Alveolar Edema Must Be Cleared for the Acute Respiratory Distress Syndrome Patient to Survive

Jacob Iasha Sznajder

Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois

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When asked "how do we treat the pulmonary edema of a patient with hypoxemic respiratory failure?" house-staff and attending physicians commonly respond: "diuretics combined with sodium and fluid restriction." This response reflects a bias in our therapeutic strategies for patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) to decrease alveolar edema formation. Although it is well established that increased permeability of the alveolo- capillary barrier favors edema formation, a less recognized fact is that the balance between edema formation and edema clearance is of critical importance for the patient to recover from lung injury. In this issue of the Journal (pp. 1376-1383) Ware and Matthay (1) emphasize the importance of impaired lung edema clearance in determining outcome in patients with ALI/ARDS and report that patients with impaired ability to clear edema had worse outcomes.

The rationale for this study stems from previous clinical reports and animal studies describing the mechanisms by which alveolar fluid reabsorption is impaired during lung injury (2). In the present study, Ware and Matthay evaluated edema fluid from 79 patients obtained by aspirating secretions from the endotracheal tube via a small-bore catheter. Because protein removal from the airspaces is slower than fluid, the estimate of fluid clearance was assessed by measuring edema fluid protein concentration over time, where the magnitude of protein change equated the rate of fluid clearance. Ware and Matthay found that alveolar fluid clearance was impaired in a majority of ARDS patients, and clearance was impaired in more patients with sepsis as the underlying cause of ARDS. Patients with more rapid edema clearance rates had a shorter duration of mechanical ventilation and lower mortality (1). These findings contrast with data from patients with hydrostatic pulmonary edema where the majority (75%) of patients had normal levels of clearance and only a minority had impaired ability to clear edema (6). Importantly, patients with ALI/ARDS and maximal levels of alveolar fluid clearance had better outcomes.

Almost 20 years ago it was first reported that alveolar fluid clearance was effected by active Na⁺ transport (7). Clearance mechanisms differ from mechanisms regulating edema formation, where changes in pulmonary filtration coefficient, hydrostatic and oncotic pressure gradients regulate the extent of edema formation. Alveolar fluid clearance is regulated by active Na⁺ transport where Na⁺ moves vectorially across the alveolar epithelium mostly via apical sodium channels and basolaterally located Na,K-ATPase (Na⁺ pump) with water following isosmotically into the interstitium and the pulmonary circulation (8). There is accumulating evidence, mostly from animal models of lung injury, that increasing sodium transport by up-regulating alveolar epithelial Na⁺ channels and Na⁺ pumps increases lung edema clearance (2, 5). Specifically, several reports have demonstrated that in models of lung injury catecholamines such as terbutaline, isoproterenol, dobutamine, and dopamine up-regulate the function of Na⁺ channels and Na,K-ATPase resulting in increased alveolar fluid reabsorption (2, 3, 5). This effect is rapid. Increases in lung edema clearance are observed within 15 min of treatment. Catecholamines regulate the recruitment of functional Na⁺ pumps from intracellular compartments, which are inserted into the plasma membrane of alveolar epithelial cells within minutes of dopamine or isoproterenol stimulation (9). These effects are dependent on the dynamic interaction between intracellular protein-transporting vesicles and the microtubules and actin cytoskeleton, as pretreatment with colchicine prevents the recruitment of functional Na,K-ATPase from intracellular pools into the plasma membrane (9).

Recent studies have reported that alveolar fluid reabsorption can also be increased by activating the transcription and translation of Na⁺ channels and Na,K-ATPase genes. For example, dexamethasone, aldosterone, as well as the growth factors KGF and EGF, increase alveolar fluid reabsorption and may represent additional therapeutic options for patients with ALI/ARDS. Although recombinant gene technology is not yet part of the clinical armamentarium for the treatment of pulmonary edema, it has been reported that overexpression of Na,K-ATPase genes increased Na,K-ATPase function in alveolar epithelial cells increasing fluid reabsorption in normal lungs and in a model of hyperoxic lung injury (10).

The alveolar epithelium needs to reabsorb the edema fluid for patients with ARDS to improve. This concept was introduced about 10 yr ago (4). Why is it then that strategies to increase lung edema clearance have not been more widely implemented? Several reasons appear to contribute and are reflected in some of the limitations of this interesting study by Ware and Matthay.

First, presently there are no accurate means of quantifying bedside whether lung edema is being cleared. The methodology presented by Ware and Matthay appears to be accurate in the laboratory, as reflected by their current and previous reports. However, it is cumbersome to aspirate adequate samples of edema fluid from the endotracheal tube and to quantify edema clearance at the bedside. Most patients do not have large quantities of free flowing edema to be collected, sequentially assayed, and compared with serum protein measurements.

Second, there are no noninvasive means to accurately assess changes of pulmonary edema. Sequential chest computerized tomography scanning, magnetic resonance imaging, positron emission tomography, scanning, impedance plethysmography, and dye dilution techniques have not been systematically studied to assess temporal changes in extravascular lung edema. These estimates can be further confounded by substantial changes in edema formation as well as changes in tidal volumes or positive end-expiratory pressure.

Third, an argument can be made that most patients with ARDS are already treated with catecholamines. In fact Ware and Matthay state that the rate of alveolar fluid clearance did not correlate with catecholamine levels and thus suggest that alveolar fluid clearance in these patients could occur predominantly by catecholamine-independent mechanisms. However, this conclusion cannot be drawn from the current study as Ware and Matthay have not tested whether clearance is catecholamine-dependent but simply correlated these variables. There are several examples of therapeutic interventions in which a benefit was not demonstrated until the intervention had been specifically tested. For example, investigators have previously reported no association/correlation between lung edema and outcome in patients with ARDS. However, subsequent studies, including the present report, suggest that ARDS patients with more rapid clearance and less edema have better outcomes.

In summary, Ware and Matthay demonstrate that alveolar edema clearance is impaired in patients with ARDS and that decreased clearance is associated with higher mortality, which is important new information. Hopefully, the findings from this and previous studies will promote more prospective studies of therapeutic strategies aimed at increasing alveolar edema clearance in ALI/ARDS patients. For example, prospective studies could be designed to determine whether catecholamine treatment improves indirect measures of clearance (gas exchange and compliance), shortens ventilator days, and improves survival. The development of simpler and more accurate methods to assess changes in edema clearance will certainly facilitate such investigations.

Acknowledgments: The author is grateful to Drs. S. Budinger, K. Ridge, and P. Sporn for their valuable suggestions.

Supported by HL-48129 and HL-65161.

	References

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