This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xie, A. Articles by Dempsey, J. A. Search for Related Content PubMed PubMed Citation Articles by Xie, A. Articles by Dempsey, J. A.

Apnea–Hypopnea Threshold for CO₂ in Patients with Congestive Heart Failure

Departments of Medicine and Preventive Medicine, University of Wisconsin, and the Middleton Memorial Veterans Hospital, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Ailiang Xie, M.D., Ph.D., Pulmonary Physiology Laboratory, William S. Middleton Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705. E-mail: axie{at}facstaff.wisc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
To understand the pathogenesis of central sleep apnea (CSA) in patients with congestive heart failure (CHF), we measured the end-tidal carbon dioxide pressure (PET_CO2) during spontaneous breathing, the apnea–hypopnea threshold for CO₂, and then calculated the difference between these two measurements in 19 stable patients with CHF with (12 patients) or without (7 patients) CSA during non–rapid eye movement sleep. Pressure support ventilation was used to reduce the PET_CO2 and thereby determine the thresholds. In patients with CSA, 1.5–3% CO₂ was supplied temporarily to stabilize breathing before determining the thresholds. Unlike patients without CSA whose eupneic PET_CO2 increased during sleep (37.7 ± 1.4 mm Hg versus 40.2 ± 1.5 mm Hg, p < 0.01), patients with CSA showed no rise in PET_CO2 from wakefulness to sleep (37.5 ± 0.9 mm Hg versus 38.2 ± 1.0 mm Hg, p = 0.2). Patients with CHF and CSA had their eupneic PET_CO2 closer to the threshold PET_CO2 than patients without CSA (PET_CO2 [eupneic PET_CO2 – threshold PET_CO2] was 2.8 ± 0.3 mm Hg versus 5.1 ± 0.7 mm Hg for apnea, p < 0.01; 1.7 ± 0.7 versus 4.1 ± 0.5 mm Hg for hypopnea, p < 0.05). In summary, patients with CHF and CSA neither increase their eupneic PET_CO2 during sleep nor proportionally decrease their apnea–hypopnea threshold. The resultant narrowed PET_CO2 predisposes the patient to the development of apnea and subsequent breathing instability.

Key Words: congestive heart failure • apnea threshold

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Nearly half the patients with congestive heart failure (CHF) have periodic breathing and central sleep apnea (CSA) (1, 2). Previous studies have emphasized the critical importance of hypocapnia in the pathogenesis of the CSA (3, 4). The chronic hyperventilation observed in these patients (5, 6) has been proposed to drive the arterial carbon dioxide pressure (Pa_CO2) toward the hypocapnic apnea threshold, thereby predisposing the patients to periodic breathing (4, 6). An increased chemosensitivity (7–9) has also been reported in these patients and considered to be a major contributor to the periodic breathing (10). However, hyperventilation and hypocapnia alone are insufficient to account for breathing instability in humans (11–14) or animals (15). More important than the degree of hyperventilation is the difference between the eupneic Pa_CO2 and the apnea threshold carbon dioxide pressure (PCO₂). For example, in sleeping dogs, metabolic acidosis decreases the apnea threshold more than it decreases the eupneic PCO₂. As a result of the consequent greater difference between the eupneic PCO₂ and the apnea threshold, the dog is less susceptible to periodic breathing during metabolic acidosis (15). In contrast, hypoxia reduces the eupneic Pa_CO2 more than the apnea threshold PCO₂, thereby narrowing the difference between the two and predisposing to apnea both humans (16) and dogs (15). These findings indicate that the difference between the eupneic and threshold PCO₂ may be a crucial determinant of the susceptibility to apnea.

We hypothesized that the eupneic Pa_CO2 is closer to the apnea–hypopnea threshold in CHF patients with CSA compared with those patients without CSA. Accordingly, we measured the apnea–hypopnea threshold and eupneic PCO₂ and then calculated the proximity between the two in patients with stable CHF with or without CSA. In an attempt to identify the factors affecting the relationship between the eupneic PCO₂ and the apnea–hypopnea threshold, we also examined the influence of sleep state on PCO₂ and the ventilatory response to PCO₂ below eupnea in the two groups.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
We studied 19 patients with stable CHF: 12 with CSA (CSA group) and 7 without CSA (control group) (see Table 1). The CSA group had an apnea/hypopnea index (AHI) of 10 or more per hour of sleep with at least 80% of the respiratory events central in nature. The control group had an AHI of 5 or less per hour of sleep. The patients in the two groups were matched with respect to age, sex, body mass index (BMI), and left ventricular ejection fraction (LVEF). The study was approved by the University of Wisconsin Health Sciences Human Subjects Committee, and all patients provided informed written consent before the study.

If patients had spontaneous periodic breathing during sleep that lasted longer than 30 minutes, 1.5–3% CO₂ was administrated to eliminate apneas and hypopneas and thereby stabilize their breathing. If the stable breathing pattern persisted, the patients were switched to room air for another five minutes followed by pressure support trials as described previously. If the periodic breathing returned within a five-minute room air period, CO₂ was again administered until the breathing pattern was stabilized. CO₂ inhalation was then stopped, and the apnea–hypopnea threshold was determined by the following method.

Sleep eupneic PET_CO2 and other ventilatory parameters were measured during stable status, which means stable NREM sleep with rhythmic breathing. Apnea was defined as the absence of inspiratory effort on the mask pressure and absence of flow and chest/abdomen movement for at least 10 seconds (Figures 1 and 2) . Hypopnea was defined as two or more untriggered efforts detected on the mask pressure tracing associated with a 50% or greater reduction in tidal volume. The apnea–hypopnea thresholds were determined by averaging PET_CO2 of the 3 successive breaths that had the lowest PET_CO2 of the last 10 breaths before either the first hypopnea or the first apnea. The eupneic PET_CO2 was measured during the three to five minutes of spontaneous stable breathing before each trial and averaged for all trials. Trials that resulted in awakening or arousal were excluded from analysis.

View larger version (32K): [in this window] [in a new window]   Figure 1. Polygraph record of a pressure support trial in a sleeping patient. The baseline period shows spontaneous, stable breathing with CPAP of 2 cm H2O. When the pressure support value was increased to 10 cm H2O (12/2 cm H2O), the reduction of PETCO2 was sufficient to cause an apnea as manifested by absence of flow for longer than 10 seconds. The initial apnea was followed by a hypopnea characterized by several untriggered breaths, indicating an inspiratory effort below 2 cm H2O. The apnea threshold was determined as the mean PETCO2 of the lowest three consecutive breaths preceding the first apnea (indicated by the thick horizontal line). On the VT channel, inspiration is up, and expiration is down.

View larger version (27K): [in this window] [in a new window]   Figure 2. Polygraph record of a spontaneous apnea in a sleeping subject. Exogenous CO2 had previously stabilized the breathing pattern and had been stopped for five minutes. The patient was breathing spontaneously on room air with CPAP of 2 cm H2O. Before the apnea, oscillation of ventilation was noted, but rhythmic breathing persisted. An apnea occurred, as manifested by absence of flow for longer than 10 seconds. The apnea threshold was determined as the mean PETCO2 of the lowest three consecutive breaths preceding the first apnea (indicated by the thick horizontal line).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Characteristics of Patients with and without CSA
The characteristics of patients with and without CSA are shown in Table 1. By design, the AHI was significantly and pathologically higher in the CSA group, compared with the control group (50 ± 7 events per hour versus 3 ± 0 events per hour, p < 0.01), which associated with a greater arousal index (29 ± 5 events per hour versus 9 ± 2 events per hour, p < 0.01). Both groups consisted of elderly men (61 ± 4 yr versus 62 ± 4 yr, p > 0.05) with moderate increase in weight (BMI 29 ± 3 versus 30 ± 1, p = 0.56). In five subjects of the control group and eight subjects of the CSA group, CHF was secondary to ischemic cardiomyopathy, with the remainder of patients having nonischemic dilated cardiomyopathy. Patients in the two groups had a similar degree of severe left ventricular dysfunction as indicated by a low LVEF (31 ± 4% versus 26 ± 2%, p = 0.21). The two groups were also similar with respect to their pulmonary function and medications. In the control group, six subjects were on angiotensin-converting enzyme inhibitors, four were on diuretics, four were on digoxin, and five were on a beta-blocker. In the CSA group, 10 patients were on angiotensin-converting enzyme inhibitors, 10 were on diuretics, 6 were on digoxin, and 4 were on a beta-blocker. In the control group, two patients had mitral regurgitation, and none had atrial fibrillation or pulmonary hypertension. In the CSA group, four patients had atrial fibrillation, five had mitral regurgitation, and three had pulmonary hypertension on the basis of echocardiographic criteria.

Effect of Sleep on Breathing Pattern and Eupneic PCO₂
During periods of stable breathing, we examined the effect of sleep on eupneic PCO₂, breathing frequency, tidal volume, and minute ventilation. There was no difference in PET_CO2 during wakefulness (37.7 ± 1.4 mm Hg versus 37.5 ± 0.9 mm Hg, p > 0.05) or during sleep (40.2 ± 1.5 mm Hg versus 38.2 ± 1.0 mm Hg, p > 0.05) between the two groups. However, the increase in PET_CO2 from wakefulness to sleep was smaller in the CSA group compared with the control group. Patients in the control group showed a consistent and significant rise in eupneic PET_CO2 at the onset of sleep (from 37.7 ± 1.4 mm Hg to 40.2 ± 1.5 mm Hg, p < 0.01) compared with patients with CSA (37.5 ± 0.9 mm Hg versus 38.2 ± 1.0 mm Hg, p = 0.2; see Figure 3) . Sleep did not significantly affect breathing patterns in either the control or CSA group in terms of frequency (15.0 ± 0.6 breaths per minute versus 14.9 ± 1.7 breaths per minute in the control group; 13.5 ± 1.1 breaths per minute versus 15.5 ± 0.9 in the CSA group), tidal volume (570 ± 65 ml versus 504 ± 61 ml in the control group; 599 ± 71 ml versus 562 ± 35 ml in the CSA group), or minute ventilation (8.5 ± 1.0 L/min versus 7.0 ± 0.5 L/min in the control group; 8.9 ± 0.7 L/min versus 8.6 ± 0.6 L/min in the CSA group). Sleep arterial oxygen saturation (Sa_O2) during stable breathing was 96 ± 1% in the control group and 95 ± 1% in the CSA group, and the difference was not statistically significant.

View larger version (22K): [in this window] [in a new window]   Figure 3. Awake and asleep eupneic PETCO2 during stable breathing and apnea threshold during sleep. In the control group () there was a consistent and significant increase in eupneic PCO2 during sleep (from 37.7 ± 1.4 to 40.2 ± 1.5 mm Hg, p < 0.01). In the CSA group (), there was no difference in eupneic PCO2 between sleep and wakefulness (37.5 ± 0.9 versus 38.2 ± 1.0 mm Hg, p = 0.2). In both groups, the apnea threshold was below both the sleep and awake eupneic PETCO2. The threshold was closer to eupnea level in the CSA group compared with the control group. Two data points are missing for the apnea threshold in the control group because two of these patients produced only hypopneas and no apneas. One data point is missing for awake eupnea in the CSA group because one patient did not have a stable breathing during wakefulness. *p < 0.05 compared with awake PETCO2; +p < 0.05 compared with sleep as well as awake PETCO2.

View larger version (12K): [in this window] [in a new window]   Figure 4. Difference between eupneic and threshold PETCO2. The horizontal dashed line represents the average eupneic PETCO2 for all patients in the control and CSA groups during stable breathing with no pressure support before apnea and/or hypopnea trials. The vertical bar represents the difference between the eupneic PETCO2 (top of bar) and the threshold PETCO2 (bottom of bar) for each subgroup, with the open bar showing the hypopneic trials and the solid bar showing the apneic trials. Note the significantly smaller difference in the CSA group compared with the control group (apnea: 2.8 ± 0.3 mm Hg versus 5.1 ± 0.7 mm Hg, p < 0.01; hypopnea: 1.7 ± 0.7 mm Hg versus 4.1 ± 0.5 mm Hg, p < 0.05). *p < 0.05 PETCO2 (eupnoeic - threshold PETCO2) in the CSA group compared with the control group. , Hypopnea; , apnea.

View larger version (12K): [in this window] [in a new window]   Figure 5. Hypocapnic ventilatory response to CO2 below the eupneic PCO2 in control () and CSA () groups. The horizontal lines represent the mean value in each group. The ventilatory response was significantly greater in the CSA group than in the control group (3.86 ± 0.79 L/min per mm Hg versus 1.47 ± 0.18 L/min per mm Hg). *p < 0.05 compared with control slope.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Patients with CHF and CSA showed a decreased proximity of eupneic PET_CO2 to the threshold PET_CO2 and a greater hypocapnic ventilatory response below eupnea compared with patients with CHF but without CSA. These findings shed light on the pathophysiologic interaction between cardiac dysfunction and ventilatory control instability, because the narrow proximity of eupneic and threshold PET_CO2 makes a transient reduction of PCO₂ much more likely to fall below the apnea threshold, and the increased ventilatory sensitivity below eupneic PCO₂ makes the respiratory system more sensitive to any reduction of CO₂. Thus, both abnormalities predispose patients to periodic breathing. Although a low eupneic PCO₂ has been reported, and a eupneic PCO₂ close to the apneic threshold has been suggested as the main mechanism of CSA (3, 4, 6), previous studies have not precisely measured the threshold during steady-state conditions in CSA or compared it with age-, BMI-, and heart function–matched control subjects. Our study also extends the previous body of work regarding the ventilatory response to added chemical stimuli above the eupneic value (7, 8) by looking at the respiratory sensitivity to a withdrawal of chemical stimulus below eupneic value, which directly addresses the vulnerability of the respiratory system to a transient reduction of CO₂. It is not clear what causes the eupneic PCO₂ to be closer to the threshold in patients with CSA. On the basis of our data, the small difference between the two results from a combination of a relatively lower eupneic PCO₂ and a disproportionately high apnea–hypopnea threshold.

Effect of Sleep on Eupneic PCO₂
Unlike the control patients, patients with CSA demonstrated an unusual response to the sleeping state, in that their PET_CO2 did not increase in going from wakefulness to sleep. This disparity has been previously reported (4). In normal subjects, the hypercapnic effect of sleep persists even in the presence of ventilatory stimulation or inhibition with progesterone or hypoxia or with metabolic alkalosis (18). These findings suggest that the sleeping state in our patients is associated with an added ventilatory drive that offsets the removal of the ventilatory drive associated with wakefulness.

Nonchemical ventilatory stimulation resulting from pulmonary congestion might be a source of the additional ventilatory drive during sleep (4, 19). Although our control and CSA patients had similar pulmonary function and LVEF, we cannot exclude the possibility of a higher pulmonary capillary wedge pressure or mean pulmonary arterial pressure in the patients with CSA (20). Our patients with CSA had a higher incidence of atrial fibrillation and mitral regurgitation. Both disorders are associated with increased left ventricular end-diastolic volume and filling pressure, which in turn have been reciprocally related to the increase in Pa_CO2 from wakefulness to sleep (4). The elevation of interstitial pressure may stimulate pulmonary irritant and juxtacapillary receptors, resulting in rapid shallow ventilation and consequent hypocapnia (21). The manifestation of the ventilatory stimulation associated with pulmonary vascular congestion is more prominent in unconscious, compared with conscious, dogs (22). Thus, the failure of the PCO₂ of our patients with CSA to increase normally during sleep may be related to increasing pulmonary vascular congestion during sleep and an unmasking of the enhanced ventilatory response by the sleeping state. However, evidence against a vagal mechanism for the hyperventilation and CSA is provided by the observation that a patient with CHF after bilateral lung transplantation showed a lower eupneic PCO₂ and CSA despite vagal denervation (23).

Relatively High Apnea-Hypopnea Threshold
If the ventilatory drive during sleep was enhanced in patients with CSA, we would expect a proportional lowering of the apnea threshold. On the contrary, the apnea–hypopnea thresholds were not different compared with the control patients. As a result, the patients with CSA demonstrated a closer proximity of the eupneic PCO₂ to the apnea–hypopnea threshold. This finding contrasts with the effect of other ventilatory stimulants that were studied in sleeping dogs, including metabolic acidosis and almitrine (15). With these ventilatory stimulants, the apnea threshold was decreased out of proportion to the reduction of the eupneic PCO₂, and thus, the proximity of the eupneic PCO₂ to the apnea threshold was widened.

A ventilatory stimulant that is somewhat analogous to our observations in the patients with CSA is hypoxia (16). Hypoxia narrows the difference between eupneic PCO₂ and threshold PCO₂ by failing to proportionally reduce the threshold in the face of a reduction of eupneic PCO₂. In the present study, however, the CSA group had an Sa_O2 that was similar to that of the control group and was within the normal range. Therefore, we do not believe that hypoxia contributed to the narrow proximity in our patients with CSA. Because both CHF and hypoxia facilitate periodic breathing in association with a narrowed difference between eupneic PCO₂ and threshold PCO₂, we cannot eliminate the possibility that the high threshold in these two conditions may have a common mechanism.

Implications for Periodic Breathing
The narrowed proximity of the eupneic PCO₂ to the apnea threshold has two important implications for the development of periodic breathing in patients with CHF. First, this narrowed proximity is consistent with an increased sensitivity of ventilation to reductions in PCO₂ below the eupneic PCO₂ in a manner similar to what has been reported regarding the ventilatory response to PCO₂ above eupnea (7–9). We detected a higher ventilatory response to CO₂ below the eupneic value in patients with CSA compared with the control group. In the control group, the ventilatory response below eupnea was 1.5 L/minute per mm Hg, which is similar to the 1.6–1.9 L/minute per mm Hg in normal subjects without heart dysfunction or sleep-disordered breathing (16, 24, 25). In the CSA group, the ventilatory response to CO₂ below eupnea was 3.9 L/minute per mm Hg, which is similar to the 3–6 L/minute per mm Hg in normal subjects during hypoxia (16, 26). This increased ventilatory control system gain both above and below eupnea will exaggerate the ventilatory overshoot and undershoot associated with oscillations in respiratory drive and thereby predispose patients to ventilatory instability.

The second important consequence of the close proximity of the apnea threshold to the eupneic PCO₂ is the enhanced susceptibility to apnea and the destabilizing effect of apnea itself on the breathing pattern. The occurrence of apnea introduces a profound delay between the rising chemical stimuli that accumulate during the apnea and the eventual ventilatory response (27). In the study of Leevers and associates, reinitiation of breathing was not observed after an apnea until the chemical stimuli accumulated to hypercapnic and hypoxic levels compared with eupnea. When ventilation is resumed at the termination of the apnea, the high level of chemical stimuli results in a ventilatory overshoot that serves to perpetuate the periodic breathing pattern. Thus, apnea itself, by introducing phase delays between the accumulating chemical stimuli and the ventilatory response, can contribute to ventilatory instability.

Methodologic Considerations
As an indication of the threshold, we chose the PET_CO2 from the 3 consecutive breaths that had the lowest PET_CO2 of the last 10 breaths before each apnea or hypopnea, rather than the breath immediately preceding the apnea/hypopnea. Our rationale for this approach was based on the observation that the time from lowest PET_CO2 in each hyperpnea–apnea cycle to the onset of apnea has been shown to be the same as lung to ear circulatory delay, suggesting that the lowest PET_CO2 sensed at the peripheral chemoreceptors might be best correlated with the subsequent apnea (3).

In patients with CSA, we chose to stabilize the breathing pattern with exogenous CO₂ rather than to determine the threshold during the non–steady state periodic breathing. The strength of this approach is related to the following consideration. Determination of the apnea threshold during periodic breathing would be influenced by the previous apnea-induced asphyxia and associated arousal. To avoid this problem, we first stabilized the breathing pattern with 1.5–3% CO₂, then stopped the CO₂ administration for at least five minutes, and finally recorded the threshold at the first appearance of apnea and hypopnea. Previous studies have shown that five minutes is sufficient time to return the ventilation and PCO₂ back to baseline following even higher levels of CO₂ (4–6%) (28). In the eight patients who required CO₂ to stabilize their breathing pattern, PET_CO2 (eupneic PCO₂- - threshold PCO₂) was actually larger than in the four patients who did not receive CO₂ and had their threshold determined with pressure support (3.3 ± 0.3 mm Hg versus 1.4 ± 0.4 mm Hg). Thus, we do not believe that CO₂ inhalation had an independent effect in producing the systematic narrowing of the eupneic PCO₂–threshold relationship that we observed in our patients with CSA compared with the control patients.

The apnea–hypopnea threshold determination could have been affected by the method used to lower the PCO₂, pressure support ventilation versus spontaneous breathing. It has been demonstrated that positive pressure ventilation produces neuromechanical inhibition to the respiratory drive (29), which might introduce hypopnea despite the isocapnic conditions (30). In our study, pressure support ventilation was used in all of the control patients but in only part of the patients with CSA. To assess the apnea–hypopnea threshold determined by pressure support versus spontaneous reduction in PCO₂, we compared the threshold values in seven patients with CSA who had their apnea threshold determined by both the pressure support and spontaneous breathing techniques. The relationship between eupneic PET_CO2 and threshold was similar with both techniques, indicating that the difference we observed between the CSA and control groups was not related to the use of different measuring techniques. The lack of influence of pressure support on the apnea–hypopnea threshold may be due to the lower pressure support level used in the CSA group. Because the pressure support level required to produce apnea or hypopnea was higher in the control than in the CSA group, the mechanical inhibition of ventilatory drive would have been higher in the control group. If neuromechanical inhibition increased the susceptibility to apnea or hypopnea in the control group, we may have actually underestimated the difference in the threshold between the control and CSA groups.

We investigated the possibility that variation in medication usage could account for the differences in eupneic PCO₂ and apnea–hypopnea threshold that were observed in patients with and without CSA. Most patients in both groups were on angiotensin-converting enzyme inhibitors, diuretics, beta-blockers, and digoxin. Zolpidem was used in all patients to facilitate sleep and minimize arousal from sleep. This medicine at a dosage of 10 mg has been shown to have no effect on respiration in terms of occlusion pressure, ventilation, Pa_CO2, Sa_O2, ventilatory response to CO₂, or respiratory disturbance index (31–35). Therefore, it is unlikely that zoplidem affected the apnea–hypopnea threshold in our study; even if an anticipated effect was present, it would be present in both groups and thus not alter our conclusions.

In summary, patients with CHF and CSA demonstrate a pattern of ventilatory stimulation that is unique compared with other nonhypoxic ventilatory stimulants. First, they do not hypoventilate during sleep to the degree observed in control patients. Secondly, the apnea–hypopnea threshold is not proportionally reduced, and the sensitivity of the ventilatory response to CO₂ below eupnea is enhanced. These two abnormalities result in a narrowed difference between the eupneic PCO₂ and the ventilatory threshold, which in turn is associated with an unusual susceptibility to apnea and breathing pattern instability.

	Acknowledgments

 
The authors would like to thank General Clinical Research Centre of University Wisconsin for assistance.

	FOOTNOTES

 
Supported by the VA Research Service, NIH R01 HL62561-02, and UW General Clinical Research Center.

Received in original form October 9, 2001; accepted in final form December 21, 2001

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 

1. Javaheri S, Parker TJ, Wexler L, Michaels SE, Stanberry E, Nishyama EH, Roselle GA. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med 1995;122:487–492.[Abstract/Free Full Text]
2. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 1998;97:2154–2159.[Medline]
3. Lorenzi-Filho G, Rankin F, Bies I, Bradley TD. Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med 1999;159:1490–1498.[Abstract/Free Full Text]
4. Tkacova R, Hall ML, Liu PP, Fitzgerald FS, Bradley TD. Left ventricular volume in patients with heart failure and Cheyne-Stokes respiration during sleep. Am J Respir Cri Care Med 1997;156:1549–1555.[Abstract/Free Full Text]
5. Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure: relationship to arterial PCO2. Chest 1993;104:1079–1084.[Abstract/Free Full Text]
6. Naughton MT, Benard DC, Tam A, Rutherford R, Bradley TD. The role of hyperventilation in the pathogenesis of central sleep apnea in patients with congestive heart failure. Am Rev Respir Dis 1993;148: 330–338.[Medline]
7. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med 1999;341:949–954.[Abstract/Free Full Text]
8. Solin P, Roebuck T, Johns DP, Walters EH, Naughton MT. Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. Am J Respir Crit Care Med 2000;162:2194–2200.[Abstract/Free Full Text]
9. Wilcox I, McNamara SG, Dodd MJ, Sullivan CE. Ventilatory control in patients with sleep apnoea and left ventricular dysfunction: comparison of obstructive and central sleep apnoea. Eur Respir J 1998;11:7–13.
10. Khoo MCK. Theoretical models of periodic breathing. In: D. T. Bradley and J. S. Floras, editors. Sleep apnea: implications in cardiovascular and cerebrovascular disease. New York: Marcel Dekker, Inc.; 1999. p. 355–384.
11. DeBacker WA, Verbraecken J, Willemen M, Wittesaele W, DeCock W, deHeyning PV. Central apnoea index decreases after prolonged treatment with acetazolamide. Am J Respir Crit Care Med 1995;151:87–91.[Abstract]
12. Javaheri S, Parker TJ, Wexler L, Liming LD, Lindower P, Roselle GA. Effect of theophylline on sleep disordered breathing in heart failure. N Engl J Med 1996;335:562–567.[Abstract/Free Full Text]
13. Perez-Padilla R, West P, Lertzman M, Kryger MH. Breathing during sleep in patients with interstitial lung disease. Am Rev Respir Dis 1985;132:224–229.[Medline]
14. Skatrud JB, Dempsey JA, Iber C, Berssenbrugge A. Correction of CO₂ retention during sleep in patients with chronic obstructive pulmonary diseases. Am Rev Respir Dis 1981;124:260–268.[Medline]
15. Nakayama H, Smith CA, Dempsey JA. Effects of background ventilatory stimuli on the apneic threshold (AT) in sleep dogs [abstract]. Am J Respir Crit Care Med 2001;163:A179.
16. Xie A, Skatrud JB, Dempsey JA. Effect of hypoxia on the hypopnoeic and apnoeic threshold for CO₂ in sleeping humans. J Physiol 2001;535: 269–278.[Abstract/Free Full Text]
17. Rechtschaffen A, Kales A. A manual for standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: National Institutes of Health; 1968.
18. Dempsey JA, Skatrud JB. A sleep-induced apneic threshold and its consequences. Am Rev Respir Dis 1986;133:1163–1170.[Medline]
19. Solin P, Bergin P, Richardson M, Kaye DM, Walters EH, Naughton MT. Influence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation 1999;99:1574–1579.[Abstract/Free Full Text]
20. Egan JJ, Kalra S, Yonan N, Hasleton PS, Brooks N, Woodcock AA. Pulmonary diffusion abnormalities in heart transplant recipients: relationship to cytomegalovirus infection. Chest 1993;104:1085–1089.[Abstract/Free Full Text]
21. Churchill ED, Cope O. The rapid shallow breathing resulting from pulmonary congestion and edema. J Exp Med 1929;49:531–537.[Abstract]
22. Giesbrecht GG, Younes M. Respiratory response to pulmonary vascular congestion in intact conscious dogs. J Appl Physiol 1993;74:345–353.[Abstract/Free Full Text]
23. Solin P, Snell GI, Williams TJ, Naughton MT. Central sleep apnoea in congestive heart failure despite vagal denervation after bilateral lung transplantation. Eur Respir J 1998;12:495–498.[Abstract]
24. Henke KG, Arias A, Skatrud JB, Dempsey JA. Inhibition of inspiratory muscle activity during sleep: chemical and nonchemical influences. Am Rev Respir Dis 1988;138:8–15.[Medline]
25. Meza S, Mendez M, Ostrowski M, Younes M. Susceptibility to periodic breathing with assisted ventilation during sleep in normal subjects. J Appl Physiol 1998;85:1929–1940.[Abstract/Free Full Text]
26. Skatrud JB, Dempsey JA. Interactions of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813–822.[Abstract/Free Full Text]
27. Leevers AM, Simon PM, Dempsey JA. Apnea after normocapnic mechanical ventilation during NREM sleep. J Appl Physiol 1994;77: 2079–2085.[Abstract/Free Full Text]
28. Xie A, Skatrud JB, Puleo DS, Morgan BJ. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol 2001;91:1555–1562.[Abstract/Free Full Text]
29. Lake FR, Finucane KE, Hillman DR. Diaphragm inhibition with positive pressure ventilation: quantification of mechanical effects. Respir Physiol 1999;118:149–161.[CrossRef][Medline]
30. Wilson CR, Satoh M, Skatrud JB, Dempsey JA. Non-chemical inhibition of respiratory motor output during mechanical ventilation in sleeping humans. J Physiol 1999; 518:605–618.[Abstract/Free Full Text]
31. Beaumont M, Goldenberg F, Lejeune D, Marotte H, Harf A, Lofaso F. Effect of zolpidem on sleep and ventilatory patterns at simulated altitude of 4,000 meters. Am J Respir Crit Care Med 1996;153:1864–1869.[Abstract]
32. Cohn MA. Effects of zolpidem, codeine phosphate and placebo on respiration: a double-blind, crossover study in volunteers. Drug Saf 1993;9: 312–319.[Medline]
33. Maillard D, Thiercelin JF, Fuseau E, Rosenzweig P, Attali P. Effects of zolpidem versus diazepam and placebo on breathing control parameters in healthy human subjects. Int J Clin Pharmacol Res 1992;12:27–35.[Medline]
34. McCann CC, Quera-Salva MA, Boudet J, Frisk M, Barthouil P, Borderies P, Meyer P. Effect of zolpidem during sleep on ventilation and cardiovascular variables in normal subjects. Fundam Clin Pharmacol 1993;7:305–310.[Medline]
35. Quera-Salva MA, McCann C, Boudet J, Frisk M, Borderies P, Meyer P. Effects of zolpidem on sleep architecture, night time ventilation, daytime vigilance and performance in heavy snorers. Br J Clin Pharmacol 1994;37:539–543.[Medline]

This article has been cited by other articles:

				D. Yumino and T. D. Bradley Central Sleep Apnea and Cheyne-Stokes Respiration Proceedings of the ATS, February 15, 2008; 5(2): 226 - 236. [Abstract] [Full Text] [PDF]

				P. Agostoni, A. Apostolo, and R. K. Albert Mechanisms of Periodic Breathing During Exercise in Patients With Chronic Heart Failure Chest, January 1, 2008; 133(1): 197 - 203. [Abstract] [Full Text] [PDF]

				K. J. Cummings, M. Swart, and P. N. Ainslie Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2 J Appl Physiol, May 1, 2007; 102(5): 1891 - 1898. [Abstract] [Full Text] [PDF]

				D. J. Eckert, A. S. Jordan, P. Merchia, and A. Malhotra Central Sleep Apnea: Pathophysiology and Treatment Chest, February 1, 2007; 131(2): 595 - 607. [Abstract] [Full Text] [PDF]

				A. Xie, J. B. Skatrud, B. Morgan, B. Chenuel, R. Khayat, K. Reichmuth, J. Lin, and J. A. Dempsey Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans J. Physiol., November 15, 2006; 577(1): 319 - 329. [Abstract] [Full Text] [PDF]

				B. J. Chenuel, C. A. Smith, J. B. Skatrud, K. S. Henderson, and J. A. Dempsey Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog J Appl Physiol, July 1, 2006; 101(1): 76 - 83. [Abstract] [Full Text] [PDF]

				S. Javaheri Acetazolamide Improves Central Sleep Apnea in Heart Failure: A Double-Blind, Prospective Study Am. J. Respir. Crit. Care Med., January 15, 2006; 173(2): 234 - 237. [Abstract] [Full Text] [PDF]

				D. P. White Pathogenesis of Obstructive and Central Sleep Apnea Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1363 - 1370. [Abstract] [Full Text] [PDF]

				S. Thomson, M. J. Morrell, J. J. Cordingley, and S. J. Semple Ventilation is unstable during drowsiness before sleep onset J Appl Physiol, November 1, 2005; 99(5): 2036 - 2044. [Abstract] [Full Text] [PDF]

				K. G. Johnson and D. C. Johnson Bilevel Positive Airway Pressure Worsens Central Apneas During Sleep Chest, October 1, 2005; 128(4): 2141 - 2150. [Abstract] [Full Text] [PDF]

				D. Wang, H. Teichtahl, O. Drummer, C. Goodman, G. Cherry, D. Cunnington, and I. Kronborg Central Sleep Apnea in Stable Methadone Maintenance Treatment Patients Chest, September 1, 2005; 128(3): 1348 - 1356. [Abstract] [Full Text] [PDF]

				A. Xie, J. B. Skatrud, R. Khayat, J. A. Dempsey, B. Morgan, and D. Russell Cerebrovascular Response to Carbon Dioxide in Patients with Congestive Heart Failure Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 371 - 378. [Abstract] [Full Text] [PDF]

				B. J. Chenuel, C. A. Smith, K. S. Henderson, and J. A. Dempsey Increased propensity for apnea via dopamine-induced carotid body inhibition in sleeping dogs J Appl Physiol, May 1, 2005; 98(5): 1732 - 1739. [Abstract] [Full Text] [PDF]

				S. Javaheri, K. F. Almoosa, K. Saleh, and C. L. Mendenhall Hypocapnia Is Not a Predictor of Central Sleep Apnea in Patients with Cirrhosis Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 908 - 911. [Abstract] [Full Text] [PDF]

				A. Khan, M. Qurashi, K. Kwiatkowski, D. Cates, and H. Rigatto Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea J Appl Physiol, April 1, 2005; 98(4): 1171 - 1176. [Abstract] [Full Text] [PDF]

				M. H. Wilkinson, K.-L. Sia, E. M. Skuza, V. Brodecky, and P. J. Berger Impact of changes in inspired oxygen and carbon dioxide on respiratory instability in the lamb J Appl Physiol, February 1, 2005; 98(2): 437 - 446. [Abstract] [Full Text] [PDF]

				J. A. Dempsey Crossing the apnoeic threshold: causes and consequences Exp Physiol, January 1, 2005; 90(1): 13 - 24. [Abstract] [Full Text] [PDF]

				J. A Dempsey, C. A Smith, T. Przybylowski, B. Chenuel, A. Xie, H. Nakayama, and J. B Skatrud The ventilatory responsiveness to CO2 below eupnoea as a determinant of ventilatory stability in sleep J. Physiol., October 1, 2004; 560(1): 1 - 11. [Abstract] [Full Text] [PDF]

				M. J. Tobin The Role of a Journal in a Scientific Controversy Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 511 - 511. [Full Text] [PDF]

				T. D. Bradley The ups and downs of periodic breathing: Implications for mortality in heart failure J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2182 - 2184. [Full Text] [PDF]

				R. N. Khayat, A. Xie, A. K. Patel, A. Kaminski, and J. B. Skatrud Cardiorespiratory Effects of Added Dead Space in Patients With Heart Failure and Central Sleep Apnea Chest, May 1, 2003; 123(5): 1551 - 1560. [Abstract] [Full Text] [PDF]

				I. Mitrouska, E. Kondili, G. Prinianakis, N. Siafakas, and D. Georgopoulos Effects of Theophylline on Ventilatory Poststimulus Potentiation in Patients with Brain Damage Am. J. Respir. Crit. Care Med., April 15, 2003; 167(8): 1124 - 1130. [Abstract] [Full Text] [PDF]

				T. D. Bradley and J. S. Floras Sleep Apnea and Heart Failure: Part II: Central Sleep Apnea Circulation, April 8, 2003; 107(13): 1822 - 1826. [Full Text] [PDF]

				H.A.K. Browne, L. Adams, A.K. Simonds, and M.J. Morrell Ageing does not influence the sleep-related decrease in the hypercapnic ventilatory response Eur. Respir. J., March 1, 2003; 21(3): 523 - 529. [Abstract] [Full Text] [PDF]

				S. Javaheri Pembrey's Dream: The Time Has Come for a Long-term Trial of Nocturnal Supplemental Nasal Oxygen to Treat Central Sleep Apnea in Congestive Heart Failure Chest, February 1, 2003; 123(2): 322 - 325. [Full Text] [PDF]