Pathophysiology

An understanding of the pathophysiology of ARDS with its associated fluid maldistribution and accumulation is essential for developing an approach to management. While ARDS can be triggered by a wide range of pulmonary and extrapulmonary processes, the syndrome shares a common pattern of an acutely developed alveolarcapillary injury. The early phase of ARDS is characterized by diffuse alveolar damage, with disruption of the alveolar epithelial and endothelial cell layers. As a result of increased alveolar-capillary permeability, protein-rich pulmonary edema fluid accumulates in the alveolar spaces, along with neutrophils, macrophages, and erythrocytes. Fibrin-rich hyaline membranes form along the denuded basement membrane [5]. Airspace filling is likely exacerbated by epithelial injury and a decrease in the capacity of the injured alveolar epithelium to reabsorb edema fluid [6]. Edema reabsorption requires that the fluid leak be reduced not only by reduction of endothelial permeability but also by restoration of the functional, more impermeable epithelial layer.

Increased interstitial hydrostatic pressure and pulmonary edema weight have been suggested to be among the key mechanisms of atelectasis formation according to the “sponge theory of ARDS,” postulating a fall in lung compliance combined with compression and collapse of dependent small airways [7]. In ARDS, the greater the degree of pulmonary microvascular permeability, the more outward fluid filtration from microvessels will occur, at any given level of pulmonary vascular hydrostatic pressure [8]. Also, if the pulmonary vascular hydrostatic pressure increases as frequently occurs during fluid resuscitation, the increase in pulmonary edema is even more pronounced. With severe ARDS, pulmonary hypertension may develop with increased pulmonary capillary pressure and/or cardiac failure adding a hydrostatic component to the edema formation. Although alveolar-capillary barrier dysfunction primarily causes the pulmonary edema seen in this disease, reduced colloid osmotic pressure may contribute to the generation and persistence of pulmonary edema as well [9]. In fact, hypoproteinemia is one of the strongest predictors of the development of ARDS among patients with sepsis [10].

In noninjured lungs, pulmonary edema is strictly controlled by the lymphatic drainage system, which constantly removes extravascular lung water (EVLW) from the interstitial tissue and drains it into the superior vena cava via the thoracic duct. In the early stages of ARDS, the increase in interstitial edema is regulated by a compensatory increase of lymphatic drainage. However, as the amount of interstitial edema increases, lymphatic drainage is overwhelmed, and interstitial edema enters the alveoli [11, 12]. The first accumulation site for this pulmonary edema is the loose peri-bronchovascular connective tissue of the lung hila, since this area has both low resistance to fluid flux and major compliance. While interstitial pressure in this area remains low, there is little resorption of interstitial edema, and the pressure gradient remains in favor of further transudation from pulmonary vasculature toward the interstitium thereby worsening fluid maldistribution. Lung weight increases from the accumulation of pulmonary edema producing compression atelectasis with impairment of pulmonary mechanics and gas exchange. Furthermore, increased intrathoracic pressure resulting from positive-pressure mechanical ventilation leads to the activation of feedback systems designed to maintain intravascular volume and arterial pressures [13]. In particular, the renal aldosterone-angiotensin system is activated leading to water and salt retention. Therefore, in ARDS, in addition to the original inflammatory protein-rich edema accumulation, there is a superimposed tendency to retain the infused fluids with further water accumulation.