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Normal lung function requires dry, open alveoli overlying perfused capillaries with intact gas exchange and a normal work of breathing. It requires coordinated interaction of several key physiological processes plus appropriate lung immune and inflammatory responses. Three interrelated pathophysiologic abnormalities typify events that cause or precipitate ALI/ARDS.
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1. Increased microvascular permeability (noncardiogenic pulmonary edema)
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Normal pulmonary capillaries are selectively permeable, with serum proteins confined to intravascular spaces, while smaller molecules and water cross endothelial membranes by hydrostatic and osmotic forces. As discussed in Chap. 7, the Starling's equation describes forces directing fluid movement between the vessels and the interstitium:
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At least four mechanisms promote fluid retention in capillaries to prevent interstitial edema and alveolar flooding. First, airspace liquid is cleared by apical Na+ transporters in alveolar epithelial cells. Second, larger plasma proteins like albumin maintain osmotic gradients favoring water reabsorption. Third, tight junctions between pulmonary endothelial cells prevent leakage. Fourth, interstitial lymphatics return alveolar fluid to the circulation. Abnormalities in Starling's forces during ALI/ARDS include:
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Decreased σ during sepsis, causing larger proteins like albumin to enter the interstitium, so that protein-rich edema floods alveoli.
Reduced πMV from excessive IV infusions and/or reduced acute phase protein synthesis, favoring increased transvascular fluid flux into distal airspaces.
Increased PMV from IV fluids to treat hypovolemia, or decreased venous return due to increased intrathoracic pressures during positive-pressure ventilation.
Increased πPMV from plasma proteins entering alveolar interstitium, or from loss of alveolar epithelial Na+ transport, both retarding alveolar liquid clearance.
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These cause gravitationally dependent alveolar edema, first evident in inferior lung zones of supine patients (Fig. 28.3), worsening V̇A/ Q̇ mismatch and reducing PaO2.
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2. Alveolar instability and de-recruitment with decreased lung compliance: pathophysiology and potential for ventilator-associated lung injury
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As described in Chap. 5, compliance quantifies changes in lung volumes (ΔV) that are caused by distending airway or intrapleural pressures (ΔP) as occur during spontaneous respiration. Compliance (ΔV/ΔP) is often reduced in ALI/ARDS, leading to alveolar instability and collapse when approaching end-expiratory pressures. This de-recruitment of formerly functioning alveoli results from several factors:
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Alveolar edema inactivates surfactant as plasma proteins leak into airspaces.
Edematous alveoli show increased surface tension, and are prone to collapse (ie, they undergo atelectasis) during end-expiratory pauses in patients with ALI/ARDS. Such distal airspaces fail to expand cyclically during inspiration due to excessively high alveolar opening pressures (see Chaps. 5 and 6).
Functional residual capacity (FRC) declines in ALI/ARDS patients, who often breathe rapidly and shallowly to maximize their V̇E while minimizing the work of breathing that would be required to expand their noncompliant or "stiff" lungs.
Superimposed mechanical ventilation-associated lung injury (VALI) may occur, especially at VT's exceeding 10 mL/kg of predicted body weight (PBW) that were historically used to ventilate adults with ALI/ARDS.
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When previously normal alveoli become atelectatic due to alveolar flooding and inflammatory exudates, mechanical ventilation of patients with high VT's to sustain V̇E is equivalent to forcing each positive-pressure inspiration into infant-sized lungs. At the same time, alveoli that are not yet edematous receive excessive ventilation that is redirected toward the open lung and away from atelectatic regions (Figs. 28.3 and 28.4). This dilemma sets the stage for three forms of VALI that are not mutually exclusive:
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barotrauma: pressure-related lung injury
volutrauma: alveolar over-distention injury
cyclical shear stress from excessive tidal swings in alveolar diameters
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3. Dysregulated and excessive acute lung inflammatory responses
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ALI/ARDS reflects excessive inflammation in the alveolar interstitium and airspaces (Fig. 28.5), involving massive neutrophil influx due to upregulated adhesion molecules on PMNs and vascular endothelia. The inflammation is sustained by additional chemotactic signals and host-derived mediators. As a result, PMNs in bronchoalveolar lavage fluid (BALF) may approach 50% of all cells recovered, versus ≤3% PMNs in BALF from healthy volunteers. Major inflammatory mediators in this acute phase include:
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cytokines, notably TNF-α, IL-1β, IL-6, IL-8, IL-10, G-CSF, and GM-CSF;
chemokines, such as macrophage inhibitory factor and chemoattractant protein;
arachidonic acid metabolites, including prostanoids and leukotrienes;
oxyradicals/oxidants, including superoxide anion and peroxynitrite;
proteases that degrade alveolar structures and enhance inflammation;
fibrin, following activation of tissue factor and the coagulation system.
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Together, these processes cause acute lung dysfunction, tachypnea with distress, declining PaO2 by blood gases or declining SaO2 by pulse oximetry, and chest radiographs or CT scans showing bilateral infiltrates. Of note, such infiltrates may be asymmetric in patients with coexisting chronic obstructive pulmonary disease. Thus progressively impaired gas exchange occurs, with V̇A/ Q̇ mismatch and physiological shunt causing hypoxemia. Additionally, physiological dead space may increase despite a constant V̇E, retarding CO2 elimination. Ventilator-induced rises in intrathoracic pressure also inhibit venous return, with fewer alveoli perfused despite ongoing ventilation. In advanced cases of ALI/ARDS, CO2 excretion falls and PaCO2 rises.
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CLINICAL CORRELATION 28.1
Transfusion-related acute lung injury (TRALI) is an important form of ALI/ARDS with similar clinical features but is temporally related to transfusion of blood products. TRALI is the leading cause of transfusion-related death in the United States. Patients affected with TRALI typically develop fever with cough, dyspnea, and hypoxemia within 6 hours of receiving red cells, platelets, or fresh frozen plasma.