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1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Foundation, Rochester, Minnesota 59055; and 2 Departments of Physiology and 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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We studied the capacity of four "normal" and six lung transplant subjects to entrain neural respiratory activity to mechanical ventilation. Two transplant subjects were studied during wakefulness and demonstrated entrainment indistinguishable from that of normal awake subjects. We studied four normal subjects and four lung transplant subjects during non-rapid eye movement (NREM) sleep. Normal subjects entrained to mechanical ventilation over a range of ventilator frequencies that were within ±3-5 breaths of the spontaneous respiratory rate of each subject. After lung transplantation, during which the vagi were cut, subjects did demonstrate entrainment during NREM sleep; however, entrainment only occurred at ventilator frequencies at or above each subject's spontaneous respiratory rate, and entrainment was less effective. We conclude that there is no absolute requirement for vagal feedback to induce entrainment in subjects, which is in striking contrast to anesthetized animals in which vagotomy uniformly abolishes entrainment. On the other hand, vagal feedback clearly enhances the fidelity of entrainment and extends the range of mechanical frequencies over which entrainment can occur.
vagal afferents; state; non-rapid eye movement sleep; Hering-Breuer reflex
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WHEN RESPIRATORY ENTRAINMENT is present, a fixed and repetitive coupling exists between mechanical inflation and neural inspiratory activity. Entrainment may occur at a 1-to-1 ratio (one mechanical inflation to one neural respiratory effort), but other integral ratios may be seen, as well as aperiodic, chaotic behavior in the transition between different integral ratio entrainment patterns (16). Most respiratory entrainment studies have been performed in anesthetized animals (3, 12, 16). The respiratory system will not entrain to mechanical ventilation after bilateral vagotomy in anesthetized animals (11, 16, 22), which, in addition to other findings, has lead to the conclusion that the Hering-Breuer reflex plays an essential role in entrainment. Evidence of the Hering-Breuer reflex during respiratory entrainment may be either 1) a shortening of neural inspiratory time (TI) when machine inflations precede neural TI or 2) expiratory time (TE) prolongation when machine inflations begin late in neural TI or early in TE. Entrainment has also been studied in anesthetized humans (8), and the Hering-Breuer reflex seemed important for entrainment in that study as well. TE was prolonged in these subjects when mechanical inflations occurred during the inspiratory-expiratory transition (late TI). Finally, mathematical models that incorporated the inspiratory and expiratory effects of the Hering-Breuer reflex have successfully reproduced the integral entrainment ratios and aperiodic patterns seen in anesthetized cats (16).
Simon et al. (21) recently investigated entrainment in awake and sleeping "normal" humans during normocapnia and mild hypercapnia. They found that 1:1 entrainment at a constant mechanical ventilator volume (1.5 times each subject's spontaneous volume) was maintained over a much wider range in awake humans than in anesthetized animals and humans. TI was shortened in sleeping normal subjects when mechanical inflation occurred slightly before or early in neural inspiration and entrainment persisted during sleep, but at 1-to-2 and 1-to-1 entrainment ratios, more typical of previous studies in anesthetized animals. Furthermore, the range of machine frequencies in which entrainment occurred was smaller during sleep compared with wakefulness. The greater mechanical ventilator frequency range of entrainment in conscious subjects suggests that there were either additional entraining stimuli present during wakefulness or cortical influences modified the respiratory control system to enhance and expand the range of 1:1 entrainment.
In the present study, we tested the hypothesis that vagally mediated afferent information is required for entrainment in awake and sleeping humans. We pursued this hypothesis because debate continues about the importance of the Hering-Breuer reflex in the control of ventilation in humans. We studied normal subjects and subjects that had undergone either heart-lung or double-lung transplantation in which the lungs were denervated. In this way, we were able to re-examine the roles of the vagus and the Hering-Breuer reflex in entrainment responses in the absence of anesthesia. In previous studies of entrainment after vagotomy in animals, the animals were anesthetized as well as vagotomized. Anesthesia may reduce mechanoreceptor activity (14), reduce central sensitivity to a variety of respiratory stimuli, and diminish the mechanical output of the respiratory system, thereby blunting the strength of the Hering-Breuer reflex and any other stimuli that may provide entraining cues.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. We recruited 11 lung transplant patients that had undergone either a double-lung or heart-lung transplant within the past 10 years. The patients were all in stable, good health at the time of the studies. One woman and five men, aged 39-59 yr, were able to complete the study. Two of the patients were studied during wakefulness, and four were studied during non-rapid eye movement (NREM) sleep. Seven of the eleven transplant recipients were unable to sleep under the conditions of the experiment. We recruited 11 normal adult volunteers with no history of cardiopulmonary disease. We obtained data from four normal, healthy volunteers (three women and one man), aged 18-35 yr. The remaining seven subjects were unable to sleep under the conditions of the experiment. None of the subjects had a background in respiratory physiology nor did they know the objectives of the study or train for the study. The Institutional Review Board of the Mayo Clinic approved the study, and informed consent was obtained from all subjects.
Measurements. Subjects were ventilated through a nasal continuous positive airway pressure mask attached to a Puritan-Bennett 7200 ventilator (Carlsbad, CA) that was modified for research purposes. The auditory alarm functions on the ventilator were disabled. In addition, when needed, 12% CO2 in O2 was added to the inspired gas via the O2 inlet to adjust the inspired CO2 fraction to a target end-tidal CO2 (PETCO2).
After calibration, measurements of airway pressure and flow were obtained from the analog output of the ventilator. tidal volume (VT) was obtained by integrating flow. End-tidal gas was sampled from a port attached to the mask. The CO2 concentration was measured with a calibrated infrared capnostat (model 1260, Novametrix, Wallingford, CT). Diaphragmatic electromyographic (EMG) activity on the right side of the chest was monitored with surface electrodes (Red Dot, 3M, St. Paul, MN) placed in the anterior axillary line over the sixth and seventh intercostal spaces. Inspiratory activity and respiratory timing were measured from the diaphragm EMG recordings. Electroencephalographic (EEG) activity (monitored from the C4-A1 and CZ-OZ leads), the submental EMG, and the electrooculographic activity were used to document sleep stages. EMG and EEG activities were processed using a TECA-42 EMG instrument (Pleasantville, NY). All signals were displayed and recorded using an Astro-Med, MT 8000-strip chart recorder (West Warwick, RI) and recorded on magnetic media using a computer acquisition program (LabVIEW, National Instruments, Austin, TX).Experimental protocol.
The same protocol was used in normal and transplant subjects. All
studies were performed on supine subjects in beds. Subjects participating in the sleep protocols were asked to deprive themselves of sleep (<2 h) the night before the study and told to avoid
caffeinated beverages for 12 h before the study began. The
protocols had three periods in which we measured 1)
spontaneous eucapnic ventilation, 2) spontaneous respiratory
rate during mechanical ventilation, and 3) entrainment at
respiratory rates above and below the spontaneous mechanical
ventilation rate. The awake protocols began after the subject
acclimated to the lab and was relaxed or, if it was a sleep study, once
stable stage II or III-IV NREM sleep was established. The spontaneous,
isocapnic ventilation trial consisted of a 5-min observation period
during which the subject breathed unassisted in the flow-by mode. The
ventilator settings were as follows: continuous positive airway
pressure = 0 cmH2O, baseline flow = 20 l/min, and
flow sensitivity = 3 l/m. Average eupneic tidal volume
(VT) and PETCO2 were measured
during the final 3 min of this period. In the second phase of the
protocol, preset volume ventilation was administered for 5 min. The
subject triggered each breath during preset volume ventilation, but
VT was fixed and equal to 130% of the spontaneous
VT. The inspiratory flow rate was 25-35 l/min in a
square waveform. The machine backup rate was 2 breaths/min (bpm), with
a flow-by threshold of 3 l/min that allowed each subject to choose his
or her own respiratory rate. The rate of subject-triggered ventilator
breaths at constant VT and flow rate was labeled the
"spontaneous respiratory rate." The average spontaneous respiratory
rate was measured during the last 3 min of this period. CO2
was added to the ventilator to maintain
PETCO2 equal to the level present in
spontaneous breathing during NREM sleep, but
PETCO2 was allowed to vary in the studies performed during wakefulness. In the third period of the protocol, ventilator trigger mechanisms were disabled, and machine rates were
initially set equal to or 1 bpm above the spontaneous respiratory rate
for each subject. Every 3 min, the machine rate was varied 1 bpm below
or above the spontaneous respiratory rate. Phase angles (
) were
calculated (see below) from data obtained in the last 1.5 min of each
3-min trial. In waking subjects, the trial was terminated at low
machine rates when the subject complained of respiratory discomfort and
at high machine rates when the expiratory phase of the machine cycle
was not long enough to allow expiratory flow to return to zero or when
inspiratory EMG activity was undetectable. In sleeping studies, trials
were terminated at low ventilator frequencies by arousal of the subject
and at high ventilator frequencies when the EMG signals were lost or
expiratory flow failed to return to zero. Neuromechanical inhibition of
surface EMG activity occurred in all subjects at a ventilator frequency
above the spontaneous rate. No data were taken from the ventilator
frequencies at or above the frequency that surface EMG activity first
started to drop out, because we could not reliably track
breath-by-breath changes in when the EMG signal was erratic.
Data analysis and statistics.
The onset of the subject's neural respiratory activity was determined
from the onset of surface EMG activity of the diaphragm. We determined
the phase relationships between the onset of surface EMG activity and
the machine cycle with methods described previously (21).
The phase delay is the time in seconds from the onset of spontaneous
inspiration to the onset of machine inflation. The , which describes
the relationship between machine onset and surface EMG onset, was
determined by calculating the phase delay, dividing by the cycle time
of the ventilator, and multiplying by 360°
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![−ventilator onset time)&cjs0823; ventilator cycle duration]<IT>×360.</IT>](/content/vol89/issue2/fulltext/760/img002.gif)
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of 0° when
machine inflation and surface EMG onset occurred at the same time. When
surface EMG activity preceded machine inflation, was between 
180
and 0°, and, when surface EMG activity occurred during or after
machine inflation, was between 0 and +180°.
In analyses of the Hering-Breuer reflex, neural TI was
obtained from the duration of inspiratory activity measured from
surface EMG activity and compared at different in each subject
studied during NREM sleep. The diaphragm EMG was often contaminated by the EKG signal, and the termination of respiratory muscle EMG activity
was difficult to measure exactly. We selected only the breaths that had
a clearly defined termination of EMG activity. We selected the
measurable TI values from all ventilator frequencies during
sleep to obtain TI values over the entire range of .
We calculated the average and standard deviation of at each machine
frequency for each subject using methods appropriate for angles
(10). We took a mathematical approach to the definition of
entrainment and defined entrainment as a statistically significant (P < 0.05) and unique concentration of around a
mean value. If the distribution of was homogeneous from 180
to +180° (i.e., no significant single ), then we determined
whether there were significant concentrations of from 180 to 0°
and from 0 to 180°. Occasionally, a single cluster of was arrayed
around 0°, but we identified these as two significant clusters
because the ranges we examined for significant concentrations were
arbitrarily separated at 0°. To avoid defining two clusters when only
one might exist, we tested that concentrations were unique by
shifting the range of a mean ±60° and then recalculating that
mean . If significant concentrations of could be identified in
multiple ranges of phase angles, then the were not unique, and we
concluded that entrainment was not present. If significant and unique
concentrations of were found in both of these ranges, then a 1:2
entrainment existed. No other stable entrainment ratios were seen. We
chose the simplest entrainment ratio that identified significant and unique mean . For example, if we identified significant 1:1
entrainment, we did not look further for other entrainment ratios. When
entrainment occurred, the standard deviation provided a measure of the
tightness of phase locking.
This statistical approach to entrainment is more stringent than visual
inspection, but something may be lost. In the transitional zone between
1:2 and 1:1 entrainment, subjects often had brief periods of 1:2
entrainment that were followed by longer periods of 1:1 entrainment.
Our statistical analysis defined this as 1:1 entrainment with greater
variability than a consistent pattern of 1:1 entrainment throughout the
test period. Thus our analysis may underestimate the true extent of
entrainment in favor of a stricter, more rigorous definition. We are
unlikely to have overestimated the occurrence of entrainment in the
transplant subjects, but, by the same token, brief periods of
entrainment simply did not meet our threshold criterion.
Angles are periodic and, therefore, are not normally distributed. For
this reason, statistical inferences were made using the von Mises
distribution, which is analogous to a normal distribution but
appropriate for periodic functions. Probability distribution functions
for at each machine frequency were calculated from the mean angle
and a concentration parameter that is inversely related to the variance
(10). The individual probability curves were summed across
subjects as a function of machine rate expressed relative to the
spontaneous rate. The summed probabilities at each machine frequency
were normalized to keep the area under each probability curve constant
among the machine frequencies; the probability distribution across
machine frequencies was plotted in three dimensions (breath order, ,
and relative probability) using Matlab (Math Works, Natick, MA).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patient characteristics and respiratory variables during
wakefulness and sleep.
The clinical characteristics of the transplant subjects are summarized
in Table 1. The individual and average
VT and spontaneous respiratory frequencies during
mechanical ventilation and the range of frequencies in each subject for
all conditions studied are shown in Table
2.
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Effect of wakefulness on entrainment responses.
Figure 1 shows a phase scatter plot for
one of the two lung transplant subjects studied during wakefulness. A
1:1 entrainment was apparent over a wide range of machine frequencies.
The standard deviations around each were also small. This subject
had larger standard deviations around each than the other lung
transplant subject studied during wakefulness. We compared the and
the standard deviations in these two lung transplant subjects to the range of seen in normal, waking subjects in the study of Simon et
al. (21). In Fig. 2, the
mean and the 95% confidence intervals for normal subjects are
plotted as functions of the mechanical ventilator rate expressed in
each subject, relative to the spontaneous respiratory rate, which was
set equal to zero. The of transplant subjects fall close to or
within the 95% confidence intervals of the normal subjects. A one-way
ANOVA appropriate for periodic functions (10) was
performed on the mean , which was determined by combining all
mechanical ventilator frequencies and subjects within each group
(normal vs. transplant subjects). This analysis did not reveal any
difference in between transplant patients and normal subjects
during wakefulness. Furthermore, did not consistently change as a
function of ventilator frequency in either normal subjects or
lung transplant patients. Just as in normal subjects, the in lung
transplant subjects hovered around 0° as the machine rate increased
or decreased relative to the spontaneous rate. It was our hypothesis
that lung transplant subjects could not entrain to the ventilator
during wakefulness or sleep. We did not feel compelled to study
additional awake lung transplant subjects, because the ready
occurrence of entrainment in the two lung transplant subjects disproved
the first half of our hypothesis.
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Effect of NREM sleep on entrainment responses.
Figure 3 shows phase scatter plots from
three representative sleeping subjects during mechanical ventilation.
The data were taken from one normal subject (A) and from two
lung transplant subjects (B and C). The normal
subjects exhibited 1:1 entrainment around and above the spontaneous
rate. As the ventilator rate was lowered below the spontaneous rate,
the entrainment pattern bifurcated into 1:2 entrainment (one mechanical
inflation for two neural efforts). This pattern was typical of the
other normal subjects during NREM sleep in this study and that of Simon
et al. (21). At a machine frequency of 12, there was only
one significant concentration of , with a mean value of 63°.
There were intermittent episodes of 1:2 entrainment, but these did not
occur with sufficient frequency to reach statistical significance. This
pattern of intermittent 1:2 entrainment and less well-focused
entrainment phase angles is typical in the region of the bifurcation
from 1:1 to 1:2 entrainment in normal subjects. The neural effort
lagged the mechanical inflation (positive ) at machine frequencies
above the spontaneous rate and led mechanical inflation below the
spontaneous rate (negative ). There was a smooth transition
from high ventilator rates and positive to low ventilator rates and
negative in normal subjects, and was often close to zero at the
spontaneous rate.
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data
during NREM sleep are shown in Fig. 3B represents one
extreme among the responses of the lung transplant subjects; this
subject was the least able of any subject studied to establish stable
entrainment to the ventilator. One-to-one entrainment was seen at only
two machine rates above the spontaneous rate. In contrast to normal
subjects, we saw no stable 1:2 entrainment in this or any other lung
transplant subject. Figure 3C shows the other extreme of
responses among transplant subjects. This subject established stable
1:1 entrainment at all frequencies except the spontaneous rate. We
could not study any frequencies below the spontaneous rate without
causing arousal from sleep. Among the four transplant subjects, tended to be positive at ventilator rates above the spontaneous rates
and negative at ventilator rates below the spontaneous rates. However,
the pattern was less consistent, and the trajectory of from
positive to negative was less distinct than in normal subjects.
We constructed three-dimensional composite probability distribution
curves that reflect the relative likelihood (z axis) of from 180 to 180° (y axis) at each ventilator rate
(x axis) expressed relative to the spontaneous rate for
normal and lung transplant subjects (Fig.
4, A and B,
respectively) during NREM sleep. In normal subjects, the were
tightly concentrated (large concentration parameters and large relative
probabilities) at each ventilator frequency. The trajectory from
positive above the spontaneous rate to negative below the
spontaneous rate was clear. There was also a clear bifurcation of
probabilities ~2-3 breaths below the spontaneous rate, which
reflected 1:2 entrainment. As a result, the distribution of
probabilities resembled a discrete mountain ridge rising from a low
plain, until low mechanical ventilator frequencies were reached, when a
new ridge rose ~180° out of phase with the dominant ridge. In
striking contrast, the composite relative probability distribution for
lung transplant subjects started with a single well-formed ridge at
mechanical frequencies above the spontaneous rate but degenerated into
a low-lying ridge with outlying hills off the main ridge near the
spontaneous rate and a flat plateau at ventilator frequencies below the
spontaneous rate. These composite figures demonstrate that entrainment
was less common in transplant subjects, especially at ventilator rates below the spontaneous rate. We analyzed the probability of entrainment using Fisher's exact test and compared the frequency of entrainment across all ventilator rates examined in normal and transplant subjects.
The probability of entrainment at any particular mechanical ventilator
rate was significantly less in transplant subjects (P < 0.001), and, if entrainment did occur in transplant subjects, it was
more likely to occur at ventilator frequencies above the spontaneous
rate.
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Aperiodic oscillations vs. stochastic noise in lung transplant subjects. In anesthetized animals models that systematically varied both the ventilator VT and frequency (13, 16), a wide variety of integral entrainment ratios occurred, and, in transitional zones between integral entrainment ratios, the neural respiratory rate became aperiodic. There was no fixed coupling of neural activity to the ventilator frequency when the neural respiratory rate was aperiodic, but neural respiratory activity was continually influenced by vagal feedback derived from the ventilator effect on the timing and magnitude of mechanical inflation of the lung. Therefore, no fixed coupling between mechanical inflation and neural inspiration was seen, but the events were not independent. This aperiodic pattern may be a manifestation of "noise" in the system or a manifestation of deterministic chaos (16).
In respect to our method of defining entrainment, one may legitimately ask two questions. 1) Have we imposed entrainment order on data that were actually aperiodic? And, if no entrainment was present, were the data truly aperiodic? In Fig. 5, we plotted individual from sequential breaths at a single
ventilator frequency in the normal subject and for two ventilator
frequencies in the transplant subject shown in Fig. 3, A and
B, respectively. In the normal subject, we found 1:2
entrainment at this frequency (11 bpm), and inspection of the
-breath order plot reveals stable 1:2 entrainment that is consonant
with the statistical analysis. A constant pattern across sequences
of breaths was typical of stable entrainment in both normal and
transplant subjects, and we do not believe that we imposed entrainment
order where there was none. In respect to the second question, we
studied only one VT, making our study a more limited
exploration of VT and frequency effects on
entrainment than that performed on anesthetized animals. We never saw
aperiodic behavior in the normal subjects we studies, although Simon et
al. (21) did see aperiodic behavior in a previous study of
normal sleeping subjects. In the transplant subjects, we could not
identify entrainment by statistical criteria at some ventilator
frequencies, but the lack of stable periodic coupling between the
ventilator and the subject's inspiratory activity alone is not proof
of aperiodic behavior in the sense used by previous investigators.
Aperiodic behavior is described as breathing patterns in the
transitional zones between stable entrainment ratios in vagally intact
anesthetized animals in which inflation modifies neural activity but in
irregular and unpredictable ways, i.e., the neural respiratory rate and
the ventilator rate were coupled but only weakly (15,
16).
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and
the that would occur if the subject had a fixed respiratory
frequency independent of and unaffected by mechanical inflations have
been plotted together as a function of ventilator breath order. In Fig.
5B, for example, the ventilator rate was 11 bpm. If the
subject's respiratory rate were 13.7, bpm, then every breath taken by
the subject would differ by a of 53°, and the subject would lag
the ventilator by a consistent time and on each breath. The results
of a similar calculation comparing predicted differences at a
ventilator rate of 16 bpm and a neural ventilatory rate of 14.2 bpm is
shown in Fig. 5C. The neural respiratory rates were chosen
with malice aforethought to emphasize the similarity of the predicted
and actual . Nonetheless, this modeling demonstrates that the relationship between two independent neural and mechanical ventilatory
rates may fit the data reasonably well, particularly at the lower
ventilator rate (Fig. 5B). Applying a similar analysis to
other ventilator frequencies at which phase angles were not entrained
often revealed patterns of relationships that imply the presence of
two independent oscillators (as opposed to the weakly coupled
oscillators that are present in aperiodic patterns). The neural
frequency tended to be closer to the spontaneous rate, regardless of
the ventilator rate when ventilator and neural events were not
coupled. Hence, the duration of neural activity was
consistently shorter than the ventilator cycle at low ventilator rates
(Fig. 5B) and longer than the ventilator cycle at high
ventilator rates (Fig. 5C). This analysis indicates that the
lack of entrainment need not imply aperiodic behavior in the neural
activity; the neural oscillator may be perfectly periodic but
completely independent of the equally periodic mechanical inflation.
Distinguishing between deterministic chaos (coupled oscillators with
nonlinear dynamics) and stochastic noise (independent oscillators)
requires an appallingly large amount of data (2).
Unfortunately, we do not have enough data at each ventilator frequency
to make these distinctions. We can only raise the possibility that the
behavior was not aperiodic but a manifestation of two independent oscillators.
Assessing the quality of entrainment.
As described above, entrainment was less likely to occur in transplant
subjects, but we also tested the hypothesis that, when entrainment
occurred, it was less well focused. To analyze the fidelity of
entrainment, we pooled the standard deviations from each mean in
which entrainment was present from all subjects within the normal and
transplant groups. We compared four groups: lung transplant subjects
during wakefulness and NREM sleep and normal subjects during
wakefulness and NREM sleep. The data from the normal, waking subjects
were taken from five subjects studied previously during wakefulness
(21). The results of this comparison are shown in Fig.
6. A one-way ANOVA appropriate for
periodic data revealed that significant differences existed among the
groups, and unpaired tests between groups, using P values
adjusted for multiple comparisons, indicated that the standard
deviations in lung transplant subjects during sleep were significantly
greater than in any other condition. Furthermore, the standard
deviations were not different between normal and transplant subjects
during wakefulness. Thus, when entrainment was present during NREM
sleep, it was less accurately fixed to particular in the lung
transplant subjects.
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Effect of neural TI on timing between machine and
respiratory cycles.
The role of the vagus has been implicit in our description of
entrainment in normal and transplant subjects. We explicitly examined
the effect of mechanical inflation of the lungs on neural TI in all sleeping subjects. In Fig.
7, neural TI that was
determined from the diaphragm EMG has been expressed as a function of
the of muscle activity. When was positive, the mechanical
inflations preceded neural activity, lung volume increased early in
neural TI, inspiratory activity was terminated prematurely,
and neural TI was shortened. This response is a
manifestation of the inspiration-inhibiting Hering-Breuer reflex and
requires vagal feedback. Shortening of TI at positive was seen in all four normal subjects. In contrast, TI
remained constant at all in the lung transplant group. The capacity
to entrain to mechanical ventilation varied slightly among the
transplant subjects, but there was no evidence, based on the changes in
TI shown in Fig. 7, that the lungs were more or less
effectively denervated in particular subjects.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In multiple studies of anesthetized animals, vagotomy abolished entrainment to mechanical ventilation. This led to the hypothesis that vagal feedback was required for entrainment. The responses of the transplant subjects observed in the present study demonstrate that there is no absolute requirement for vagal feedback to produce entrainment either during wakefulness or sleep. The transplant subjects were clearly less able to establish entrainment as the ventilator frequency deviated from each subject's spontaneous frequency, and entrainment of neural respiratory activity, when present, was less tightly phase locked to the ventilator.
Entrainment during wakefulness. Entrainment in vagotomized patients during wakefulness was indistinguishable from entrainment seen in normal awake subjects by Simon et al. (21). Furthermore, the ranges of ventilator frequencies in which entrainment occurred were broader during wakefulness than during sleep in both normal and vagotomized lung transplant subjects. Hering-Breuer reflexes, which are thought to play an important role in entrainment (13, 15), are not readily demonstrable in awake humans (7, 9, 19, 20). Thus the ready entrainment of lung transplant patients to mechanical ventilation and the paucity of Hering-Breuer reflex control of ventilation in awake normal subjects lead us to conclude that other stimuli and reflexes promote respiratory entrainment in awake humans, regardless of the state of the vagi. Possible entraining stimuli range from simple auditory cues from the ventilator to forebrain influences on respiratory control (5). Conscious or unconscious efforts to optimize the comfort of the ventilatory pattern may also contribute to each subject's efforts to match neural respiratory timing to the mechanical events controlled by the ventilator. The power of entraining cues and the sense of comfort during wakefulness cannot be underestimated; the range of entrainment around the spontaneous respiratory rate was consistently greater during wakefulness than during sleep.
Entrainment during sleep.
Conscious factors promoting entrainment are lost during sleep, but
vagal reflexes are probably more active. In normal subjects during
sleep, 1:1 entrainment was easily established and could be maintained
at ventilator frequencies within ~ ±15% of each subject's
spontaneous rate (compare Figs. 4A and 5A).
Moreover, 1:2 entrainment was demonstrable in approximately one-half of the normal subjects at frequencies ~15-35% below the
spontaneous rate (21). The pattern of 1:1 entrainment that
bifurcated into 1:2 entrainment as the ventilator frequency was reduced
progressively below each subject's spontaneous rate resembles the
entrainment responses of vagally intact anesthetized humans and
animals. The influence of the Hering-Breuer reflex was apparent in
normal subjects when we examined TI as a function of (Fig. 7A). TI was longer when neural inspiration
led mechanical inspiration, and volume-related feedback increased late
in TI and in the TI-TE transition
(this occurs when the spontaneous rate is greater than the mechanical rate). TI was shorter when mechanical inflation led neural
inflation, resulting in increased volume feedback early in
TI. Finally, a pattern of integral entrainment ratios
identical to that seen in anesthetized animals was predicted from
mathematical models that explicitly included the Hering-Breuer reflex
as a volume-dependent, time-varying inspiratory off-switch and
expiratory on-switch (15). For all these reasons, we
believe that entrainment in normal sleeping subjects reflected a strong
influence of the Hering-Breuer reflex. Therefore, we were surprised to
see any evidence of entrainment in the lung transplant subjects.
However, statistically significant entrainment occurred in all lung
transplant subjects at one or more ventilator frequencies. Entrainment
occurred at far fewer frequencies in the transplant subjects compared
with the normal subjects. First, we never saw 1:2 entrainment
in transplant subjects. Second, 1:1 entrainment in normal subjects
generally occurred symmetrically, within ±2-3 bpm around the
spontaneous rate, but entrainment was never seen below the spontaneous
rate in the lung transplant subjects. In other words, the transplant
subjects could increase their neural respiratory rate to match the
mechanical ventilator, but they could not slow their neural respiratory
rate when the ventilator rate was reduced. Entrainment at or close to
the spontaneous frequency requires modulations of neural TI and TE that are probably too small for us to detect. We
detected TI modulation in normal subjects at entrainment
rates 1-3 bpm different from the spontaneous rate and should have
seen TI modulation in the lung transplant subjects that
entrained to machine frequencies 1-3 breaths above the spontaneous
rate. However, there was no evidence of modulation of
TI in any of the transplant subjects, regardless of whether
neural TI preceded or followed the onset of mechanical
ventilation. Because the transplant subjects did not change
TI, they must have modulated TE. When
entrainment occurred at ventilator frequencies greater than the
spontaneous rate, it implied that the transplant subjects were able to
shorten neural TE because we saw no -related changes in
TI. However, they were not able to lengthen TE
to establish entrainment at ventilator frequencies below the
spontaneous rate. The entraining stimulus seemed to elicit a response
that preferentially shortened TE when the neural
respiratory rate was slower than the mechanical ventilator frequency,
but entraining stimuli were unable to sufficiently prolong
TE to establish entrainment at mechanical ventilatory frequencies slower than the spontaneous rate. Unfortunately,
TE data were not available to us to permit confirmation of
this supposition.
, but we found no
evidence that vagal afferents remaining after transplantation modified
TI. The relationship between the observed changes in Ti and may be a relatively insensitive index of vagal afferent activity (although our data in normal subjects suggest the contrary), and regrowth of the vagus may have partially re-inervated the lungs. In a previous study, the Hering-Breuer reflex exerted a more powerful effect on TE than on TI
(1), but the Hering-Breuer reflex was more effective in
prolonging rather than in shortening TE. This response is
not consistent with the asymmetrical TE shortening that is
necessary to explain the occurrence of entrainment only at ventilator
frequencies greater than the spontaneous respiratory rate. Thus, as
best we could tell, we found no evidence of Hering-Breuer reflex
mechanisms in the lung transplant subjects.
There are other possible reflex mechanisms responsible for our
findings. Upper airway afferents provide information related to
airflow, temperature, pressure, and airway CO2
(23). Whereas these stimuli might provide entraining cues,
none of the reflex responses to upper airway stimulation provides the
asymmetrical control of TE that is required to explain the
pattern of entrainment in the transplant subjects. Chest wall afferents
may also provide entraining stimuli, although chest wall reflexes
usually inhibit phrenic activity and shorten TI
(17) and do not account for the pattern of timing changes
we observed in the lung transplant subjects. However, the respiratory
rhythm was entrained to intercostal afferent information by repetitive
electrical stimulation of intercostal nerves in anesthetized and
vagally intact cats (18). Phrenic afferents may
provide an entraining signal, but no specific reflex effects on
respiratory timing have been described that fit the responses of the
transplant subjects (6). Finally, arterial PCO2 and PO2 fluctuate
with each ventilatory cycle and may provide periodic carotid
chemosensory stimulation that is capable of entraining ventilation, but
we know of no identified reflex arising from any of these stimuli that
affects TI and TE in the way predicted to
enhance entrainment in transplant subjects at ventilator frequencies above the spontaneous rate. However, we do recognize that afferent information from a variety of sources persists after lung
transplantation and may provide effective cues to entrainment.
We saw entrainment, in an admittedly attenuated form, in sleeping lung
transplant subjects. In contrast, vagotomy in anesthetized cats
abolishes entrainment. Decerebrate, unanesthetized cats readily entrain
to the ventilator, and vagotomy abolishes entrainment in this model as
well. One might argue that sleeping humans are simply more sensitive to
entraining stimuli than vagotomized animals that are anesthetized or
decerebrate. However, it seems more likely that sleep does not reduce
central nervous system sensitivity to afferent stimuli as completely as
anesthesia. The lack of entrainment in decerebrate cats argues that the
brain stem alone cannot support entrainment in the absence of vagal
feedback. Therefore, entrainment during NREM sleep in the lung
transplant subjects may originate from some suprapontine, but
subconscious integration of respiratory-related afferent information.
In summary, we studied entrainment to mechanical ventilation
during sleep in normal subjects and vagotomized lung transplant patients. The transplant subjects entrained well during
wakefulness. Furthermore, they demonstrated significant
entrainment during sleep at ventilatory frequencies equal to or greater
than the spontaneous respiratory rate. However, entrainment in
transplant subjects occurred over a narrower range of mechanical
ventilator frequencies than in normal subjects, and, when entrainment
did occur, the standard deviations around each entrained were
larger in transplant subjects. We conclude that there is no absolute requirement for vagal feedback to induce entrainment in sleeping subjects; this is in striking contrast to anesthetized animals in which
vagotomy uniformly abolishes entrainment. On the other hand, vagal
feedback clearly enhances the fidelity of entrainment and extends the
range of mechanical frequencies in which entrainment can occur.
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ACKNOWLEDGEMENTS |
|---|
We thank Merilyn L. Jensen, RTT, for technical assistance.
| |
FOOTNOTES |
|---|
This work was supported by a Mayo Foundation Grant, National Center for Research Resources Grant MO1-RR-00585, and National Heart, Lung, and Blood Institute Grants HL-29068 and HL-19827
Address for reprint requests and other correspondence: P. M. Simon, Dept. of Physiology, Borwell Bldg., Dartmouth Medical School, Lebanon, NH 03756
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. §1734 solely to indicate this fact.
Received 17 December 1999; accepted in final form 25 March 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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), mean phase angles (
), and
standard deviations (error bars) are plotted for each ventilator
frequency. Mean phase angle and standard deviation were plotted only if
a significant (P 
0.05) concentration of phase angles
about some mean occurred. This subject's standard deviations about
each phase angle were larger than those of the other transplant subject
studied during wakefulness.
