(Chest. 2002;122:340S-343S.)
© 2002
American College of Chest Physicians
Alveolar Fluid Clearance in Patients With ARDS*
Does It Make a Difference?
Michael A. Matthay, MD, FCCP
* From the Departments of Medicine, Anesthesia, and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA.
Correspondence to: Michael A. Matthay, MD, FCCP, Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California at San Francisco, 505 Parnassus Ave, M-917, San Francisco, CA 94143-0624; e-mail: mmatt{at}itsa.ucsf.edu
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Abstract
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Experimental methods to quantify alveolar fluid clearance have been adapted for our studies in patients with acute lung injury (ALI) or ARDS. We recently completed a study of 79 patients with ALI/ARDS that was designed to examine alveolar fluid clearance in the setting of alveolar epithelial injury from ALI/ARDS. Pulmonary edema fluid and plasma were sampled serially in the first 4 h after endotracheal intubation and the initiation of positive-pressure ventilation. Net alveolar fluid clearance was calculated from sequential edema fluid protein measurements. Patients with maximal alveolar fluid clearance had a significantly lower mortality rate and a shorter duration of mechanical ventilation. Several mechanisms may account for the decrease in the rate of alveolar fluid clearance in ALI/ARDS patients, including hypoxia, reactive oxygen species, reactive nitrogen species, and the loss of an intact epithelial barrier in the distal airspaces of the lung. Despite the epithelial injury in patients with ALI/ARDS, some experimental studies have suggested that alveolar fluid clearance could be increased with therapy using cyclic adenosine monophosphate agonists or other pharmacologic agents.
Key Words: acute lung injury • pulmonary edema
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Introduction
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Acute lung injury (ALI) and ARDS are common causes of acute respiratory failure in critically ill patients.1
Although much has been learned about the pathophysiology of ALI/ARDS, the resolution phase of ALI/ARDS is still incompletely understood. Early ALI/ARDS is characterized by alveolar epithelial and lung endothelial injury, leading to increased permeability pulmonary edema, alveolar filling, and acute respiratory failure. The reabsorption of pulmonary edema fluid from the alveolar space is necessary for the resolution of ALI/ARDS.
Several experimental studies have demonstrated that intact alveolar epithelial fluid transport function is critical for the resolution of experimental pulmonary edema and ALI. The basic mechanisms that drive the removal of edema fluid from the distal airspaces of the lung have been established over the last 2 decades.2
3
It is now understood that the clearance of edema fluid depends on active ion transport, which is driven at least in part by sodium transport, although a role for chloride transport has been recently established especially in the presence of cyclic adenosine monophosphate (cAMP) stimulation.4
5
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Alveolar Fluid Clearance in Patients
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For several years, our research group has measured the rate of fluid clearance from the airspaces of the lung by measuring protein concentrations in sequential samples of undiluted edema fluid obtained from patients.6
7
8
This method was adapted from validated measures of airspace fluid clearance in several experimental studies in small and large animals.3
The collection of sequential samples of undiluted edema fluid from the distal airspaces of the lung is performed with a standard suction catheter that is placed in a wedged position.8
The results of our first study6
of the resolution of pulmonary edema in patients with ARDS suggested that the capacity to remove alveolar edema fluid early in the course of lung injury could be a valuable measure of intact epithelial transport function with potential prognostic value as well. In this initial 1990 study of 16 patients with ARDS, we found that the capacity to remove alveolar edema fluid early in the course of lung injury was associated with a better outcome, specifically a lower mortality rate. Recently, we completed a larger study of 79 patients with ALI. In this study, patients had pulmonary edema fluid sampled sequentially within the first 4 h after intubation. The measurement of the pulmonary edema fluid protein concentration was used to determine whether alveolar fluid clearance had occurred, and, if so, whether the rate of clearance was submaximal or maximal. The results demonstrated that the majority of patients with ALI had impaired alveolar fluid clearance compared to control patients with hydrostatic pulmonary edema.8
Overall, the mean alveolar fluid clearance rate was 6% per hour. Of the patients studied, 56% had impaired alveolar fluid clearance (ie, < 3% per hour), 32% had submaximal clearance (ie, 
3% and < 14% per hour), and 13% had maximal clearance (ie, 14% per hour). These findings contrast with those of our 1999 study7
of 65 patients with hydrostatic pulmonary edema in whom the mean alveolar fluid clearance rate was 13% per hour, and in which only 25% of patients had impaired clearance and 75% had intact alveolar fluid clearance.
Furthermore, the patients with maximal alveolar fluid clearance in the first 4 h had a significantly greater survival rate compared to patients with impaired or submaximal alveolar fluid clearance (Fig 1
). The results confirm the primary hypothesis that a decrease in the capacity of the alveolar epithelial barrier to remove alveolar edema fluid is an important determinant of a poor outcome.
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Figure 1. Plot of hospital mortality of the following two groups of patients with ALI or ARDS: those with maximal alveolar fluid clearance (ie, 14% per hour); and those with impaired or submaximal alveolar fluid clearance (ie, < 14% per hour). Columns represent the hospital mortality rate in each group. The hospital mortality rate of patients with maximal alveolar fluid clearance was significantly lower (p < 0.02). Reproduced with permission from Ware and Matthay.8
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Mechanisms That Impair Epithelial Fluid Clearance in Clinical Lung Injury
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What are the mechanisms that may impair alveolar fluid clearance in patients with clinical lung injury? Experimentally, severe injury to the endothelial barrier can result in persistent alveolar flooding and can prevent any net alveolar fluid clearance. For example, severe acid-induced lung injury in rabbits can result in relentless alveolar flooding and a markedly impaired alveolar fluid clearance.9
10
On the other hand, experimental evidence indicates that ALI with severe increased permeability pulmonary edema can be followed within a few hours by the recovery of the ability to remove alveolar edema fluid, even in the presence of morphologic evidence of endothelial and epithelial injury.11
There are several potential mechanisms that may explain the inability of the epithelial barrier to transport fluid effectively in the presence of ALI. For example, moderate levels of hypoxia impair alveolar fluid clearance in rats. In rats that were subjected to moderate hypoxia (8%) for 24 h, there was a 50% decrease in alveolar fluid clearance.12
Interestingly, there was no evidence for a reduction in the gene expression or the quantity of protein for the major sodium transport proteins, the 
, ß, and 
subunits of epithelial sodium transporter (ENaC) or the 1 or ß1 subunits of NaKATPase. Furthermore, the decrease in alveolar fluid clearance was rapidly reversible with the administration of a cAMP agonist. Thus, it appears that the hypoxia-induced decrease in alveolar fluid clearance may occur because of an inability to insert an adequate number of sodium transport proteins into the membrane, which is an hypothesis that is consistent with recent work13
showing that the cAMP agonists can augment the insertion of sodium transport proteins into the membrane.
Another important mechanism that may account for reduced alveolar fluid clearance in patients is the generation of reactive oxygen species and reactive nitrogen species. In one of our experimental studies,14
severe hypovolemic shock in rats prevented the normal increase in alveolar fluid clearance that should occur with the administration of a cAMP agonist. Interestingly, the evidence from this study, as well as that from prior studies,15
16
indicated that the mechanism depended on neutrophils and the generation of oxygen radicals. Furthermore, the most recent data indicate that inhibitors of inducible nitric oxide synthase reversed the shock-induced decrease in alveolar fluid clearance by a nuclear factor kappa-B-dependent mechanism.14
There is some evidence from our clinical studies7
that shock may be associated with an impaired alveolar fluid clearance in the setting of hydrostatic pulmonary edema. Furthermore, one of our studies17
also demonstrated that elevated levels of nitrite and nitrate in the pulmonary edema fluid of patients with hydrostatic and ALI pulmonary edema fluid were associated with a significant decrease in alveolar fluid clearance (Fig 2
).
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Figure 2. Box-plot summary of the mean interval edema fluid nitrate and nitrite concentration vs two categories of alveolar fluid clearance. The maximal alveolar fluid clearance is shown as 14% per hour, and the submaximal/impaired alveolar fluid clearance is < 14% per hour. The horizontal lines represent the median, the box encompasses the 25th to 75th percentiles, and the error bars encompass the 10th to 90th percentiles. * = p < 0.05 (Mann-Whitney U test). Reproduced with permission from Zhu et al.17
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Experimental data also indicate that a more traditional tidal volume ventilation of 12 mL/kg in acid-injured rat lungs decreases alveolar fluid clearance by injuring both the endothelial and epithelial barriers of the lung.18
When a lung-protective tidal volume ventilation strategy of 6 mL/kg was instituted, the degree of lung injury and pulmonary edema was markedly reduced, and the ability of the alveolar epithelial barrier to remove edema fluid was restored to approximately 50% of normal capacity. Interestingly, when a further reduction of tidal volume to 3 mL/kg was used, the degree of pulmonary edema was reduced even further. Alveolar fluid clearance was nearly normal in these rats. Furthermore, the measurement of a biochemical marker of type I epithelial cell injury indicated that the release of this marker was most attenuated with the lowest tidal volume (ie, 3 mL/kg). Thus, alveolar epithelial injury and the ability to remove edema fluid from the distal airspaces of the lung may depend on mechanical factors that augment injury in the presence of already established lung injury, so called ventilator-associated lung injury.
The extent to which these mechanisms function in the clinical setting in patients with ARDS needs to be explored further. There is some preliminary evidence that dysfunction of alveolar epithelial type II cells may be an important factor, as reflected by a worse outcome in patients with a reduced level of surfactant protein D (SP-D) in the edema fluid within 24 h of the onset of ALI.19
One prior study20
also found that lower levels of SP-D in the BAL fluid of patients with ARDS was associated with a higher mortality rate. The lower levels of SP-D in the distal airspaces of the lung early in the course of ALI suggest that the alveolar type II epithelial cells are not producing or releasing this surfactant protein normally, which is a potential marker of biological dysfunction of the epithelial barrier early in the course of lung injury. There is also evidence that surfactant proteins may be nitrated and inactivated in patients with ALI.17
Thus, both experimental and clinical studies support the hypothesis that injury to the alveolar epithelial barrier, probably to both alveolar type I and type II cells, is an important factor in determining the severity of lung injuries and poor outcomes in patients with clinical lung injuries.
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Strategies to Augment the Rate of Alveolar Fluid Clearance in Clinical Lung Injury
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There are several experimental models in which endogenous or exogenous cAMP stimulation has resulted in an up-regulation of alveolar fluid clearance. For example, in the setting of septic or hypovolemic shock, the marked rise in plasma epinephrine levels increases the rate of alveolar fluid clearance in rats.21
22
Also, the exogenous administration of cAMP agonists has been shown to increase the resolution of alveolar and lung edema in a model of hydrostatic pulmonary edema in rats,23
and similar effects have been reported with isoproterenol or dopamine treatment in a hydrostatic stress model in perfused rat lungs.24
Furthermore, three different studies25
26
27
have reported that exogenous ß-adrenergic agonist treatment hastens the resolution of alveolar edema in rats with hyperoxic lung injuries. Also, a recent clinical study indicated that nebulized beta-2 adrenergic agonist therapy achieves therapeutic levels in pulmonary edema fluid of patients with ALI/ARP. Future therapeutic approaches might also include gene therapy strategies for upregulating alveolar fluid clearance.32
33
Therefore, it is conceivable that the exogenous administration of cAMP agonists might accelerate the resolution of pulmonary edema in the presence of clinical lung injury. However, more study will be needed to test this hypothesis, recognizing the multiplicity of mechanisms that might down-regulate or up-regulate net fluid clearance in the clinical setting.28
For example, alveolar epithelial type II cell hyperplasia can increase alveolar fluid clearance, even if the rate of sodium transport per cell is decreased.29
Conversely, a sufficiently injured, denuded alveolar epithelium might make it impossible for any pharmacologic intervention to be successful because of the extent of epithelial injury.30
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Summary
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In conclusion, there is excellent evidence that impaired alveolar epithelial fluid clearance early in the course of clinical lung injury correlates well with a poor clinical outcome. The mechanisms for altered epithelial barrier transport include the loss of type I and type II cells by apoptosis or necrosis, as well as cellular dysfunction induced by hypoxia and reactive oxygen species and reactive nitrogen species. It is conceivable that an increase in net alveolar fluid clearance and the resolution of alveolar edema could be achieved in patients with ALI by cAMP agonist therapy or potentially by the administration of other vasoactive agents.
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Acknowledgements
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I appreciate the assistance of Rebecca Cleff in the preparation of this manuscript.
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Footnotes
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This research was supported by National Institutes of Health grants HL51854 and HL51856.
Abbreviations: ALI = acute lung injury; cAMP = cyclic adenosine monophosphate; SP-D = surfactant protein D
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References
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- Ware, LB, Matthay, MA (2000) The acute respiratory distress syndrome. N Engl J Med 342,1334-1349[Free Full Text]
- Matalon, S, O’Brodovich, H Sodium channels in alveolar epithelial cells: molecular characterization, biophysical properties, and physiological significance. Annu Rev Physiol 1999;61,627-661[CrossRef][ISI][Medline]
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- Jiang, X, Ingbar, DH, O’Grady, SM Adrenergic stimulation of Na+ transport across alveolar epithelial cells involves activation of apical Cl- channels. Am J Physiol 1998;275,C1610-C1620
- Fang, XH, Fukuda, N, Barbry, P, et al Novel role for CFTR in fluid absorption from the distal airspaces of the lung. J Gen Physiol 2002;119,199-208[Abstract/Free Full Text]
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- Folkesson, HG, Matthay, MA, Hébert, CA, et al Acid aspiration induced lung injury in rabbits is mediated by interleukin-8 dependent mechanisms. J Clin Invest 1995;96,107-116[ISI][Medline]
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- Planes C, Blot-Chabaud M, Matthay MA, et al. Hypoxia and beta-2 agonists regulate cell surface expression of the epithelial sodium channel in native alveolar epithelial cells. J Biol Chem 2003 (in press)
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- Frank, JA, Gutierrez, JA, Jones, K, et al Low tidal volume reduces epithelial and endothelial injury in acid-induced rat lungs. Am J Respir Crit Care Med 2002;165,242-249[Abstract/Free Full Text]
- Cheng, IW, Ware, LB, Greene, KE, et al Prognostic value of surfactant proteins A and D in patients with acute lung injury. Crit Care Med 2002;(in press)
- Greene, KE, Wright, JR, Steinberg, KP, et al Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 1999;160,1843-1850[Abstract/Free Full Text]
- Pittet, J-F, Wiener-Kronish, JP, McElroy, MC, et al Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats. J Clin Invest 1994;94,663-671[ISI][Medline]
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Abstract
Introduction
