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* From the Division of Pulmonary and Critical Care Medicine (Dr. Chesnutt), Department of Medicine, Oregon Health Sciences University, Portland, OR; the Department of Physiology (Dr. Folkesson), Northeastern Ohio Universities College of Medicine, Rootstown, OH; and the Division of Pulmonary and Critical Care Medicine (Drs. Nuckton, Golden, and Matthay), Departments of Medicine and Anesthesia, and Cardiovascular Research Institute, University of California, San Francisco, CA.
Correspondence to: Mark S. Chesnutt, MD, Division of Pulmonary and Critical Care Medicine, UHN-67, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd, Portland, Oregon 97201-3098; e-mail: chesnutm{at}ohsu.edu
Abstract
Study objective: To measure the in vivo rate of alveolar epithelial fluid clearance of the human lung in patients with pulmonary alveolar phospholipoproteinosis (PAP).
Design: Prospective clinical study.
Setting: The medical-surgical ICUs of a university teaching hospital.
Patients: Four patients with idiopathic PAP requiring therapeutic lung lavage.
Interventions: Large-volume lung lavage with isotonic saline solution using fiberoptic bronchoscopy followed by serial sampling of alveolar fluid using a wedged bronchial catheter.
Measurements and results: The rate of alveolar epithelial fluid clearance was calculated by measuring the concentration of protein in sequential samples. Alveolar epithelial fluid clearance over the first hour after lung lavage was 53 ± 14% (mean ± SD). Sequential samples in two patients indicated a sustained high rate of clearance over several hours. Plasma and alveolar fluid epinephrine levels were in the normal range in two patients.
Conclusions and significance: Alveolar fluid clearance is rapid after lung lavage in patients with PAP and appears to be driven by catecholamine-independent mechanisms. The rapid rate of alveolar epithelial fluid transport explains why patients with PAP tolerate large-volume lung lavage.
Key Words: alveolar epithelial fluid transport • lung lavage • pulmonary alveolar phospholipoproteinosis • pulmonary edema
Large -volume lung lavage is well established as the method of choice when it is necessary to remove the phospholipoproteins that accumulate in the alveoli of patients with pulmonary alveolar phospholipoproteinosis (PAP) and that are responsible for the functional and gas-exchange abnormalities observed in this disorder.1 2 The procedure is well tolerated by most patients despite concerns regarding the effect of a large-volume isotonic saline solution lavage on the lung. The short-term feasibility and success of the procedure seems to depend on the capacity of the lung to rapidly remove the residual alveolar fluid that remains in the lung after lavage. However, the rate and mechanism for removal of residual alveolar fluid after lung lavage in PAP has not been investigated.
Experimental studies of normal lung and acute lung injury have established that the normally tight alveolar epithelial barrier removes excess alveolar fluid primarily by active sodium transport.3 4 5 6 7 8 9 10 Water crosses the alveolar barrier to maintain iso-osmolar conditions, probably in part by transmembrane water channels or aquaporins in the alveolar epithelium.9 11 12 13 Deletion of these water channels in transgenic mouse models indicated that maximal rates of alveolar fluid clearance (AFC) do not depend on their presence.14 Basal AFC has been measured in several animal species, and ranges from 3 to 20%/h.3 4 5 8 14 15 16 17 The only estimate of the ability of the human alveolar barrier to remove alveolar fluid in the absence of preexistent pulmonary edema comes from ex vivo studies of human lung and has been reported to be relatively slow: basal rate of 3%/h; ß-agonist stimulated rate of 7%/h.18
The primary objective of this study was to measure the in vivo rate of alveolar epithelial fluid clearance of the human lung in patients with PAP. To accomplish this objective, we prospectively analyzed serial alveolar fluid samples from patients with PAP after large-volume therapeutic lung lavage.
Materials and Methods
Patient Selection
From 1990 to 1999, four patients with idiopathic PAP were
prospectively identified by one of the investigators as requiring
therapeutic lung lavage. One of these patients required two separate
therapeutic lung lavages during this time period. Patients were
admitted to the adult ICUs at Moffitt-Long Hospital, University of
California, San Francisco. The patients were interviewed and their
charts were reviewed to determine the cause of their PAP as well as any
other lung disorders. The University of California, San Francisco
Committee on Human Research approved this study.
Therapeutic Lung Lavage
Patients were sedated with IV narcotics and sedatives. A
critical-care specialist performed oral endotracheal intubation using
direct laryngoscopy. Mechanical ventilation was delivered using a
volume ventilator with positive end-expiratory pressure of 5 cm
H2O, fraction of inspired oxygen of 1.0, and a
tidal volume of 9 to 11 mL/kg of measured body weight. A fiberoptic
bronchoscope inserted through the endotracheal tube was used to carry
out sequential segmental lung lavage. The procedure was performed in
one lung or the equivalent of one lung (ie, bilateral upper
or lower lobes of lungs) depending on the distribution and severity of
alveolar involvement as evidenced on a preprocedure chest CT scan. In
each lung segment lavaged, serial 50-mL aliquots of isotonic saline
solution warmed to 37.0°C were instilled and aspirated through the
bronchoscope. The procedure was continued as tolerated by the patient
or until the lavage fluid cleared (range of lavage aliquots per lung
segment, 7 to 10; total instilled volume for an entire procedure:
average, 2.8 L; range, 1.7 to 4.2 L). An average of 1.1 L (range, 0.64
to 1.9 L) of saline solution remained in the lung after the procedure.
Patients remained intubated for an average of 16 h (range, 1 to
27 h) after the procedure.
Collection of Clinical Samples
Alveolar fluid samples were obtained using a sterile 14-gauge
suction catheter that was inserted through the endotracheal tube and
wedged into the distal airways as previously described and
validated.3
19
20
21
Samples were collected immediately
after the termination of lung lavage and then hourly until each patient
was extubated. After collection, samples were centrifuged at
3,000g, and the total protein concentrations in the
supernatants were measured by the biuret method.19
21
Matched plasma samples were also collected. Epinephrine levels in
plasma and alveolar liquid fluid were measured using standard methods
in two patients.22
Calculation of AFC
AFC was estimated by comparing the final and initial alveolar
liquid fluid protein concentrations using the following equation:
AFC = 100 x [1 - (initial protein concentration/final protein
concentration)].9
Results
Four patients (three men, one woman; age range, 22 to 35 years) with idiopathic PAP were studied. The AFC rate over the first hour was 53 ± 14% (mean ± SD), as measured in four patients (Fig 1 ). Also, AFC was measured in the same patient after two separate lavage procedures. The AFC rates in the first hour in each of two separate lavage procedures were 53% and 69% in this patient (Fig 1 , patient 4).
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Plasma epinephrine and norepinephrine levels obtained after the lavage were in the normal range (< 300 to 400 pg/mL)23 in two patients: patient 2 (1-h values: epinephrine, 92 pg/mL; norepinephrine, 271 pg/mL) and patient 3 (30-min values: epinephrine, 173 pg/mL; norepinephrine, 329 pg/mL).
Discussion
There was a rapid rate of clearance of fluid from the alveolar spaces after large volume isotonic saline solution lavage in patients with PAP. These results probably explain why patients with PAP tolerate large-volume therapeutic lung lavage. The rapid clearance rate is remarkable in view of previous measurements of AFC in the human lung. In the ex vivo human lung, basal AFC was only 3%/h and increased to 7%/h after stimulation with a ß-adrenergic agonist.18 In patients in the resolution phase of hydrostatic pulmonary edema, maximal alveolar fluid clearance was 25 ± 15%/h.21 In patients with acute lung injury, the mean AFC has been reported to be 18 ± 15%/h.19 In addition, AFC rates in patients with reperfusion lung injury after lung transplantation range from < 1%/h over a 24-h period to 32%/h over a 2-h period.24 Experimental studies in several species show intermediate and fast rates of AFC under basal and stimulated conditions. The most rapid stimulated clearance rates, for example, have been measured in rats (40 to 50%/h)25 26 and mice (30 to 50%/h).14
The measurement of the capacity of the alveolar epithelial barrier to remove excess fluid from the distal airspaces of the lung is based on measuring the concentration of protein in alveolar fluid in sequential samples using a wedged 14-gauge suction catheter. Several studies3 8 indicate that this method is accurate. In one experimental study in dogs, alveolar micropuncture samples were compared to simultaneously obtained fluid from the distal airspaces of the lung with a wedged catheter; the data demonstrated an excellent correlation between the albumin concentration in the alveolar micropuncture samples and in the fluid obtained from the wedged catheter.4
This study confirms and extends the work of Alberti et al,27 who reported changes in the composition of BAL fluid collected from patients with idiopathic alveolar proteinosis after therapeutic lung lavage. Alberti et al27 reported an abrupt increase in the BAL fluid protein concentration within the first hour after BAL with 100 mL of saline solution, followed by a plateau over the next few hours. However, the rate of AFC was not determined in that study.
In spite of the intra-alveolar pathologic changes in PAP, this study demonstrates that the alveolar epithelium is functionally intact in patients with PAP. In fact, the actual high rates of AFC indicate that vectorial salt and water transport from the distal airspaces is not impaired in PAP.
While the catecholamine data were limited to two patients in this
study, the very fast rates in vivo of human AFC in this
study do not appear to be driven by catecholamine-dependent mechanisms.
All patients were anesthetized for the lavage procedure with both
narcotics and sedatives, thus reducing the likelihood of elevated
endogenous catecholamines. This is an important issue because animal
models of acute lung injury because of septic shock and hypovolemic
shock indicate that increases in endogenous epinephrine levels can
increase the rate of alveolar epithelial sodium transport and net
alveolar liquid clearance.22
28
Several
catecholamine-independent mechanisms have been associated with an
increase in alveolar epithelial sodium transport and net AFC:
transforming growth factor-
,29
epidermal growth
factor,30
prolonged exposure to hyperoxic
gas,7
31
32
and alveolar epithelial type II cell
hyperplasia.26
Interestingly, mild hyperplasia of type II
pneumocytes has been observed in the lungs of PAP
patients.33
34
It is possible, of course, that there is
some unknown mechanism uniquely associated with PAP that upregulates
AFC.
In summary, alveolar epithelial fluid clearance is rapid (53 ± 14%/h) after lung lavage in patients with PAP and appears to be driven by catecholamine-independent mechanisms. The rapid rate of alveolar epithelial fluid transport explains why patients with PAP tolerate large-volume BAL. Also, the study provides the first data demonstrating a rapid rate of AFC from the in vivo human lung in the absence of preexistent pulmonary edema.
Footnotes
Abbreviations: AFC = alveolar fluid clearance; PAP = pulmonary alveolar phospholipoproteinosis
Supported in part by National Institutes of Health grants HL51854 and HL51856, and American Lung Association of California research program grants for Drs. Chesnutt and Folkesson.
Received for publication April 20, 2000. Accepted for publication November 28, 2000.
References
This article has been cited by other articles:
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 A. Perez IV, H. O. Coxson, J. C. Hogg, K. Gibson, P. F. Thompson, and R. M. Rogers Use of CT Morphometry To Detect Changes in Lung Weight and Gas Volume Chest, October 1, 2005; 128(4): 2471 - 2477. [Abstract] [Full Text] [PDF]
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