CHEST RADIOGRAPH AND CHEST COMPUTED TOMOGRAPHY IN ACUTE LUNG INJURY

The interpretation of the chest radiograph is central to these definitions of ALI and ARDS. However, there is considerable interobserver variability in both chest radiograph interpretation and in the definition of an infiltrate. In the American–European Consensus Conference definition the infiltrate must be bilateral and consistent with pulmonary oedema,² whereas the LIS rates the number of quadrants with alveolar consolidation³ and the Delphi definition requires bilateral airspace disease. The intention of these descriptions is fairly clear and excludes opacity due to pleural effusion, nodules, masses, collapse and pleural thickening. However, it is desirable to improve interobserver agreement and this will require training and more specific definitions.

Chest computed tomography (CT)⁵ has proved extremely helpful in pathophysiological studies of ALI, has demonstrated the heterogeneity of lung inflation and is commonly used to assist clinical management. Autopsy and chest radiographs of ALI show a uniform process affecting both lungs; however, chest CT early in the course of ALI in supine patients demonstrated that there was a dorsal dependent increase in lung density, and that the ventral lung was relatively normal. In addition, CT frequently showed previously undiagnosed pneumothorax, pneumomediastinum and pleural effusion. After the second week of mechanical ventilation CT scans may demonstrate altered lung architecture and emphysematous cysts or pneumatoceles.

CT numbers or Hounsfield units can be assigned to each voxel (∼2000 alveoli in a standard 10-mm slice).⁵ These data can then be used to assess what proportion of a region of interest is non-aerated, poorly aerated, normally aerated or hyperinflated. Initially a single basal lung slice was studied, but it is clear that far more information can be obtained by studying the whole lung, and by using thinner slices. This allows: (1) reconstruction of the upper and lower lobes (the middle lobe is difficult to separate); (2) the same section of lung to be studied at different levels of inflation or PEEP (the lung also moves in a cephalocaudad direction with respiration); and (3) a broader picture of the lung to be obtained (lung damage is heterogeneous in ALI). However, whole-lung CT demands considerable exposure to ionising radiation, and different information, perhaps more pertinent to mechanical ventilation, is obtained from dynamic CT.

Clinical assessment of chest CT is discussed in Chapter 35, and CT findings in ALI are discussed below, in the section on clinical management.

PULMONARY FUNCTION IN SURVIVORS

Respiratory function is most abnormal soon after discontinuation of mechanical ventilation, but usually returns towards normal by 6–12 months. Although a variety of abnormal pulmonary function tests may be found, impaired diffusing capacity is the most common. This is rarely symptomatic, but occasional patients have severe restrictive disease, and this is correlated with their cumulative LIS.⁹

QUALITY OF LIFE IN SURVIVORS

Compared with disease-matched ICU patients who do not develop ARDS, patients with ARDS have a more severe reduction in both pulmonary and general health-related quality of life.¹⁰ Many patients have reduction in exercise tolerance that may be attributable to associated critical-illness neuropathy and myopathy; nerve entrapment syndromes and heterotopic calcification play a role in a minority.⁷ Depression, anxiety and posttraumatic stress disorder are also common (20–50% of survivors).⁷ However, it is unclear whether neuropsychological disability is a direct consequence of the illness, or related to the associated stress. Finally, most survivors have cognitive impairments such as slowed mental processing, or impaired memory or concentration, and these correlate with the period and severity of desaturation < 90%.¹¹ Although these data suggest that ARDS confers a specific risk of impaired quality of life, the mechanism is unclear. However, they do caution against permissive hypoxaemia as a strategy to reduce ventilator-induced lung injury (VILI).

BIOLOGICAL MARKERS AS PREDICTORS OF ALI

In addition to identifying these clinical risk groups, there has been considerable interest in identifying possible biological markers that could be used to predict the development of ALI. Although greater specificity may be gained from sampling the epithelial lining fluid (e.g. using bronchoalveolar lavage fluid), an ideal biological marker would be more simply sampled, such as plasma. Numerous proteins, such as the cytokines interleukin (IL)-1, tumour necrosis factor-α (TNF-α) and IL-10, and von Willebrand’s factor antigen are elevated in at-risk patients and patients with ALI and ARDS; however, they are not predictive. In relatively small studies both ferritin¹² and surfactant protein B¹³ have been shown to be predictive of ARDS. Although ferritin likely represents a non-specific oxygen free-radical response, the leakage of surfactant protein B from the alveolus into the blood is lung-specific.

THE ALVEOLOCAPILLARY BARRIER

The normal lung consists of 300 million alveoli with alveolar gas separated from the pulmonary microcirculation by the extremely thin alveolocapillary barrier (0.1–0.2 μm thick). Since the endothelial pore size is 6.5–7.5 nm, and the epithelial pore size is almost one-tenth that, at 0.5–0.9 nm, the epithelium is the major barrier to protein flux.¹⁵ The surface area of the alveoli is estimated to be 50–100 m², which is made up predominantly of alveolar type I cells, with the metabolically active type II cells accounting for ∼10% of the surface area. In turn, these cells are covered by the epithelial lining fluid, with an estimated volume of 20 ml, ∼10% of which is surfactant with the remained filtered plasma water and low-molecular-weight proteins, and a small number of cells, mainly alveolar macrophages and lymphocytes.

In ALI the alveolocapillary barrier is damaged with bidirectional leakage of fluid and protein into the alveolus and leakage of surfactant proteins and alveolar cytokines into the plasma. There is also disruption of the epithelial barrier, surfactant dysfunction and proliferation of alveolar type II cells as the progenitor of type I cells. The outcome of this process must reflect a balance between repair and fibrosing alveolitis. As discussed above, the precise sequence of events causing and maintaining damage of the alveolocapillary barrier is complex and uncertain and likely varies depending on the underlying cause. For example, indirect causes of ALI may initially cause pulmonary endothelial injury followed by recruitment of inflammatory cells and epithelial damage, while direct causes of ALI may initially cause epithelial injury and secondary recruitment of inflammatory cells.

NEUTROPHILS IN ACUTE LUNG INJURY

Neutrophils are the most abundant cell type found in both the epithelial lining fluid (e.g. bronchoalveolar lavage fluid) and alveoli in histological specimens from early in the course of ALI. Although neutrophil migration across the endothelium or epithelium does not cause injury, when activated they release reactive oxygen species, cytokines, eicosanoids and a variety of proteases that may make an important contribution to tissue damage in ALI. Following bone marrow demargination, activated neutrophils adhere to the endothelium on their passage to the alveolus, and this may be accompanied by an early, transient leukopenia. Although neutrophils have an important role in host defence due to their bactericidal activity, there is a marked (50–1000-fold) increase in the release of cytotoxic compounds when they are activated by adherence to the endothelium, epithelium or contact with interstitial extracellular matrix proteins.¹⁶ The factors involved in adhesion of neutrophils are complex and involve the integrin family of proteins, selectins and a number of adhesion molecules.

In models of ALI, antibodies to adhesion molecules (e.g. CD11b/CD18 antibodies) ameliorate lung injury, suggesting a crucial and central role of this cell type. However, ALI occurs in neutropenic patients, and was not more common when granulocyte colony-stimulating factor was administered to patients with pneumonia.¹⁷ Clearly, other cell types play an important role, and neutrophil chemoattractants such as IL-8 must be present in the lung prior to neutrophil accumulation.

OTHER CELL TYPES INVOLVED IN ACUTE LUNG INJURY

Pulmonary endothelial cells, platelets, interstitial and alveolar macrophages and alveolar type II cells also play important roles in alveolar inflammation. Pulmonary endothelial cells express a variety of adhesion molecules and cyclooxygenase-2 (COX-2); secrete endothelin and cytokines, including IL-8;¹⁸ stimulate procoagulant activity; and ‘cross-talk’ with the alveolar macrophages and type II cells. They will be involved in generalised endothelial activation, and are subject to mechanical stress, secondary to both vascular pressure and to their close association with the alveolus. Von Willebrand’s factor antigen is synthesised by vascular endothelial cells, and although this may explain its lack of specificity for ALI, its plasma levels are a good marker of endothelial injury.¹⁹

Microvascular thrombosis is common in ALI, and contributes to pulmonary hypertension and wasted ventilation. Although platelet aggregation may contribute to ALI through release of thromboxane A₂, serotonin, lysosomal enzymes and platelet-activating factor, they are less important than the other cell types.

Alveolar macrophages are the most common cell type normally found in bronchoalveolar lavage fluid, and, together with interstitial macrophages, play an important role in host defence and modulation of fibrosis. They are capable of releasing IL-6 and a host of mediators, similar to the activated neutrophil, including TNF-α and IL-8 in response to stretch,²⁰ and may amplify lung injury. However, depletion of alveolar macrophages does not reduce neutrophil recruitment or outcome from tracheal instillation of Pseudomonas aeruginosa,²¹ questioning the central role of this cell type. Macrophages also release a number of factors such as transforming growth factor-α and platelet-derived growth factor that stimulate fibroblast proliferation, deposition of collagen and glycosaminoglycans, angiogenesis and lung fibrosis.

Alveolar epithelial type II cells are extremely metabolically active; they manufacture and release surfactant, control alveolar water clearance using ion pumps, express cytokines which in turn interact with surfactant production and are the progenitor of type I cells following injury. In response to both stretch and endotoxin, type II cells express IL-8 and TNF-α, with the latter cytokine augmenting Na⁺, and hence water, egress from the alveolus.²²

CHEMOKINES IN ACUTE LUNG INJURY

The expression and secretion of chemokines (chemoattractant cytokines) at sites of inflammation are probably key proximal steps in initiating the inflammatory cascade. IL-8 appears particularly important in initiating ALI because of its ability to induce chemotaxis and activation of neutrophils. IL-8 is elevated in ALI bronchoalveolar lavage fluid within hours of the initiating insult and before recruitment of neutrophils, and in a manner that reflects subsequent morbidity and mortality. In animal models of sepsis and acid aspiration, instillation of antibodies against IL-8 prevents the recruitment of neutrophils and protects the lung. Indeed, the recruitment and retention of neutrophils require the generation and maintenance of a localised chemotactic/haptotactic gradient.²³

Mediators in acute lung injury

From the discussion above it is clear that numerous mediators, derived from a number of different cell types, play important roles in the pathophysiology of ALI. These include cytokines, chemokines, complement, reactive oxygen species, eicosanoids, platelet-activating factor, nitric oxide, proteases, growth factors and lysosomal enzymes. As the alveolocapillary barrier becomes injured, these are no longer compartmentalised in the alveolus, and many of these proteins have been measured in blood as well as in the epithelial lining fluid. Care must be taken when interpreting these data as immunologic levels may not reflect biologic activity; inhibitors or binding proteins may complex with the active protein or epitope and interfere with immunologic detection; and the ultimate biological effect will depend upon a balance of proinflammatory and anti-inflammatory effects.

Although many of the over 40 biologically active cytokines are implicated in ALI, TNF-α, IL-1β, IL-6 and IL-8 are the most important. However, even greater increases are found in their cognate receptors or antagonists, such as the counterregulatory cytokine IL-10, so that their biological impact is markedly reduced.²⁴ Despite numerous studies, measurement of cytokines in blood or epithelial lining fluid has not proven predictive of the development of ALI or of mortality.

RESOLUTION OF ACUTE LUNG INJURY AND THE DEVELOPMENT OF FIBROSING ALVEOLITIS

Although elevated levels of type III procollagen peptide are found in the epithelial lining fluid soon after diagnosis, histological evidence of fibrosing alveolitis (mesenchymal cells and new vessels in alveoli) is not usually found until at least 5 days following the onset of ALI. In the majority of patients there is clinical resolution of ALI provided that the underlying cause is promptly and effectively treated. Alveolar oedema resolves with active transport of Na⁺ by the type II cells followed by passive clearance of water through transcellular aquaporin channels, and repair of the alveolocapillary barrier is associated with improved outcome. Type II cells proliferate and cover the denuded epithelium before differentiating into type I cells. Both proapoptotic and antiapoptotic (granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF)) factors are found in the alveolus during this phase; however, little is known regarding control over the delicate balance between repair and fibrosis.