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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Decreases in ventilator inflation time (TI,vent) can cause tachypnea, probably as a response to lung inflation. The response may differ in chronic obstructive pulmonary disease (COPD) because time-constant inhomogeneities could foster overdistention of some lung units during early inflation, causing neural inspiratory time to be shorter than in healthy subjects. We tested the hypothesis that a decrease in TI,vent causes tachypnea, prolongation of exhalation, and a decrease in intrinsic positive end-expiratory pressure (PEEPi). Ten patients with stable COPD received assist-control ventilation through a mouthpiece. Decreases in TI,vent, achieved through increases in flow from 30 to 90 L/min, increased frequency, from 16.1 ± 1.0 (SE) to 20.8 ± 1.5 breaths/min (p < 0.001), time for exhalation, from 2.1 ± 0.2 to 2.3 ± 0.2 s (p < 0.025), and decreased PEEPi, from 7.0 ± 1.3 to 6.4 ± 1.1 cm H2O (p < 0.01). Decreases in TI,vent, achieved by decreasing inspiratory pause from 2 to 0 s, increased frequency, from 12.9 ± 0.8 to 18.1 ± 1.6 breaths/min (p < 0.001), time for exhalation, from 2.0 ± 0.2 to 2.6 ± 0.3 s (p < 0.001), and decreased PEEPi, from 6.4 ± 1.1 to 5.5 ± 0.9 cm H2O (p < 0.01). In both experiments, decreases in TI,vent reduced inspiratory effort (p < 0.01). In conclusion, strategies to reduce TI,vent in patients with COPD caused tachypnea, yet prolonged the time for exhalation with consequent decrease in PEEPi.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In a patient receiving mechanical ventilation, respiratory frequency can have a major effect on carbon dioxide tension and the mechanical properties of the lungs (1). Studies have shown that shortening the imposed ventilator inflation time both in healthy volunteers (2) and in critically ill patients (6) can increase frequency. The effect of ventilator inflation time on respiratory frequency appears to be mediated by the response of the respiratory controller to lung inflation: neural inhalation is terminated when a critical lung volume is reached during lung inflation at different inspiratory flows; and neural exhalation is prolonged when mechanical inflation is carried over into the time for exhalation (4, 7).
Alterations in respiratory frequency secondary to changes in ventilator inflation time are particularly important in patients with chronic obstructive pulmonary disease (COPD): an increase in frequency accompanied by a decrease in expiratory time may induce or aggravate dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEPi), a frequent cause of patient-ventilator dysynchrony (8). The presence of time-constant inhomogeneities in the lungs of patients with COPD, when stable or in a decompensated state, may also influence the effects of a change in ventilator inflation time on neural inspiratory time (TI) and neural expiratory time (TE). During early inflation, time-constant inhomogeneities could predispose to delayed inflation of some lung regions and the overdistention of other regions. Early overdistention of some regions could result in continued mechanical inflation during neural exhalation; the latter phenomenon, in turn, can prolong the time of exhalation (7). A prolonged time for exhalation fosters lung emptying and, thus, hyperinflation might lessen when inspiratory flow is increased in patients with COPD, despite an increase in frequency. Such a possibility contrasts with the known effect of increased flow in healthy subjects, which tends to shorten exhalation time (4, 5). Conversely, when the ventilator inflation time is altered through manipulation of the inspiratory pause setting it may have the same effects on frequency and time of exhalation in patients with COPD as in healthy subjects, because a prolonged inspiratory time helps to compensate for time-constant inhomogeneities.
We hypothesized that a decrease in the ventilator inflation time, whether achieved by an increase in inspiratory flow or a decrease in inspiratory pause, will cause an increase in respiratory frequency, prolongation of the time for exhalation, and a decrease in PEEPi in ambulatory patients with COPD.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Ten men with stable, moderate to severe COPD were studied (Table 1). Patients were informed that the study was "to test the effect on your breathing of changing the speed at which a breath is given by the respirator," but were not told specific hypotheses. The study was approved by the local ethics committee. Informed consent was obtained from all patients.
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Esophageal (Pes) and gastric pressures (Pga) were measured with balloon-tipped catheters. Airway pressure (Paw) was measured at the mouthpiece.
Protocols
After placement of pressure transducers and uncalibrated inductive plethysmographic bands, seated patients were ventilated through a mouthpiece connected to a Puritan Bennett 7200 ventilator. Paw and flow were recorded between the Y-piece of the ventilator circuit and mouthpiece. Initially, patients breathed in continuous positive airway pressure (CPAP) mode with positive end-expiratory pressure (PEEP) of zero (10 to 15 min). The ventilator was then set in assist-control mode: PEEP of zero, inspiratory flow of 60 L/min (square-wave profile), and back-up frequency at 1 breath/min (to ensure triggering of all breaths). Tidal volume was that which subjects inhaled during CPAP, and then changed by 50-100 ml every minute until patients felt comfortable (845 ± 52 [SE] ml). Patients acclimated to these "baseline" settings over 5-10 min before protocols were performed.
Targeted flow. The aim of the targeted flow protocol was to determine whether flow-associated increases in frequency during mechanical ventilation of patients with COPD are sufficient to effect a change in PEEPi. Once patients had acclimated to baseline ventilator settings, flows of 30, 60, and 90 L/min were applied. At least 23 transitions were recorded in each patient.
Targeted inspiratory pause. The aim of the targeted inspiratory pause protocol was to determine the effect of a change in ventilator inflation time on frequency and PEEPi while flow and tidal volume were kept constant. Once patients had acclimated to baseline ventilator settings, inspiratory pauses of 0, 0.5, 1.3, and 2 s were randomly applied for at least 5 breaths each. At least 18 transitions were recorded in each patient.
Data Analysis
Data were recorded and digitized at 500 Hz. To minimize confounding influence from CO2 flux on breathing pattern, analysis was confined to 4 breaths before and 4 breaths after a transition in each protocol. Analysis included breath-by-breath determination of frequency,
time of inflation, and time for exhalation calculated from the flow signal. PEEPi was measured as the change in Pes from onset of inspiratory effort to onset of inspiratory flow; PEEPi was corrected for expiratory muscle contribution (9). Pressure output of inspiratory muscles
was estimated by calculating the swing in Pes (
Pes) from the beginning of inspiratory effort to maximal negative deflection in Pes. Paw
at 0.1 s (P0.1) after commencing tidal inspiration against the occluded
airway was measured as previously described (10). For the 4 breaths
before and after each transition, mean values of the above-described
variables were calculated; the values of each variable for each perturbation were pooled and means were calculated for each subject. Data
were analyzed by analysis of variance with repeated measurements.
Correlation coefficients between different variables were calculated
by regression analysis.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CPAP
During the last minute of CPAP, tidal volume in 9 of 10 patients was 673 ± 57 ml and respiratory frequency was 16.1 ± 1.6 breaths/min; PEEPi, Pes, and P0.1 were 5.0 ± 1.1, 14.6 ± 1.5, and 1.1 ± 0.1 cm H2O, respectively.
Targeted Flow Protocol
An increase in delivered flow from 30 L/min to 60 and 90 L/
min caused increases in frequency from 16.1 ± 1.0 breaths/min to 19.0 ± 1.4 and 20.8 ± 1.5 breaths/min, respectively (p < 0.001), and decreases in time of inflation from 1.8 ± 0.1 s to
1.0 ± 0.1 and 0.7 ± 0.1 s, respectively (p < 0.001). The decrease in time of inflation was correlated with the rise in frequency (r = 
0.62, p < 0.001). Despite the increase in frequency (Figure 1), PEEPi decreased from 7.0 ± 1.3 cm H2O to
6.3 ± 1.1 and 6.4 ± 1.1 cm H2O (p < 0.01) when flow was, respectively, increased from 30 L/min to 60 and 90 L/min (Figure 2, left and Figure 3). The latter effect was likely a consequence of the overall increase in time available for exhalation:
2.1 ± 0.2, 2.4 ± 0.2, and 2.3 ± 0.2 s for respective flows of 30, 60, and 90 L/min (p < 0.025) (Figure 2, right). The increase in
flow from 30 L/min to 60 and 90 L/min caused decreases in P0.1
from 1.6 ± 0.2 cm H2O to 1.3 ± 0.1 and 1.4 ± 0.2 cm H2O, respectively (p < 0.025) (Figure 4, left), and in Pes, from 13.3 ± 1.3 cm H2O to 10.6 ± 1.1 and 10.2 ± 1.0 cm H2O, respectively
(p < 0.0001) (Figure 4, right).
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Targeted Inspiratory Pause Protocol
A decrease in the applied inspiratory pause from 2 to 0 s
caused frequency to increase from 12.9 ± 0.8 to 18.1 ± 1.6 breaths/min (p < 0.001) (Figure 5), and PEEPi to decrease
from 6.4 ± 1.1 to 5.5 ± 0.9 cm H2O (p < 0.01) (Figure 5, right
and Figure 6). The latter effect was likely a consequence of the
increase in time available for exhalation: from 2.0 ± 0.2 to 2.6 ± 0.3 s (p < 0.001) (Figure 7). The decrease in time of inflation
was negatively correlated with the rise in frequency (r = 0.58, p < 0.001). The decrease in the imposed inspiratory
pause caused decreases in P0.1, from 1.7 ± 0.2 to 1.5 ± 0.2 cm
H2O (p < 0.025) (Figure 8, left), and in Pes, from 11.4 ± 1.5 to 10.3 ± 1.3 cm H2O (p < 0.01) (Figure 8, right).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During noninvasive ventilation of ambulatory patients with moderate to severe COPD (using tidal volumes sufficient to ensure comfort), alterations in imposed ventilator inflation time, whether achieved by increasing delivered inspiratory flow or by decreasing ventilator inspiratory pause, produced increases in frequency and decreases in PEEPi and inspiratory effort.
Effects of Varying Ventilator Inflation Time on Breath Components
A decrease in ventilator inflation time achieved by increasing inspiratory flow produced changes in respiratory frequency, similar to those reported in patients and healthy subjects (2- 6). Likewise, alterations in ventilator inflation time, achieved by manipulating the ventilator inspiratory pause setting, caused changes in frequency similar to those seen in healthy subjects (4). To our knowledge, this is the first report of the effect of alterations in imposed inspiratory pause on frequency in patients with COPD.
The mechanism responsible for the increase in frequency secondary to an increase in inspiratory flow is probably the inhibition of inspiration that results from attaining a critical delivered volume above functional residual capacity (5, 11), and not from an increase in inspiratory flow per se, at least for flows between ~ 48 and ~ 90 L/min (see Figure 8 in Fernandez and coworkers [5]).
During the targeted flow protocol, we observed an increase in time available for exhalation as a function of the increase in delivered flow (Figure 2, right). This finding contrasts with our observations in healthy subjects (4), for whom an increase in flow from 30 to 90 L/min led to a decrease in time from exhalation from 3.0 ± 0.3 to 2.7 ± 0.2 s. In the healthy subjects, the response of exhalation time is probably a consequence of the known link between the duration of neural TI and subsequent neural TE (12). That the responses in time available for exhalation differed in the patients with COPD and healthy subjects may be a consequence of time-constant inhomogeneities in the patients.
For a given delivered volume in patients with COPD, a low inspiratory flow (e.g., 30 L/min) may cause the tidal volume to reach most, if not all, lung units. When flow is tripled to 90 L/ min, fewer lung units will have time to accommodate the administered tidal volume, at least during early inflation. In such a situation, vagal afferents in lung units with fast time constants will fire earlier during a rapid inflation than during a slower inflation. In turn, early discharge of the vagus will curtail neural TI. With a short neural TI, a rapid and more inhomogeneous inflation is also likely to cause overinflation in some lung regions to persist into neural exhalation. In turn, stimulation of the vagus during neural TE, the equivalent of afferent vagal discharge throughout the time that inflation is maintained during neural TE, can lead to an increase in duration of neural TE (7). Such prolongation is proportional to the intensity and duration of the vagal stimulation (7). This mechanism for neural TE prolongation is likely responsible for the observed increase in time available for exhalation accompanying the increase in inspiratory flow rate in patients with moderate to severe COPD (Figure 2, right).
The increase in frequency associated with the decrease in inspiratory pause, the targeted inspiratory pause protocol, can be reconciled with the known effects of lung inflation, and thus vagal stimulation, on neural TE. The duration of neural TE has been shown to decrease in proportion to the decrease in time that the vagus is stimulated at a constant level during exhalation, the equivalent of lung inflation during exhalation (7). This mechanism for shortening of neural TE is likely responsible for the observed increase in frequency that accompanied the decrease in inspiratory pause. Moreover, the delay between the end of vagal stimulation during exhalation and the onset of the next inhalation is not constant; instead, it increases as the duration of vagal stimulation decreases (at least for short-lasting vagal stimulations) (see Figure 8B in Zuperku and coworkers [7]). This inspiratory delay (7) is analogous to the time elapsing between the end of the applied inspiratory pause and the next inspiration, a period designated as the time available for exhalation.
Effect of Varying Ventilator Inflation Time on PEEPi
A decrease in ventilator inflation time, whether obtained by increasing inspiratory flow or by decreasing inspiratory pause, resulted in a decrease in PEEPi. This decrease in PEEPi occurred despite the concurrent increase in frequency. The likely mechanism for the decrease in PEEPi was the increase in time available for exhalation, which favors emptying of lung units with slow time constants.
Effect of Varying Ventilator Inflation Time on Respiratory Drive and Effort
Investigations of the response of respiratory drive to a decrease
in ventilator inflation time (achieved through an increase in
inspiratory flow) have yielded inconsistent results, with reports of an increase (healthy subjects [2, 13]), a decrease (healthy subjects [14]), and no change (healthy subjects [3, 14, 15]; patients with respiratory failure [16]). These discrepancies may
stem from limitations of techniques used to measure respiratory motor output
P0.1, Pes0.1, dp/dt, diaphragmatic electromyogram (17)and differences in the subjects studied and
mode of flow delivery (assist control ventilation, proportional
assist ventilation, and pressure support).
Despite the limitations of P0.1 as a measure of respiratory
drive, the flow-associated decrease in P0.1 did parallel the decrease in Pes (Figure 4). The likely early termination of neural TI (associated with an increase in inspiratory flow) together with a reduction in threshold loading (decrease in
PEEPi) are the probable mechanisms for the flow-associated
decreases in P0.1 and Pes (Figure 4). That an increase in inspiratory flow decreases respiratory drive (P0.1) and inspiratory effort (Pes) is consistent with previous reports of the effect of flow on respiratory work (16, 18) and pressure-time
product (18) in ventilator-supported patients.
An alternative, but not mutually exclusive, mechanism for
the flow-associated decrease in Pes stems from the effects of
flow on the force-velocity relationship of the respiratory muscles (19). For a given neural output, an increase in inspiratory flow, per se, can contribute to a decrease in the pressure
output of the inspiratory muscles, according to the dictates of
the force-velocity relationship (20, 21).
Between the commencement of the inspiratory effort and
the nadir in Pes, the rate of change in Pes increased from 12.7 ± 1.3 cm H2O/s at a flow of 30 L/min to 16.8 ± 2.4 cm H2O/s at
flow of 90 L/min. If the force-velocity relationship of the respiratory muscles had been solely operational, the rate of
change in Pes should have decreased. The observed increase
in the rate of change in Pes supports the contention of Corne
and coworkers (13) that the respiratory centers can compensate for a flow-induced deterioration in the intrinsic properties
of the respiratory muscles by increasing neural output. Explaining the flow-associated decrease in Pes solely in terms
of the force-velocity relationship fails to account for the flow-associated decrease in P0.1, especially because P0.1 is measured
under quasi-isometric conditions. Recordings of the motor
unit discharges of the inspiratory muscles would shed light on
a possible flow-associated modulation of respiratory drive. A
decrease in CO2 is not likely to have contributed to the decreases in P0.1 and Pes; the changes were seen within 4 breaths of changing flow, sooner than any possible change in
PCO2.
At a constant tidal volume, an elevated PEEPi (such as
with low flow rates in the targeted flow protocol) was likely to
be accompanied by a higher end-inspiratory lung volume than
when PEEPi was smaller (as with high flow rates in the targeted flow protocol). A higher end-inspiratory lung volume is
conducive to the deterioration of the length-tension relationship of inspiratory muscles. Nevertheless, both P0.1 and Pes
were greater when flow was least and hyperinflation was
greatest when flow was highest and hyperinflation was least.
Greater mechanical unloading at high flow rates (15, 16) may
be responsible for the preceding observations.
Shortening of ventilator inflation time through decreasing
inspiratory pause caused decreases in P0.1 and Pes (Figure 8), similar to the effects of shortening of ventilator inflation time through an increase in flow. These decreases in P0.1 and Pes probably result from the decrease in threshold loading, as reflected by PEEPi, and possibly from a better concordance between mechanical and neural values of TI. Because flow was
kept constant in the targeted inspiratory pause protocol, force-
velocity relationships of the inspiratory muscles should not
have been affected by the change in ventilator inflation time.
In contrast with the targeted flow protocol, the rate of fall in
Pes during inspiration was not affected by the duration of ventilator inflation time in the targeted inspiratory pause protocol
(data not shown).
Minute ventilation achieved in our patients during the targeted flow and inspiratory pause protocols was higher than
during CPAP ventilation. The higher minute ventilation must
have been accompanied by a decrease in PCO2. Nevertheless, a
fall in PCO2 cannot account for the associated changes in P0.1
and Pes, because acute respiratory alkalosis does not impair
respiratory muscle contractility (22).
Clinical Implications
The primary aim of the current study was to investigate the physiologic response to mechanical ventilation, rather than to assess its therapeutic utility. Nevertheless, the results have several important clinical implications. One, patients who are critically ill and mechanically ventilated are often tachypneic and hyperinflated (8). Under these circumstances, flow is commonly increased to achieve a decrease in ventilator inflation time and, thus, allow more time for exhalation. That this tactic can also cause tachypnea (2) has led to doubts that the time for exhalation will be prolonged. The data presented show that a decrease in ventilator inflation time does indeed allow more time for exhalation despite the development of tachypnea. Higher inspiratory flow also decreased respiratory drive and effort, changes conducive to improved patient-ventilator interaction. Conversely, prolongation of inspiratory pause time to decrease frequency can be counterproductive because it leads to worsening of hyperinflation, accompanied by increases in respiratory drive and effort (Figure 8). Two, the mode of ventilation, assist control, is widely used (23). Three, a square-wave flow pattern was selected because that configuration is commonly used in patients with airway obstruction, as it enables monitoring of airway resistance. Use of square configuration also enables comparison of our findings with those of other investigators (2, 6). Four, tidal volume during assist-control ventilation, tailored to the patient's comfort, was higher than that during CPAP ventilation and that recorded nonobtrusively during spontaneous breathing (447 ± 35 ml) (24). Several investigators have noted that the tidal volume needed to achieve comfort during assist-control ventilation exceeds that during spontaneous breathing (2, 25). Accordingly, we decided to avoid the risk of dyspnea with lower tidal volumes, as we were concerned that dyspnea would influence the response of frequency to changes in flow. Of note, tidal volumes in the current protocol were similar to those noted in patients with COPD during noninvasive ventilation (790 ± 37 ml) (26). Five, we studied patients while awake, and, thus, behavioral responses may have contributed to the observed changes in respiratory frequency (25, 27). While it is obviously inappropriate to extrapolate the findings to the sleeping state, mechanically ventilated patients spend most of the time awake (28).
In summary, the changes of frequency and time for exhalation in response to a decrease in ventilator inflation time in patients with COPD were similar, but not identical, to those seen in healthy subjects. When ventilator inflation time was shortened by decreasing inspiratory pause, frequency increased and, as in healthy subjects, the time available for exhalation increased. When ventilator inflation time was shortened by increasing flow, frequency increased but, unlike healthy subjects, the time available for exhalation also increased. The different response in patients may have resulted from early vagal discharge secondary to local overdistention of lung regions with fast time constants. The ventilator inflation time-associated small increase in time for exhalation was, at least partly, responsible for a small decrease in PEEPi despite the rise in frequency. The decreases in ventilator inflation time also produced small decreases in effort, probably as a result of a reduction in threshold loading and, possibly, through the effect of ventilator settings on the intrinsic properties of the respiratory muscles. In conclusion, ventilator strategies that reduced ventilator inflation time in patients with COPD caused tachypnea, yet prolonged the time for exhalation with consequent decrease in intrinsic positive end-expiratory pressure. The decrease in threshold load, and possibly early termination of neural inhalation at high flow rates, may be responsible for the accompanying decrease in patient inspiratory effort.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Franco Laghi, M.D., Division of Pulmonary and Critical Care Medicine, Edward Hines, Jr. VA Hospital, 111N, 5th Avenue and Roosevelt Road, Hines, IL 60141. E-mail: flaghi{at}lumc.edu
(Received in original form January 28, 2000 and in revised form December 21, 2000).
Acknowledgments: Supported by grants from the Veterans Administration Research Service, the American Lung Association of Metropolitan Chicago, the Gaylord and Dorothy Donnelley Foundation, and the RML Specialty Hospital.
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References |
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ABSTRACT
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METHODS
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DISCUSSION
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