Download Periodicity of Obstructive Sleep Apnea in Patients With and Without

Periodicity of Obstructive Sleep Apnea
in Patients With and Without Heart
Failure*
Clodagh M. Ryan, MB; and T. Douglas Bradley, MD
Study objective: To determine whether the duration of the apnea-hyperpnea cycle is longer in
patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA) than in patients
with OSA alone, and whether this is related to prolonged circulation time.
Design: Retrospective study.
Setting: Sleep laboratory of a university teaching hospital.
Patients and intervention: Male patients with OSA and CHF (n ⴝ 22) or without CHF (n ⴝ 18)
underwent overnight polysomnography.
Measurements and results: Hyperpnea duration, time to peak tidal volume (VT), and lung-to-ear
circulation time (LECT) were measured in all patients. Compared to the non-CHF patients, those
with CHF had significantly longer hyperpneas (25.7 ⴞ 7.8 s vs 17.6 ⴞ 5.6 s, p < 0.001) and LECT
(14.9 ⴞ 3.4 s vs 9.0 ⴞ 1.8 s, p < 0.001) [mean ⴞ SD]. There was also a significant relationship
between LECT and hyperpnea duration (r ⴝ 0.67, p < 0.001).
Conclusion: In patients with CHF, prolonged lung-to-chemoreceptor circulation time influences
the cycling characteristics of OSA such that it prolongs hyperpnea and sculpts a pattern
resembling Cheyne-Stokes respiration. These findings further suggest that the increased tendency to periodic breathing in CHF may predispose to, or alter the physiologic manifestations of
OSA.
(CHEST 2005; 127:536 –542)
Key words: circulatory delay; congestive heart failure; obstructive sleep apnea; periodic breathing
Abbreviations: AHI ⫽ apnea-hypopnea index; CHF ⫽ congestive heart failure; CPAP ⫽ continuous positive airway
pressure; CSA ⫽ central sleep apnea; LECT ⫽ lung-to-ear circulation time; OSA ⫽ obstructive sleep apnea;
Ptcco2 ⫽ transcutaneous Pco2; Sao2 ⫽ arterial oxygen saturation; Vt ⫽ tidal volume
sleep apnea (OSA) commonly occurs
O inbstructive
patients with congestive heart failure (CHF).
1
Long-term relief of OSA in patients with CHF by
continuous positive airway pressure (CPAP) causes
significant improvements in cardiac function.2– 4
Therefore, it is important to determine what factors
are involved in the pathophysiology of OSA in the
*From the Sleep Research Laboratory of the Toronto Rehabilitation Institute, and the University of Toronto Centre for Sleep
Medicine and Circadian Biology, Toronto, ON, Canada.
Supported by a grant from the Canadian Institutes of Health
Research (MOP 11607).
Dr. Ryan is supported by unrestricted Research Fellowships
from Respironics Inc. and The Toronto Rehabilitation Institute,
and Dr. Bradley by a Senior Scientist Award from the Canadian
Institutes of Health Research.
Manuscript received May 21, 2004; revision accepted August 19,
2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: T. Douglas Bradley, MD, Toronto General
Hospital/University Health Network, EC 6 –248, 200 Elizabeth
St, Toronto, ON, M5G 2C4, Canada; e-mail: douglas.bradley@
utoronto.ca
setting of CHF. It has been hypothesized that a
primary periodic breathing disorder may play a role
in the pathophysiology of some cases of OSA.5,6
According to this hypothesis, instability of the upper
airway is a result rather than the cause of the
periodic breathing. If periodicity of breathing contributes to upper airway occlusion, then evidence for
this is likely to be found in subjects predisposed to
periodic breathing during sleep, such as those with
CHF. Patients with CHF frequently suffer from a
form of periodic breathing known as Cheyne-Stokes
respiration.7 Cheyne-Stokes respiration is characterized by apneas alternating with prolonged hyperpneas, during which there is a slowly waxing and
waning pattern of tidal volume (Vt). Although there
have been a few reports of upper airway obstruction
during Cheyne-Stokes respiration, there has been no
systematic examination of a potential relationship
between OSA and Cheyne-Stokes respiration in patients with CHF.8
In patients with OSA and normal ventricular
function, obstructive apneas are usually terminated
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Clinical Investigations
by a hyperpnea with an abrupt rise and rapid decline
in Vt prior to the onset of the next apnea. In
contrast, if OSA occurred in the setting of CHF, and
was related to an underlying periodic breathing
disorder, rises and falls in Vt during hyperpnea
might be more gradual owing to increased lung to
chemoreceptor circulation time.9,10 This pattern of
hyperpnea would resemble the waxing and waning
pattern of Vt associated with Cheyne-Stokes respiration and central sleep apnea (CSA). To test this
hypothesis, we compared hyperpnea duration, lungto-chemoreceptor circulation time, and time-to-peak
Vt in patients with OSA either with or without CHF.
Materials and Methods
Subjects
Patients with CHF due to either ischemic cardiomyopathy or
nonischemic dilated cardiomyopathy were referred for overnight
sleep studies because of a history suggestive of OSA, including
loud snoring plus at least one of the following: restless sleep,
excessive daytime sleepiness, morning headaches, or witnessed
apneas. The diagnosis of CHF was based on a history of at least
one episode of pulmonary edema with exertional dyspnea accompanied by left ventricular dysfunction, defined by a left ventricular ejection fraction ⬍ 45% by equilibrium radionuclide angiography or two-dimensional echocardiography. Patients had to have
exertional dyspnea (New York Heart Association functional class
II or III) despite clinical stability and optimal medical therapy for
at least 1 month prior to entry. Patients without CHF referred to
the sleep laboratory and subsequently found to have OSA were
recruited as control subjects. All CHF and control subjects were
free of neurologic and respiratory disease, and the control
subjects were free of cardiovascular disease as assessed by history
and physical examination. The diagnosis of OSA in both groups
was based on the presence of at least 10 apneas and hypopneas
per hour of sleep observed on an overnight polysomnogram, of
which at least 85% had to be obstructive in nature. The Human
Subjects Review Committee of the University of Toronto approved the protocol, and all subjects provided written informed
consent prior to participation in the study.
Polysomnography
Overnight polysomnography was performed in all patients
according to standard techniques previously described for our
laboratory.10 Sleep stages were scored using standard criteria.11 A
respiratory inductance plethysmograph (Respitrace; Ambulatory
Monitoring; White Plains, NY) calibrated for Vt against a
spirometer was used to measure thoracoabdominal movements.12
Arterial oxygen, saturation (Sao2) was measured continuously
using a pulse oximeter (Nellcor N200; Tyco International Healthcare; Pleasanton, CA) placed on the ear. Transcutaneous Pco2
(Ptcco2) was measured continuously with a transcutaneous capnograph (Kontron Medical, Hoffman LaRoche; Basel, Switzerland), previously validated against arterial Pco2.10 Mean Ptcco2
and mean Sao2 were estimated by averaging the highest and
lowest values every 30 s throughout sleep. Obstructive apneas
were defined as a reduction in Vt to ⬍ 100 mL for at least 10 s
associated with out-of phase thoracoabdominal movements.13
Obstructive hypopneas were defined as a ⬎ 50% reduction in Vt
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from baseline (but Vt ⱖ 100 mL), lasting for at least 10 s
accompanied by out-of phase thoracoabdominal movements.13,14
The number of apneas and hypopneas per hour of sleep was
defined as the apnea-hypopnea index (AHI).
We confined our data analysis to stage 2 non-rapid eye
movement sleep for several reasons. First, this was the dominant
stage in all subjects. Second, apnea-hyperpnea cycles were most
commonly present during this stage. Third, the cardiovascular
and respiratory systems are under predominantly metabolic
regulation during this stage, and therefore are not subject to
behavioral influences. Finally, by analyzing all data from a single
sleep state, we were able to control for the potential effects of
sleep state on apnea-hyperpnea characteristics. During episodes
of recurrent obstructive apneas in stage 2 sleep, the respiratory
cycle was divided into two phases: the apneic phase and the
hyperpneic phase. The apnea duration was defined as the time
between the end of inspiration of the breath preceding the onset
of apnea and the onset of inspiration during the breath that
terminated the apnea. The hyperpnea duration was defined as
the time between the onset of inspiration of the first breath
terminating the apnea and the end of the inspiration of the breath
preceding the next apnea. Cycle duration was calculated as the
sum of the apnea and the hyperpnea durations. Time to peak Vt
was defined as the interval from the onset of the breath
terminating the apnea to the largest Vt.9
Lung-to-ear circulation time (LECT) was used as an estimate
of lung-to-carotid chemoreceptor circulation time. We have
previously validated this technique against cardiac output as a
measure of circulation time in patients with sleep apnea, with and
without CHF.9 LECT was taken as the interval from the onset of
the first breath terminating the obstructive apnea to the nadir of
the subsequent dip in Sao2 measured at the ear. Ten consecutive
apnea-hyperpnea cycles during the first episode of stage 2 sleep
were analyzed in each subject.
Statistical Analyses
Data are expressed as mean ⫾ SD. Statistical analyses were
performed using SigmaStat 2.03 (SPSS; Chicago, IL). Continuous variables were compared using two-tailed, unpaired t tests for
variables with normally distributed data, and Mann-Whitney
rank-sum test for variables with nonnormally distributed data.
Relationships among variables were analyzed using least-squares
linear regression where appropriate; p ⬍ 0.05 was considered
statistically significant.
Results
Subject Characteristics
Eighteen men with OSA alone were matched for
age (47.3 ⫾ 11 years vs 54.3 ⫾ 11 years) and body
mass index (31.5 ⫾ 7 vs 31.5 ⫾ 7 kg/m2) to 22 men
with OSA and CHF. The cause of CHF was coronary
artery disease in 12 subjects and idiopathic dilated
cardiomyopathy in 10 subjects. In patients with
CHF, severe left ventricular dysfunction was evidenced by a mean left ventricular ejection fraction of
26.8 ⫾ 9.7%. Medical therapy for heart failure in the
CHF and OSA group consisted of angiotensin-converting enzyme inhibitors or angiotensin II receptor
blockers in 21 patients, ␤-blockers in 15 patients,
diuretics in 16 patients, and digoxin in 12 patients.
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537
Data for the entire sleep period appear in Table 1.
Subjects had moderately severe OSA as indicated by
their AHI. The two groups were well matched for
AHI, sleep efficiency, sleep-stage distribution, frequency of arousals, mean and minimum Sao2, and
mean Ptcco2.
Respiratory Data From Stage 2 Sleep
Figures 1, 2 are representative polysomnographic
recordings during stage 2 sleep from patients with
OSA alone and patients with CHF and OSA, respectively. They demonstrate that LECT, hyperpnea
duration, and total cycle duration are greater in the
patient with CHF and OSA than in the patient with
OSA. Following apnea termination in the patient
with OSA, there was an abrupt rise and rapid decline
in Vt. In contrast, in the patient with CHF and OSA,
there was a gradual rise and slow decline in Vt
similar to the waxing and waning pattern of Vt
typically seen during Cheyne-Stokes respiration in
CHF patients with CSA. As shown in Table 2, the
LECT, hyperpnea, and cycle duration were all significantly greater in the CHF and OSA group than in
the OSA group. The number of breaths per hyperpnea was also significantly greater in the subjects
with OSA and CHF, although the respiratory rate
during hyperpnea was similar in both groups. Apnea
duration was similar in the two groups. There were
no significant differences in mean or minimum Sao2
and mean Ptcco2 between the groups. LECT correlated significantly with hyperpnea duration, breaths
per hyperpnea, and time to peak Vt (Fig 3). However, LECT was not related to apnea duration
(r ⫽ 0.06, p ⫽ 0.70).
Figure 1. Typical polysomnographic recording from a patient
with OSA but without CHF. Out-of-phase ribcage and abdominal
movements during apneas indicate obstruction. Hyperpnea duration (B to D) is 17.7 s, cycle duration (A to D) is 43.1 s, and
LECT from the end of apnea (B) to the maximum dip in Sao2 (C)
is 9.9 s. LECT is short in keeping with normal cardiac function.
Note that during hyperpnea, there is an abrupt rise and rapid
decline in Vt.
related to differences in circulation time. The pattern in patients with CHF is characterized by a
longer hyperpnea with more breaths, and a more
gradual rise and fall in Vt than in patients without
CHF. As a result, the periodic breathing cycle is
longer in patients with CHF. We also found that
hyperpnea duration was directly proportional to
lung-to-chemoreceptor circulation time as estimated
Discussion
This study demonstrates that the pattern of OSA
differs in patients with and without CHF, and is
Table 1—Polysomnographic Data From Total
Sleep Time*
Variables
OSA
(n ⫽ 18)
CHF and OSA
(n ⫽ 22)
AHI, /h
Total sleep time, h
Sleep efficiency, %
Arousals, /h
Stage 1, %
Stage 2, %
Slow wave sleep, %
Rapid eye movement, %
Mean Sao2, %
Minimum Sao2, %
Mean Ptcco2, mm Hg
37.9 ⫾ 17
4.5 ⫾ 1.6
73.6 ⫾ 21.7
32.5 ⫾ 16.2
10.6 ⫾ 9.2
67.7 ⫾ 12.7
7.4 ⫾ 7.4
11.7 ⫾ 5.3
94.5 ⫾ 2.2
80.0 ⫾ 9.0
44.7 ⫾ 6.7
36.8 ⫾ 20
5.2 ⫾ 1.1
77.2 ⫾ 11.5
33.2 ⫾ 15.2
10.6 ⫾ 8.5
67.7 ⫾ 9.9
9.6 ⫾ 7.6
14.3 ⫾ 8.4
94.2 ⫾ 2.2
78.0 ⫾ 8.9
44.5 ⫾ 5.1
*Data are presented as mean ⫾ SD. There were no significant
differences between the groups for any variable.
Figure 2. Typical polysomnographic recording from a patient
with CHF and OSA. Out-of-phase ribcage and abdominal movements during apnea indicate obstruction. Compared to the
patient without CHF in Figure 1, hyperpnea duration (B to D,
40 s), cycle duration (A to D, 56.9 s), and LECT (B to C, 13.5 s)
are substantially longer. In contrast to Figure 1, Vt gradually
rises to a peak during hyperpnea and gradually declines to apnea.
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Clinical Investigations
Table 2—Respiratory Data From Stage 2 Sleep*
Variables
OSA (n ⫽ 18)
CHF and OSA (n ⫽ 22)
p Value
Apnea duration, s
Hyperpnea duration, s
Breaths/hyperpnea, No.
Time to peak Vt, s
Cycle duration, s
LECT, s
Respiratory rate during hyperpnea, breaths/min
Mean Sao2, %
Minimum Sao2, %
⌬Sao2, %
Mean Ptcco2, mm Hg
20.9 ⫾ 7.6
17.6 ⫾ 5.6
4.0 ⫾ 0.8
3.9 ⫾ 0.8
38.5 ⫾ 9.7
9.0 ⫾ 1.8
17.0 ⫾ 2.8
94.5 ⫾ 2.2
82.8 ⫾ 9.5
4.8 ⫾ 2.9
44.3 ⫾ 6.6
22.6 ⫾ 7.8
25.7 ⫾ 7.8
6.3 ⫾ 1.4
6.2 ⫾ 1.5
48.7 ⫾ 11.4
14.9 ⫾ 3.4
18.6 ⫾ 3.5
94.3 ⫾ 2.1
83.4 ⫾ 6.7
4.8 ⫾ 2.2
44.4 ⫾ 5.1
NS
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.005
⬍ 0.001
NS
NS
NS
NS
NS
*Data are presented as mean ⫾ SD. NS ⫽ not significant; ⌬Sao2 ⫽ difference between peak and nadir oxygen saturation during cycle duration.
by LECT. These findings are analogous to those of a
previous study9 in which we compared the pattern of
periodic breathing in CHF patients with CSA to that
in patients with idiopathic CSA who did not have
CHF. We also found that patients with CHF had
longer hyperpnea and periodic breathing cycles than
did those without CHF. In that study, differences in
the character of periodic breathing were related to
differences in cardiac function. Patients with CHF
had longer hyperpneas and periodic breathing cycles
than those without CHF, and hyperpnea duration
was directly proportional to LECT. Furthermore,
Figure 3. Linear regression plots demonstrating a significant relationship between LECT and
hyperpnea duration (top left, A), breaths/hyperpnea (top right, B), and time to peak Vt (bottom, C) in
patients with OSA alone, and in patients with both CHF (F) and OSA (E).
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539
LECT was inversely proportional to cardiac output
so that the longer LECT in the patients with CHF
was related to their lower cardiac output. Thus,
lower cardiac output influenced hyperpnea and periodic breathing cycle durations through prolongation of lung to chemoreceptor circulation time. The
present data extend those of the previous study by
demonstrating that prolonged lung to chemoreceptor circulation time also influences the pattern of
periodic breathing in patients with OSA. Thus in
both instances, prolonged circulation time related to
CHF sculpts a more gradual, waxing-waning pattern
of hyperpnea that is the hallmark of Cheyne-Stokes
respiration.
The Cheyne-Stokes pattern of hyperpnea in the
patients with CHF and OSA was characterized objectively by a longer time to peak Vt and a greater
number of breaths per hyperpnea than in the nonCHF group. These data indicate that once apneainduced chemical and mechanical stimuli cause
arousal from sleep and restoration of pharyngeal
patency, the slower rate at which blood courses
through the lungs plus the prolonged lung-to-chemoreceptor circulation time in the patients with
CHF and OSA causes a more gradual fall in Sao2
and, therefore, a more gradual rise in chemoreceptor
stimulation and Vt than in the non-CHF group.
However, LECT appears not to influence apnea
duration, just as in the case of CSA.9 These data
indicate that obstructive apnea duration must be
determined by other factors such as upper airway
properties, and the degrees of apnea-related asphyxia and inspiratory effort.15
This raises the question as to the underlying
pathophysiology of the upper airway occlusion in
patients with CHF and OSA. These patients shared
the same predisposing features of OSA with the
non-CHF group, including obesity, habitual snoring,
male gender, and middle age.16 They also suffered
from symptoms typical of OSA, including restless
sleep. Therefore, the patients with CHF and OSA
may simply have acquired OSA on the basis of these
typical features and upper airway narrowing alone.
However, other factors may be at play, such as
fluid shifts in the neck related to CHF and volume
overload. Shepard et al17 showed that alteration in
fluid volume in the neck and thorax can affect
pharyngeal function and anatomy. In supine subjects, fluid was shifted from the legs to the neck and
thorax by elevating the legs. This increased the
collapsibility of the pharynx. They speculated that
edema of the neck and upper airway could narrow
the pharyngeal lumen and predispose to pharyngeal
collapse. Since patients with CHF frequently suffer
from fluid overload, congestion of the neck by
jugular venous distension or pharyngeal mucosal
edema might contribute to the development of
upper airway narrowing and instability in these
patients when recumbent during sleep. Although we
have no data directly related to this possibility, the
potential role of engorgement of the neck and
pharyngeal edema in narrowing the upper airway
and facilitating collapse warrants further investigation in patients with CHF.
Upper airway narrowing and increased compliance are crucial predisposing factors for upper airway collapse in most cases of OSA.18 Here, a primary
collapse of the pharynx at the onset of sleep is
thought to induce periodic obstructive apneas and
hyperpneas. The role of a primary periodic breathing
disorder related to respiratory control system instability in OSA is less certain.1 In one study, Alex et al8
observed upper airway occlusion at the beginning
and end of mixed apneas during Cheyne-Stokes
respiration in patients with CHF. They hypothesized
that upper airway occlusion could be entrained by an
underlying periodic breathing disorder. Support for
this theory has also been provided by Badr et al,19
who demonstrated progressive pharyngeal narrowing
during induced hypocapnic central apnea. Furthermore, in some patients with CHF, the type of sleep
apnea can change overnight from predominantly
OSA to predominantly CSA in association with a
decrease in Pco2.20 These data suggest that in some
patients with CHF and OSA, there is an underlying
periodic breathing disorder that could induce upper
airway collapse during the waning portion of the
ventilatory cycle due to withdrawal of inspiratory
drive to the pharyngeal dilator muscles.
Most mathematical models of periodic breathing
are based on the “respiratory control system instability hypothesis.” This hypothesis explains periodic
breathing as reflecting abnormalities of the negative
feedback system in which the time required for the
chemoreceptors to sense a change in the feedback
signal (ie, Paco2 and Pao2) is prolonged. This temporal dissociation between alterations in the feedback signals and their sensing at the chemoreceptors
is one of the factors, along with increased chemosensitivity, that destabilizes the respiratory control system and predisposes to periodic breathing. The
magnitude of these feedback delays and the sensitivity of the chemoreceptors provides a measure of
susceptibility to periodic breathing.21 Thus, on the
basis of this theory, prolonged lung-to-chemoreceptor circulation time, as observed in our patients with
CHF and OSA, would predispose to respiratory
control system instability, and thus to periodic
breathing. However, chemosensitivity in patients
with CHF and OSA has been shown not to be
elevated.22 Furthermore, mean Sao2 and Ptcco2
during sleep were within normal limits and did not
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Clinical Investigations
differ between our patients with CHF and OSA or
patients with OSA, indicating similar levels of chemostimulation.
Instability of the chemical control system of respiration has been the subject of recent investigation
by Younes et al.23 Using proportional assist ventilation to assess ventilatory stability in the upper airways of subjects with severe OSA stabilized with
CPAP, they have demonstrated a more unstable
chemical control system in those patients with severe
OSA, leading to periodic breathing with central
apneas and hypopneas. They hypothesized that the
greater susceptibility to periodic breathing in patients with severe OSA may be related to differences
in upper airway resistance, which is dependent on
the balance between the collapsing effect of increasing diaphragmatic efforts and the dilating effects of
recruitment of upper airway dilators. Therefore,
contrary to the respiratory control system instability
hypothesis, they proposed that greater instability in
chemical control may be a consequence rather than
a cause of recurrent obstructive apneas.
A final possibility, is that the patients with CHF
and OSA had OSA prior to the development of CHF,
following which the consequent increased circulatory delay and prolongation of chemical feedback
signals to the chemoreceptor entrained the rhythm
of their apnea-hyperpnea cycle by prolonging hyperpnea. The observation that short-term application of
CPAP to patients with CHF and OSA immediately
alleviates upper airway obstruction and OSA favors
this hypothesis.24 The present data do not allow us to
distinguish the relative importance of each of these
potential mechanisms in shaping the pattern of the
obstructive apnea-hyperpnea cycle. It is likely that
the relative contribution of each of these mechanisms varies from one individual to another. However, it is apparent that the presence of CHF, and
associated increased lung-to-chemoreceptor circulatory delay, influences the pattern of OSA such that it
prolongs hyperpnea and sculpts a pattern resembling
Cheyne-Stokes respiration.
Our findings lead us to conclude that the increased
circulatory delay and tendency to periodic breathing in
CHF may predispose to, or alter the physiologic manifestations of OSA. However, the potential roles of
circulatory delay and periodic breathing in the pathophysiology of upper airway obstruction in patients with
CHF and OSA remains unclear. Nevertheless, since
long-term relief of upper airway obstruction by CPAP
causes significant improvements in cardiac function in
patients with CHF,2– 4 more research should be directed at determining the underlying pathophysiology
of OSA in this setting.
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