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(Chest. 2006;129:1330-1336.)
© 2006 American College of Chest Physicians

Closing Capacity and Gas Exchange in Chronic Heart Failure*

Roberto Torchio, MD; Carlo Gulotta, MD; Pietro Greco-Lucchina, MD; Alberto Perboni, MD; Laura Montagna, MD; Marco Guglielmo, MD and Joseph Milic-Emili, MD

* From the Fisiopatologia Respiratoria (Drs. Torchio, Gulotta, Perboni, and Guglielmo), Ospedale San Luigi Gonzaga, Orbassano, Turin, Italy; the Department of Cardiology (Drs. Greco-Lucchina and Montagna), Ospedale San Luigi Gonzaga, Orbassano, Turin, Italy; and Meakins-Christies Laboratories (Dr. Milic-Emili), McGill University, Montreal, QC, Canada.

Correspondence to: Roberto Torchio, MD, Fisiopatologia Respiratoria, Ospedale San Luigi Gonzaga, I-10043 Orbassano, Torino, Italy; e-mail r.torchio{at}inrete.it

Abstract

Background: Although it is commonly assumed that pulmonary congestion and edema in patients with chronic heart failure (CHF) promotes peripheral airway closure, closing capacity (CC) has not been measured in CHF patients.

Purpose: To measure CC and the presence or absence of airway closure and expiratory flow limitation (FL) during resting breathing in CHF patients.

Methods: In 20 CHF patients and 20 control subjects, we assessed CC, FL, spirometry, blood gas levels, control of breathing, breathing pattern, and dyspnea.

Results: The patients exhibited a mild restrictive pattern, but the CC was not significantly different from that in control subjects. Nevertheless, airway closure during tidal breathing (ie, CC greater than functional residual capacity [FRC]) was present in most patients but was absent in all control subjects. As a result of the maldistribution of ventilation and the concurrent impairment of gas exchange, the mean (± SD) alveolar-arterial oxygen pressure difference increased significantly in CHF patients (4.3 ± 1.2 vs 2.7 ± 0.5 kPa, respectively; p < 0.001) and correlated with systolic pulmonary artery pressure (r = 0.49; p < 0.03). Tidal FL is absent in CHF patients. Mouth occlusion pressure 100 ms after onset of inspiratory effort (P0.1) as a percentage of maximal inspiratory pressure (PImax) together with ventilation were increased in CHF patients (p < 0.01 and p < 0.005, respectively). The increase in ventilation was due entirely to increased respiratory frequency (fR) with a concurrent decrease in PaCO2. Chronic dyspnea (scored with the Medical Research Council [MRC] scale) correlated (r2 = 0.61; p < 0.001) with fR and P0.1/PImax.

Conclusions: In CHF patients at rest, CC is not increased, but, as a result of decreased FRC, airway closure during tidal breathing is present, promoting the maldistribution of ventilation, ventilation-perfusion mismatch, and impaired gas exchange. The ventilation is increased as result of increased fR, and PImax is decreased with a concurrent increase in P0.1, implying that there is a proportionately greater inspiratory effort per breath (P0.1/PImax). These, together with the increased fR, are the only significant contributors to increases in the MRC dyspnea score.

Key Words: closing volume • hypocapnia • hypoxemia • maximal inspiratory pressure • peripheral airway closure

Collins et al1 reported that the ratio of closing volume (CV) to vital capacity (VC) was increased in patients with chronic heart failure (CHF), and suggested that pulmonary congestion and edema promote peripheral airway closure. This is in line with the study by Hughes and Rosenzweig,2 who showed that in isolated perfused dog lungs the volume of trapped gas increased with increased lung water and was greater in the more dependent parts of the lung in which interstitial pulmonary edema was most prominent on histologic examination. They postulated that enhanced air trapping was caused by premature peripheral airway closure due to the presence of cuffs of edema fluid in the loose connective tissue around the extraalveolar peripheral airways before there was any significant change in alveolar wall thickness. An increase in the CV/VC ratio, however, can be due to an increase in CV and/or a decrease in VC. Clearly, the notion that pulmonary congestion and edema promote peripheral airway closure requires validation by the direct assessment of closing capacity (CC), as follows: CC = residual volume (RV) + CV. Collins et al1 also reported that in CHF patients CV exceed the expiratory reserve volume (ERV), implying that the opening and closure of the peripheral airway is present during tidal breathing. Furthermore, they suggested that the ensuing maldistribution of ventilation should lead to impaired gas exchange within the lung, but they did not measure blood gas levels.

Accordingly, in seated CHF patients and control subjects we assessed the following: (1) the magnitude of CC; and (2) the presence or absence of flow limitation (FL) and airway closure during tidal breathing. Measurements include spirometry, body plethysmography, blood gases, and control of breathing.

Materials and Methods

Patients
The study was carried out in 20 stable ambulatory patients (18 men) with congestive heart failure due to cardiomyopathy (6 after ischemia) without pleural effusions. None had been hospitalized within 20 days preceding the study. None were current smokers, but nine patients were ex-smokers. All patients received therapy with diuretics (carvedilol, 15 patients; digitalis, 9 patients; oral anticoagulant therapy [dicumarol], 7 patients; and dobutamine IV, 1 patient). Within 1 month prior to entering our study, Weber class was determined by cardiopulmonary exercise testing3: Weber class B, 7 patients; Weber class C, 10 patients; and Weber class D, 3 patients. Heart failure was defined as symptomatic left ventricular dysfunction, with a left ejection fraction of < 0.45 documented by bidimensional echocardiography. Patients were excluded if they had primary pulmonary, neurologic, or myopathic disease. The echocardiographic ejection fraction and systolic pulmonary artery pressure (sPAP) were measured within the 2 weeks preceding entry into our study. The mean ejection fraction was 23% (range, 9 to 34%) [Table 1 ]. Twenty healthy subjects (control subjects) who were matched for sex and age were also studied with the same protocol as for the CHF patients. All control subjects were nonsmokers, but nine patients were ex-smokers (Table 1). The study was approved by the local ethics committee, and informed consent was obtained from each subject.


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  		Table 1.. Anthropometric Characteristics and Baseline Respiratory Data in a Seated Position in CHF Patients and Control Group*

 
Experimental Protocol
Chronic dyspnea was scored using the modified Medical Research Council (MRC) scale based on six increasing grades (0 to 5).4 Dyspnea at rest was measured by a modified Borg scale, ranking magnitude from 0 (none) to 10 (maximal).5

Each patient underwent a spirometric, plethysmographic, and pulmonary diffusion (ie, diffusing capacity of the lung for carbon monoxide [DLCO]) study in the sitting position. Using a plethysmograph (Autobox 2800; SensorMedics; Yorba Linda, CA), airway resistance (Raw) was measured at a panting frequency of < 1 Hz. Spirometric and plethysmographic volumes were assessed according to European Respiratory Society (ERS).6 DLCO was measured with a water-sealed spirometer (Biomedin; Padua, Italy) using helium for the measurement of alveolar volume (VA).6 Predicted values of Raw were from Peslin,7 and those for DLCO were from the ERS.6 With the patient in the sitting position, arterial PO2 and PCO2 were measured (ABL 735; Radiometer; Copenhagen, Denmark).

Breathing pattern and mouth occlusion pressure 100 ms after onset of inspiratory effort (P0.1),8 maximal inspiratory pressure (PImax),9 CV, CC, and alveolar plateau slope ({Delta}N2)10 were measured (VMAX 229; SensorMedics), as previously described. The PImax was measured at RV according to American Thoracic Society/ERS criteria9 with predicted values obtained from Black and Hyatt.11

The CV and {Delta}N2 were measured in triplicate by a single-breath N2 test11 with the mean taken as the final value. The CV was expressed in liters or as the percentage of VC measured during the single-breath exhalation. By adding RV to CV, the CC (in liters) was obtained and was also expressed as the percentage of total lung capacity (TLC) [ie, CC/TLC ratio]. Predicted CV/VC and CC/TLC ratios were obtained from Buist and Ross.12 From these predicted ratios, the predicted values of CV and CC (in liters) were computed using predicted values of VC and TLC,6 respectively.

Tidal FL was assessed with the negative expiratory pressure (NEP) technique.13 A NEP of –5 cm H2O was applied (Direc/NEP System 200A; Raytech Instruments; Vancouver, BC, Canada) 0.2 s after the onset of expiration. Flow-volume curves obtained without and with NEP were superimposed; patients in whom the expiratory flow with NEP was the same as the reference flow during part of the whole expiration were considered to have FL.13

The alveolar oxygen tension used to compute the alveolar-arterial oxygen pressure difference (P[A-a]O2) was estimated using the following equation: alveolar oxygen tension = ([PB – 47) x FIO2]) – PaCO2/R, where PB is barometric pressure, FIO2 is the fractional O2 concentration of inspired air, and R is the respiratory quotient, which was assumed to be 0.8.

Statistical Analysis
The data are presented as mean ± SD. Correlation coefficients were obtained with the Spearman ({rho}) nonparametric test for MRC score and the Pearson test (r) for all other parameters. In a stepwise multivariate analysis, we also used the Pearson multiple correlation for determining the MRC score because the Poisson fit was almost identical to that obtained with the Pearson correlation. Where appropriate, paired and unpaired Student t tests were used. Statistical analysis was performed using a statistical software package (SPSS Statistical Package; SPSS; Chicago, IL).

Results

Table 1 provides the anthropometric characteristics and baseline respiratory data for control subjects and CHF patients. In the control subjects, all baseline respiratory data were within normal limits; the MRC and Borg scores were zero, while the CHF patients exhibited slightly higher levels of MRC and Borg dyspnea scores.

In CHF patients, the FEV1/FVC ratio was within normal limits, while TLC and its subdivisions were reduced. This is also shown in Figure 1 , where, for comparative purposes, volumes are expressed as the percentage of the predicted TLC.14


Figure 1
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  		Figure 1.. Lung volumes expressed as a percentage of the predicted TLC. Left, A: control subjects. Right, B: observed values in CHF patients. Values are given as mean ± SD (bars).

 
There were no significant differences in lung function between nonsmokers and ex-smokers in both CHF patients and control subjects, except for RV (percent predicted), which in control subjects was significantly (p < 0.05) lower in nonsmokers than in ex-smokers (Table 2 ).


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  		Table 2.. Respiratory Data of All CHF Patients and Control Subjects, Stratified in Nonsmokers and Ex-smokers*

 
The increased Raw and decreased DLCO levels in CHF patients were probably due mainly to the reduced functional residual capacity (FRC) because the specific airway conductance (sGaw) and DLCO/VA ratio values were in the normal range. None of the CHF patients or control subjects exhibited tidal FL.

The {Delta}N2 and CV/VC ratio were increased in CHF patients relative to control subjects (Table 3). The increase in the CV/VC ratio was due entirely to decreased VC because there was no significant difference in CV between CHF patients and control subjects.


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  		Table 3.. {Delta}N2, CV, and CC in CHF Patients and Control Subjects*

 
Also, no significant difference was found in CC, expressed both in liters and percent predicted. In fact, the CC was, on average, actually lower in CHF patients than in control subjects, although not significantly. This is also seen in Figure 1, which also shows that in CHF patients the CC was, on average, higher than FRC (CC was greater than FRC in 13 of the 20 CHF patients). In contrast, in all 20 control subjects CC was lower than FRC. In both CHF patients and control subjects, the CC percent predicted did not differ significantly between nonsmokers and ex-smokers (Table 2).

Resting ventilation and P0.1 were higher in CHF patients than in control subjects (Table 4 ), with the increase of minute ventilation (VE) resulting from increased respiratory frequency (fR). While the tidal volume (VT)/inspiratory time (TI) ratio was significantly higher in CHF patients (reflecting the higher P0.1), TI/total breathing cycle time (TTOT) ratio was the same in CHF patients and control subjects. The P0.1/PImax ratio (percentage) was, on average, more than twice as large in CHF patients as in control subjects, reflecting in part the increased P0.1 and in part the decreased PImax.


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  		Table 4.. Control of Breathing Data and Blood Gases in CHF Patients and Control Subjects*

 
As a result of the increased VE, the PaCO2 was lower in CHF patients than in control subjects.1516 The PaO2 was also significantly lower in CHF patients than in control subjects, while the P(A-a)O2 was increased, reflecting the fact that in most of our CHF patients (13 of 20) the CC was higher than the FRC. This implies opening and closing of peripheral airway closure during tidal breathing with maldistribution of ventilation and impaired gas exchange, as reflected by the increased P(A-a)O2. In control subjects, P(A-a)O2 correlated best with age (r = 0.65; p < 0.002), while in CHF patients it did not correlate with age but with sPAP (r = 0.49; p < 0.03).

Significant correlations were found for MRC score with PImax, P0.1/PImax ratio, fR, and PaCO2. However, according to stepwise multivariate regression analysis, the only significant independent predictors of MRC score were fR (in breaths/min) and P0.1/PImax ratio (percentage):

Formula
where r = 0.78, r2 = 0.61, and p < 0.001.

Discussion

The new findings of this study are that in CHF patients at rest (mostly in Weber class B and C), the following conditions prevail: (1) CC is not increased; (2) as a result of decreased FRC, however, airway closure with compromised pulmonary gas exchange is present during tidal breathing; (3) tidal FL is absent; (4) ventilation is increased as a result of increased fR with a concurrent decrease in PaCO2; and (5) PImax is decreased. Together with the concurrent increase in P0.1, this implies a proportionately greater inspiratory effort per breath (P0.1/PImax ratio). These, together with the increased fR, are the only significant contributors to the MRC dyspnea score.

Lung Volumes
In line with the results of most previous reports,11417 our patients exhibited a reduction in TLC and FRC but normal FEV1/FVC ratio. In contrast, Yap et al14 found a significant reduction in TLC but not in FRC. Their patients, however, were studied just after a period of acute decompensation, which may be associated with the presence of FL and dynamic hyperinflation with the patient in the sitting position.18 Hart et al19 found no reduction of either TLC or FRC in 10 CHF patients; half of their patients, however, had CHF due to coronary artery disease. In the present study, only 30% of the patients (6 of 20) had a history of coronary artery disease. The reduction of FRC (gas), which in our patients averaged 11% of the predicted TLC (Fig 1), was probably mainly due to space competition of gas with solids and/or liquids (eg, cardiomegaly, congestion, or interstitial edema). Assuming an equal elastance of the lung and chest wall at FRC, the chest wall volume should have also increased by 11% of the predicted TLC (ie, an amount equal to the reduction of FRC [gas]).20 However, TLC was reduced more than FRC, namely, 19% of the predicted TLC. This probably reflects the PImax decrease due to (1) chest wall expansion by an increased volume of the heart and blood, (2) an intrinsic weakness of the inspiratory muscles, and (3) increased elastic lung recoil pressure due to pulmonary congestion2122 and/or fibrosis.23 A decrease in the force of skeletal muscles (including inspiratory muscles) has been documented in CHF patients by many authors.17242526 Other functional abnormalities, such as the increased Raw shown in Table 1, probably mainly reflect the reduced thoracic gas volume in CHF patients. Indeed, while the Raw was abnormal, sGaw was within normal limits.

CC and Gas Exchange
In CHF patients, Collins et al1 found an increased CV/VC ratio relative to normal control subjects and, in line with the results of previous studies,21,23 suggested that pulmonary congestion and edema promote the premature closure of peripheral airways. In our CHF patients, the CV/VC ratio was also significantly increased, but the CV was not abnormal. This implies that the increase in CV/VC ratio was due entirely to decreased VC. There also was no significant difference in CC between CHF patients and control subjects, indicating that in our CHF patients there was "no premature airway closure." In fact, in CHF patients the CC was actually smaller than that in control subjects, although not significantly. This may reflect the fact that pulmonary fibrosis23 and/or vascular engorgement2122 may render the peripheral airways more resistant to collapse. In line with the findings of Collins et al,1 however, in most of our patients (13 of 20) the CC exceeded the FRC (ie, during tidal breathing there was cyclic opening and closing of peripheral airways with a concurrent maldistribution of ventilation and a risk of mechanical injury to the peripheral airways).27 As a result of this maldistribution of ventilation, PaO2 decreased and P(A-a)O2 increased (Table 4).

The {Delta}N2 was increased in CHF patients, providing further evidence for the presence of pulmonary mixing inhomogeneity. It is not clear whether the increased {Delta}N2 resulted from the enhancement of the gravity-dependent inhomogeneity within the lung or was an expression of the local differences in elastic properties of the alveolar walls.11 In CHF patients with chronic pulmonary hypertension and edema, the pulmonary capillary and tissue membranes undergo remodeling, which may result in changes in elastic properties.22 The remodeling at the level of alveolar-capillary membranes could also contribute to decreased DLCO (Table 1). In fact, in CHF patients there is a reduced alveolar-capillary diffusion transfer, which is inversely related to pulmonary vascular resistance.28 This may explain the fact that in our CHF patients the values of DLCO normalized for VA (and DLCO/VA ratio) remained significantly lower than those in the control subjects.

Ventilation and Breathing Pattern
In line with previous reports,151617 VE was increased in CHF patients with a concurrent decrease in PaCO2. The increase in VE was due entirely to increased fR since the VT was the same in CHF patients and control subjects.

In line with the findings of Ambrosino et al17 the TI/TTOT ratio was the same in CHF patients as in control subjects, whereas the inspiratory drive, as reflected by P0.1 and the VT/TI ratio, was significantly higher in CHF patients. The mechanisms for the increased inspiratory drive in CHF patients are poorly understood. It is of interest, however, to note that, despite the increased P0.1 and VT/TI ratio and the decreased PImax, the CHF patients exhibited a normal VT at rest. In CHF patients, lung compliance is decreased due to congestion or fibrosis,212223 and, under these conditions, the respiratory muscles usually try to conserve energy by decreasing VT and increasing fR. A possible explanation for the finding of increased central drive without a decrease in the VT would be the difference in operational length compensation of the diaphragm.29 Patients with CHF have smaller lungs and longer resting length of their diaphragms, which results in greater force generation for the same output during quiet breathing.29 This implies greater inspiratory effort with weaker inspiratory muscles, leading to an increased Borg dyspnea score at rest.

Dyspnea
The resting values of P0.1/PImax ratio and fR were also the only significant predictors of the level of MRC dyspnea. In fact, the P0.1/PImax ratio (percentage) and the fR explained 61% of the variance in MRC score. This suggests that the increased inspiratory load and effort, as implied by higher than normal values for the P0.1/PImax ratio and fR, is a cause of dyspnea in CHF patients.

Several studies in CHF patients303132 have failed to demonstrate a direct relationship between dyspnea and cardiac function data such as pulmonary capillary wedge pressure. In the present study, neither MRC dyspnea score nor Borg dyspnea score at rest correlate with sPAP and ejection fraction. On the other hand, some previous studies193233 have suggested increased inspiratory muscle load relative to inspiratory muscle capacity as a cause of dyspnea and exercise intolerance. Furthermore, McParland et al25 reported that in CHF patients PImax as well as maximal expiratory pressure were reduced, both being significantly correlated with dyspnea during daily activities. The present results support the notion that inspiratory force and loading play a significant role in eliciting dyspnea, as shown by the significant relationship of the level of MRC score and the resting values of P0.1/PImax ratio (percentage) and fR (equation 1). However, the relationship of these resting measurements to the mechanisms of dyspnea during exercise remains to be elucidated in CHF patients.

The absence of FL with the patient in the seated position is not surprising in CHF patients. FL was found in a small percentage of seated patients with acute heart failure.1834 In contrast, FL is frequently observed in patients in the supine position, which is correlated to orthopnea and can be reversed by therapy.34 The ERV reduction secondary to FRC reduction (because of cardiomegaly and vascular engorgement) can decrease ERV predisposing the patient to FL. In CHF patients, cardiac diameters and vascular engorgement would be smaller than in patients with acute heart failure, and this factor could explain why none of our CHF patients had FL in a sitting position.

In conclusion, the present results show that in CHF patients, relative to control subjects, the CC does not change while FRC decreases. Due to the decrease of FRC, most patients exhibit airway closure during tidal breathing with maldistribution of ventilation and impaired gas exchange within the lung (decreased PaCO2 and increased P[A-a]O2). The impaired gas exchange is partly compensated by increased pulmonary ventilation, which is associated with increased inspiratory effort due to fR. Since PImax is reduced, the association of increased inspiratory effort in the face of decreased potential force may explain the fact that CHF patients complain of dyspnea at rest (Borg score) and also exhibit chronic dyspnea (MRC score).

Footnotes

Abbreviations: CC = closing capacity; CHF = chronic heart failure; CV = closing volume; DLCO = diffusing capacity of the lung for carbon monoxide; ERS = European Respiratory Society; ERV = expiratory reserve volume; FL = expiratory flow limitation; fR = respiratory frequency; FRC = functional residual capacity; MRC = Medical Research Council; {Delta}N2 = alveolar plateau slope; NEP = negative expiratory pressure; P(A-a)O2 = alveolar-arterial oxygen pressure difference; PImax = maximal inspiratory pressure; P0.1 = mouth occlusion pressure 100 ms after onset of inspiratory effort; Raw = airway resistance; RV = residual volume; sGaw = specific airway conductance; sPAP = systolic pulmonary artery pressure; TI = inspiratory time; TLC = total lung capacity; TTOT = total respiratory time; VA = alveolar volume; VC = vital capacity; VE = minute ventilation; VT = tidal volume

Received for publication August 23, 2005. Accepted for publication October 28, 2005.

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