Apnea Hypopnea Threshold for CO 2 in Patients with Congestive Heart Failure

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1 Apnea Hypopnea Threshold for CO in Patients with Congestive Heart Failure Ailiang Xie, James B. Skatrud, Dominic S. Puleo, Peter S. Rahko, and Jerome A. Dempsey Departments of Medicine and Preventive Medicine, University of Wisconsin, and the Middleton Memorial Veterans Hospital, Madison, Wisconsin 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 CO ) during spontaneous breathing, the apnea hypopnea threshold for CO, and then calculated the difference between these two measurements in 19 stable patients with CHF with (1 patients) or without (7 patients) CSA during non rapid eye movement sleep. Pressure support ventilation was used to reduce the PET CO and thereby determine the thresholds. In patients with CSA, 1.5 3% CO was supplied temporarily to stabilize breathing before determining the thresholds. Unlike patients without CSA whose eupneic PET CO increased during sleep ( mm Hg versus mm Hg, p 0.01), patients with CSA showed no rise in PET CO from wakefulness to sleep ( mm Hg versus mm Hg, p 0.). Patients with CHF and CSA had their eupneic PET CO closer to the threshold PET than patients without CSA CO ( PET CO [eupneic PET threshold CO PET ] was mm Hg versus CO mm Hg for apnea, p 0.01; versus mm Hg for hypopnea, p 0.05). In summary, patients with CHF and CSA neither increase their eupneic PET CO during sleep nor proportionally decrease their apnea hypopnea threshold. The resultant narrowed PET CO predisposes the patient to the development of apnea and subsequent breathing instability. Keywords: congestive heart failure; apnea threshold Nearly half the patients with congestive heart failure (CHF) have periodic breathing and central sleep apnea (CSA) (1, ). 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 CO ) 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 CO and the apnea threshold carbon dioxide pressure (PCO ). For example, in sleeping dogs, metabolic acidosis decreases the apnea threshold more than it decreases the eupneic PCO. As a result of the consequent greater difference between the eupneic PCO and the apnea threshold, the dog is less susceptible to periodic breathing during metabolic acidosis (15). In contrast, hypoxia reduces the eupneic Pa CO more than the apnea threshold PCO, thereby narrowing the difference between the (Received in original form October 9, 001; accepted in final form December 1, 001) Supported by the VA Research Service, NIH R01 HL6561-0, and UW General Clinical Research Center. Correspondence and requests for reprints should be addressed to Ailiang Xie, M.D., Ph.D., Pulmonary Physiology Laboratory, William S. Middleton Veterans Hospital, 500 Overlook Terrace, Madison, WI axie@facstaff.wisc.edu Am J Respir Crit Care Med Vol 165. pp , 00 DOI: /rccm OC Internet address: two and predisposing to apnea both humans (16) and dogs (15). These findings indicate that the difference between the eupneic and threshold PCO may be a crucial determinant of the susceptibility to apnea. We hypothesized that the eupneic Pa CO 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 PCO 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 PCO and the apnea hypopnea threshold, we also examined the influence of sleep state on PCO and the ventilatory response to PCO below eupnea in the two groups. METHODS Subjects We studied 19 patients with stable CHF: 1 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. Protocol Before the sleep study, all patients had routine pulmonary function tests, performed at least two hours after a meal. LVEF was measured using two-dimensional echocardiography. Nocturnal polysomnography (17) was performed to classify subjects with and without CSA. On the second night, patients breathed through a full-face mask attached to a mechanical ventilator as previously described (16). After a 15-minute period of stable wakefulness, zolpidem (10 mg) was administrated to all subjects. The ventilator was set in the pressure support mode. During stable non rapid eye movement (NREM) sleep, each threshold determination was initiated with a 3 5-minute period of spontaneous breathing at a low value of continuous positive airway pressure (CPAP; 6 cm H O) that was sufficient to eliminate any evidence of flow limitation on the inspiratory flow signal. The inspiratory pressure was increased to 6 cm while the expiratory pressure was maintained at CPAP value. If no apnea or hypopnea occurred after two minutes, the inspiratory pressure was increased in -cm H O increments at twominute intervals, with the end-expiratory pressure unchanged. When apneas and/or hypopneas occurred, the patient was returned to baseline CPAP and spontaneous breathing. If patients had spontaneous periodic breathing during sleep that lasted longer than 30 minutes, 1.5 3% CO 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, CO was again administered until the breathing pattern was stabilized. CO inhalation was then stopped, and the apnea hypopnea threshold was determined by the following method. Sleep eupneic PET CO and other ventilatory parameters were measured during stable status, which means stable NREM sleep with

2 146 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 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 ). 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 CO of the 3 successive breaths that had the lowest PET CO of the last 10 breaths before either the first hypopnea or the first apnea. The eupneic PET CO 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. Data Analysis Comparisons of the eupneic PET CO (control versus CSA and awake versus sleep within the same group), threshold PET CO, and the difference between eupneic and threshold PET CO (control versus CSA and apnea versus hypopnea within the same group) were made using twoway repeated measures analysis of variance. Post hoc analysis was performed with a Student Newman Keuls test. The ventilatory response was calculated by dividing V E (eupneic V E apneic or hypopneic V E ) by PET CO (eupneic PET CO apnea or hypopnea threshold PET CO ). The slopes of the ventilatory responses of the two groups were compared using Student s unpaired t test. Data are reported as mean standard error in the text, table, and figures. p Values less than 0.05 were considered statistically significant. RESULTS 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 (9 5 events per hour versus 9 events per hour, p 0.01). Both groups consisted of elderly men (61 4 yr versus 6 4 yr, p 0.05) with moderate increase in weight (BMI 9 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 6 %, p 0.1). The two groups were also similar with respect to their pulmonary function and medications. In the control group, Figure 1. Polygraph record of a pressure support trial in a sleeping patient. The baseline period shows spontaneous, stable breathing with CPAP of cm H O. When the pressure support value was increased to 10 cm H O (1/ cm H O), the reduction of PET CO 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 cm H O. The apnea threshold was determined as the mean PET CO of the lowest three consecutive breaths preceding the first apnea (indicated by the thick horizontal line). On the V T channel, inspiration is up, and expiration is down. 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 PCO During periods of stable breathing, we examined the effect of sleep on eupneic PCO, breathing frequency, tidal volume, and minute ventilation. There was no difference in PET CO during wakefulness ( mm Hg versus mm Hg, p 0.05) or during sleep ( mm Hg versus mm Hg, p 0.05) between the two groups. However, the increase in PET CO 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 CO at the onset of sleep (from mm Hg to mm Hg, p 0.01) compared with patients with CSA ( mm Hg versus mm Hg, p 0.; see Figure 3). Sleep did not significantly affect breathing patterns in either the control or CSA group in terms of frequency ( breaths per minute versus breaths per minute in the control group; breaths per minute versus in the CSA group), tidal volume ( ml versus ml in the control group; ml versus ml in the CSA group), or minute ventilation ( L/min versus L/min in the control group; L/min versus L/min in the CSA group). Sleep arterial oxygen saturation (Sa O ) during stable breathing was 96 1% in the control group and 95 1% in the CSA group, and the difference was not statistically significant. Proximity of Eupneic PET co to Threshold during Sleep In the control group, four patients developed both apneas and hypopneas, one patient had only apneas, and two patients had only hypopneas. As a result, we analyzed the apnea threshold in five patients and the hypopnea threshold in six patients. In the CSA group, all 1 patients had apneas, but only 10 patients had hypopneas. As shown in Figures 3 and 4, the apnea hypopnea threshold was not statistically different between the control group versus the CSA group (apnea threshold mm Hg versus mm Hg, p 0.05; hypopnea threshold mm Hg versus mm Hg, p 0.05). However, PET CO (eupneic PET CO threshold PET CO ) was significantly smaller in the CSA group than in the control group (apnea: mm Hg versus mm Hg, p 0.01; hypopnea: mm Hg versus mm Hg, p 0.05). Although PET CO (eupneic apnea threshold) tended to be greater than PET CO (eupnoeic hypopnea threshold) in both groups, the difference was not significant. Another way of examining the relationship between the reduction of PET CO and the development of periodic breathing was to calculate the ventilatory response to CO below eupnea. As shown in Figure 5, the ventilatory response was significantly greater in the CSA group than in the control group ( L/minute per mm Hg versus L/minute per mm Hg, p 0.05). Effect of Pressure Support on Apnea Hypopnea Threshold Because not all subjects had their apnea hypopnea threshold determined with pressure support, we examined whether the

3 Xie, Skatrud, Puleo, et al.: Apnea Threshold in Heart Failure 147 Figure. Polygraph record of a spontaneous apnea in a sleeping subject. Exogenous CO had previously stabilized the breathing pattern and had been stopped for five minutes. The patient was breathing spontaneously on room air with CPAP of cm H O. 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 PET CO of the lowest three consecutive breaths preceding the first apnea (indicated by the thick horizontal line). threshold was different if it was determined with pressure support versus a spontaneously falling PET CO. In the seven patients from the CSA group who had both spontaneous and ventilator-induced apneas or hypopneas, the apnea hypopnea threshold was almost identical with the two methods (spontaneously falling PET CO versus ventilator-induced: mm Hg versus mm Hg, p 0.05, for apnea threshold and mm Hg versus mm Hg, p 0.05, for hypopnea threshold). In addition, the nadir of Sa O immediately before the onset of apnea was % for spontaneous apneas and % for the ventilator-induced apneas. The difference was not statistically significant. DISCUSSION Patients with CHF and CSA showed a decreased proximity of eupneic PET CO to the threshold PET CO 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 CO makes a transient reduction of PCO much more likely to fall below the apnea threshold, and the increased ventilatory sensitivity below eupneic PCO makes the respiratory system more sensitive to any reduction of CO. Thus, both abnormalities predispose patients to periodic breathing. Although a low eupneic PCO has been reported, and a eupneic PCO 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 TABLE 1. DESCRIPTION OF PATIENTS WITH AND WITHOUT CENTRAL SLEEP APNEA Control CSA p-value Number 7 1 Age, yr BMI, kg/m AHI, number per hour LVEF, % FVC, % of pred FEV1/FVC, % Definition of abbreviations: AHI, apnea/hypopnea index; BMI, body mass index; Control, patients with congestive heart failure without CSA; CSA, patients with congestive heart failure and central sleep apnea; FVC, forced vital capacity; FEV 1 /FVC, forced expiratory volume in one second over the forced vital capacity; LVEF, left ventricular ejection fraction. 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 CO. It is not clear what causes the eupneic PCO 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 PCO and a disproportionately high apnea hypopnea threshold. Effect of Sleep on Eupneic PCO Unlike the control patients, patients with CSA demonstrated an unusual response to the sleeping state, in that their PET CO 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 (0). Our patients with CSA had a higher incidence of atrial Figure 3. Awake and asleep eupneic PET CO during stable breathing and apnea threshold during sleep. In the control group ( ) there was a consistent and significant increase in eupneic PCO during sleep (from to mm Hg, p 0.01). In the CSA group ( ), there was no difference in eupneic PCO between sleep and wakefulness ( versus mm Hg, p 0.). In both groups, the apnea threshold was below both the sleep and awake eupneic PET CO. 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 PET CO ; p 0.05 compared with sleep as well as awake PET CO.

4 148 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 4. Difference between eupneic and threshold PET CO. The horizontal dashed line represents the average eupneic PET CO 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 PET CO (top of bar) and the threshold PET CO (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: mm Hg versus mm Hg, p 0.01; hypopnea: mm Hg versus mm Hg, p 0.05). *p 0.05 PET CO (eupnoeic threshold PET CO ) in the CSA group compared with the control group., Hypopnea;, apnea. 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 CO 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 (1). The manifestation of the ventilatory stimulation associated with pulmonary vascular congestion is more prominent in unconscious, compared with conscious, dogs (). Thus, the failure of the PCO 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 PCO and CSA despite vagal denervation (3). 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 PCO to the apnea hypopnea threshold. This Figure 5. Hypocapnic ventilatory response to CO below the eupneic PCO 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 ( L/min per mm Hg versus L/min per mm Hg). *p 0.05 compared with control slope. 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 PCO, and thus, the proximity of the eupneic PCO 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 PCO and threshold PCO by failing to proportionally reduce the threshold in the face of a reduction of eupneic PCO. In the present study, however, the CSA group had an Sa O 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 PCO and threshold PCO, 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 PCO 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 PCO below the eupneic PCO in a manner similar to what has been reported regarding the ventilatory response to PCO above eupnea (7 9). We detected a higher ventilatory response to CO 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 L/minute per mm Hg in normal subjects without heart dysfunction or sleep-disordered breathing (16, 4, 5). In the CSA group, the ventilatory response to CO 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, 6). 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 PCO 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 (7). 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 CO from the 3 consecutive breaths that had the lowest PET CO 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 CO 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 CO sensed at the periph-

5 Xie, Skatrud, Puleo, et al.: Apnea Threshold in Heart Failure 149 eral chemoreceptors might be best correlated with the subsequent apnea (3). In patients with CSA, we chose to stabilize the breathing pattern with exogenous CO 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% CO, then stopped the CO 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 PCO back to baseline following even higher levels of CO (4 6%) (8). In the eight patients who required CO to stabilize their breathing pattern, PET CO (eupneic PCO - threshold PCO ) was actually larger than in the four patients who did not receive CO and had their threshold determined with pressure support ( mm Hg versus mm Hg). Thus, we do not believe that CO inhalation had an independent effect in producing the systematic narrowing of the eupneic PCO 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 PCO, pressure support ventilation versus spontaneous breathing. It has been demonstrated that positive pressure ventilation produces neuromechanical inhibition to the respiratory drive (9), 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 PCO, 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 CO 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 PCO 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 CO, Sa O, ventilatory response to CO, 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 CO below eupnea is enhanced. These two abnormalities result in a narrowed difference between the eupneic PCO and the ventilatory threshold, which in turn is associated with an unusual susceptibility to apnea and breathing pattern instability. Acknowledgment : The authors would like to thank General Clinical Research Centre of University Wisconsin for assistance. References 1. 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