayed and recorded the data.Experimental protocols. Each experiment consisted of three parts, completed on 2 consecutive days. During the first day, we estimated the passive mechanical characteristics of the respiratory system of each subject [respiratory system resistance (Rrs) and respiratory system elastance (Ers)]. Next, we determined the threshold of detection of respiratory assistance in each subject when the assist was confined to early or late inspiration. Finally, we studied the response of each subject to a pseudorandom binary sequence of flow-assisted ventilation delivered early or late during inspiration. The timing of the assist was accomplished by averaging 20 control breaths before the pseudorandom binary sequence of assisted breaths to determine the average duration of TI. Assist was applied for a time equal to 50% of the average TI. For early assist (Eassist), flow was augmented starting at the onset of inspiration. For late assist (Lassist), flow was augmented from the point of the breath equal to 50% of the average TI until the breath terminated spontaneously. On the second day, the threshold of detection for assist applied throughout inspiration (Tassist) was determined, and flow assist was applied throughout inspiration by using a pseudorandom binary sequence.
Estimation of respiratory mechanics. We used a modification of the interrupter method to estimate Ers and Rrs (7, 22). Each subject was ventilated by using controlled ventilation to achieve passive ventilation. Subjects were invariably hypocapnic during this period. Flow rate, Pm, and VT were monitored continuously to ensure passive ventilation. The airway was occluded every five to eight breaths for 400-600 ms after delivery of 60-80% of a subject's VT. Occlusions were judged satisfactory when no respiratory effort was visible during the breath, when flow and pressure profiles were similar to previous breaths, and when the occlusion plateau was constant. Approximately 20 satisfactory occlusions were recorded from each subject. Ers was calculated from the difference between the plateau pressure and the end-expiratory pressure divided by the VT of that breath. Rrs was calculated from the difference between Pm measured immediately before the occlusion and the subsequent plateau pressure divided by the flow immediately preceding the occlusion.
Determination of 50% threshold of sensation.
We used a forced choice protocol to determine the threshold of
perception when flow assist was delivered early, late, or throughout inspiration (13). The levels of flow assistance varied
from imperceptible to well above the perceptual threshold. After each assisted breath, the subject was "forced" to decide whether the ventilator "helped" or "did not help" on that breath. The
ventilator randomly applied five levels of assist, ranging from 20 to
70%, and three unassisted breaths followed each assisted breath. Each 20-breath sequence of assisted breaths was repeated 11 times in a
randomized-block design. The first 20-breath sequence from each protocol was discarded from the analysis. The probability of detection of ventilator assistance (P) was calculated at each level of
assistance by using logits {1 logit = ln[P/(1 
P)]}. We defined the perceptual threshold as
the level of assistance that was detected 50% of the time. For each
subject, logits were plotted as a function of percent assistance, and
linear regression was used to fit the data. The x-axis
crossing in this analysis is equal to the 50% threshold of
sensation for Eassist, Lassist, or
Tassist.
Pseudorandom binary sequence assist protocols. In each breathing trial, 267 sequential breaths were measured. This long sequence of breaths was the sum of three treatment sequences: a control set of 70 unassisted breaths, a test set of 127 breaths that were either assisted or unassisted, as determined by a pseudorandom binary sequence, and a final 70 unassisted control breaths. The control sequences of 70 unassisted breaths recorded before and after the pseudorandom binary sequence improve the estimation of the low-frequency response characteristics of the system that occur during the initiation and conclusion of the pseudorandom binary sequence of breaths. The pseudorandom binary sequence provides a broad-band perturbating input to the respiratory system that has the characteristics of an impulse (an example of a pseudorandom binary sequence and a discussion of the logic of this approach are provided in Fig. 1 of Ref. 2). The order of the Eassist and Lassist trials was randomized, and a 10-min rest period was allowed between trials. On the next day, Tassist trials were conducted.
Determination of first-breath response of respiratory variables.
Respiratory variables [VT, VT/TI,
TI, expiratory time (TE)], instantaneous
respiratory muscle pressure (Pmus) output, Pmus, inspiratory flow
integrated per breath (flow), and Pm were calculated on-line by
using programs written in LabVIEW and MATLAB (Math Works, S. Natick,
MA). Continuous measurements of flow, VT, and Pm and the
values of Ers and Rrs determined previously in each subject were used
to calculate inspiratory Pmus as follows
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![AIC ≈ log[(1 + 2<IT>n/N</IT>)<IT> × V</IT>]](/content/vol93/issue3/fulltext/903/img004.gif)
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Statistics.
Data were expressed as means ± SD. A two-tailed one-sample
t-test was used to determine whether the change in a
respiratory variable (assisted breaths compared with control breaths)
was significantly different from zero. Changes in respiratory variables as a result of flow assist applied at different times during
inspiration and the change in ETCO2 among the
control periods before and after the pseudorandom binary sequence were
assessed with a one-way repeated-measures ANOVA. When the ANOVA
indicated that significant differences existed among treatment
conditions, paired comparisons were made by using t-tests
with P values adjusted by the Bonferroni method. A
P value of 
0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All eight subjects completed all of the protocols. Subject
characteristics, Ers, Rrs, 50% threshold of sensation for
Eassist, Lassist, and Tassist are
shown in Table 1. The threshold of
detection of flow assist was significantly different among all
treatments (Eassist, Lassist, and
Tassist; P < 0.05 for each of the three comparisons). Subjects were least able to detect Lassist
and best able to detect Tassist.
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Response to respiratory system unloading with flow assist.
The changes in inspiratory flow and VT from a single
subject are shown in Fig. 1. During
Eassist, flow was augmented only during the first half of
inspiration, and, during Lassist, flow was augmented only
during the second half of inspiration; however, during
Tassist, flow was augmented throughout inspiration. In this
subject, flow assist resulted in significant increases in peak
inspiratory flow (relative to unassisted breaths) during all three
assist protocols (Eassist, Lassist, and
Tassist). Although Lassist and
Tassist resulted in a small increase in VT,
Eassist did not change VT significantly. The
average changes in the inspiratory flow and VT waveforms
for all subjects are shown in Fig. 2, and the average first-breath responses from all subjects are shown in
Tables 2 and
3. There was a significant increase in
Pm during all three types of assisted breaths (P 0.031). Although peak inspiratory flow increased significantly
regardless of the timing of the flow assist, there was no significant
change in VT during Eassist (P = 0.895). On the other hand, Lassist and
Tassist significantly increased VT
(P = 0.035 and 0.001, respectively), but the size of the increase in VT between Lassist and
Tassist was not significantly different. A
repeated-measures ANOVA and a multiple-comparison analysis indicated
that the increase in VT during Lassist and Tassist was significantly greater than during
Eassist (P < 0.05). The
VT/TI of the first-breath response increased
significantly with all types of inspiratory assist (P 0.027). There was a significant decrease in Pmus during
Eassist (P = 0.020), but there was no
significant change during Lassist or Tassist. A
repeated-measures ANOVA and a multiple-comparison analysis indicated
that Eassist resulted in a significantly greater reduction
in Pmus than Tassist (P < 0.05). There
was a significant decrease in TI during Eassist (P = 0.011) but no significant change during
Lassist or Tassist. A repeated-measures
ANOVA and a multiple-comparison analysis indicated that
Eassist resulted in a significantly greater reduction in TI than did Lassist and Tassist
(P < 0.05). There were no significant changes in
TE during any type of flow assist.
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Fit of the linear model. To determine whether the modeled responses were fully described with the linear model, a cross-correlation function was calculated between the model residuals and the input data for each of the six variables analyzed on each of the 3 experimental days for each of the eight subjects. Results from the cross-correlation analysis of these 144 impulse-response analyses indicated that 15 (10.4%) contained an attribute of the response that was not described fully by the linear approximation. There was no clear pattern to the distribution of trials in which nonlinear elements contributed to the response. Hence, these data do not change the findings of this study but do indicate a small, nonlinear component in the modeled responses in some of the variables for some of the subjects.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We reinvestigated the Hering-Breuer reflex in awake human subjects
by using a pseudorandom binary sequence of imperceptible flow-assist
ventilation applied early, late, or throughout inspiration. The
respiratory responses to the pseudorandom binary sequence of flow
assist (VT, VT/TI, TE,
Pmus, and Pm) were modeled with linear difference equations to
construct the impulse responses of the respiratory system. The
application of Eassist, Lassist, or
Tassist resulted in a significant increase in
VT/TI. Although the largest increase in
VT occurred when flow assist was applied late or throughout
inspiration, TI and/or Pmus were reduced only when
flow-assist ventilation was applied during early inspiration. These
data suggest that vagal feedback can modulate breathing on a
breath-by-breath basis, particularly when the stimulus is limited to
early inspiration.
Limitations of the method.
We used the interrupter technique to measure respiratory mechanics in
our subjects. Although we took great effort to assure passive
ventilation, it is possible that some of the subjects were incompletely
relaxed during the measurements, thus adding error into the calculation
and variability into the data. This may account for the greater
variability found in our measurements of respiratory mechanics than in
other studies (17). In addition, an error in the
estimation of Ers and Rrs would affect the calculation of Pmus and
Pmus. Although such an error would result in a change in the
magnitude of Pnus and Pmus, it would not change the direction of the response.
Pmus, are small relative to the actual change in Pmus
we measured. Therefore, we feel confident that the decline in Pmus
originates primarily from reflex modulation of muscle activity rather
than from intrinsic mechanical properties of respiratory muscles.
Perception of flow assistance. The threshold of detection of flow-assist ventilation was lowest during Tassist, and the greatest average subthreshold assist was applied during Lassist. However, there were no significant differences among the average Pm during each assist protocol, although greater pressures were often applied during Lassist. These data suggest that perception of Pm varies throughout inspiration. The stimulus associated with flow assist is reflected in Pm, and it appears that subjects were more sensitive to Pm during early inspiration than during late inspiration. To the extent that conscious perception of assist is based on the same stimuli that mediate respiratory reflexes, this finding suggests that there is some gating of sensory information in which the respiratory system attends to or is more sensitive to afferent information early during the inspiratory cycle. It is also possible that sensory receptors may be more sensitive in the lower pressure range, but we know of no studies of pulmonary receptors demonstrating differential sensitivity in the range of pressures we applied.
Comparison with previous studies.
We have previously shown that passive overinflation of the lungs with
proportional-assist ventilation resulted in a small but significant
reduction in TI (3); however, the relative contributions from flow or volume assist could not be separated. We
subsequently found that a pseudorandom binary sequence of imperceptible flow Tassist reduced Pmus, whereas a similar application
of volume assist did not change respiratory timing (4). In
the present study, we demonstrated that flow assist is a more potent
inhibitory stimulus in early inspiration compared with late
inspiration. The application of flow assist throughout inspiration did
not duplicate our previous findings (3) in that
TI was not significantly reduced by the Tassist
protocol in the present study. In our original study, we
applied combined volume and flow assist throughout TI, and
the total Pm was almost twice that present during the flow-only Tassist protocol in the present study. Despite the markedly
reduced level of total assist, TI actually diminished in
seven of eight subjects, although the magnitude of the change was small
and not statistically significant. Thus we feel that the failure to
demonstrate a reduction in TI during Tassist
with flow assist alone probably reflects the lower level of assist both
early (since Eassist did decrease TI) and over
the entire breath (since combined assist of greater magnitude shortened
TI in our previous study). Much larger steady-state
increases in inspiratory flow in mechanically ventilated subjects also
shorten TI (6, 16, 20). The results of the
present study indicate that more subtle changes in inspiratory flow may
also modulate the timing of inspiratory efforts on a breath-by-breath
basis if the assist is given early during inspiration.
Reflex modulation of TI and Pmus.
The reduction in TI is probably reflex in origin, and the
afferent information is probably carried by the vagus nerve. Previous studies of steady-state increases in inspiratory flow demonstrated a
decrease in TI (6) and an increase in
respiratory rate during mechanical ventilation that was not affected by
breathing route (oral or nasal) or upper airway anesthesia. This
suggests that at least some of the receptors mediating the flow-related
responses are located in the lungs or chest wall (9).
There are chest wall reflexes that modify TI
(21), but TI is shortened by distorting the
chest wall and increasing the load on the chest wall. In the present
study and in previous studies of steady-state changes in inspiratory
flow, the effect of increased flow was to unload the system, which one
would not expect to shorten TI on the basis of the chest
wall reflex described above. Thus we conclude that the reflex
shortening of TI and reduction in Pmus are mediated by
vagal mechanisms.
Pmus during Eassist are consistent with
these effects of the Hering-Breuer reflex but inconsistent with
previous work, suggesting that lung volume feedback terminated
inspiration prematurely by earlier attainment of a greater volume
threshold (5). There was no increase in VT at
the end of inspiration in the Eassist protocol and,
therefore, no possibility of earlier attainment of a greater
end-inspiratory volume. Fernandez et al. (6) have pointed
out that it may be more appropriate to view the Hering-Breuer reflex as
a response to flow-sensitive receptors since previous experiments that
augmented volume to shorten TI necessarily increased inspiratory flow (5). Our findings, which used
single-breath unloading to increase inspiratory flow early in
inspiration, are consistent with the results of Fernandez et al. using
step changes in inspiratory flow, and we agree with their
interpretation: Flow-related inhibition of TI and Pmus
is probably a manifestation of the Hering-Breuer reflex.
Eassist shortened TI and reduced Pmus more
effectively than Lassist did. This may reflect greater
sensitivity to flow-related information early in the inspiratory cycle,
and the greater threshold of detection of assist late during
inspiration points toward this conclusion. However, there simply is not
much TI left to modify during Lassist, and we
cannot conclude for certain that the different effects of
Eassist and Lassist derive from a temporal
variation in the sensitivity to flow within TI. Moreover,
it would be peculiar to develop a negative-feedback system with
decreasing sensitivity to the stimulus as the threshold was approached.
We think it is more likely that the Eassist acts as a
conditioning subthreshold stimulus that actually reduces the threshold
for termination of TI. This phenomenon was investigated by
Younes and Polachek (23), who found that subthreshold
electrical stimulation of the vagus nerve early in TI
reduced the level of vagal stimulation necessary to terminate
inspiration later in TI. Thus Eassist may
provide similar subthreshold, vagally mediated feedback that
"sensitizes" the system to volume- or flow-related feedback later
during inspiration. If this is correct, the lower threshold of
detection of flow assist early in TI may indicate that a
conditioning stimulus early in TI also enhances the sensory
information or cortical processing of sensory information used by
subjects to detect the flow assist.
Younes and Polachek (23) also studied the effect of vagal
stimulation within a breath on subsequent breaths. They described late
"paradoxical" responses in subsequent breaths. The responses were
paradoxical in that shortening TI by electrical stimulation of the vagus nerve prolonged subsequent inspiratory durations, although
the paradoxical effect waned over 6-8 s after the stimulus. We
observed no effect of flow assist on TI or TE
of subsequent breaths in this study, although we did see a trend toward
paradoxical responses in TI in a previous study
(3). Detecting the effects of vagal stimulation on
subsequent breaths requires a stable respiratory drive (the cats used
by Younes and Polachek were anesthetized, ventilated, and chemoreceptor
and baroreceptor denervated to reduce nonvagal inputs to respiratory
drive). In intact humans, the moment-to-moment variation in respiratory
drive is complex, and this may reduce our ability to identify the
delayed effects of vagal feedback consistently, although they may be
apparent in some subjects (3).
In summary, the Hering-Breuer reflex has been demonstrated in
anesthetized or sleeping humans by using either airway occlusions or
large step changes in inspired volume. These methods cannot be applied
to humans during wakefulness without the activation of cortical and/or
humoral responses. Therefore, we chose a technique that would allow the
application of a stimulus with a magnitude small enough not to elicit
cortical or humoral responses, but strong enough to evoke a reflex
response. The application of an imperceptible pseudorandom binary
sequence of mechanical flow-assist ventilation resulted in a
significant increase in inspiratory flow, regardless of the timing of
the application; however, only during Eassist was there a
small, but significant, reduction in TI and Pmus. These
findings are consistent with previous studies of vagal control of
inspiratory duration and respiratory motor output in anesthetized or
decerebrate animals. Thus the Hering-Breuer reflex appears to be active
in conscious humans, and vagal feedback modulates breathing on a
breath-by-breath basis.
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ACKNOWLEDGEMENTS |
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We thank Dr. Magdy Younes for lending a prototype Winnipeg Proportional Assist Ventilator to us and Dr. Donald Bartlett, Jr. for insightful editorial suggestions.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-07449 and HL-19827 (to Donald Bartlett, Jr.).
Address for reprint requests and other correspondence: B. F. BuSha, Dept. of Physiology, Dartmouth Medical School, 1 Medical Center Drive, Borwell Bldg., Lebanon, NH 03756 (E-mail: brett.bu.sha{at}dartmouth.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 10, 2002;10.1152/japplphysiol.00153.2002
Received 27 February 2002; accepted in final form 10 May 2002.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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  L. Kubin, G. F. Alheid, E. J. Zuperku, and D. R. McCrimmon Central pathways of pulmonary and lower airway vagal afferents J Appl Physiol, August 1, 2006; 101(2): 618 - 627. [Abstract] [Full Text] [PDF]
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