Download Effects of positive-pressure ventilation on the spontaneous

J Appl Physiol 96: 1155–1160, 2004.
First published November 7, 2003; 10.1152/japplphysiol.00578.2003.
Effects of positive-pressure ventilation on the spontaneous baroreflex
in healthy subjects
Ingo Fietze,1 Dietrich Romberg,2 Martin Glos,1 Susanne Endres,1
Heinz Theres,1 Christian Witt,1 and Virend K. Somers3
1
Center of Sleep Medicine, Department of Cardiology and Pulmology, Charité-Universitary
Medicine Berlin, D-10117 Berlin; 2Department of Electrical Engineering, University of Applied Sciences,
D-06336 Koethen, Germany; and 3Mayo Clinic, Rochester, Minnesota 55905
Submitted 4 June 2003; accepted in final form 4 November 2003
baroreflex sensitivity; heart rate variability; blood pressure variability
THERE IS COMPELLING EVIDENCE that phases of respiration have
distinct and powerful effects on both vagal and sympathetic
cardiovascular control. Changes in respiratory patterns, during
hyperventilation for example, influence cardiac and vascular
function not only by changes in blood gas chemistry, but also
by modulating neural circulatory control mechanisms (42). The
significance of these interactions in conditions of health and
disease are being increasingly recognized (2, 12, 23, 44) and
may be especially relevant to disease conditions affecting both
the cardiovascular and respiratory systems, such as heart failure and obstructive sleep apnea (OSA).
Cessation of air exchange as occurs during sleep-disordered
breathing also results in sympathetic activation and increases in
blood pressure (46). Treatment of these sleep-related breathing
disorders with noninvasive positive-pressure ventilation (PPV)
as applied by a continuous positive airway pressure (CPAP)
device has very significant effects on autonomic tone and
baroreflex function (2, 5, 27). Both long-term and short-term
Address for reprint requests and other correspondence: I. Fietze, CharitéUniversitary Medicine Berlin, Dept. of Cardiology and Pulmology, Center of
Sleep Medicine, Luisenstr. 13a, D-10117 Berlin, Germany (E-mail:
[email protected]).
http://www.jap.org
applications of PPV have been shown to improve autonomic
balance and baroreflex sensitivity in OSA patients with heart
failure (28, 44). Autonomic circulatory control and baroreflex
function are important in the pathophysiology and prognosis of
cardiovascular diseases in patients with breathing disorders.
The baroreflex sensitivity (BRS) is usually quantified by
vasoactive drug administration that raises or lowers systemic
arterial pressure or by direct engagement of carotid baroreceptors with neck chamber devices (15). The need for intravenous
infusions or neck chamber devices limits the use of these
methods, especially in large populations, monitoring, or follow-up studies. Recent studies have suggested that transfer
function analysis of spontaneous fluctuations of arterial blood
pressure and R-R intervals offers a noninvasive and perhaps
more “physiological” method for assessing BRS, especially in
free living conditions (10, 31, 35, 38) with good BRS reproducibility (18).
Although noninvasive PPV is widely used in conditions of
cardiovascular and respiratory dysfunction, the hemodynamic
and reflex consequences of PPV application on cardiovascular
control per se are poorly understood. Prior study examining the
effects of PPV on the spontaneous baroreflex in humans was
limited to the setting of deep slow patterned breathing at one
breath every 10 s (45). We tested the hypothesis that the
short-term application of PPV using a bilevel mode in healthy
awake subjects, even in the absence of sleep-disordered breathing, would cause acute alterations in neural circulatory control
mechanisms.
METHODS
Subjects. Fifty-five (26 women, 29 men) healthy volunteers (mean
age 46.5 ⫾ 10.5, range 28–64 yr) participated in the study. All gave
their written, informed consent. The study was approved by the
Institutional Human Subjects Review Committee. Sleep-related
breathing disorders were excluded by two nights of standard polysomnography.
ECG, lung function test, blood analysis, and sleep and health
questionnaires were performed before subjects entered the study.
Subjects with heart rhythm disorders, obstructive or restrictive respiratory disturbances, and acute or chronic illness evident on these
laboratory data were excluded from the study. None of the subjects
was receiving acute or chronic medications.
Protocol. The study protocol was approved by the Institutional
Ethics Committee. All recordings were performed between 9 and 11
AM during wakefulness in a quiet room. Subjects were studied in a
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.
8750-7587/04 $5.00 Copyright © 2004 the American Physiological Society
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Fietze, Ingo, Dietrich Romberg, Martin Glos, Susanne Endres,
Heinz Theres, Christian Witt, and Virend K. Somers. Effects of
positive-pressure ventilation on the spontaneous baroreflex in healthy
subjects. J Appl Physiol 96: 1155–1160, 2004. First published November 7, 2003; 10.1152/japplphysiol.00578.2003.—To determine
the short-term effects of noninvasive positive-pressure ventilation
(PPV) on spontaneous baroreflex sensitivity, we acquired time series
of R-R interval and beat-to-beat blood pressure in 55 healthy volunteers (mean age 46.5 ⫾ 10.5 yr) who performed breathing on four
occasions at frequencies of 12 and 15 breaths/min without positive
pressure (control) and also using PPV of 5 mbar. By using spectral
and cross-spectral analysis, R-R interval variability and systolic blood
pressure variability as well as the gain (␣-index) of the baroreceptor
reflex were estimated for the low-frequency and high-frequency (HF)
bands. Compared with control breathing, PPV at 12 breaths/min and
15 breaths/min led to an increase in mean R-R (P ⬍ 0.001) and blood
pressure (P ⬍ 0.05). The ␣-index of the HF band increased significantly for both respiratory frequencies (P ⬍ 0.05) due to PPV. These
results indicate that short-term administration of PPV in normal
subjects elicits a significant enhancement in the HF index of the
baroreflex gain. These findings may contribute to understanding the
mechanisms, indications, and effectiveness of positive pressure
breathing strategies in treating cardiorespiratory and other disease
conditions.
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POSITIVE-PRESSURE VENTILATION AND SPONTANEOUS BAROREFLEX
J Appl Physiol • VOL
cago, IL). Differences were considered significant when a two-tailed
P value of ⬍0.05 was found.
RESULTS
Of the 55 subjects studied, results from five subjects were
excluded from analysis because of extrasystolic activity or
artifacts throughout the study.
Hemodynamic changes. Generally, similar changes in hemodynamic variables were observed during PPV for both respiratory frequencies. R-R intervals and DBP showed a significant
increase, whereas SBP increased with PPV at 12 breaths/min,
but the increase fell short of significance at 15 breaths/min
respiratory frequency (Table 1).
Time series. A representative set of resampled time series of
R-R intervals and SBP measured from one subject during all
settings of the study protocol is demonstrated in Fig. 1. The
presence of the breathing frequency is clearly visible in the
R-R interval plots. It should be noted from the SBP waveforms
that the larger amplitude LF fluctuations are not related directly
to the breathing pattern.
Spectral analysis. Figure 2 shows the power density spectra
of HRV and SBPV for the corresponding time series depicted
in Fig. 1. The spectra for HRV show a dominant HF component at the respiratory frequency. Corresponding but smaller
peaks can be also seen in the SBP spectra. In contrast, LF (less
Table 1. Autonomic and baroreflex indexes during
control breathing and PPV
Respiratory Frequency
(12 breaths/min)
Variable
Control
PPV
Respiratory Frequency
(15 breaths/min)
Control
PPV
914.7⫾16.8
38.55⫾21.5
32.28⫾23.1
128.9⫾2.92
64.29⫾2.30
969.4⫾18.0‡
42.16⫾17.8
39.37⫾22.9‡
134.4⫾3.44
67.86⫾2.57*
1.045⫾0.13
13.33⫾1.55
0.447⫾0.03
20.41⫾2.69
0.553⫾0.03
1.006⫾0.17
18.03⫾2.16
0.420⫾0.03
26.70⫾3.20†
0.580⫾0.03
6.950⫾0.92
0.351⫾0.04
0.132⫾0.02
7.365⫾1.36
0.379⫾0.05
0.107⫾0.02
12.25⫾6.46
6.747⫾0.55
16.95⫾1.81
14.32⫾7.53
7.476⫾0.63
20.62⫾2.11*
Time domain
RR, ms
RR-variance, ms
RMSSD, ms
SBP, mmHg
DBP, mmHg
902.6⫾15.4
38.94⫾19.0
32.19⫾22.6
129.6⫾3.04
64.45⫾1.91
957.1⫾17.4‡
43.47⫾21.0*
37.20⫾22.8‡
134.7⫾2.79*
68.63⫾2.14*
LF/HF ratio
LF, ms2
LF-norm
HF, ms2
HF-norm
0.657⫾0.08
16.32⫾1.60
0.375⫾0.02
34.08⫾4.15
0.625⫾0.02
0.550⫾0.07
15.35⫾1.41
0.355⫾0.03
38.29⫾5.85*
0.645⫾0.03
HRV
SBPV
LF/HF ratio
LF, mmHg2
HF, mmHg2
3.442⫾0.42
0.295⫾0.02
0.168⫾0.02
5.844⫾1.26
0.283⫾0.03
0.167⫾0.03
␣-Index
␣TOT,
ms/mmHg
␣LF, ms/mmHg
␣HF, ms/mmHg
12.93⫾6.45
7.743⫾0.52
18.58⫾1.98
13.90⫾6.88†
7.993⫾0.64
21.48⫾2.35†
Values are means ⫾ SE. Control, control breathing at 0 mbar; PPV, positive
pressure ventilation at 5 mbar; RR, R-R intervals in ECG; RR-Variance,
variance of R-R intervals in ECG; RMSSD, root mean square of successive
differences of R-R intervals in ECG; SBP, systolic blood pressure; DBP,
diastolic blood pressure; HRV, heart rate variability; LF, low frequency;
LF-norm, normalized LF units; HF, high frequency; HF-norm, normalized HF
units; TOT, mean of LF and HF; SBPV, systolic blood pressure variability.
PPV vs. Control: *P ⬍ 0.05, †P ⬍ 0.01, ‡P ⬍ 0.001.
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45° head-up lying position. Each subject was trained in metronomecontrolled breathing at frequencies of 12 and 15 breaths/min. After an
adaptation of ⬃10 min, data acquisition of ⬃6 min in each case was
performed at each of the following low settings: 1) breathing at a
frequency of 12 breaths/min without PPV (control) and with PPV of
5 mbar, and 2) breathing at a frequency of 15 breaths/min without
PPV (control) and with PPV of 5 mbar. PPV was applied by use of a
nasal bilevel positive airway pressure device with timed mode to
control respiratory frequency under ventilated conditions and to make
breathing more comfortable.
Signal acquisition. Heart rate was estimated from successive R-R
intervals in ECG lead II. Continuous measurements of beat-to-beat
blood pressure were obtained with the Portapres system (TNO-TPD,
Amsterdam, The Netherlands). Noninvasive monitoring of the blood
pressure has been shown to correspond closely to intra-arterial blood
pressure measurements both at rest and during rapid changes in blood
pressure (32) and to be adequate for more complex time and frequency domain analysis of blood pressure variability and baroreceptor
sensitivity (14).
Respiratory effort was recorded by use of a thoracic belt containing
a piezo-crystal transducer (Pro-Tech Services, Woodinville, WA). All
signals were recorded simultaneously with an EMBLA digital polysomnographic recorder (Flaga, Reykjavik, Iceland). The sampling rate
was 200 Hz for the ECG and blood pressure signals and 50 Hz for the
respiration signal.
Signal analysis. All recordings were analyzed by use of a custommade Matlab software package (version 5.3, The MathWorks, Natick,
MA). After filtering (Butterworth band pass, 0.7–30 Hz) of the
recordings, beat-to-beat time series of R-R intervals (R-R), systolic
blood pressure (SBP) and diastolic blood pressure (DBP) were determined. Artifacts were eliminated and corrected manually. Intervals of
180 consecutive beats were selected for R-R (ms), SBP (mmHg), and
DBP (mmHg), interpolated with cubic splines, and resampled with 4
cycles/beat. After trend elimination and windowing (Hanning, n ⫽
256), the fast Fourier transformation, based on Welch’s method (47),
was calculated to obtain the power spectral density for R-R variability
(HRV) and SBP variability (SBPV). Frequency unit dimensions were
changed by means of the mean heart rate in the corresponding
breathing protocol. The low-frequency (LF) and the high-frequency
(HF) bands of HRV and SBPV were calculated by integration of the
spectral components (LF: 0.04–0.15 Hz; HF: 0.15–0.4 Hz). In addition, the LF and HF components of HRV were measured in normalized units, which represent the relative value of each power component in proportion to the total power of the HF and LF bands (25). For
further analysis of the autonomic balance, the ratio LF/HF was
calculated.
The baroreflex function was described by the gain (␣-index)
between HRV and SBPV calculated separately for the LF (0.08–0.12
Hz) and HF (breathing frequency) band by using spectral and crossspectral analysis (31, 37).
The ␣-index was obtained from the square root of the ratio between
spectral power densities of HRV and SBPV for the HF and LF bands.
Accordingly, ␣HF indicates the gain of the baroreflex loop in the HF
band, whereas ␣LF indicates the gain of the reflex loop in the LF band
(38). The overall gain (␣TOT) was calculated as ␣TOT ⫽ 0.5䡠(␣HF ⫹
␣LF) (24).
Statistics. Results are given as mean ⫾ SE values. Mean values for
R-R, SBP, and DBP were calculated as the average of the corresponding time series. Nonparametric Wilcoxon’s rank test was used to
evaluate differences between control and PPV measurements at both
respiratory frequencies. The squared coherence function K2(f), which
ranges between zero and unity, was used to evaluate the statistical
reliability of the cross-spectral analysis at each frequency. Estimations
of the phase ␸(f) were accepted if the squared coherence function K2
exceeded 0.56 (10, 37). Statistical analyses were performed by using
the software package SPSS for Windows (version 10.0, SPSS, Chi-
POSITIVE-PRESSURE VENTILATION AND SPONTANEOUS BAROREFLEX
1157
Fig. 1. Examples of respiration (A), corresponding R-R intervals (B), and corresponding systolic blood pressure (C) for all 4
settings of the protocol: 12/0 ⫽ 12 breaths/min and 0 mbar; 12/5 ⫽ 12 breaths/min and positive-pressure ventilation (PPV) at 5
mbar; 15/0 ⫽ 15 breaths/min and 0 mbar; 15/5 ⫽ 15 breaths/min and PPV at 5 mbar.
Autonomic and baroreflex indexes. The mean values of the
indexes of cardiovascular autonomic control and baroreflex
function are summarized in Table 1. Significant differences
between control breathing and PPV were present for the HF
component of the HRV as well as for the ␣-index at both
respiratory frequencies. PPV did not cause any differences in
SBPV characteristics.
DISCUSSION
The application of PPV is gaining increasing recognition as
a potential therapeutic approach in OSA (48) and in central
sleep apnea (41). Chronic nocturnal positive pressure therapy
Fig. 2. Examples of corresponding power
spectra for heart rate variability (A) and
systolic blood pressure variability (B) with
respiration frequencies (RF) of 12 breaths/
min (top) and 15 breaths/min (bottom) for
control breathing at 0 mbar (dotted lines)
and PPV at 5 mbar (solid lines). The corresponding spectral lines for RF 12 breaths/
min (0.2 Hz) and RF 15 breaths/min (0.25
Hz) are indicated (vertical dashed lines).
J Appl Physiol • VOL
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than ⬃0.05 Hz) spectral power was more apparent for systolic
blood pressure than R-R intervals.
Cross-spectral analysis. In Fig. 3, the frequency distribution
of the ␣-index is shown for the time series depicted in Fig. 1.
For PPV, the spectra for the ␣-index revealed a marked
predominance of the respiratory frequency component. The
reliability of the estimation of both measures was assessed by
the coherence function. All breathing protocols yielded a
significant relationship (coherence ⬎0.56) between HRV
and SBPV spectra in most of the 50 patients (at 12 breaths/
min: 43 patients during control and 36 patients during PPV;
at 15 breaths/min: 39 patients during control and 34 patients
during PPV).
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POSITIVE-PRESSURE VENTILATION AND SPONTANEOUS BAROREFLEX
Fig. 3. Examples of corresponding spontaneous baroreflex sensitivity (␣-index) for
time series of R-R interval and systolic
blood pressure for RF of 12 breaths/min (A)
and 15 breaths/min (B) for control breathing
at 0 mbar (dotted lines) and PPV at 5 mbar
(solid lines). The corresponding spectral
lines for RF 12 breaths/min (0.2 Hz) and RF
15 breaths/min (0.25 Hz) are indicated (vertical dashed lines).
J Appl Physiol • VOL
in whom application of PPV results in very significant decreases in blood pressure levels, because of elimination of
apneic events (1, 42). This may be caused, in part, by the
different operating points and other characteristics of the
baroreceptor reflex in both populations (2, 7, 44). We noted an
increase in the ␣-index of the HF band, suggesting an enhanced
HF component of baroreflex gain. To our knowledge, the only
prior study investigating the effects of PPV application on
spontaneous baroreflex function in healthy awake subjects was
performed by Torok et al. (45). In a small group of subjects,
effects of breathing were examined at a very LF (6 breaths/
min) on baroreflex gain. They noted that whereas the slow
breathing frequency enhanced baroreflex gain, application of
PPV did not result in any further alteration. It is relevant that
other studies have demonstrated a very significant effect of
slow breathing on neural circulatory control, in particular,
enhanced baroreflex gain (4, 13). Thus the profound effects of
slow breathing on baroreflex gain may obscure the direct
effects of PPV per se on neural circulatory control. Our study
elicited a distinct increase in the HF ␣-index of the baroreflex
due to PPV in the absence of slow breathing. The absence of
further enhancement of baroreflex gain in the study by Torok
et al. suggests that the ability of respiration to modulate the
baroreflex is limited and that the increased gain induced by the
LF breathing pattern cannot be extended further by the application of PPV. In addition, the sequence method used by Torok
et al. does not take into account the confounding influences of
respiration on heart rate and blood pressure (13, 37). By
contrast, the present study employs more reliable and comprehensive methods for assessing baroreflex function by using
spectral and cross-spectral analysis of HRV and SBV (9, 33,
35). In addition, controlled breathing frequencies of 12 and 15
breaths/min simulate more normal breathing patterns.
Mechanisms for the enhanced baroreflex gain may include a
reduction in cardiac filling pressures and transmural pressure
gradients and their consequent effects on the interactions between the cardiopulmonary and arterial baroreceptors (11, 12,
24, 29). PPV-mediated deactivation of cardiopulmonary receptors (as a consequence of reduced cardiac transmural pressure)
may potentiate arterial baroreflex gain. The cardiopulmonary
reflex deactivation may also help explain the increased blood
pressure during PPV. PPV-mediated deactivation of those
receptors registering filling pressure in the atria and great veins
would elicit an increase in peripheral sympathetic vasocon-
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for heart failure patients with central sleep apnea improves
cardiac hemodynamics (6, 28, 41). Important data from Sin et
al. (41) show improvements even in quality of life and transplant-free survival. In patients with congestive heart failure,
there is evidence that a reduction in the baroreflex sensitivity is
associated with poorer prognosis (22, 26, 44). Interestingly,
PPV has been shown to cause acute decreases of heart rate and
blood pressure as well as acute increases of baroreflex sensitivity in congestive heart failure patients with OSA (19, 44).
PPV also lowers blood pressure and increases baroreflex gain
in patients with refractory hypertension and OSA (23). Hypertension, heart failure, and OSA are each associated with impaired neural circulatory control mechanisms. Thus short-term
effects of PPV in disease conditions include an improvement in
autonomic control of cardiovascular function, especially in
baroreflex gain. Only very limited data (45) are available on
the acute effects of PPV on neural circulatory control in
healthy normal subjects.
Our study shows that in healthy awake normal subjects,
administration of even modest levels of positive end expiratory
pressure at 5 mbar results in significant changes in hemodynamics and in measurements of neural circulatory control with
increases in blood pressure, decreases in heart rate, and an
increase in the HF component of the ␣-index of baroreflex
gain.
At breathing frequencies of both 12 and 15 breaths/min,
application of PPV prolonged R-R interval and increased blood
pressure. The increase in the R-R interval due to application of
PPV may be caused by the reflex response to increased blood
pressure, as well as by a decrease in sinoatrial stretch and an
increase in parasympathetic control of heart rate (17). In
addition, inhibition in sympathetic neural control of heart rate
may be secondary to stimulation of pulmonary stretch receptors by PPV-induced increases of end-expiratory lung volume
(39). Because of the increased time for filling associated with
R-R prolongation, the subsequent stroke volume, and thus the
pulse pressure, would increase in accordance with the FrankStarling law. This is in line with the significant increase in the
SBP and DBP during PPV (16, 36, 40) confirmed by our
results. However, an additional mechanism for the blood pressure increase may be reflexive arteriolar constriction described
as an early effect of baroreceptor stimulation (36).
Blood pressure responses to application of PPV in healthy
awake subjects show striking differences to patients with OSA,
POSITIVE-PRESSURE VENTILATION AND SPONTANEOUS BAROREFLEX
GRANTS
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
This study was supported by the Deutsche Forschungsgemeinschaft (DFG
Fi 584/1-4). V. K. Somers is supported by National Institutes of Health Grants
HL-65176, HL-61560, HL-70602, HL-73211, and M01-RR-00585
21.
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strictor traffic (16). This enhanced sympathetic vasoconstriction may contribute to the increase in blood pressure, which,
acting via the arterial baroreflex, would slow the heart rate. We
also cannot exclude that changes in reflex gain may in part be
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in arterial pressure by way of changes in the R-R period when
the system is operating toward stability (31).
The arterial baroreflex serves as a pressure buffer system
against increases and decreases in arterial pressure. In this
respect, the baroreflex has been thought to be the link between
SBPV and HRV (31, 33). The increase in the HF component of
R-R variability during PPV, in the absence of any change in
respiratory frequency, supports the likelihood of a baroreflexmediated contribution to the R-R prolongation (30). On the
other hand, there is some evidence that heart rate changes
related to respiration may contribute to SBPV, suggesting
fundamental relationships between SBPV and HRV (21, 43).
Tidal volume was not controlled in this study, because the
conscious mental effort to control both respiratory frequency
and tidal volume may itself alter autonomic activity (13, 34). In
addition, it has been previously found that changes in tidal
volume are less important than breathing frequency (3, 20).
However, we used a breathing protocol incorporating a stepwise change in respiratory frequency as recommended by
Cooke et al. (8), who showed that subjects automatically
(presumably with the aid of chemoreceptors) adjust their tidal
volumes and maintain normal end-tidal CO2 levels during
stepwise frequency breathing.
In conclusion, our data show that short-term administration
of PPV in normal subjects elicits significant increases in R-R
interval and blood pressure as well as an enhancement of the
HF index of the baroreflex gain. Clinical studies of the effects
of PPV have shown in patients with OSA and hypertension
(23) and heart failure (42) that PPV induces increases in
baroreflex gain in the context of a fall in blood pressure. These
patients also have baseline impairment in baroreflex gain. Our
data show that, even in healthy normal subjects, application of
PPV still induces an increase in baroreflex gain, but in association with an increase in blood pressure. These findings may
contribute to understanding the physiological effects of positive pressure breathing and its differential consequences when
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