Pulmonary alveolar proteinosis

Background: Prone positioning may improve oxygenation in patients with acute lung injury/ARDS. However, the beneficial effect of prone positioning on gas exchange has never been investigated in patients with diffuse pulmonary infiltrates who breathe spontaneously.

Objective: To evaluate the effect of body position on gas exchange in patients with idiopathic pulmonary alveolar proteinosis (PAP) with special reference to the benefit of prone positioning.

Design: A prospective study.

Setting: Tertiary medical center.

Patients and methods: Eight patients with PAP were studied on 25 occasions using spirometry, body plethysmography, and single-breath diffusing capacity of the lung for carbon monoxide (DLCO). Arterial blood gas levels were measured in the sitting position and in four lying positions randomly while patients breathed room air. To serve as control subjects, 16 age-matched healthy hospital personnel were studied. To evaluate the impact of oxygen therapy on positional effect in gas exchange, arterial blood gas levels were measured in the supine and prone positions in some PAP patients while breathing 40% oxygen.

Results: Normal to varying degrees of restrictive ventilatory defect and gas exchange impairment, as evidenced by DLCO, Pa[O.sub.2], and alveolar-arterial oxygen pressure difference (P[A-a][O.sub.2]), were found in PAP patients. The ventilatory function parameters correlated positively with Pa[O.sub.2] and negatively with P(A-a)[O.sub.2]. The values of Pa[O.sub.2] and P(A-a)[O.sub.2] measured in four lying positions showed no significant difference in both PAP patients and healthy control subjects. Furthermore, the differences in Pa[O.sub.2] and P(A-a)[O.sub.2] between measurements made in the supine and prone positions and the ratio of Pa[O.sub.2] measured in the prone position/Pa[O.sub.2] measured in the supine position were comparable between PAP patients and healthy control subjects. Arterial blood gas levels showed no significant difference between measurements made in PAP patients in the supine and prone positions while breathing 40% oxygen.

Conclusions: Positional change did not significantly affect gas exchange, and no benefit of prone positioning was found in both PAP patients and healthy control subjects. Further studies are needed to verify the benefit of prone ventilation in patients with diffuse pulmonary disorders who breathe spontaneously.

Key words: gas exchange; postural effect; prone positioning; pulmonary alveolar proteinosis

Abbreviations: ALI = acute lung injury; DLCO = diffusing capacity of the lung for carbon monoxide; FRC = functional residual capacity; KCO = diffusing capacity of the lung for carbon monoxide corrected by alveolar volume; P(A-a)[O.sub.2] = alveolar-arterial oxygen pressure difference; P(A-a)[O.sub.2]-L = alveolar-arterial oxygen pressure difference measured in the left decubitus position; P(A-a)[O.sub.2]-P = alveolar-arterial oxygen pressure difference measured in the prone position; [DELTA]P(A-a)[O.sub.2]-PS = alveolar-arterial oxygen pressure difference measured in the prone position--alveolar-arterial oxygen pressure difference measured in the supine position; P(A-a)[O.sub.2]-R = alveolar-arterial oxygen pressure difference measured in the right decubitus position; P(A-a)[O.sub.2]-S = alveolar-arterial oxygen pressure difference measured in the supine position; PA[O.sub.2] = alveolar oxygen tension; Pa[O.sub.2]-L = Pa[O.sub.2] measured in the left lateral decubitus position; Pa[O.sub.2]-P = Pa[O.sub.2] measured in the prone position; [DELTA]Pa[O.sub.2]-PS = Pa[O.sub.2] measured in the prone position--Pa[O.sub.2] measured in the supine position; Pa[O.sub.2]-R = Pa[O.sub.2] measured in the right lateral decubitus position; Pa[O.sub.2]-S = Pa[O.sub.2] measured in the supine position; PAP = pulmonary alveolar proteinosis; TLC = total lung capacity

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Lung volumes and gas exchange may be affected by positional change. (1-4) Functional residual capacity (FRC) has been reported (2) to be lower when measured with the subject in the supine than when measured in the prone position, and this reduction of FRC occurred mainly in the dorsal lung regions. (5) As a consequence, prone positioning was advocated by Bryan (6) in 1974 as a means to expand the dependent lung regions. Clinically, prone positioning has been applied to patients with acute lung injury (ALI)/ARDS since 1976 (7) as a strategy to improve oxygenation and to lessen the risk of ventilator-induced lung injury. (7-15) In terms of gas-exchange improvement, the reported (16) response rate of prone positioning ranged from 57 to 100%. Despite the promising response rate, prone positioning has not yet been accepted as a usual practice in the ICU. The lack of consensus on the optimal timing and duration of prone positioning, the lack of apparent criteria in patient selection, the lack of reliable parameters in predicting the favorable response of prone ventilation, and the varying severity and diversity of underlying causes of ARDS/ALI in patients who have been enrolled in studies (9,13,15,16) have led to inconclusive results in the use of treatment with prone positioning. Furthermore, a randomized controlled study (15) indicated that there was no significant benefit of prone positioning on long-term survival in patients with ARDS.

The mechanisms underlying improved oxygenation in patients with ALI/ARDS who have been treated by prone positioning remain speculative. An increase in FRC, (8,17) facilitation of the clearance of airway secretions, (8) improvement in the compliance of the respiratory system, (17) the recruitment of collapsed lung, (10,18) better ventilation/perfusion matching, (10,19) and decreased lung compression by the heart (20) all have been suggested. To dissect the mechanisms underlying gas-exchange improvement by prone positioning, several studies (19,21-31) were conducted using animals or healthy subjects, which gave contradictory results. Distinct lung conditions (healthy vs injured), respiratory status (spontaneous breathing vs mechanical ventilation), species difference (human vs animals), and different methodology used may account for these discrepancies.

The studies on prone positioning in patients with diffuse pulmonary diseases other than ALI/ARDS have been limited. (14) Prone positioning has proven to be valuable in improving oxygenation in ventilated patients with hydrostatic pulmonary edema, but not in ventilated patients with idiopathic pulmonary fibrosis. (14) To our knowledge, the benefit of prone positioning has never been evaluated in patients with diffuse pulmonary disorders who could breathe spontaneously. To study the effect of positional change on gas exchange in patients with diffuse pulmonary diseases can be clinically attractive and relevant, since these patients may have compromised cardiopulmonary function and may be restricted to bed for a prolonged period. Knowledge of the effect of positional change on gas exchange in such patients can prevent patients from experiencing unexpected hypoxemia, can help to maintain patients in a position that offers favorable gas exchange, and may obviate the need for assisted ventilation.

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease that is characterized by the deposition of surfactant within the alveoli. (32) The typical radiologic features of PAP are bilateral, relatively symmetric airspace ground-glass haziness, and/or consolidation intermixed with interstitial involvement. In addition, varying degrees of restrictive ventilatory defects and impairment of gas exchange are usually observed in these patients.3a Compared with ALI/ARDS or other diffuse pulmonary diseases, PAP has several advantages with regard to studying the effect of positional change on gas exchange, including the relative homogeneity of the disease, the absence of sepsis, the absence of acute inflammation of lung parenchyma or pulmonary vascular disorders, the lack of compromised circulatory hemodynamics, and the lack of instant change of disease status or activity. Accordingly, to explore the effect of positional change on gas exchange in patients with diffuse pulmonary diseases, PAP patients seem more suitable than those with ALI/ARDS.

In this study, we intended to evaluate the effect of body position on gas exchange in PAP patients, with special reference to the benefits of prone positioning. To serve as control subjects, healthy hospital personnel were also examined.

MATERIALS AND METHODS

Patients

Eight patients with PAP proved by cytologic examination of BAL fluid (34) and/or pathologic examination of transbronchial lung biopsy specimens at Taipei Veterans General Hospital were included in this study. One of eight patients had diabetes mellitus and hypertension that had been treated with hypoglycemic and antihypertensive agents. Other patients denied cardiac and other major medical illnesses. Chest radiographs and CT scans revealed bilateral and relatively symmetric pulmonary infiltrates with varying degrees of involvement and intensity at the time of the PAP diagnosis. The elevation of blood lactate dehydrogenase level was the sole abnormality in blood biochemistry measurements in all patients. The results of pulmonary function testing showed varying degrees of restrictive ventilatory defect and gas exchange impairment at the time of PAP diagnosis.

The clinical course was available in all eight patients, and each patient was followed up for at least 1 year. Therapeutic lung lavage was required in three of the eight patients. Nearly complete resolution was observed in one patient after six instances of therapeutic whole-lung lavage. Therapeutic whole-lung lavage was required twice a year in another one patient. The remaining patient received therapeutic lobar bronchoscopic lavage with remarkable improvement, as evidenced by the results of serial imaging studies and pulmonary function testing. The disease improved spontaneously in three patients and remained stationary in two patients.

To serve as control subjects, 16 age-matched hospital personnel without cardiopulmonary diseases and other major medical illnesses were enrolled into this study. All had normal chest radiograph findings and normal results of pulmonary function testing.

Pulmonary Function Testing

The Institutional Review Board of Taipei Veterans General Hospital approved this study, and informed consent was obtained from all subjects studied. Pulmonary function testing, including spirometry, plethysmography, and single-breath diffusing capacity of the lung for carbon monoxide (DLCO), and analyses of arterial blood gases were performed in all subjects. Spirometry was performed (model 2130 Spirometer; SensorMedics; Yorba Linda, CA) in the sitting position a minimum of three times. The best values of FVC and FE[V.sub.1] were selected for analysis in accordance with American Thoracic Society recommendations. (35) Total lung capacity (TLC) was measured with a body plethysomograph (6200 Autobox DL; SensorMedics). The DLCO was measured in the sitting position using the single-breath method, with a minor modification. (36,37) The exchange time, t, is the sum of the breath-holding time plus two thirds of the inspiratory time and one half of the collecting time for the samples of expired breath. (38)

After completion of the pulmonary functioning testing as described above for at least 30 min, the effect of positional change on gas exchange was evaluated in all studied subjects by analyses of arterial blood gas levels obtained Alveolar oxygen tension (Pa[O.sub.2]) in the sitting and four lying positions in random order. Arterial blood samples were obtained via indwelling radial artery catheters 15 min after the assumption of a new position while the studied subjects breathed room air. Blood samples for pH, Pa[O.sub.2], and PaC[O.sub.2] values were analyzed immediately (ABL III; Radiometer; Copenhagen, Denmark). Alveolar oxygen tension (PA[O.sub.2]) was calculated by the following equation: PA[O.sub.2] = (barometric pressure--47) x fraction of inspired Oxygen--PaC[O.sub.2]/R. R, an exchange ratio, was assumed to be 0.8 in this study. The alveolar-arterial oxygen pressure difference (P[A-a][O.sub.2]) was calculated by subtracting Pa[O.sub.2] from PA[O.sub.2].

In PAP patients undergoing therapeutic lung lavage, the studies of pulmonary function testing and the effect of positional change on gas exchange were evaluated before and at least 3 months after they had undergone therapeutic lavage. In those patients who were stable or whose condition had improved, the time interval between the two studies was > 6 months. To evaluate whether the effect of prone positioning on gas exchange in PAP patients was affected by oxygen therapy, arterial blood gas levels were measured in the supine and prone positions randomly while the patient breathed 40% oxygen via a Venturi mask.

Statistical Analysis

A statistical comparison of the data between two groups was carried out using the unpaired Student t test. A statistical within-group comparison of the data was examined by using the paired Student t test or one-way analysis of variance. The relationship between gas exchange data (ie, DLCO, Pa[O.sub.2], and P[A-a][O.sub.2]) that was obtained in the sitting position and ventilatory function parameters (ie, TLC, FVC, FE[V.sub.1], and FRC) was examined by using the linear correlation coefficient. Appropriate nonparametric tests were used if needed. A p value of < 0.05 was considered to be statistically significant.

RESULTS

From March 2000 to August 2003, eight PAP patients with varying degrees of severity were examined on 25 occasions. To serve as healthy control subjects, 16 age-matched hospital personnel were studied. The clinical and pulmonary function data for PAP patients and healthy control subjects are summarized in Table 1. Compared to healthy subjects, PAP patients had normal ventilation to varying degrees of restrictive ventilatory defect and gas exchange impairment, as evidenced by decreased values of DLCO, DLCO corrected by alveolar volume (KCO), and Pa[O.sub.2], and by increased values of P(A-a)[O.sub.2]. The correlations between ventilatory function parameters and the values of Pa[O.sub.2] and P(A-a)[O.sub.2] in PAP patients are summarized in Table 2. By and large, the ventilatory function parameters (TLC, FVC, and FE[V.sub.1]) correlated positively with Pa[O.sub.2] and negatively with P(A-a)[O.sub.2].

The arterial blood gas levels and P(A-a)[O.sub.2] values obtained in PAP patients and healthy control subjects while in the four lying positions are summarized in Tables 3 and 4, respectively. In the PAP group (Table 3), the mean ([+ or -] SD) pH (7.426 [+ or -] 0.024) was highest when measured in the supine position, followed by 7.424 [+ or -] 0.023 in the prone position, 7.420 [+ or -] 0.022 in the left lateral decubitus position, and 7.420 [+ or -] 0.021 in the right lateral decubitus position. The mean Pa[O.sub.2] was highest (73.2 [+ or -] 21.3 mm Hg) in the prone position (Pa[O.sub.2]-P) and lowest (71.4 [+ or -] 20.8 mm Hg) in the supine position (Pa[O.sub.2] S). The mean Pa[O.sub.2] was similar between measurements made in the right lateral decubitus position (Pa[O.sub.2]-R) [72.4 [+ or -] 20.5 mm Hg] and in the left lateral decubitus positions (Pa[O.sub.2]-L) [72.4 [+ or -] 19.8 mm Hg]. The mean PaC[O.sub.2] was highest (36.2 [+ or -] 3.1 mm Hg) when measured in the right lateral decubitus position, followed by 35.6 [+ or -] 3.4 mm Hg in the prone position, 35.5 [+ or -] 3.5 mm Hg in the left lateral decubitus position, and 35.1 [+ or -] 3.3 mm Hg in the supine position. The difference between pH values measured in the supine position and in the right lateral decubitus position could be due to the difference in measured PaC[O.sub.2] (p = 0.022) between the two positions. The mean P(A-a)[O.sub.2] was lowest (32.04 [+ or -] 21.95 mm Hg) when measured in the right lateral decubitus position (P[A-a][O.sub.2]-R), followed by 32.08 [+ or -] 22.79 mm Hg in the prone position (P[A-a][O.sub.2]-P), 33.00 [+ or -] 22.01 mm Hg in the left lateral decubitus position (P[A-a][O.sub.2]-L), and 34.51 [+ or -] 23.24 mm Hg in the supine position (P[A-a][O.sub.2]-S). There was no significant difference in the values of Pa[O.sub.2] and P(A-a)[O.sub.2] obtained in the four lying positions in PAP patients.

In the healthy control group, the mean values of pH, Pa[O.sub.2], PaC[O.sub.2], and P(A-a)[O.sub.2] were comparable in four lying positions (Table 4). The mean Pa[O.sub.2]-P (91.0 [+ or -] 5.5 mm Hg) was highest, followed by Pa[O.sub.2]-L (90.8 [+ or -] 6.2 mm Hg), Pa[O.sub.2]-R (89.7 [+ or -] 7.4 mm Hg), and Pa[O.sub.2]-S (89.6 [+ or -] 6.8 mm Hg). The mean P(A-a)[O.sub.2]-L (10.48 [+ or -] 5.90 mm Hg) was lowest, followed by P(A-a)[O.sub.2]-P (10.54 [+ or -] 6.13 mm Hg), P(A-a)[O.sub.2]-R (11.17 [+ or -] 7.21 mm Hg), and P(A-a)[O.sub.2]-S (11.32 [+ or -] 5.52 mm Hg).

The data on Pa[O.sub.2]-R--Pa[O.sub.2]-L, Pa[O.sub.2]-P--Pa[O.sub.2]-S ([DELTA]Pa[O.sub.2]-PS), [DELTA]P(A-a)[O.sub.2]-R--P(A-a)[O.sub.2]-L, P(A-a)[O.sub.2]-P--P(A-a)[O.sub.2]-S ([DELTA]P[A-a][O.sub.2]-PS), Pa[O.sub.2]-P/Pa[O.sub.2]-S ratio, and P(A-a)[O.sub.2]-P/P(A-a)[O.sub.2]-S ratio were compared between the two groups (Table 5). In PAP patients, the Pa[O.sub.2]-P/ Pa[O.sub.2]-S ratio ranged from 0.9 to 1.2 (mean, 1.0 [+ or -] 0.1). Compared to Pa[O.sub.2]-S, Pa[O.sub.2]-P was higher on 14 occasions, was equal on 1 occasion, and was lower on 10 occasions. The P(A-a)[O.sub.2]-P/P(A-a)[O.sub.2]-S ratio ranged from 0.2 to 2.6 (mean, 1.0 [+ or -] 0.4). Compared to P(A-a)[O.sub.2]-S, P(A-a)[O.sub.2]-P was lower on 15 occasions, was equal on 1 occasion, and was higher on 9 occasions. The [DELTA]Pa[O.sub.2]-PS and Pa[O.sub.2]-P/ Pa[O.sub.2]-S ratio did not correlate well with TLC, FVC, and FE[V.sub.1] or with the severity of gas exchange impairment, as evidenced by DLCO, Pa[O.sub.2], and P(A-a)[O.sub.2] in PAP patients.

In healthy control subjects, the Pa[O.sub.2]-P/Pa[O.sub.2]-S ratio ranged from 0.9 to 1.2 (mean, 1.0 [+ or -] 0.1). Compared to Pa[O.sub.2]-S, Pa[O.sub.2]-P was higher in seven control subjects, was equal in one control subject, and was lower in eight control subjects. The P(A-a)[O.sub.2]-P/P(A-a)[O.sub.2]-S ratio ranged from 0.3 to 2.5 (mean, 1.0 [+ or -] 0.7). Compared to P(A-a)[O.sub.2]-S, P(A-a)[O.sub.2]-P was lower in nine control subjects and was higher in seven control subjects.

To evaluate the impact of oxygen treatment on the effect of positional change on gas exchange in PAP patients, arterial blood gas and P(A-a)[O.sub.2] were measured in the prone and supine positions (Table 6) while the patients breathed 40% oxygen via a Venturi mask. The data obtained in the prone and supine positions showed no significant difference.

DISCUSSION

The differences in lung function of subjects with disease measured in various lying positions are of interest and clinical significance compared to those obtained with patients in the sitting position, because these are the positions usually assumed during diagnostic examination, general anesthesia, surgery, and more severe illness. In patients with compromised cardiopulmonary function, the differences in gas exchange while in four lying positions are of considerable importance since patients may be kept in such positions for a prolonged period. To prevent unexpected hypoxemia and to improve oxygenation by turning the patients in a favorable lying position, it is clinically attractive and relevant to know the impact of positional change on gas exchange in patients with compromised cardiopulmonary function.

Prone positioning has been suggested as a ventilatory strategy to improve oxygenation and lung mechanics in patients with ALI/ARDS for decades. Despite the numerous reports demonstrating that prone positioning could improve oxygenation in patients with ALI/ARDS, the underlying mechanisms remain speculative. Prone positioning by reducing pleural pressure diminishes atelectasis and results in a relatively even distribution of ventilation. This, in conjunction with the more homogeneous distribution of perfusion found with therapy using prone positioning, reduces shunting, improves ventilation/perfusion matching, and thus improves oxygenation. (31,39,40) Other putative mechanisms include the reduction of physiologic and alveolar dead space, the alternation in extravascular lung water or pulmonary capillary permeability, enhanced secretion removal or drainage, and reduced compression of the lungs by heart and mediastinal structures in the prone positioning.

However, the beneficial effect of prone positioning has not yet been well-investigated and well-demonstrated in patients with bilateral pulmonary diseases other than ALI/ARDS who are able to breathe spontaneously. The distribution of ventilation and perfusion, and ventilation/perfusion matching differ significantly in healthy subjects during spontaneous breathing or in a state of being paralyzed and assisted with mechanical ventilation. (39,40) Furthermore, the differences in lung pathology between ALI/ARDS and other pulmonary diseases may have impact on lung and chest wall mechanics, and thus may affect ventilation/perfusion matching and gas exchange. As a consequence, it remains unknown whether the beneficial effect of prone positioning observed in patients with ALI and ARDS can be applied to patients with diffuse pulmonary diseases who do not require assisted ventilation.

In the present study, we investigated the effect of positional change on gas exchange in patients with PAP and healthy subjects. Our results indicated that the values of Pa[O.sub.2] and P(A-a)[O.sub.2] showed no significant difference when measured in four lying positions in either PAP patients or healthy subjects. Furthermore, the [DELTA]Pa[O.sub.2]-PS and [DELTA]P(A-a)[O.sub.2]-PS values were comparable between PAP patients and healthy subjects. Compared to Pa[O.sub.2]-S and P(A-a)[O.sub.2]-S, Pa[O.sub.2]-P values were higher (14 of 25 occasions) and P(A-a)[O.sub.2]-P values were lower (15 of 25 occasions) in PAP patients. Favorable oxygenation was obtained in the prone position in only 7 of 16 healthy control subjects. The Pa[O.sub.2]-P/Pa[O.sub.2]-S ratio was comparable between PAP patients and healthy control subjects. Furthermore, the Pa[O.sub.2]-P/Pa[O.sub.2]-S ratio was not > 120% in all PAP patients. Accordingly, in terms of gas exchange, prone positioning showed no significant benefit in both PAP patients and healthy subjects while they breathed room air. In addition, we demonstrated that the values of arterial blood gases obtained in the supine and prone positions showed no significant difference while PAP patients breathed 40% oxygen.

It is unknown why prone positioning did not improve gas exchange in PAP patients and healthy subjects. Marked differences in the distribution of ventilation and perfusion, and the resultant ventilation/perfusion matching between spontaneous breathing and mechanical ventilation, and the effect of sedation and muscle relaxation on lung and chest wall mechanics in mechanically ventilated patients may explain this in part. These observations may be supported by our findings that [DELTA]Pa[O.sub.2]-PS, [DELTA]P(A-a)[O.sub.2]-PS, and the Pa[O.sub.2]-P/Pa[O.sub.2]-S ratio were comparable between PAP patients and healthy subjects who were able to breath spontaneously. That the beneficial effect of prone positioning on gas exchange is counteracted by the presence of different lung pathologies between ALI/ ARDS and PAP cannot be excluded. However, it seemed that the role, if any, of oxygen therapy in this situation was limited, since the data on arterial blood gases obtained in PAP patients breathing 40% oxygen in the supine and prone positions were comparable.

In summary, our results indicated that positional change did not significantly affect gas exchange, as reflected by the Pa[O.sub.2] and P(A-a)[O.sub.2] values in PAP patients or healthy subjects. Prone positioning did not improve oxygenation in both PAP patients and healthy subjects. The benefit of prone positioning in patients with diffuse pulmonary disorders who breathe spontaneously deserves further study for verification.

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* From the Institute of Clinical Medicine (Dr. Lin), School of Medicine (Dr. Chang), National Yang-Ming University, Taipei, Taiwan, Republic of China; and the Chest Department (Ms. Chen and Ms. Chang), Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.

This work was supported by a grant from the Taipei Veterans General Hospital (TVGH91-02-04A).

Manuscript received April 13, 2004; revision accepted October 7, 2004.

Correspondence to: Shi-Chuan Chang, MD, PhD, FCCP, Chest Department, Taipei Veterans General Hospital, No. 201 Section 2, Shih-Pai Rd, Shih-Pai, Taipei 112, Taiwan, Republic of China; e-mail: scchang@vghtpe.gov.tw

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