Background Breathing is controlled by a negative-feedback systemin which an increase in the partial pressure of arterial carbondioxide stimulates breathing and a decrease inhibits it. Althoughenhanced sensitivity to carbon dioxide helps maintain the partialpressure of arterial carbon dioxide within a narrow range duringwaking hours, in some persons a large hyperventilatory responseduring sleep may lower the value below the apneic threshold,thereby resulting in central apnea. I tested the hypothesisthat enhanced sensitivity to carbon dioxide contributes to thedevelopment of central sleep apnea in some patients with heartfailure.
Methods This prospective study included 20 men who had treated,stable heart failure with left ventricular systolic dysfunction.Ten had central sleep apnea, and 10 did not. The patients underwentpolysomnography and studies of their ventilatory response tocarbon dioxide.
Results Patients who met the criteria for central sleep apneahad significantly more episodes of central apnea per hour thanthose without central sleep apnea (mean [±SD], 35±24vs. 0.5±1.0 episodes per hour). Those with sleep apneaalso had a significantly larger ventilatory response to carbondioxide than those without central sleep apnea (5.1±3.1vs. 2.1± 1.0 liters per minute per millimeter of mercury,P=0.007), and there was a significant positive correlation betweenventilatory response and the number of episodes of apnea andhypopnea per hour during sleep (r=0.6, P=0.01).
Conclusions Enhanced sensitivity to carbon dioxide may predisposesome patients with heart failure to the development of centralsleep apnea.
Normally, the rate and depth of breathing are regulated by anegative-feedback system that maintains the partial pressureof arterial carbon dioxide within a narrow range throughoutlife. Changes in the partial pressure of carbon dioxide leadto changes in ventilation, so that the greater the sensitivityto carbon dioxide, the greater the ventilatory response.
Among normal persons there is considerable variation in sensitivityto carbon dioxide, which may in part be related to familial(genetic) influences.1,2,3,4 In a study of patients with chronicobstructive pulmonary disease, Mountain and associates1 foundthat diminished sensitivity to carbon dioxide, which presumablypreceded the onset of pulmonary disease, increased the riskof chronic hypercapnia in patients with established pulmonarydisease. Similarly, Moore et al.5 described a patient with afamilial diminution in sensitivity who had respiratory failure.
The results of these studies,1,5 given our understanding ofthe operation of the negative-feedback system that controlsventilation, suggest that in persons with cardiopulmonary disorders,an increase in carbon dioxide sensitivity minimizes perturbationsin the partial pressure of arterial carbon dioxide, thus protectingthem against the long-term pathologic consequences of hypercapnia.Although this protective mechanism is advantageous during wakinghours, the increased sensitivity can potentially destabilizebreathing during sleep.6,7,8,9
During sleep, ventilation decreases and the partial pressureof carbon dioxide rises by 3 to 6 mm Hg. If during sleep thepartial pressure of carbon dioxide decreases below a certainlevel, referred to as the apneic threshold, which is close tothe waking level, ventilation ceases (a condition called centralsleep apnea), and the partial pressure of carbon dioxide isrestored to its previous level.
The partial pressure of carbon dioxide may fluctuate duringsleep. In persons with increased sensitivity to carbon dioxide,the negative-feedback system that controls breathing elicitsa large ventilatory response when the partial pressure of carbondioxide rises; the consequent hyperventilation, by driving thepartial pressure of carbon dioxide below the apneic threshold,results in central apnea. As a result of the apnea, the partialpressure of carbon dioxide rises again, which leads to an increasein ventilation. In this way, cycles of central apnea and hyperventilationrecur during sleep.
Although central sleep apnea is a relatively rare condition,10it is common in patients with heart failure.11,12,13,14 In aprospective study of 81 ambulatory patients with treated, stableheart failure due to systolic dysfunction, my colleagues andI found that about 40 percent of the patients had central sleepapnea.14
On the basis of the correlation in normal persons between sensitivityto arterial carbon dioxide during waking hours and ventilatoryoscillation during sleep8 and considering the increased sensitivityto carbon dioxide of patients with idiopathic central sleepapnea,15 I tested the hypothesis that enhanced sensitivity tocarbon dioxide may contribute to the development of centralsleep apnea in patients with heart failure.
Methods
Patients
Twenty patients with heart failure were studied, 10 of whomhad central sleep apnea and 10 of whom did not.14 The patientswere part of a prospective study designed to determine the prevalenceand mechanisms of sleep apnea in heart failure. The detailsof that study have been published previously.14,16,17 The protocolwas approved by the institutional review board of the Universityof Cincinnati, and written informed consent was obtained fromall patients.
All 20 patients underwent polysomnographic studies after a nightof adaptation in the sleep laboratory. Within 24 hours beforeor after the polysomnographic studies, radionuclide ventriculography,pulmonary-function tests, and tests to measure the ventilatoryresponse to carbon dioxide were performed. Samples of venousblood and arterial blood for measurement of electrolytes andarterial-blood gases were obtained in the morning, before theventilatory response was measured.
Polysomnography
Polysomnography was performed with the use of standard techniques,as described previously.18,19 To determine the stages of sleep,an electroencephalogram (with two channels), chin electromyogram(with one channel), and electro-oculogram (with two channels)were obtained. Thoracoabdominal excursions were measured qualitativelyby respiratory inductance plethysmography (Respitrace, AmbulatoryMonitoring, Ardsley, N.Y.) or with pneumatic respiration transducers(Grass Instruments, Quincy, Mass.) placed over the rib cageand abdomen. Airflow was monitored qualitatively with an oronasalthermocouple (model TCTIR, Grass Instruments). Arterial-bloodoxyhemoglobin saturation was recorded with the use of a pulseoximeter. These variables were recorded on a multichannel polygraph(model 78D, Grass Instruments).
An episode of apnea was defined as the cessation of inspiratoryairflow for at least 10 seconds. An episode of obstructive apneawas defined as the absence of airflow in the presence of rib-cageand abdominal excursions. An episode of central apnea was definedas the absence of rib-cage and abdominal excursions and theabsence of airflow. Hypopnea was defined as a reduction in airflowlasting 10 seconds or more and associated with at least a 4percent decrease in arterial oxyhemoglobin saturation, an electroencephalographicarousal,20 or both. The number of episodes of apnea and hypopneaper hour is referred to as the apnea–hypopnea index. Thenumber of episodes of obstructive apnea and hypopnea per houris referred to as the obstructive apnea–hypopnea index,and the number of episodes of central apnea per hour is referredto as the central-apnea index. The apnea–hypopnea indexwas used to define the presence or absence of clinically importantsleep apnea, as previously described14 (15 episodes per hourindicated the presence of apnea, and <15 episodes per hourindicated its absence). In addition, patients with central sleepapnea had to have a central-apnea index of at least five episodesper hour.
The number of episodes of arousal per hour is referred to asthe arousal index. The results of all the polysomnographic studieswere pooled and scored without knowledge of any laboratory data,including the carbon dioxide ventilatory response.
Studies of Pulmonary Function and Ventilation
Pulmonary-function tests, measurements of maximal inspiratoryand expiratory pressures, and arterial-blood gas and pH measurementswere performed as described previously.21,22 Measurements ofventilation, oxygen consumption, carbon dioxide production,and the ventilatory response to carbon dioxide (the hypercapnicventilatory response) were performed in our laboratory as describedpreviously.22,23,24 In brief, the tests were performed whilethe patients were sitting, wearing a nose clip, and breathingthrough a mouthpiece connected to a low-resistance, two-wayvalve. Measurements were started several minutes after a steadystate had been achieved, as evidenced by the finding of a stableend-tidal partial pressure of carbon dioxide. First, minuteventilation, oxygen consumption, and carbon dioxide productionwere measured.22 The hyperoxic hypercapnic ventilatory response22,23,24was determined by Read's rebreathing method.25 Linear regressionwas used to determine the slope according to the following equation:ventilation = S x (the partial pressure of carbon dioxide–B),where S is the slope of the hypercapnic ventilatory responseand B is the intercept (on the x axis, which represents thepartial pressure of carbon dioxide) of the line that relatesventilation to the partial pressure of carbon dioxide. The mean(±SD) value for the slope of the ventilatory responseto carbon dioxide in 10 normal men in our laboratory was 2.92±0.92liters per minute per millimeter of mercury (range, 1.02 to4.1).22
In conducting the tests of ventilatory response, extreme cautionwas exercised to ensure uniformity in technique. All the testswere performed by one investigator. The patients were not allowedto drink caffeinated products on the morning of the tests. Testswere performed at least two hours after a meal, and the patientswere asked to empty their bladders before the tests. The patientswere familiarized with the equipment and breathed through themouthpiece for several minutes before measurement began. Anassistant monitored the patients continuously to ensure thatthey remained awake.
To compare the hypercapnic ventilatory response between patientswith and those without central sleep apnea, the slope of theresponse was adjusted for the patients' body-surface area, oxygenconsumption, carbon dioxide production, maximal voluntary ventilation,and forced vital capacity, since these factors affect the ventilatoryresponse.
Characteristics of the Patients
Ten of the patients with heart failure did not meet the criteriafor sleep apnea (i.e., they had scores on the apnea–hypopneaindex of <15 episodes per hour14). In these patients, theapnea–hypopnea index ranged from 0 to 6.8 episodes perhour, the obstructive apnea–hypopnea index was 0, andthe central apnea index ranged from 0 to 3.2 episodes per hour.In the 10 patients with heart failure who did meet the criteriafor central sleep apnea, the apnea–hypopnea index rangedfrom 19.5 to 107.2 episodes per hour, the obstructive apnea–hypopneaindex ranged from 0 to 0.8 episode per hour, and the central-apneaindex ranged from 6.1 to 79.1 episodes per hour. None of thepatients had apneic episodes during waking hours.
The patients in the two groups were matched with respect tothe results of their pulmonary-function tests, although somedifferences did exist. The patients in the two groups were alsosimilar with respect to their medications. Medications includedan angiotensin-converting–enzyme inhibitor (in 10 patientswithout central sleep apnea and 8 patients with central sleepapnea), furosemide (in 8 and 9 patients, respectively), digoxin(in 10 and 9 patients, respectively), and hydralazine (in 1patient in each group). None of the patients were receivingbeta-blockers, morphine derivatives, benzodiazepines, theophylline,or acetazolamide.
Statistical Analysis
The Mann–Whitney test was used to assess differences betweenpatients with and those without central sleep apnea, and chi-squareanalysis was used to analyze proportions. A two-sided P valueof less than 0.05 was considered to indicate statistical significance.Values are reported as means. Spearman rank correlation wasused to analyze the apnea–hypopnea index in relation tothe unadjusted slope of the ventilatory response to carbon dioxideand the slope adjusted for body-surface area, oxygen consumption,carbon dioxide production, maximal voluntary ventilation, andforced vital capacity. All the calculations were done with InStatsoftware, version 2.03 (GraphPad, San Diego, Calif.).
Results
There were no significant differences between the patients whomet the criteria for central sleep apnea and those who did notwith respect to demographic characteristics or various laboratorymeasurements (Table 1), the results of pulmonary-function tests(except for the percentage of predicted forced expiratory volumein one second) (Table 2), or measurements of ventilation (Table 3).Table 4 lists the characteristics of sleep and disorderedbreathing events and oxyhemoglobin saturation during sleep inthe patients. Among patients with central sleep apnea, the meancentral-apnea index was 35±24 episodes per hour. As aresult, these patients had arterial oxyhemoglobin desaturationand an excessive number of arousals from sleep (Table 4). However,total sleeping time and the proportion of time spent in eachstage of sleep did not differ significantly between these patientsand those without central sleep apnea.
Table 4. Characteristics of the Patients during Sleep.
The unadjusted slope of the ventilatory response to carbon dioxidewas significantly greater among patients with heart failurewho had central sleep apnea than among those who did not haveapnea (Table 3), although there was some overlap in values (Figure 1).This difference remained significant when the ventilatoryresponse was adjusted for body-surface area, forced vital capacity,maximal voluntary ventilation, oxygen consumption, and carbondioxide production. The ventilatory response to carbon dioxidebefore and after adjustment for these variables was 2.3 to 3.5times as great in patients with central sleep apnea as in thosewithout it (Table 3). Furthermore, there were significant correlationsbetween the apnea–hypopnea index and the slope of theven-tilatory response before adjustment (r=0.6, P=0.01) andafter adjustment for forced vital capacity (r=0.6, P=0.008),maximal voluntary ventilation ratio (r=0.6, P=0.005), carbondioxide production (r=0.6, P= 0.003), and oxygen consumption(r=0.6, P=0.005).
Figure 1. The Slopes of the Ventilatory Response to Carbon Dioxide in Patients with and Those without Central Sleep Apnea.
Individual values are shown for the unadjusted slope of the ventilatory response to carbon dioxide and for the slope as adjusted for body-surface area, forced vital capacity, maximal voluntary ventilation, and oxygen consumption. Values adjusted for maximal voluntary ventilation and oxygen consumption were multiplied by 100. P values are for the comparisons between the two groups of patients. Mean values are given in Table 3.
Discussion
The principal finding of this study is that patients with heartfailure who had central sleep apnea had a significantly greatersensitivity to carbon dioxide (by a factor of 2.3 to 3.5) thanpatients with heart failure who did not have central sleep apnea,as assessed by the ventilatory response to carbon dioxide. Therewas also a significant, positive correlation between sensitivityto carbon dioxide and the number of episodes of apnea and hypopneaper hour during sleep.
An enhanced sensitivity to carbon dioxide could destabilizebreathing during sleep. During sleep, the partial pressure ofcarbon dioxide rises and becomes the most potent stimulus ofrhythmic breathing.27 If the partial pressure of carbon dioxidedecreases below the apneic threshold, breathing ceases. Thisstate of central apnea results in an increase in the partialpressure of carbon dioxide, which in the presence of enhancedsensitivity to carbon dioxide elicits a large hyperventilatoryresponse. This response may in turn lower the partial pressureof carbon dioxide below the apneic threshold. The result isperiodic breathing with recurring cycles of apnea and hyperventilation.
In this study, in addition to differences in sensitivity tocarbon dioxide between patients with and those without centralsleep apnea, there was a significant and positive correlationbetween sensitivity and the number of episodes of apnea andhypopnea per hour. This finding further emphasizes the potentialdestabilizing effect of enhanced sensitivity to carbon dioxideon breathing during sleep in patients with heart failure.
The administration of oxygen decreases the number of episodesof central sleep apnea in patients with heart failure.11,12,13In a study of patients with heart failure and systolic dysfunction,periodic breathing improved and sensitivity to carbon dioxidedecreased significantly after one week of nocturnal administrationof supplemental nasal oxygen.28 Although the exact cause-and-effectrelation cannot be determined, the results of that study suggestthat the decreased sensitivity to carbon dioxide may have contributedto the improvement in periodic breathing during sleep.
Mechanisms underlying the initiation and maintenance of centralsleep apnea are complex.29,30 In addition to sensitivity, otherfactors have been implicated. The finding of a low partial pressureof arterial carbon dioxide during waking hours is highly predictiveof central sleep apnea, since the level may drop below the apneicthreshold during sleep.31,32,33 Likewise, a low metabolic rate34and low functional residual capacity6,7,9 may contribute toperiodic breathing during sleep. In the current study, therewere no significant differences between groups in the partialpressure of carbon dioxide, oxygen consumption and carbon dioxideproduction (measures of metabolic rate), or functional residualcapacity. Circulation time was not measured; however, a prolongedcirculation time may not be a key factor in the genesis of centralsleep apnea, but it may be important in determining the lengthof ventilatory cycles35,36 and in maintaining periodic breathing.36In experiments in dogs,36 circulation time had to be increasedseveralfold before spontaneous periodic breathing could occur,and even then, it occurred in a minority of the animals.
In this study there was some overlap in the ventilatory responseto carbon dioxide between patients with and those without centralsleep apnea (Figure 1), a finding that emphasizes the importanceof other mechanisms in the development of central sleep apnea.One critical factor is the apneic threshold during sleep, andwhether this threshold differs between patients with heart failurewho have central sleep apnea and those who do not have sleepapnea.
It is well known that increased sensitivity of the respiratorysystem to carbon dioxide or hypoxia may destabilize breathingduring sleep. The relative contributions of the peripheral arterialchemoreceptors (the carotid bodies) and of the central chemoreceptors(those within the medulla of the brain stem) to the enhancedsensitivity and the consequent periodic breathing and centralsleep apnea remain unclear, although it is generally believedthat the central chemoreceptors have the larger role in sensitivityto carbon dioxide. In one study, during periods of natural sleepin unanesthetized dogs, hypocapnia that was confined to thecarotid body did not result in central apnea.37 This findingsupports the role of the central chemoreceptors in the genesisof central sleep apnea.30,37 However, the sensitivity of thechemoreceptors may further change under conditions of heartfailure. The increased sensitivity to carbon dioxide in heartfailure appears to be specific to central but not obstructivesleep apnea.38
Both acquired and genetic factors may affect the ventilatoryresponse to carbon dioxide.1,2,3,4,5,37 In the current study,the two groups of patients with heart failure were well matched:differences in sex, age, body-mass index, base-line ventilation,partial pressures of arterial carbon dioxide and oxygen, metabolicrate, respiratory-muscle strength, and pulmonary function, allof which can affect the ventilatory response,39 did not accountfor the large and significant differences in sensitivity tocarbon dioxide between the two groups. In addition, the meanvalues for arterial blood pressure, heart rate, and left ventricularejection fraction, as well as the cardiovascular medications,were similar in the two groups. Of the medications they used,only hydralazine is a known respiratory stimulant.40 One patientin each group was receiving hydralazine.
Loss of sleep has been shown to decrease sensitivity to carbondioxide,41 but in the current study, the mean total sleepingtime was similar in the two groups. Sleep was more often interrupted(fragmented) in the patients who had central sleep apnea, butsleep fragmentation in the absence of sleep loss has not beenshown to affect sensitivity to carbon dioxide.42
The variation in ventilatory drive that has been noted amongrandomly selected normal persons is considerably smaller withinfamilies, and strong correlations in ventilatory drive amongfamily members have been reported.2,3 The clustering and correlationof ventilatory drive among family members suggest that thereare familial (presumably genetic) influences on the chemicalcontrol of ventilation. It is therefore conceivable that inmy patients, familial enhancement of the ventilatory responseto carbon dioxide predisposed them to the development of centralsleep apnea after the onset of heart failure. This suppositionis consistent with observations in patients with chronic obstructivepulmonary disease, a disorder in which diminished sensitivityto carbon dioxide (of a familial nature) predisposes patientsto hypercapnia.1 However, among normal persons, the range ofthe ventilatory response to carbon dioxide is broad.2 Alternatively,patients with heart failure who have central sleep apnea couldhave spontaneously increased sensitivity to carbon dioxide,independent of familial or genetic influences.
In summary, in this study, patients with heart failure who hadcentral sleep apnea had enhanced sensitivity to carbon dioxide.In addition, the degree of sensitivity was correlated with theseverity of central sleep apnea, a finding that supports thepossibility that increased sensitivity has a destabilizing effecton breathing during sleep.
Supported by Merit Review grants from the Department of VeteransAffairs.
I am indebted to Candice R. Brown for technical assistance andto Faye A. Jones for secretarial assistance.
Source Information
From the Pulmonary Service, Veterans Affairs Medical Center, and the Department of Medicine, University of Cincinnati College of Medicine — both in Cincinnati.
Address reprint requests to Dr. Javaheri at the Pulmonary Section (111F), VA Medical Center, 3200 Vine St., Cincinnati, OH 45220, or at javaheri,shahrokh{at}cincinnati.va.gov.
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15 episodes per hour indicated the presence of apnea, and <15 episodes per hour indicated its absence). In addition, patients with central sleep apnea had to have a central-apnea index of at least five episodes per hour. 
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