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Normal Pulmonary Capillary Blood Volume in Patients With Chronic Infiltrative Lung Disease and High Pulmonary Artery Pressure*

November 28, 2004

Study objectives: Pulmonary capillary blood volume (Qc), a component of diffusing capacity of the lung for carbon monoxide (DLCO), is increased in postcapillary pulmonary hypertension due to valve disease, but is decreased in primitive and thromboembolic pulmonary hypertension. This study was performed to evaluate which way pulmonary Qc is affected in patients with chronic infiltrative lung disease according to the value of systolic pulmonary artery pressure (SPAP).

Patients and methods: Twenty-four patients who were nonsmokers and had chronic infiltrative lung disease secondary to connective tissue disease (12 patients), asbestosis (1 patient), sarcoidosis (5 patients), or of unknown origin (6 patients), and 8 control subjects underwent pulmonary function tests and Doppler echocardiography.

Measurements and results: Total lung capacity, alveolar-arterial oxygen pressure difference, DLCO, and conductance of the alveolar- capillary membrane (Dm) did not differ between patients with low SPAP (LPAP) [ie,

Conclusions: We thus conclude that pulmonary Qc is not decreased as expected in patients with chronic infiltrative lung disease and high pulmonary artery pressure. A high Qc/Dm ratio should encourage the physician to look for HPAP compatible with pulmonary hypertension, whatever the etiology of lung infiltrative disease. (CHEST 2004; 126:1460-1466)

Key words: Doppler echocardiography; interstitial lung diseases; pulmonary diffusing capacity; pulmonary hypertension

Abbreviations: CO = carbon monoxide; DLCO = diffusing capacity of the lung for carbon monoxide; Dm = conductance of the alveolar- capillary membrane; HPAP = high systolic pulmonary artery pressure; LPAP = low systolic pulmonary artery pressure; PFT = pulmonary function tests; Qc = capillary blood volume; SPAP = systolic pulmonary artery pressure; TLC = total lung capacity; VA = alveolar volume

Diffusing capacity of the lung for carbon monoxide (DLCO) is a simple test that evaluates the efficiency of pulmonary gas exchange. DLCO soon becomes altered in patients with interstitial lung disease, and is widely used to assess the severity of, evolution of, and response to therapy of patients with this disease.1,2

DLCO is also frequently impaired in patients with primary precapillary pulmonary hypertension,3,4 a vascular disease that is associated with vasoconstriction and remodeling of the pulmonary vasculature.5,6 The alteration of DLCO depends on the respective changes in capillary blood volume (Qc) and the conductance of the alveolar-capillary membrane (Dm). These two components of DLCO can be conveniently determined using the method of Roughton and Forster7 and Forster.8 DLCO impairment is thought to be related to decreased pulmonary Qc in patients with primary, precapillary, pulmonary hypertension3,4.

Renzoni et al9 observed in surgical lung biopsy specimens obtained from patients with fibrosing alveolitis and systemic sclerosis that vessel density is reduced in gas exchange areas, suggesting that pulmonary Qc is decreased in fibrotic lungs. Pulmonary hypertension is a major cause of morbidity and mortality in patients with lung fibrosis.10 As the therapeutic targets of vasoactive agents that reduce pulmonary hypertension in patients with lung fibrosis11 are localized in the precapillary pulmonary vasculature, this pulmonary hypertension is, in part, likely to be of precapillary origin. It is thus reasonable to think that pulmonary Qc would be lower in patients with chronic infiltrative lung disease and pulmonary hypertension than in those without pulmonary hypertension.

The aim of the study was to evaluate whether pulmonary Qc is lower in patients with chronic infiltrative lung disease and elevated systolic pulmonary artery pressure (SPAP). Dm, which is proportional to the surface exchange area and inversely proportional to the diffusing distance between alveolar gas and RBCs, was used to evaluate the severity of infiltrative lung disease.

MATERIALS AND METHODS

Patients

This study was performed in accordance with institutional guidelines and was approved by the ethics committee. All subjects gave their informed consent.

Twenty-four patients who were nonsmokers (mean [ SD] age, 51.7 14.6 years) and had chronic infiltrative lung disease secondary to connective tissue disease (12 patients), asbestosis (1 patient), sarcoidosis (5 patients), or unknown origin (6 patients) underwent pulmonary function tests (PFTs) and Doppler echocardiography in our department between March 2000 and September 2002. Chronic infiltrative lung disease was diagnosed on the basis of compatible history, physical examination findings, chest radiograph, and typical high-resolution CT scan findings (ie, honeycombing was observed in all patients). These patients had no clinical or echocardiographic signs or history of heart failure. No patient had received treatment that was specific for pulmonary or systemic arterial hypertension. There was no difference in Doppler echocardiographic and PFT parameters between patients with connective tissue disease and other patients. Eight healthy subjects from our medical or technical staff (mean age, 43 6.5 years) with no history of cardiopulmonary disease or smoking, and with normal chest radiograph and physical examination findings underwent PFTs and Doppler echocardiography. and served as control subjects.

PFTs

Lung volumes were measured (PFT-Masterscreen; Jaeger; Wursburg, Germany), and total lung capacity (TLC) was calculated from functional residual capacity, which was determined by the helium dilution method. The spirometry technique met international standards. The reference values used are those of the European Respiratory Society.12,13 Arterial blood sampling was made with patients in the sitting position. Blood sample was analyzed for PO^sub 2^, PCO^sub 2^, pH, and hemoglobin concentration (ABL550; Radiometer; Copenhagen, Denmark).

Alveolar volume (VA) was obtained subtracting dead space from TLC (VA = TLC – VD, where VD dead space volume, arbitrarily set to 0.15 L). DLCO was measured with the single-breath technique (Masterlab; Jaeger). Values were corrected for hemoglobin concentration. Results were expressed as a percentage of predicted values.14 The two components of DLCO, Dm and Qc. were determined using the following equation: 1/DLCO = 1/Dm + 1/θQc.7 The reaction rate of carbon monoxide (CO) with hemoglobin θ is proportional to hemoglobin concentration. 1/θ is assumed to be a linear function of alveolar oxygen tension (PAO^sub 2^) [in kilopascalsj, as follows: 1/ θ = 14.6/Hb [(0.001 PAO^sub 2^) + 1.034] (where Hb is the subject’s hemoglobin concentration in grams per deciliter).

DLCO is measured at different alveolar O2 concentrations, a plot of 1/DLCO against 1/θ is obtained, and 1/Dm is given by the y- intercept and 1/Qc is given by the slope of the straight line.” We previously verified the linearity of the relation under our experimental conditions using two or three different alveolar O2 concentrations (ie, 20.1%, 35%, and 92%) in 11 subjects (7 patients and 4 control subjects). In the present study, two alveolar O2 concentration values (ie, 20.1% and 92%) were used. All measurements were obtained in duplicate. The reproducibility of the technique is regularly assessed in our laboratory. Dm and Qc are given as the percentage of predicted values.14

Cardiovascular Function Tests

SPAP was noninvasively assessed by Doppler echocardiography (models SSA-380A and SSA-370A; Toshiba Medical Systems: Tokyo, Japan) from tricuspid regurgitation using the modified Bernoulli equation. Continuous-wave Doppler recordings were obtained from either the apical or the parasternal windows. Only Doppler signals resulting in a clearly defined envelope of velocities were considered to be suitable for analysis. Since application of the modified Bernoulli equation (pressure drop = 4V^sup 2^. where V = velocity) to the peak of the tricuspid regurgitant velocity provides a close estimate of the peak pressure gradient between the right ventricle and the right atrium, the right ventricle systolic pressure was derived by adding an estimate of mean right atrium pressure to the peak right ventricle-right atrium gradient. The mean right atrium pressure was estimated by evaluating the magnitude of the inferior vena cava collapse with inspiration. Because no patient had pulmonic stenosis or right ventricle outflow tract obstruction, right ventricle systolic pressure was considered to be equal to the pulmonary artery systolic pressure. 15 Two of our patients underwent right heart catheterization. Their SPAP values (70 and 45 mm Hg) were similar to those obtained by Doppler echocardiography (SPAP, 65 and 46 mm Hg). Left ventricular ejection fraction was calculated by the method of Teichholz. Some of the patients underwent PFTs and Doppler echocardiography within 12 to 18 months, and pulmonary Qc and SPAP values were found to be in agreement with the data of th\e present study (data not shown).

Patients were divided into the following two groups: those with a low SPAP (LPAP) [ie,

Statistical Analysis

All values are expressed as the mean SD. Comparisons between groups were made using analysis of variance. Post-test comparisons were made using the Bonferroni test. Regression analyses were performed with the mean least squares method. A stepwise regression analysis (F in, 4; F out, 4) was used to identify the determinants of SPAP. A p value of

RESULTS

Ten patients had SPAP values of 30 mm Hg (ie, HPAP). The mean HPAP value was 41.3 8.2 mm Hg, and the mean LPAP value was 26 3.2 mm Hg (control subjects. 27.8 1.3 mm Hg: p

The male/female ratio and age were similar in patients and control subjects (Table 1). No difference in the duration of the disease since diagnosis was observed between patients with HPAP (3.9 3.7 years) and LPAP (1.7 1.6; p = 0.11).

Individual spirometry and blood gas data are smnmarized in Table 1. TLC was decreased in all patients (p 70% in all subjects and did nut differ between the groups.

DLCO was impaired in all patients (p

The sensitivity of the Qc measurement was verified by assessing the effect of body position in five healthy control subjects. The mean Qc was larger when measured with the patient in the supine position (108.3 12.4 mL) than when measured in the erect position (79.5 5.1 mL; p

Dm wits similarly considerably reduced in all patients (Fig 2, top left, A). By contrast, pulmonary Qc was significantly higher in HPAP patients than in LPAP patients (p

Table 1-PFTs and Doppler Echocardiography*

FIGURE 1. DLCO in patients with HPAP and LPAP, and in healthy control subjects. Top, A: DLCO was decreased in all patients compared to control subjects. Bar = mean value. Bottom, B: there was no difference among the three groups for DLCO scaled by alveolar volume (ie, DLCO/VA [the Krogh factor]).

A scatterplot shows how patients and control subjects were distributed in the Dm-Qc plane (Fig 3). For the same Qc value. Dm was considerably lower in HPAP patients than in control subjects. Among all parameters obtained with PFTs, Qc (positively, p

FIGURE 2. DLCO components in patients with HPAP and LPAP, and in healthy control subjects. Top left, A: Dm was reduced to the same extent in the two groups of patients. NS = nonsignificant. Top right, B: pulmonary Qc was reduced in LPAP patients hut not in HPAP patients. Bottom left, C: Qc/DLCO ratio was higher in HPAP patients than in LPAP patients and control subjects. Bottom right, D: Qc/Dm ratio was very significantly higher in HPAP patients than in LPAP patients and control subjects.

DISCUSSION

To our knowledge, this is the first study that has considered pulmonarv Qc in patients with chronic infiltrative lung disease in relation to pulmonary artery pressure level. The main finding is that Qc is often high, almost normal, in patients with chronic infiltrative lung disease and HPAP. Moreover, Qc scaled by Dm to account for infiltrative disease severity correlates with SPAP.

We found that DLCO was low in patients with chronic infiltrative lung disease, which is in agreement with the results of numerous previous studies,17 hut that it was not lower in patients with HPAP than in those with LPAP (Fig 1. top, A). DLCO is decreased in patients with scleroderma and pulmonary hypertension,18,19 and could he used to predict the development of isolated pulmonary hypertension (limit, 30 mm Hg) in patients with limited scleroderma.20 However, patients with mild pulmonary hypertension are not likely to he identified by non-invasive studies like DLCO.19 As a matter of fact, there was no difference in DLCO between patients with and without HPAP in our study, perhaps because few patients had severe pulmonary hypertension. A possible explanation for this absence of difference is that DLCO is a composite measure, with the effect of a larger Qc in patients with HPAP being obscured by the variable Dm alteration.

FIGURE 3. A scatterplot of Dm vs Qc in patients with chronic infiltrative lung disease and in healthy control subjects. Qc was higher in HPAP patients ([black circle]) than in LPAP patients ([white circle]). whereas Dm values were similar The Qc in HPAP patients was similar to that in control subjects ([black square]).

The estimation of SPAP by Doppler echocardiography is widely used and is the method of choice for survevs because it is noninvasive.16 Doppler echocardiography frequently overdiagnoses pulmonary hypertension in patients with severe lung disease (who are waiting for lung transplantation), but a correlation with SPAP measured by cardiac catheterization is acceptable,21 as this has already been demonstrated in patients with pulmonary hypertension of a different etiology.16,22 Because increased pulmonary pressure due to heart failure is also known to increase pulmonary Qc,23,24 we eliminated the association with congestive heart failure by showing that all patients had normal left ventricular ejection tractions.

FIGURE 4. A scatterplot of the Qc/Dm ratio vs SPAP. A significant correlation between the two parameters was found in patients with calculable SPAP (r = 0.68; p

We used a well-established simplified technique14 for Dm and Qc determination. This technique is extensively used in clinical studies.3,4,23,25-28 Its sensitivity was sufficient for detecting a 30% change in pulmonary Qc between measurements made with the patient in the erect and supine positions, as previously described.29

Multilinear analysis suggests that when disease severitv (ie, a decrease in Dm and PaO^sub 2^,) is taken into account. HPAP is highly correlated to Qc (p

The remodeling of precapillary arterioles in severe primary or secondary pulmonary hypertension involves an increase in vascular smooth muscle cell mass and endothelial cell proliferation. This remodeling leads to medial hypertrophy, concentric obliteration of the lumen, and vascular plexiform structures terminated in aneurysm- like dilatation lesions.5,6 The inhibition of apoptosis, and the facilitation of endothelial cell growth and angiogenesis have been related to the lack of the transcription factor peroxisome proliferator-activated receptor γ in angiogenic lesions of lung tissue from patients with primary and secondary pulmonary hypertension.33 Angiogenesis, together with vascular dilatations, may help to maintain pnlmonan Qc in patients with severe chronic infiltrative lung disease and pulmonary hypertension. However, Renzoni and coworkers9 have reported that vessel density is markedly reduced in lung biopsy specimens from patients with interstitial lung disease, particularly those obtained from the gas exchange region. Despite an increase in the amount of tissue due to fibrosis, it can be deduced from their data (Tables 3 and 4 in Renzoni et al9) that there is on average a net decrease in the number of vessels in these lungs. However, dispersion was quite large, and between- patient differences according to the level of pulmonary artery pressure cannot be eliminated because they were not documented. It can be calculated that CO may reach distances of > 100 m during the 10-s apnea,34 making it possible to combine with hemoglobin in distant vessels. Blood-filled vessels in lung regions with fibrosis or inflammatory infiltration will thus contribute to increases in Qc, will increase the exchange surface area but lengthen the mean CO diffusion di\stance, and thus will have no important effect on Dm. Figure 3 and Table 1 show that the larger Qc in patients with HPAP is not accompanied by a greater Dm or PaO^sub 2^ as is the case for control subjects, suggesting that the additional blood volume revealed by CO measurement is not to he found in the usual capillary gas exchange region.

To our knowledge, there is no study that has investigated the pathways involved in pulmonary hypertension development based on lung fibrosis etiology (ie, connective tissue disease, sarcoidosis, or idiopathic interstitial pneumonia). Patients with pulmonary hypertension secondary to diseases as different as extrinsic allergic alveolitis, sarcoidosis, systemic sclerosis, calcinosis cutis-Raynaud phenomenon-esophageal dysfunction-sclerodactyly- telangiectasia syndrome (also termed CREST), collagen vascular overlap syndrome, bronchopulmonary dysplasia, postradiation lung fibrosis, and idiopathic pulmonary fibrosis respond similarly to treatment with nitric oxide, prostaglandin I^sub 2^, iloprost, or sildenafil.30,32 It was also shown that patients with pulmonary fibrosis secondary to sarcoidosis, scleroderma, or cryptogenic alveolitis35 have decreased exhaled nitric oxide levels compared with patients with primary pulmonary hypertension. It is worth noting that patients do not cluster, depending on chronic infiltrative lung disease etiology, along the SPAP-Qc/Dm relationship, which suggests that a common mechanism leads to HPAP and a change in CO transfer components (Fig 4).

Our findings suggest that the process that leads to an increase in SPAP, and eventually to pulmonary hypertension, may be the consequence of the same factors that promote angiogenesis. For example, the expression of transforming growth factor-β1 is altered in lungs during pulmonary hypertension.36,37 Transforming growth factor-β1 probably plays an important role in the development of fibrotic pulmonary diseases of diverse etiology38-41 and is known to stimulate angiogenesis.42

We conclude that the measurement of the two components of DLCO is a simple and noninvasive technique that may warn of an increased risk of pulmonary hxpertension in patients with chronic infiltrative lung disease. The mechanism of the maintenance of pulmonary Qc and a high Qc/Dm index in these patients is unclear, and warrants further study, in particular using morphometry techniques9 and in patients with the same primary cause for HPAP to determine the anatomic counterpart of this physiologic observation.

* From the Service de Physiologie-Explorations Fonctionnelles Hpital Bichat-Claude Bernard, Assistance Publique Hpitaux de Paris, Paris, France.

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Marcel Bonay, MD, PhD; Catherine Bancal, MD; Dominique de Zuttere, MD; Florence Arnoult, MD; Georges Saumon, MD; and Franoise Camus, MD

Manuscript received January 20, 2004; revision accepted May 7, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Marcel Bonay, MD, PhD, Service de Physiologie- Explorations Fonctionnelles, Hpital Bichat-Claude Bernard, Assistance Publique Hpitaux de Paris, 46 rue Henri Huchard, 75877 Paris cedex 18, France; e-mail: marcel.bonay@ bch.ap-hop-paris.fr

Copyright American College of Chest Physicians Nov 2004




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