Abstract
Given that the apnea–ventilation cycle length during central sleep apnea (CSA) with congestive heart failure (CHF) is ∼ 70 s, we hypothesized that rapidly responsive peripheral CO2 ventilatory responses would be raised in CHF-CSA and would correlate with the severity of CSA. Sleep studies and single breath and rebreathe hypercapnic ventilatory responses (HCVR) were measured as markers of peripheral and central CO2 ventilatory responses, respectively, in 51 subjects: 12 CHF with no apnea (CHF-N), 8 CHF with obstructive sleep apnea (CHF-OSA), 12 CHF-CSA, 11 CSA without CHF (“idiopathic” CSA; ICSA), and 8 normal subjects. Single breath HCVR was equally elevated in CHF-CSA and ICSA groups compared with CHF-N, CHF-OSA, and normal groups (0.58 ± 0.09 [mean ± SE] and 0.58 ± 0.07 versus 0.23 ± 0.06, 0.25 ± 0.04, and 0.27 ± 0.02 L/min/Pet CO2 mm Hg, respectively, p < 0.001). Similarly, rebreathe HCVR was elevated in both CHF-CSA and ICSA groups compared with CHF-N, CHF-OSA, and normal groups (5.80 ± 1.12 and 3.53 ± 0.29 versus 2.00 ± 0.25, 1.44 ± 0.16, and 2.14 ± 0.22 L/min/Pet CO2 mm Hg, respectively, p < 0.001). Furthermore, in the entire CHF group, single breath HCVR correlated with central apnea–hypopnea index (AHI) (r = 0.63, p < 0.001) and percentage central/total apneas (r = 0.52, p = 0.022). Rebreathe HCVR correlated with awake PaCO2 (r = − 0.61, p < 0.001), but not with central AHI or percantage central/total apneas independent of its relationship with single breath HCVR. In conclusion, in subjects with CHF, raised central CO2 ventilatory response predisposes to CSA promoting background hypocapnia and exposing the apnea threshold to fluctuations in ventilation, whereas raised and faster-acting peripheral CO2 ventilatory response determines the periodicity and severity of CSA.
Nonhypercapnic central sleep apnea (CSA) is induced by oscillations in respiratory drive, associated with hyperventilation and hypocapnia during non-rapid eye movement (REM) sleep, when ventilation is under negative-feedback, metabolic control (1). Central sleep apnea is most commonly seen in subjects with congestive heart failure (CHF-CSA), when it is also known as Cheyne–Stokes respiration. It is also seen, albeit less frequently, in subjects in whom no overt cardiac or neurological cause can be identified, where it is called idiopathic central sleep apnea (ICSA) (2). Obstructive sleep apnea is also frequently observed in CHF but is due to intermittent narrowing or closure of the upper airway with continued respiratory efforts, large subatmospheric intrathoracic pressure swings, and arousal-related elevations in systemic blood pressure.
Oscillating hypocapnia, induced by hyperventilation during sleep, is the key abnormality underlying both forms of CSA, such that ventilation ceases when the level of PaCO2 falls below the apnea threshold (3). Elevated rebreathe CO2 ventilatory responses, attributed to central medullary chemoreceptors, have been demonstrated in both CHF-CSA (4, 5) and ICSA (6).
An elevated single breath CO2 ventilatory response, attributed to fast-acting, peripheral chemoreceptors situated predominantly in the carotid body, has been demonstrated in ICSA (6), but not in CHF-CSA. So far, tests of peripheral chemoresponsiveness in CHF-CSA, utilizing hypoxic stimulation at rest, have failed to show any significant abnormality in CHF-CSA compared with CHF with obstructive sleep apnea (CHF-OSA) (4). However, tests of peripheral chemoresponsiveness in CHF unselected for apnea have shown elevated responses to stimulation by transient hypoxia at rest (7, 8), but not to stimulation by transient hypercapnia (9). Therefore, in CHF, the role of peripheral chemoresponsiveness in the pathogenesis of CHF-CSA remains unresolved.
In severe but stable CHF, the established CHF-CSA cycle length is approximately 70 s (10, 11), and is made up of the ventilatory length, comprising a period of increase in ventilation followed by a period of decrease in ventilation, followed by the apnea. The ventilatory and cycle lengths have been shown to closely correlate with left ventricular ejection fraction and lung-to-ear circulation time, a marker of lung-to-carotid body chemoreceptor circulation time (3, 10, 11). This typical “crescendo–decrescendo” apnea pattern, therefore, requires three changes in ventilation within each 70-s cycle. Previous studies have suggested that lung-to-ear circulation time is approximately one-third of the cycle length (10, 11). However, the estimated time for a response by central chemoreceptors to a change in alveolar Pco 2 is closer to 2–5 min (12, 13). Taken together, these observations strongly suggest that CHF-CSA is mediated by the action of more rapidly responding peripheral chemoreceptors.
Accordingly, we hypothesized the following. First, that the peripheral CO2 ventilatory response would be greater in CHF-CSA compared with CHF without sleep apnea (CHF-N) and CHF-OSA. Second, that the peripheral CO2 ventilatory response in CHF-CSA would be similarly elevated as in subjects with ICSA compared with non-CSA control groups. Third, that the duration of time to the maximal breath in the peripheral CO2 ventilatory response test would correlate with the lung-to-ear circulation time measured during sleep.
Consecutive male subjects were recruited from the heart failure service at The Alfred Heart Centre and The Alfred Sleep Disorders Service. The inclusion criteria for the CHF subjects were (a) evidence of symptomatic CHF of at least 6 mo duration and on optimal medical therapy under the direct care of a cardiologist, (b) a left ventricular ejection fraction (LVEF) ⩽ 45% and New York Heart Association (NYHA) classification ⩾ 2, and (c) a stable condition, defined as no hospital admission or medication changes within the preceding 2 wk. Subjects with ICSA were selected from our sleep clinic population on the basis of (a) at least two of following clinical features: snoring, witnessed apnea, excessive daytime sleepiness, restless sleep, nocturnal dyspnea, or nocturnal choking, (b) CSA during non-REM sleep, (c) awake PaCO2 ⩽ 45 mm Hg, and (d) normal systolic function on echocardiography or LVEF > 55%. Exclusion criteria were symptoms, physical signs, or current treatment for any neurological, respiratory, cardiac, or renal impairment. Healthy male adult volunteers, who were taking no regular medication, were enrolled from advertisements placed within our hospital. None of the normal subjects had symptoms of snoring or sleep apnea, and all underwent polysomnography, which demonstrated an apnea–hypopnea index < 5 events per hour. The Ethics Committee of the Alfred Hospital approved the study and all subjects provided written informed consent.
Ventilatory responses were measured in the morning within 3 d of the sleep study. Subjects were not taking any respiratory depressants or stimulants, had not consumed caffeinated beverages within 12 h, and were tested at least 2 h after a light breakfast. Subjects were asked to remain seated for 15 min during which time the testing procedure was explained, and seating was positioned to allow comfortable, quiet breathing through a mouthpiece.
The central CO2 ventilatory response was measured by the ventilatory response to progressive hypercapnia, based on Read's rebreathing method (rebreathe HCVR) (14). A compliant 13-L anesthetic bag was filled with a volume of a mixture comprising 7% CO2, 50% O2, and balance N2 equal to the patient's vital capacity plus 1 L. Subjects rebreathed for up to 4 min maximum, or until their end-tidal CO2 exceeded 10%, or until distressed. Breath-by-breath tidal volume and end-tidal CO2 were measured continuously, using a number 3 Fleisch pneumotach (Morgan, UK) and a rapid responding CO2 analyzer (Ametek CD - 3A, USA). A computer acquisition program using a high-resolution computer screen was custom designed to allow for analysis of these indices. The linear slope described by the relationship between ventilation to end-tidal CO2 was calculated by least-squares linear regression, and the numerical average of the slopes from each of the three runs was taken as the rebreathe HCVR, and expressed in L/ min/Pet CO2 mm Hg corrected to BTPS. An increase in end-tidal (partial) carbon dioxide pressure (Pet CO2 ) of at least 5 mm Hg was necessary for a run to count.
The peripheral CO2 ventilatory response was measured by the ventilatory response to transient hypercapnia using the single breath technique (single breath HCVR), as described by McClean and coworkers (15). Individual tidal breaths and end-tidal CO2 were measured continuously, utilizing the same equipment as above. Once stable ventilation was obtained (defined as < 20% change in tidal volume and Pet CO2 over the 10 breaths prior to the single breath hypercapnic stimulus), subjects were surreptitiously given a single tidal breath of a mixture containing 13% CO2, 21% O2, balance N2, and the raised end-tidal CO2 plateau for this breath was identified. In normal subjects, a transient increase in ventilation is typically seen within 20 s, and most frequently at about 10 s (15). The single breath HCVR was defined as the maximal increase in ventilation over baseline divided by the change in end-tidal CO2, measured within 20 s of the test inhalation, and expressed in L/min/Pet CO2 mm Hg corrected to BTPS (Figure 1A). At least five runs were performed, each separated by 4 min of rest, with the numerical average taken as the single breath HCVR.
Fig. 1. (A) Single breath HCVR in non-CHF subjects. Tracing and calculation of single breath HCVR in a typical subject without CHF. Cumulative breath-by-breath ventilation represented by inhalation on the upstroke followed by exhalation plateau. Average ventilation (ave V˙ pre) and end-tidal CO2 (ave Fet CO2 ) calculated from the five breaths (1′–5′) preceding the surreptitious delivery, at time zero, of the single hypercapnic breath challenge (13% CO2, 21% O2, balance N2). End-tidal CO2 plateau of the hypercapnic challenge breath (breath zero) is identified (Fet CO2 ). Recording interval begins at time 0 s and proceeds for 20 s during which breaths 1–4 are analyzed. The second breath posthypercapnic challenge is identified as the maximal increase in ventilation (max V˙ post) over baseline. Single breath HCVR is calculated by the equation, and expressed as L/min/Pet CO2 mm Hg corrected to BTPS. (B) Single breath HCVR in CHF subjects. Tracing and calculation of single breath HCVR in a typical subject with CHF. In CHF subjects, the same technique is used as in A, except for the modification that adjusts for the circulatory delay caused by CHF. The first 13 s post-single breath hypercapnic inhalation represents the added circulatory delay caused by CHF, and is not analyzed. Recording interval begins at 13 s and proceeds for 20 s during which breaths 3–7 are analyzed. The fifth breath post-hypercapnic challenge is identified as the maximal increase in ventilation (max V˙ post) over baseline.
[More] [Minimize]In CHF subjects, a slight modification to the single breath HCVR technique was necessary to allow for the effect of circulatory delay, which prolongs the time lag of the feedback loop from lung to carotid body chemoreceptors (Figure 1B). Previously, it had been noted that lung-to-ear circulation time in severe but stable CHF-CSA was ∼ 25 s, and in subjects without heart failure ∼ 12 s, a difference of 13 s (3, 10, 11). Therefore the usual response of the carotid body chemoreceptor, occurring at 10 s, would be expected to be delayed by a further 13 s in CHF-CSA. Consequently, the 20-s time interval used for detecting the maximal increase in ventilation after the test inhalation was begun at 13 s and terminated at 33 s (Figure 1B). In this way carotid body chemoreceptor responses, expected at approximately 23 s after the test inhalation, would be detected.
Right heart catheterization was performed by a cardiologist blinded to the sleep study results, in the morning, while awake, and within 12 h of the sleep study. Right heart pressures were recorded using a balloon-tipped flotation catheter (7F Arrow; Arrow International, Reading, PA) via the right internal jugular vein, in the supine position. The mean cardiac output was measured in triplicate by the thermodilution technique at the pulmonary artery position.
Spirometry was measured with a computerized pneumotach (Masterlab; Jaeger, Hoechberg, Germany) according to ATS guidelines (16) within 2 wk of polysomnography. Arterial blood gas tensions were measured (Model 865; Ciba Corning Diagnostics Corp., Medfield, MA) on the night of polysomnography from a radial artery sample taken while the subject was supine, awake, and rested for at least 10 min.
Overnight polysomnography was recorded onto a computerized system (Somnostar; SensorMedics Corp., Anaheim, CA). Standard techniques and scoring criteria were used for the manual determination of sleep stages (17). Electrocardiogram and heart rate were recorded continuously from precordial lead II. Arterial oxygen saturation (SpO2 ) was measured by an ear pulse oximeter (Fastrac; Sensormedics Corp. Anaheim, CA). The averaging time of the oximeter was set at 3 s. Chest and abdominal movements were monitored using respiratory effort bands with piezoelectric crystals calibrated for phase (Resp-ez; EPM Systems, Midlothian, VA). Oronasal airflow was monitored by thermocouples (Pro-Tech Services, Woodinville, WA). Snoring was monitored with a piezo snore sensor (ProTech Services). Central apnea was defined as an absence of airflow for at least 10 s associated with an absence of chest or abdominal movement. Central hypopnea was defined as a reduction in airflow for at least 10 s associated with a ⩾ 2% fall in SpO2 and in-phase chest and abdominal movement with no increase in submental electriomyelogram (EMG) or snoring. Obstructive apnea was defined as an absence of airflow for at least 10 s despite continued out-of-phase chest and abdominal movements. Obstructive hypopnea was defined as a reduction of airflow for at least 10 s associated with a ⩾ 2% fall in SpO2 despite continued out-of-phase chest and abdominal movements or snoring. A mixed apnea was defined as an apnea with a combination of both central and obstructive components. The apnea–hypopnea index (AHI) was the total number of apneas and/or hypopneas divided by the total sleep time (TST), and expressed as the number of events per hour. Arousals were defined as 3 to 15 s episodes in which there was a return of alpha activity associated with the rise in EMG activity (18).
Sleep apnea was defined as an AHI ⩾ 5 events per hour. Central sleep apnea was defined by the following criteria: (a) a central apnea and/or hypopnea index (CAHI) ⩾ 5 events per hour, (b) at least 75% of all apneas being purely central in origin, that is, apneas without any discernible respiratory effort, and at least 50% of the total AHI being purely central in origin, that is, without obstructive components (CAHI/AHI = 50%), (c) a crescendo–decrescendo ventilatory pattern usually with an arousal occurring at the peak of ventilation, (d) triggered by arousal or state change, (e) occurring during stage 1 and 2 non-REM sleep. Subjects in whom central apneas occurred in less than 75% of the total apnea count, or the overall central AHI was less than 50% of total AHI, were grouped with the CHF-OSA group.
All comparisons of characteristics between the five groups used one-way ANOVA. Tukey's post hoc analysis (honestly significant difference test) was used to identify homogeneous subsets, and to obtain alpha values in multiple pairwise comparisons. In the 32 consecutive subjects with CHF, Pearson's least-squares correlation coefficient tested the relationship between variables.
Unpaired Student's two-way t tests were used to compare (a) spirometry data between the entire 32 CHF subjects with the 19 non-CHF subjects and (b) the rebreathe HCVR data to test for significant differences between groups whose group means were not statistically different on ANOVA (ICSA versus normal subjects, CHF-OSA versus normal subjects and CHF-CSA versus ICSA).
Stepwise linear regression was used to determine the influence of single breath and rebreathe HCVR upon (a) PaCO2 and (b) markers of central sleep apnea severity (CAHI/AHI [central apneas and hypopneas/all apneas and hypopneas], CAHI [no./h], CAI/AI [central apneas/all apneas], and CA [no./h]). SPSS 9.0 (SPSS Inc., Chicago, IL) software was used. Data are expressed as mean ± standard error of the mean. A p value of < 0.05 was regarded as significant.
Fifty-one male subjects were studied. Thirty-two consecutive subjects with CHF were enrolled: 12 had CHF-CSA, 8 had CHF-OSA, and 12 had no apnea (CHF-N). Eleven consecutive subjects with ICSA and 8 normal subjects were studied. Important patient characteristics and polysomnography results are tabulated in Table 1 (top), and additional patient characteristics and polysomnography information are tabulated in Table 1 (bottom) on the website. There were no differences between these groups in terms of age and morphometry. Arterial blood gases showed similar oxygen saturation and PaO2 . The CHF-CSA group had a significantly higher pH than the ICSA and normal groups and significantly lower PaCO2 than the normal groups. There were no significant differences between the five groups in spirometry. However, taken as a group, the 32 CHF subjects had significantly reduced FEV1 and FVC values (p < 0.001), reduced lower expiratory flow rates, indicating mild expiratory flow limitation (p = 0.023), with maintained FEV1/FVC ratios (p = 0.094), compared with the 19 non-CHF subjects.
| CHF Groups | Non-CHF Groups | p ANOVA* | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CHF-N | CHF-OSA | CHF-CSA | ICSA | Normal | ||||||||
| n | 12 | 8 | 12 | 11 | 8 | |||||||
| Age, yr | 49.0 ± 3.7 | 56.4 ± 2.0 | 53.3 ± 3.3 | 46.7 ± 2.9 | 52.5 ± 6.1 | ns | ||||||
| Body mass index, kg/m2 | 27.0 ± 0.8 | 28.6 ± 1.9 | 27.0 ± 1.1 | 30.8 ± 1.6 | 27.3 ± 1.1 | ns | ||||||
| LVEF, % | 22.2 ± 2.5 | 28.4 ± 2.9 | 22.3 ± 3.2 | 66.4 ± 3.0 | na | ns† | ||||||
| PAP mean, mm Hg | 18.7 ± 3.0 | 21.5 ± 2.9 | 31.5 ± 3.1 | na | na | 0.016‡ | ||||||
| PCWP, mm Hg | 10.8 ± 3.0 | 12.4 ± 2.6 | 21.8 ± 2.3 | na | na | 0.017‡ | ||||||
| Awake arterial blood gases | ||||||||||||
| pH | 7.44 ± 0.01 | 7.42 ± 0.01 | 7.46 ± 0.01 | 7.41 ± 0.01 | 7.40 ± 0.01 | 0.010§ | ||||||
| PaCO2 , mm Hg | 44.3 ± 1.0 | 44.9 ± 1.8 | 40.2 ± 1.3 | 42.6 ± 0.8 | 45.2 ± 0.7 | 0.031‖ | ||||||
| PaO2 , mm Hg | 84.8 ± 3.6 | 81.3 ± 8.2 | 83.4 ± 2.6 | 78.0 ± 2.4 | 87.0 ± 6.0 | ns | ||||||
| SaO2 , % | 98.2 ± 0.3 | 97.4 ± 0.3 | 97.6 ± 0.3 | 97.8 ± 0.5 | 98.0 ± 0.8 | ns | ||||||
| Sleep distrubance and oximetry | ||||||||||||
| Apnea–hypopnea index, no./h | 1.8 ± 0.5 | 18.1 ± 3.3 | 30.2 ± 4.8 | 21.1 ± 4.6 | 3.2 ± 0.6 | < 0.001¶ | ||||||
| Arousal index, no./h | 20.7 ± 4.8 | 39.3 ± 12.0 | 34.1 ± 4.9 | 24.5 ± 4.8 | 10.5 ± 1.6 | 0.041** | ||||||
| Mean SpO2 , % | 95.9 ± 0.3 | 94.6 ± 0.6 | 95.4 ± 0.4 | 95.7 ± 0.5 | 95.3 ± 0.6 | ns | ||||||
| Minimum SpO2 , % | 89.2 ± 1.2 | 80.6 ± 2.8 | 83.1 ± 1.7 | 88.3 ± 1.4 | 90.5 ± 0.7 | < 0.0011-164 | ||||||
| TST with SpO2 < 90%, % | 0.2 ± 0.1 | 4.9 ± 2.4 | 2.9 ± 0.9 | 1.1 ± 0.5 | 0.2 ± 0.2 | 0.003‡ | ||||||
| Cardiovascular characteristics | ||||||||||||
| Cardiopmyopathy type | ||||||||||||
| Ischemic | 4 | 2 | 8 | |||||||||
| Idiopathic | 7 | 4 | 1 | |||||||||
| Other | 1 | 2 | 3 | |||||||||
| NYHA class | ||||||||||||
| 1 | — | — | — | 2 | 8 | |||||||
| 2 | 3 | 2 | 2 | 6 | 0 | |||||||
| 3 | 5 | 4 | 7 | 2 | 0 | |||||||
| 4 | 3 | 2 | 3 | 1 | 0 | |||||||
| Systemic mean BP, mm Hg | 77 ± 5 | 76 ± 7 | 77 ± 4 | na | na | ns | ||||||
| Body surface area, m2 | 1.98 ± 0.07 | 2.08 ± 0.07 | 1.93 ± 0.05 | 2.11 ± 0.07 | 2.04 ± 0.03 | ns | ||||||
| Cardiac index, L/min/m2 | 2.15 ± 0.22 | 2.35 ± 0.21 | 1.91 ± 0.14 | na | na | ns | ||||||
| Spirometry | ||||||||||||
| FEV1, % predicted | 82.6 ± 4.5 | 82.8 ± 9.3 | 84.6 ± 3.1 | 103.2 ± 3.7 | 102.9 ± 2.8 | ns | ||||||
| FVC, % predicted | 84.2 ± 4.5 | 84.4 ± 6.0 | 87.6 ± 2.7 | 100.3 ± 3.8 | 99.3 ± 2.9 | ns | ||||||
| FEV1/FVC, % predicted | 98.2 ± 2.9 | 96.7 ± 6.6 | 96.6 ± 3.2 | 103.0 ± 2.5 | 103.3 ± 4.4 | ns | ||||||
| FEF, % predicted | 67.1 ± 8.8 | 64.4 ± 13.6 | 56.2 ± 8.0 | 80.1 ± 6.5 | 82.3 ± 5.2 | ns | ||||||
| Sleep architecture | ||||||||||||
| Total sleep time, min | 294 ± 23 | 343 ± 16 | 306 ± 18 | 337 ± 12 | 330 ± 14 | ns | ||||||
| Sleep efficiency, % | 72 ± 5 | 83 ± 3 | 75 ± 3 | 81 ± 4 | 80 ± 3 | ns | ||||||
| Wake, % TST | 22.9 ± 4.5 | 14.3 ± 2.6 | 21.7 ± 11.2 | 16.5 ± 3.0 | 15.7 ± 3.6 | ns | ||||||
| Stages 1 and 2, % TST | 53.8 ± 3.2 | 64.5 ± 3.5 | 57.5 ± 3.6 | 57.2 ± 3.0 | 54.0 ± 3.2 | ns | ||||||
| Stages 3 and 4, % TST | 9.3 ± 1.7 | 8.0 ± 2.1 | 8.6 ± 2.4 | 8.2 ± 1.1 | 13.5 ± 2.6 | ns | ||||||
| REM, % TST | 14.1 ± 1.9 | 13.3 ± 2.1 | 11.2 ± 1.7 | 17.2 ± 1.8 | 16.7 ± 1.9 | ns | ||||||
| Sleep heart rhythm | ||||||||||||
| Mean heart rate, bpm | 58.6 ± 2.2 | 65.4 ± 3.6 | 59.8 ± 4.0 | 55.5 ± 2.2 | 52.2 ± 1.8 | 0.037§§ | ||||||
| Rhythm SR:AF:PM | 10:1:1 | 6:0:2 | 7:1:4 | 11:0:0 | 8:0:0 | |||||||
The LVEF, cardiac index, and systemic blood pressure were similar in each of the three CHF groups. The mean pulmonary artery and pulmonary capillary wedge pressure values (measured in only 25 subjects) were significantly greater in the CHF-CSA group compared with the CHF-N group (p < 0.05), but not when compared with the CHF-OSA group (p < 0.10). Total sleep time (TST), sleep efficiency, and sleep stage times (wake, stage 1 and 2, stage 3 and 4, REM) were similar across all CHF groups and the ICSA and normal groups. The central AHI (CAHI) and noncentral AHI (obstructive and mixed events) were 28.0 ± 4.3 and 2.3 ± 0.9 events per hour for the CHF-CSA group, and 4.1 ± 1.9 and 14.0 ± 3.0 for the CHF-OSA group.
There were significant differences in the characteristics of the CSA pattern between those with and without CHF. The CHF-CSA group had a longer cycle length (68.2 ± 3.9 versus 32.1 ± 1.9 s, p < 0.001), ventilatory length (42.5 ± 2.2 versus 14.5 ± 1.0 s, p < 0.001), and lung-to-ear circulation time (25.8 ± 1.7 versus 11.7 ± 0.8 s, p < 0.001) than the ICSA group. Moreover, the ventilatory:apnea length ratio was significantly greater in the CHF-CSA group compared with the ICSA group (1.70 ± 0.09 [range 1.27–2.18] versus 0.83 ± 0.05 [range 0.50–1.03], p < 0.001). However, there was only a trend toward a slightly longer apnea length in the CHF-CSA group compared with the ICSA group (25.8 ± 2.1 versus 17.6 ± 1.1 s, p = 0.071).
All subjects were able to undergo rebreathe HCVR and provide reproducible results. The mean duration of rebreathe HCVR was 31/4 min in the CHF group and 4 min in the non-CHF group. Reproducible single breath HCVR could be determined in 28 of the 32 subjects with CHF. Four CHF subjects had irregular breathing during testing and were unable to complete the single breathe HCVR.
During the single breath HCVR, the time of onset from CO2 inhalation to the maximal breath, and the breath number at which this occurred were CHF-N at 22.3 ± 1.4 s and breath 5.8 ± 0.7; CHF-OSA at 22.5 ± 1.3 s and breath 5.7 ± 0.5; CHF-CSA at 23.4 ± 1.2 s and breath 6.2 ± 0.7; ICSA at 9.8 ± 0.8 s and breath 2.8 ± 0.3; normal subjects at 10.2 ± 1.4 s and breath 2.5 ± 0.4 (Figures 1A and 1B). In those subjects with CSA (CHF-CSA and ICSA groups), the time from the CO2 inhalation to the maximal breath in the single breath HCVR test correlated significantly with the lung-to-ear circulation time measured during the sleep study (r = 0.82, p < 0.001). Furthermore, the time from CO2 inhalation to the maximal breath in the single breath HCVR test in CHF-CSA and ICSA was consistently one-third of their respective apnea–hyperpnea cycle lengths measured during sleep studies.
The group mean single breath HCVR was similar in both the CHF-CSA and ICSA groups, and significantly greater than the groups with no CSA (CHF-N, CHF-OSA, and the normal group) (Figure 2A). The non-CSA groups (CHF-N, CHF-OSA, and normal group) were not statistically different from each other.
Fig. 2. (A) Single breath HCVR (mean ± SE [range]) in CHF-N (0.23 ± 0.06 [−0.06–0.52]), CHF-OSA (0.25 ± 0.04 [0.12–0.47]), CHF-CSA (0.58 ± 0.09 [0.17–1.01]), ICSA (0.58 ± 0.07 [0.25–1.03]), and normal subjects (0.27 ± 0.02 [0.15–0.38]). p Values are multiple pairwise comparison using Tukey's post hoc analysis from the one-way ANOVA between the five groups. The first three sets of data are the three CHF groups followed by the two non-CHF comparison groups. Bar represents the mean with standard error. (B) Rebreathe HCVR (mean ± SE [range]) in CHF-N (2.00 ± 0.25 [0.83–3.58]), CHF-OSA (1.44 ± 0.16 [0.65–1.96]), CHF-CSA (5.80 ± 1.12 [1.89–14.89]), ICSA (3.53 ± 0.29 [2.49–5.91]), and normal subjects (2.14 ± 0.22 [1.45–3.05]). p Values are multiple pairwise comparison using Tukey's post hoc analysis from the one-way ANOVA between the five groups. The first three sets of data are the three CHF groups followed by the two non-CHF comparison groups. Bar represents the mean with standard error. Although not significantly different using Tukey's post hoc analysis from the one-way ANOVA between the five groups, student unpaired two-way t test shows a significant difference between ICSA and normal subjects (p = 0.002), and between CHF-OSA and normal subjects (p = 0.021) but not between CHF-CSA and ICSA (p = 0.082).
[More] [Minimize]The group mean rebreathe HCVR was significantly greater in the CHF-CSA group compared with the CHF-N, CHF-OSA, and normal groups, but not significantly greater than the ICSA group (Figure 2B) using ANOVA. The ICSA group was not significantly different from the non-CSA groups (CHF-N, CHF-OSA, and normal group).
Furthermore, in the rebreathe HCVR, student unpaired, two way t test demonstrated a significant difference between ICSA and normal subjects (p = 0.002), consistent with the findings of Xie and coworkers (6), and between CHF-OSA and normal subjects (p = 0.021) but not between CHF-CSA and ICSA (p = 0.082).
There was a highly significant correlation between rebreathe and single breath HCVR in the entire 32 subjects with CHF (r = 0.65, p < 0.001), but not in the ICSA (r = 0.39, p = 0.238) or normal (r = −0.15, p = 0.731) groups. Moreover, in the entire CHF group, single breath HCVR correlated significantly with AHI and all four measures of CSA severity, whereas rebreathe HCVR correlated with AHI and with three of four measures of CSA severity (Table 2). Multiple regression analysis comparing single breath and rebreathe HCVR demonstrated that only single breath HCVR contributed significantly to the variance of AHI and each of the measures of CSA severity. Single breath HCVR explained 40% variance of the central apnea–hypopnea index (CAHI), 42% variance of the central apnea–hypopnea index/total apnea–hypopnea index (CAHI/AHI), and 27% variance of the central apnea/ total apnea index (CAI/AI). The rebreathe HCVR, however, correlated significantly with the degree of hyperventilation (alkalosis and hypocapnia), whereas the single breath HCVR did not. Neither the single breath nor the rebreathe HCVR correlated with markers of oxygen desaturation overnight.
| Single Breath HCVR | Rebreathe HCVR | |||||||
|---|---|---|---|---|---|---|---|---|
| r | p value | r | p value | |||||
| Resting Pet CO2 , mm Hg | −0.10 | 0.615 | −0.36 | 0.041 | ||||
| PaCO2 , mm Hg | −0.33 | 0.086 | −0.61 | < 0.001 | ||||
| pH | 0.24 | 0.234 | 0.49 | 0.006 | ||||
| Apnea–hypopnea index (AHI), no./h | 0.55 | 0.003 | 0.42 | 0.017 | ||||
| Central apneas and hypopneas/all apneas and hypopneas (CAHI/AHI), % | 0.65 | < 0.001 | 0.53 | 0.003 | ||||
| Central apnea–hypopnea index (CAHI), no./h | 0.63 | < 0.001 | 0.51 | 0.003 | ||||
| Central apneas/all apneas (CAI/AI), % | 0.52 | 0.022 | 0.30 | 0.176 | ||||
| Central apnea index (CAI), no./h | 0.53 | 0.004 | 0.47 | 0.007 | ||||
| PAP mean, mm Hg | 0.56 | 0.009 | 0.47 | 0.017 | ||||
| PCWP, mm Hg | 0.48 | 0.028 | 0.39 | 0.053 | ||||
| LVEF, % | 0.07 | 0.712 | −0.24 | 0.196 | ||||
| Heart rate asleep, bpm | 0.09 | 0.654 | 0.39 | 0.028 | ||||
| Mean sleep SpO2 , % | 0.00 | 0.999 | 0.14 | 0.470 | ||||
| Minimum sleep SpO2 , % | −0.26 | 0.145 | 0.06 | 0.777 | ||||
| TST with SpO2 , 90%, % | 0.11 | 0.626 | −0.12 | 0.621 | ||||
The identification of CSA in subjects with CHF has major consequences because its presence confers an adverse prognosis (19, 20), and effective therapies exist that attenuate CSA (21). However, the pathogenesis of CHF-CSA remains poorly understood. Although elevated ventilatory response is associated with the hyperventilation and hypocapnia typical of CSA, most work to date has focused on the central CO2 ventilatory responses (4, 5), which have a response time of the order of 2– 5 minutes (12, 13). However, the average cycle length of CSA in subjects with ICSA and in subjects with CHF is 35 and 70 s, respectively (10, 11), indicating that changes in ventilation (“crescendo–decrescendo” hyperventilation and apnea) are occurring in a time frame less than what could be accommodated by the central CO2 ventilatory response time. Therefore, we sought to determine whether the periodicity and severity of CSA in CHF were more closely linked to the peripheral CO2 ventilatory response, as has been previously shown in ICSA subjects (6).
There were three major and novel findings of this study, which contribute to the understanding of the pathogenesis of CSA in subjects with CHF. First, the peripheral CO2 ventilatory response was significantly elevated in the CHF-CSA group compared with the CHF-N, CHF-OSA, and the normal groups. The timing of this response was consistent with the response time of the carotid chemoreceptor allowing for circulatory delay. Second, the peripheral CO2 ventilatory response was similarly elevated in the CHF-CSA and ICSA groups, suggesting that CSA can be generated solely by raised chemosensitivity independent of underlying cardiac function. Third, in the 32 CHF subjects as a whole, the peripheral CO2 ventilatory response correlated significantly with every index of CSA severity. In contrast, the central CO2 ventilatory response correlated with markers of awake hyperventilation (namely PaCO2 and pH), but did not independently correlate with indices of CSA.
These findings indicate that the elevated central CO2 ventilatory response lowers PaCO2 toward the apnea threshold at rest, narrowing the difference between ambient PaCO2 levels and the apnea threshold, thereby predisposing a subject with CHF to CSA, as previously suggested (4, 5). Moreover, the activity of the faster-acting peripheral CO2 ventilatory response then oscillates ventilation, and is responsible for the periodicity and severity of CSA in subjects with CHF, and thereby plays a crucial role in the pathogenesis of CHF-CSA.
Our observations regarding the importance of peripheral CO2 ventilatory responsiveness in the pathogenesis of CSA are in agreement with data from previous work of other groups. First, interventions that reduce or abolish CSA, utilizing inhaled CO2 to increase PaCO2 by as little as 1–3 mm Hg, have an onset of action in keeping with the peripheral CO2 ventilatory response. Badr and coworkers demonstrated abolition of central apneas 15 s after inhalation of supplemental CO2 in a patient with CSA (22), and Xie and coworkers demonstrated abolition of cyclical desaturation due to central apneas approximately 10 s after supplemental inhaled CO2 was given to a patient with ICSA (23). Berssenbrugge and coworkers experimentally induced central apneas by hypobaric hypoxia at constant SaO2 , and apneas were eliminated within 15 s by inhaled CO2 (24). Second, Lorenzi-Filho and coworkers showed that in subjects with CHF-CSA, the time from the breath with the minimal end-tidal fraction of CO2 during the ventilatory phase until the onset of the resultant apnea correlated significantly with lung-to-ear circulation time, a measure of lung-to-carotid body circulatory delay (25). Third, our results support those of Xie and coworkers, who reported elevated peripheral as well as central chemosensitivity in subjects with ICSA (6). Indeed our results of peripheral and central CO2 ventilatory responses in subjects with ICSA are not dissimilar from those of Xie and coworkers. Lastly Sun and coworkers, showed that CHF induced in rabbits by a pacing method led to both functional (raised chemosensitivity) and structural changes in the peripheral chemoreceptor, but had little or no effect on central chemosensitivity, implicating up-regulation of peripheral chemosensitivity in at least some subjects with CHF (26).
Other groups have failed to identify a significant difference in the peripheral ventilatory response between CHF-CSA and CHF-OSA (4). Two aspects of the techniques used by these investigators may explain their disparity with our results. First, measurements of the peripheral ventilatory response function in CHF have so far focused predominantly on hypoxic stimulation, rather than on single breath hypercapnic stimulation. The hypoxic stimulus concept was based on the notion that the faster acting peripheral chemoreceptor, located in the carotid body, was responsive primarily to hypoxia and secondarily to hypercapnia. However, recent work has challenged this concept (27-30) indicating that the major role of the peripheral chemoreceptor is in the sensation of minor perturbations in PaCO2 . So far, tests of peripheral ventilatory responses in CHF-CSA, utilizing hypoxic stimulation at rest, have shown equally elevated responses in CHF-CSA and CHF-OSA (4). Tests of peripheral hypoxic ventilatory responses in CHF, unselected for apnea, have been elevated in some but not all subjects (7, 8), and have been shown to correlate with the ventilatory response to exercise, which relates minute ventilation to CO2 output (7, 9). Second, inhalational stimuli, which target the peripheral chemoreceptor, need to consider the effect of lung-to-carotid body circulatory time, which may delay the response beyond the limits of the recording interval.
Identifying the factors responsible for the development of elevated central and peripheral CO2 ventilatory responses in CHF and ICSA was beyond the scope of this study. However, based upon previous work, two factors are likely to be contributory. First, raised pulmonary vascular pressures, which would stimulate J receptors within the pulmonary interstitium and increase pulmonary vagal afferent activity to the medulla, have been shown to increase ventilation (31-36). Both mean pulmonary and capillary wedge pressures were elevated in the CHF-CSA group, and correlated with peripheral, and to a lesser extent, central CO2 ventilatory responses, consistent with this notion. However, we found no difference in the LVEF measurement between the three CHF groups, suggesting that CHF-CSA has worse CHF on the basis of greater hemodynamic loading on the heart than CHF-OSA and CHF-N subjects. Second, elevated ventilatory responses may be secondary to elevated sympathoneural activity, acting both centrally (37) and via the influence of venous norepinephrine on peripheral chemoreceptors (38, 39). Given the close relationship between awake PaCO2 and CSA severity in CHF (3), and the correlation between peripheral and central CO2 ventilatory responses in subjects with CHF, it is possible that whatever factor is responsible for precipitating hyperventilation, it will affect both rapidly responsive peripheral and slowly responsive central CO2 ventilatory responses.
During the single breath HCVR in the CHF-CSA and ICSA subjects, we observed that the time from the single breath of CO2 to the onset of the maximal breath was one-third of their respective apnea–hyperpnea cycle lengths. These data are therefore consistent with the concept that periodic breathing cycle length can be broken into three phases, namely the crescendo, the decrescendo, and the apnea, and the sum of these three components corresponds to three times the lung-to-carotid body chemoreceptor circulatory time. Cycle length correlated with circulation time, consistent with previous studies (10, 11). Furthermore, circulation time, derived from the onset of the maximal breath after single breath hypercapnic stimulation, was similar across the three CHF groups, and between the two non-CHF groups. This would suggest that circulatory delay is not necessary for the development of CSA.
Our study failed to show any significant relationship between central or peripheral CO2 ventilatory responses and any of the markers of hypoxemia, awake or asleep. This observation is in agreement with previous studies that have suggested that hypoxemia plays little, if any, role in the pathogenesis of CHF-CSA or ICSA (25). Our observations would also be in concordance with Wilcox and coworkers who failed to demonstrate any significant differences in hypoxic peripheral ventilatory responses between CHF-CSA and CHF-OSA subjects (4). Moreover, our findings support the clinical observations that supplemental oxygen only partially ameliorates CSA in subjects with CHF (40, 41).
In summary, we observed that in subjects with CHF, those with CSA had significantly greater single breath HCVR, a marker of faster-acting peripheral CO2 ventilatory response, and rebreathe HCVR, a marker of central CO2 ventilatory response, compared with CHF subjects with OSA or no sleep apnea. There was a highly significant negative correlation between the rebreathe HCVR and awake PaCO2 levels, but no independent relationship between rebreathe HCVR and CSA severity. In contrast, the single breath HCVR correlated significantly with markers of CSA severity. These results suggest that raised central CO2 chemosensitivity drives the ambient PaCO2 close to the apnea threshold and thereby predisposes a subject to central apnea. However, it is raised peripheral CO2 chemosensitivity that is responsible for the rapid switching of ventilation and the periodicity of periodic breathing, and thereby plays a crucial role in the pathogenesis of CSA.
The authors would like to acknowledge the help of Drs. Peter Bergin, Meroula Richardson, David M. Kaye, and Henry Krum and staff of the sleep, cardiac, and lung function laboratories at The Alfred Hospital. The authors would like to acknowledge the efforts of Michael Gorman in the development of the data acquisition software and integration of computer hardware, Michael Bailey with statistical analysis, and Andrew Stanish with diagrams and illustrations.
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Dr. Solin is a recipient of a National Health and Medical Research Council of Australia scholarship.
