(Circulation. 1999;99:1190-1196.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Acute Saline Infusion Reduces Alveolar-Capillary Membrane Conductance and Increases Airflow Obstruction in Patients With Left Ventricular Dysfunction
From the Department of Cardiology, The Cardiothoracic Centre, Liverpool (S.P.), the Academic Unit, Department of Cardiology, Kingston-upon-Hull (J.G.F.C.), and the National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, Hammersmith Campus, London, UK.
Correspondence to Professor J.G.F. Cleland, Academic Unit, Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, Kingston-upon-Hull HU16 5JQ, UK.
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Abstract |
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Background—Impaired alveolar-capillary membrane conductance is the major cause for the reduction in pulmonary diffusing capacity for carbon monoxide (DLCO) in heart failure. Whether this reduction is fixed, reflecting pulmonary microvascular damage, or is variable is unknown. The aim of this study was to assess whether DLCO and its subdivisions, alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (Vc), were sensitive to changes in intravascular volume. In addition, we examined the effects of volume loading on airflow rates.
Methods and Results—Ten patients with left ventricular dysfunction (LVD) and 8 healthy volunteers were studied. DM and Vc were determined by the Roughton and Forster method. The forced expiratory volume in 1 second (FEV1), vital capacity, and peak expiratory flow rates (PEFR) were also recorded. In patients with LVD, infusion of 10 mL · kg-1 body wt of 0.9% saline acutely reduced DM (12.0±3.3 versus 10.4±3.5 mmol · min-1 · kPa-1, P<0.005), FEV1 (2.3±0.4 versus 2.1±0.4 L, P<0.0005), and PEFR (446±55 versus 414±56 L · min-1, P<0.005). All pulmonary function tests had returned to baseline values 24 hours later. In normal subjects, saline infusion had no measurable effect on lung function.
Conclusions—Acute intravascular volume expansion impairs alveolar-capillary membrane function and increases airflow obstruction in patients with LVD but not in normal subjects. Thus, the abnormalities of pulmonary diffusion in heart failure, which were believed to be fixed, also have a variable component that could be amenable to therapeutic intervention.
Key Words: capillaries • lung • heart failure • ventricular dysfunction • lung diffusion
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Introduction |
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Reduction in the pulmonary diffusing capacity for carbon monoxide (DLCO) is well described in patients with chronic heart failure.1 2 3 The extent of the reduction in DLCO correlates independently with NYHA functional class and maximal exercise performance.4 5 6 Arterial oxygen desaturation on exercise, however, is uncommon in the majority of heart failure patients,7 8 indicating that mechanisms other than hypoxia per se are important in explaining the close correlation between DLCO and exercise performance.
Studies of heart transplant recipients have demonstrated that a low
DLCO persists after transplantation despite the return to
normal of pulmonary hemodynamics and lung
volumes,9 10 11 suggesting that reduction of
DLCO in chronic heart failure may in part reflect permanent
damage to the alveolar-capillary interface. In patients with mitral
stenosis, DLCO has been partitioned into its
constituent parts: alveolar-capillary membrane conductance
(DM) and reactive conductance 
· Vc (where is
the rate of chemical reaction of CO with Vc, the volume of
pulmonary capillary blood available for gas
transfer).12 The reduction in DLCO and
DM in this patient group correlates with NYHA functional
class12 and the severity of histological
lung damage.13 Moreover, pulmonary gas transfer
may remain abnormal for up to 8 years after mitral valve
replacement,14 further supporting the hypothesis that a
reduction of DM may reflect structural damage of the
alveolar-capillary interface.
Recent studies have demonstrated that the reduction in DLCO observed in heart failure is also due predominantly to a reduction in DM.5 6 Whether this reduction in DM is fixed, reflecting solely pulmonary microvascular damage, or has a variable component is unknown. Some workers have proposed that accumulation of subclinical interstitial edema, a potentially reversible factor, might contribute to the reduced DLCO seen in chronic heart failure.1 15 16 The aim of this study was to test the sensitivity of pulmonary gas transfer as measured by DLCO and its subdivisions to acute isotonic intravascular volume expansion in patients with significant left ventricular dysfunction (LVD) compared with normal subjects. In addition, because airway obstruction occurs in patients with decompensated heart failure and improves with diuretic therapy,15 17 we wished to examine the effects of acute volume loading on lung spirometry and peak expiratory flow rate (PEFR) measurements.
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Methods |
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Subjects
This study was approved by the Hospital Ethics Committee, and all subjects gave informed written consent. Patients who were currently smoking or gave a history of respiratory disease were excluded. Ten patients (9 men, 1 woman) with a history of myocardial infarction >6 months before study and significant LVD (multigated radionuclide left ventricular ejection fraction <40%) were recruited. All were asymptomatic (NYHA class I) and had been stable for 3 months before study. None were taking any medication apart from aspirin. Their anthropometric, clinical, and pulmonary function details are summarized in Table 1
. All
were ex-smokers, but none had smoked for at least 2 years before
the study.
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We chose patients with asymptomatic LVD as opposed to patients with symptomatic heart failure for 2 reasons: (1) to avoid the use of vasoactive medication that might confound the cardiorespiratory response to acute fluid loading and introduce iatrogenic interpatient variability and (2) because administration of intravenous 0.9% saline would be potentially more hazardous in patients with symptomatic heart failure requiring diuretic therapy.
In addition, 8 healthy volunteers (7 men, 1 woman) without histories of
cardiorespiratory disease and with a normal physical examination were
also studied. Their anthropometric and pulmonary function
details are summarized in Table 1
. Three were ex-smokers, having
given up smoking >2 years previously, and the remainder were lifelong
nonsmokers.
All subjects performed a screening symptom-limited maximal exercise
test on an electronically controlled bicycle ergometer (Siemens EM840)
with a 10-W/min incremental protocol. Respiratory gas analysis
was performed on a breath-by-breath basis (Amis 2000 Respiratory Mass
Spectrometer, Innovision), and the maximal oxygen consumption at peak
exercise (M
O2) was
recorded (Table 1). None of the subjects studied terminated
exercise for reasons other than breathlessness or fatigue.
Pulmonary Function Testing
Spirometry
The forced expiratory volume in 1 second
(FEV1) and vital capacity (VC) were
measured with a dry-bellows spirometer (Vitalograph). The PEFR was also
measured (Wright's flowmeter). The best of 3 successive measurements
made was used in subsequent analysis.
Pulmonary Gas Transfer
DLCO was measured by the modified Krogh
single-breath technique (PK Morgan).18 This was performed
in duplicate with a test gas containing 0.28% CO, 14% He, 21%
O2, and the balance nitrogen. The
DLCO measurements were then repeated in duplicate with a
test gas with a higher O2 concentration (0.3%
CO, 10% He, 89.7% O2). The alveolar partial
pressure of O2
(PAO2) for all DLCO
measurements was estimated from the fractional expired
O2 concentration of the same expired gas sample
used for the measurement of DLCO (Servomex
O2 analyzer 570A). DM and Vc
were determined by the classic Roughton and Forster method, which is
described in detail elsewhere.5 18 19 We assumed that the
red cell membrane has a negligible resistance to gas exchange (ie, that
, the ratio of red cell membrane permeability to that of the red
cell interior, has an infinite value). We have shown this method to be
reliable and highly reproducible in both normal subjects and patients
with heart failure.5
Protocol
All subjects were instructed to refrain from drinking beverages
containing alcohol or caffeine for 24 hours before the study. Subjects
fasted for 4 hours before the beginning of the study. An
intravenous forearm cannula was inserted for blood sampling
and infusion of fluids.
Blood hemoglobin concentration, body weight (after micturition), FEV1, VC, PEFR, DLCO, effective alveolar volume (VA), DM, and Vc were measured as outlined above at baseline and 1 hour after the completion of a 30-minute infusion of 0.9% saline (the total volume infused was calculated as 10 mL · kg-1 body wt of the individual subject undergoing study). The values obtained for DLCO and its subdivisions were corrected for hemoglobin before and after saline infusion to allow for any dilutional effect that might have occurred. Heart rate, blood pressure, and arterial O2 saturation (SAO2) by earlobe pulse oximetry were monitored at 5-minute intervals during the course of the saline infusion and at 15-minute intervals for a period of 2 hours thereafter. All patients with LVD were reassessed 24 hours after infusion and had repeat pulmonary function tests as performed during the acute saline infusion study day.
Parallel Control Study
To assess whether there were any inherent effects of the study
protocol on the variables being measured (eg, theoretical effects
of CO backpressure, etc), 5 randomly chosen patients with LVD and 5
normal subjects underwent a control study using the exact same study
protocol but without any infusion of saline.
Effects of CO Backpressure on DLCO
Measurements
As a result of the above control study and other measurements
undertaken in our laboratory, we have found no evidence of significant
CO backpressure effects on serial DLCO, DM, or
Vc measurements in normal subjects or patients with LVD under the
present study protocol.
Statistical Analysis
All values are expressed as mean±SD unless otherwise stated.
Results at baseline presaline infusion and 1 hour after saline infusion
were compared by paired Student's t test analysis.
Unpaired t test analysis was used to compare the
data of normal subjects with those of patients with LVD. A value of
P<0.05 was considered statistically significant.
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Results |
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All subjects tolerated the infusion of 0.9% saline without side effects. The mean volume of saline infused per subject during the study was 830±90 mL. This did not produce any significant change in blood pressure, heart rate, or SAO2 (Table 2
). Hemoglobin concentration decreased
after saline infusion (from 14.3±0.9 to 14.1±0.7 g ·
dL-1, P<0.05) but had returned to
baseline values 24 hours later (14.4±0.8 g ·
dL-1). Patients with LVD had significantly
reduced values of MO2
compared with normal subjects despite being asymptomatic
(Table 1).
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Patients With LVD
Spirometry and PEFR
Baseline values of FEV1 and VC were reduced
in patients with LVD compared with normal subjects (Table 1).
Saline infusion significantly reduced FEV1
without any significant change in VC, thereby reducing the
FEV1/VC ratio (Figure 1, Table 3). PEFR was also significantly reduced
(Figure 1). Twenty-four hours later, all values had returned to
baseline (Table 3).
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Pulmonary Gas Transfer
Acute saline loading significantly reduced DLCO and
its DM component without any significant change in
pulmonary capillary volume or VA (Figures 2 and 3).
The proportion of total pulmonary diffusive resistance
attributable to the alveolar-capillary membrane
(DLCO/DM) is 50% in normal
subjects.5 20 The DLCO/DM in our
study patients was higher at baseline than this value (Table 3)
and increased further after saline infusion (Figure 3). All
values had returned to baseline 24 hours later (Table 3).
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Parallel Control Study
The results of the control study in 5 normal subjects and 5
patients with ventricular dysfunction are summarized in
Table 4. No significant changes were seen
in any of the pulmonary function tests measured. This would
imply that the changes observed during the study conducted with acute
saline infusion cannot be accounted for because of the study protocol
or CO backpressure effects in our patient population.
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Normal Subjects
In contrast to the patients with LVD, acute saline infusion had no
significant effect on FEV1, VC, PEFR,
DLCO, DM, or Vc (Table 3).
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Discussion |
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This study is the first to demonstrate that patients with asymptomatic LVD have significantly impaired resting lung function compared with normal subjects and that infusion of a relatively modest volume of isotonic saline (10 mL · kg-1 body wt) can acutely further impair gas transfer across the alveolar-capillary membrane and increase airflow obstruction. This deterioration of pulmonary function occurs within 60 minutes after the infusion of isotonic saline and is completely reversible over a 24-hour period. No changes in pulmonary function were observed in the normal subjects. Larger and more rapid infusions of isotonic saline (25 to 30 mL · kg-1 body wt infused over 20 to 30 minutes) have been shown to produce changes in pulmonary function in normal subjects,21 22 23 but any alterations produced are rapidly reversible, fully resolving within 60 minutes of completion of the infusion.
Saline Infusion and Pulmonary Diffusion
In the present study protocol, we found no significant change
in DLCO or its subdivisions in normal subjects after saline
loading. Other workers have found that saline infusion of 25 to 30
mL · kg-1 body weight over 20 to 30
minutes in normal subjects increases perfusion of the lung apices and
recruitment of pulmonary capillaries,23 resulting
in a rise in DLCO predominantly as a consequence of a
larger volume of pulmonary capillary blood being available for
gas transfer.21 The DM component of
DLCO, although decreasing immediately after saline
infusion, remains relatively unaltered overall.21 This
would suggest that although interstitial edema can occur in
normal subjects with large and rapid volume loads, clearance of
interstitial fluid is also rapid.
The response to saline infusion was very different in our patient group with LVD, DLCO decreasing predominantly because of a reduction in DM, whereas Vc did not change significantly. According to Fick's law of diffusion, the diffusion of any gas across a membrane will be dependent on the surface area and intrinsic properties of the membrane, such as its thickness and permeability. An alteration in either of these properties could therefore be responsible for the changes observed in DLCO and DM.
Alveolar-Capillary Membrane Surface Area
A reduction in lung volume or an increase in ventilation-perfusion
mismatch would reduce the surface area of alveolar-capillary membrane
available for gas transfer. No change in VC or VA occurred
in the present study after saline infusion (Table 3), and
the reduction in DM persisted even when VA was
accounted for (DM/VA, Figure 2), making
this mechanism unlikely as a cause of the impaired pulmonary
gas transfer. An increase in ventilation-perfusion mismatch would lead
not only to a reduction in the DM component of
DLCO but also to a reduction in its Vc component. Vc did
not change significantly after saline infusion; therefore,
ventilation-perfusion mismatch cannot explain the reduction in
pulmonary diffusion after saline infusion.
Intrinsic Properties of the Alveolar-Capillary Interface
The alveolar-capillary interface is formed by a number of
different physical layers, including the alveolar epithelium,
interstitial fluid, capillary endothelium,
plasma, and red cell membrane, any of which might potentially be
affected by saline infusion. The development of subclinical
interstitial pulmonary edema after acute myocardial
infarction is well described.24 Clearly, saline infusion
in our patient population with LVD could also lead to the accumulation
of interstitial fluid. This would lead to an increase in
the diffusion path length for gas exchange and thereby reduce
DM.
Recent studies in the isolated rabbit lung model have shown by electron microscopy that raising pulmonary artery pressures can lead to ultrastructural fractures (also called stress failure) of the alveolar-epithelial, alveolar-capillary basement membrane, and pulmonary capillary-endothelial layers,25 26 some of which may be reversible.27 The hemodynamic consequence of rapid saline infusion in normal subjects is to acutely increase cardiac output, pulmonary artery pressure, and right atrial pressure after the infusion, with a return to baseline levels over the course of 60 minutes.23 28 Elevation of pulmonary capillary pressures is well documented in patients with LVD.29 30 31 32 Although we did not measure hemodynamics in our study, infusion of saline could have produced a further increase in pulmonary microvascular pressures sufficient to produce "stress failure" of the alveolar-capillary interface, thereby altering the intrinsic properties of the alveolar-capillary membrane and allowing the development of subsequent interstitial edema.
Saline Infusion and Airflow Obstruction
Increased airflow obstruction is well documented in patients
with heart failure and pulmonary edema.15 17 24 In
the present study, saline infusion acutely produced a small but
significant reduction in both FEV1 and PEFR in
patients with LVD (Table 3, Figure 3), but not in the
normal subjects studied (Table 3). Several factors,
either in isolation or in combination, could be responsible for the
changes in airflow obstruction observed in patients with LVD, as
follows.
Peribronchial Compression
Peripheral airways in the lung parenchyma lie
within bronchovascular sheaths that also contain branches of the
pulmonary vasculature and lymphatics. Several authors have
proposed that the initial increase in airway resistance observed in
experimentally induced pulmonary edema is secondary to
distension of the pulmonary arteries within bronchovascular
sheaths, with subsequent compression of the smaller
peripheral airways.33 34 35 In addition, rapid
infusion of 2 L of 0.9% saline in normal subjects has been shown to
result in a transient reduction of indices of smaller airway
flow.21
FEV1 and PEFR, however, are largely determined by the caliber of the larger airways, suggesting that this mechanism is unlikely as the major cause of any reduction observed in the present study with saline infusion. In addition, morphometric studies have failed to show any reduction in the caliber of peripheral airways in experimental pulmonary edema.36
Bronchoconstriction
Unmyelinated C fibers, which are present in
bronchi, lung parenchyma, and pulmonary vasculature, have been
proposed as stretch receptors in the interstitial space
that they occupy.37 38 In the dog model, both distension
of the pulmonary vasculature and interstitial
pulmonary edema independently increased C-fiber activity,
leading to vagally mediated reflex
bronchoconstriction.37 39 40 Similar changes may have been
produced by saline infusion in our patient population.
Bronchial Vessel Dilatation
Bronchial hyperresponsiveness has been documented by several
authors in patients with heart failure.41 42 43 Cabanes et
al42 demonstrated that the bronchoconstrictor response to
inhaled methacholine can be abolished by the action of the inhaled
vasoconstrictor methoxamine in chronic heart failure. They
proposed that elevation of left ventricular filling
pressure in chronic heart failure causes dilatation of bronchial wall
blood vessels with secondary transudation of plasma, thereby leading to
an increase in airway resistance and bronchial hyperresponsiveness.
Saline infusion in the patients studied could have produced elevation
of pulmonary vascular pressures, with a similar effect on
airway function.
Conclusions
This study is the first to demonstrate that measurements of
resting DLCO, and in particular its DM
component, are not fixed in patients with LVD but rather deteriorate
with acute intravascular volume expansion. In addition, saline loading
leads to increased airflow obstruction, possibly reflecting engorgement
of bronchial blood vessels or vagally mediated bronchoconstriction.
Pulmonary function tests in patients with LVD appear to be more
sensitive to changes in intravascular volume than in normal subjects.
The challenge of saline infusion, with its consequent effects on
pulmonary function as observed in the present study, may in
some respects mirror the changes that occur during exercise. Whether or
not such changes occur during exercise or contribute to the exertional
dyspnea of heart failure merits further study.
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Acknowledgments |
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Dr Puri and Dr Cleland were supported by junior and senior research fellowships, respectively, from the British Heart Foundation.
Received May 20, 1998; revision received November 10, 1998; accepted November 30, 1998.
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M. Guazzi Alveolar-Capillary Membrane Dysfunction in Heart Failure: Evidence of a Pathophysiologic Role Chest, September 1, 2003; 124(3): 1090 - 1102. [Abstract] [Full Text] [PDF]
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S. Nanas, J. Nanas, O. Papazachou, C. Kassiotis, A. Papamichalopoulos, J. Milic-Emili, and C. Roussos Resting Lung Function and Hemodynamic Parameters as Predictors of Exercise Capacity in Patients With Chronic Heart Failure Chest, May 1, 2003; 123(5): 1386 - 1393. [Abstract] [Full Text] [PDF]
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C. C. W. Hsia Recruitment of Lung Diffusing Capacity: Update of Concept and Application Chest, November 1, 2002; 122(5): 1774 - 1783. [Abstract] [Full Text] [PDF]
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M Guazzi, G Pontone, R Brambilla, P Agostoni, and G Reina Alveolar-capillary membrane gas conductance: a novel prognostic indicator in chronic heart failure Eur. Heart J., March 2, 2002; 23(6): 467 - 476. [Abstract] [Full Text] [PDF]
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B. D. Johnson, K. C. Beck, L. J. Olson, K. A. O'Malley, T. G. Allison, R. W. Squires, and G. T. Gau Pulmonary Function in Patients With Reduced Left Ventricular Function : Influence of Smoking and Cardiac Surgery Chest, December 1, 2001; 120(6): 1869 - 1876. [Abstract] [Full Text] [PDF]
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 P Faggiano, A D'Aloia, A Gualeni, and A Giordano Relative contribution of resting haemodynamic profile and lung function to exercise tolerance in male patients with chronic heart failure Heart, February 1, 2001; 85(2): 179 - 184. [Abstract] [Full Text]
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