Clinical Features

Patients with ARDS typically present with acute respiratory distress at the same time as, or shortly after, one or more of the associated precipitating causes (see Box 73.1). Their physical examination is notable for signs of respiratory distress, rapid shallow respirations with or without scattered inspiratory crackles. They often have orthopnea but no other signs of CHF. Chest radiographs often show characteristic diffuse bilateral infiltrates without cardiac enlargement. Initially, the infiltrates may be interstitial and then progress to widespread and confluent alveolar densities.

Arterial blood gas (ABG) results in very early ARDS are notable for hypoxemia, but often, there is hypocapnia with a primary respiratory alkalosis. Pao₂ typically remains low, despite supplemental oxygen, because of the pulmonary shunt created by flooded alveoli (see Chapter 1). A high respiratory rate and an increased work of breathing rapidly lead to respiratory muscle fatigue, hypercapnia, and need for intubation and mechanical ventilation. Because many patients with ARDS have associated life-threatening conditions, such as hemorrhagic or septic shock, their ARDS may become evident only after initial stabilization and volume resuscitation.

Differential Diagnosis

The differential diagnosis is relatively short and includes cardiogenic pulmonary edema and a few acute conditions with large right-to-left shunts that cause severe hypoxemia. Examples of the latter include severe atelectasis (especially if hypoxic pulmonary vasoconstriction is blunted by vasodilators), opening of a patent foramen ovale as a result of acute pulmonary hypertension arising from a major acute pulmonary embolus, acute eosinophilic pneumonia, and diffuse alveolar hemorrhage.

Unlike AECC definitions of ARDS, the current Berlin definition does allow for concomitant ARDS and cardiogenic pulmonary edema. However, it is still important to differentiate ARDS from pulmonary edema resulting primarily from cardiac failure or fluid overload. Evidence in favor of CHF includes a cardiac history, an enlarged heart on chest radiograph, and a third heart sound. Rapid improvement after diuresis strongly suggests CHF without concomitant ARDS. If a pulmonary artery (PA) catheter is present, a pulmonary artery wedge pressure (PAWP) of ≤ 18 mm Hg supports the diagnosis of ARDS. However, PAWPs of 19 to 22 mm Hg are not uncommon after fluid resuscitation in patients previously diagnosed on clinical grounds prior to insertion of the PA catheter. Conversely, PAWPs in the 19 to 22 mm Hg range or even ≤ 18 mm Hg may be present at the time of measurement in some patients with CHF. One example of the latter is the patient who undergoes diuresis in the interval between the occurrence of pulmonary edema and PAWP determination. Another example is the patient who has “flash pulmonary edema,” in which transient ischemia-induced left ventricular dysfunction or papillary muscle dysfunction resolves before PAWP measurement. In general, cardiogenic pulmonary edema to the degree of confluent alveolar flooding and respiratory failure is associated with PAWP > ~28 to 30 mm Hg in patients with normal oncotic pressure and is primarily due to the imbalance of their Starling forces across the alveolar-capillary membrane.

Acute Exudative Phase in Early ARDS

ARDS has been recognized to progress through several pathologically distinct phases characterized by different clinical and pathologic characteristics. Early-phase ARDS, known as the exudative phase, presents as failure of the lungs alone (single-organ failure) or as failure of the lungs with failure of other organs at the same time as part of the syndrome of multiorgan system failure (MOSF). At the beginning of this phase, no morphologic changes may be seen histologically or ultrastructurally other than interstitial edema resulting from alveolar capillary barrier dysfunction. After gross alveolar edema forms, a pattern of diffuse alveolar damage (DAD) is present. On histologic examination, protein-rich edema with various inflammatory cells fills the alveoli. Hyaline membranes, made up of fibrin strands, form a pseudoepithelium over denuded alveolar basement membranes. The edema may be severe, with lungs from patients with ARDS each weighing more than 1000 g each, a figure that is several times normal.

Overdistention of alveoli resulting from large tidal volumes (“volutrauma” or ventilator-induced lung injury [VILI]) produced by positive pressure mechanical ventilation and positive end-expiratory pressure (PEEP) also contributes to the acute exudative phase by augmenting the original injury. Evidence from animal and in vitro lung experiments indicates that subjecting normal lungs to large tidal volume ventilation (by positive or negative distending pressures) results in the production and release of proinflammatory cytokines and the histologic appearance of DAD. In addition, ventilation of lungs of experimental animals at physiologically appropriate-sized tidal volumes but without any end-expiratory distending pressure, PEEP, can cause release of the same cytokines and lung injury (referred to as a repetitive opening and closing lung injury). Systemic release of these proinflammatory mediators from the lung has been associated with cellular injuries to remote organs and subsequent development of MOSF. These mechanistic findings form the basis underlying the strategy of low tidal volume mechanical ventilation, which is the only ventilation approach that has significantly improved survival in patients with ARDS.

Fibroproliferative Pattern in Late-Phase ARDS

In patients with ARDS who survive the acute exudative phase, alveolar and interstitial remodeling begins after the lung injury is widespread and well established. This may be as early as 1 week after onset and is termed the fibroproliferative phase of ARDS. Type II pneumocytes proliferate after loss of the type I cells and eventually differentiate into new type I pneumocytes to reconstitute the alveolar epithelium. In response to mediators released by the inflammatory process in ARDS with possible contributions from oxygen toxicity, fibroblasts proliferate, migrate, and produce collagen, resulting in alveolar and interstitial fibrosis.

Oxygen toxicity may contribute to the pathologic changes in most cases of late-phase ARDS, but its exact role remains uncertain. Patients with ARDS are virtually always exposed to a high oxygen concentration, which is by itself a cause of acute lung injury in animal models. The level of Fio₂ that is nontoxic for patients with injured lungs remains unknown. These fibroproliferative changes may be marked in some patients and may cause death either from progressive hypoxemic respiratory failure or from nosocomial pneumonia and sepsis.

Hypoxemia

In early-phase ARDS, the most life-threatening problem is severe hypoxemia. This arises predominantly from a large right-to-left intrapulmonary shunt through numerous fluid-filled alveoli (see Chapter 1). Its magnitude can be estimated as follows: a 5% shunt is present for every 100 mm Hg decrease in Pao₂ below 700 mm Hg while the patient is breathing 100% oxygen. For example, if Pao₂ on 100% oxygen is 200 mm Hg, then the shunt is ~25%. (This estimate is accurate only for Pao₂ values above 150 mm Hg.) Patients with ARDS who need mechanical ventilation usually have shunts in the range of 20% to 50%. Increased right-to-left shunt is the cause of the difficulty in reversing hypoxemia with supplemental oxygen, even with oxygen concentrations of 100%. For this reason, one goal of ARDS management is to decrease the shunt fraction by reopening (recruiting) alveoli that have no ventilation (i.e., whose ).

Low Compliance

Decreased lung compliance in ARDS is due to widespread interstitial and alveolar edema and atelectatic alveoli (microatelectasis). Decreased surfactant activity leads to the collapse of alveoli at end-expiration and increased hysteresis between inspiratory and expiratory pressure-volume curves. Low lung compliance results in low respiratory system compliance. For example, if a patient is on 10 cm H₂O of PEEP and has a normal respiratory system compliance of 100 mL/cm H₂O, a ventilator-delivered tidal volume of 500 mL would result in 5 cm H₂O end-inspiratory pressure in addition to the PEEP of 10 cm H₂O. Taken together, the sum results in a plateau pressure (Pplat) of 15 cm H₂O (see Figure 2.3, Chapter 2). In contrast, if the patient has ARDS and a respiratory system compliance of 20 mL/cm H₂O (again assuming 10 cm H₂O of PEEP), the same 500 mL tidal volume would result in a 25 cm H₂O addition to the PEEP of 10 cm H₂O, resulting in a Pplat of 35 cm H₂O.

Loss of alveolar surfactant activity contributes to the low lung compliance in ARDS by at least three different mechanisms: (1) edema fluid washes surfactant out of alveolar spaces, (2) injury occurring to alveolar type II pneumocytes compromises surfactant production and secretion, and (3) contact with plasma proteins inactivates surfactant. Although loss of surfactant activity contributes to the physiologic abnormalities and respiratory failure in this phase of ARDS, its relative clinical importance remains unclear because clinical trials of replacement surfactant therapy have not improved mortality.

Although the chest radiograph shows the infiltrates as diffusely uniform, computed tomographic (CT) scans of the lungs of ARDS patients indicate a more patchy distribution of fluid and atelectasis. CT scans of patients with ARDS performed at varying inspiratory pressures indicate that alveoli can be divided into three compartments: (1) completely filled and nonrecruitable alveoli, (2) atelectatic and recruitable alveoli, and (3) open alveoli (Figure 73.1). Some have regarded the recruitable and open alveoli as a “baby lung,” because they constitute a small fraction of the total lung. Lung protective strategies, such as low tidal volume ventilation, as described later, are based in part on the concept that in patients with ARDS, one is really ventilating a lung for which traditional larger sized tidal volumes (10 to 12 mL/kg predicted body weight) are much too large, resulting in alveolar overdistention and lung injury.

Increased Minute Ventilation

Patients with ARDS have increased minute ventilation. This results from marked increases in alveolar dead space, arising from microscopic level changes in ventilation-perfusion () ratios that increase the number of alveoli with greater than 1. Overall dead space to tidal volume (Vd/Vt) ratios are commonly in the 0.7 to 0.8 range (compared with a normal Vd/Vt ratio of 0.3). As a result, the minute ventilation must be increased two to three times in order to keep the Paco₂ in the normal range (see Appendix B). During mechanical ventilation this requires high inspiratory flow rates to maintain an I:E of < 1. Although high respiratory rates are needed to keep Paco₂ in the normal range while simultaneously using low tidal volume ventilation, this approach can be limited by short exhalation times and dynamic overinflation (auto-PEEP; see Chapter 2). Therefore, many clinicians allow Paco₂ to rise (permissive hypercapnia), prioritizing lung protective ventilation over maintaining normal levels of Paco₂.