The natural history of ARDS is marked by three phases—exudative, proliferative, and fibrotic—that each have characteristic clinical and pathologic features (Fig. 322-1).
In this phase (Fig. 322-2), alveolar capillary endothelial cells and type I pneumocytes (alveolar epithelial cells) are injured, with consequent loss of the normally tight alveolar barrier to fluid and macromolecules. Edema fluid that is rich in protein accumulates in the interstitial and alveolar spaces. Significant concentrations of cytokines (e.g., interleukin 1, interleukin 8, and tumor necrosis factor α) and lipid mediators (e.g., leukotriene B4) are present in the lung in this acute phase. In response to proinflammatory mediators, leukocytes (especially neutrophils) traffic into the pulmonary interstitium and alveoli. In addition, condensed plasma proteins aggregate in the air spaces with cellular debris and dysfunctional pulmonary surfactant to form hyaline membrane whorls. Pulmonary vascular injury also occurs early in ARDS, with vascular obliteration by microthrombi and fibrocellular proliferation (Fig. 322-3).
Alveolar edema predominantly involves dependent portions of the lung, with diminished aeration and atelectasis. Collapse of large sections of dependent lung markedly decreases lung compliance. Consequently, intrapulmonary shunting and hypoxemia develop and the work of breathing increases, leading to dyspnea. The pathophysiologic alterations in alveolar spaces are exacerbated by microvascular occlusion that results in reductions in pulmonary arterial blood flow to ventilated portions of the lung (and thus in increased dead space) and in pulmonary hypertension. Thus, in addition to severe hypoxemia, hypercapnia secondary to an increase in pulmonary dead space is prominent in early ARDS.
The exudative phase encompasses the first 7 days of illness after exposure to a precipitating ARDS risk factor, with the patient experiencing the onset of respiratory symptoms. Although usually presenting within 12–36 h after the initial insult, symptoms can be delayed by 5–7 days. Dyspnea develops, with a sensation of rapid shallow breathing and an inability to get enough air. Tachypnea and increased work of breathing result frequently in respiratory fatigue and ultimately in respiratory failure. Laboratory values are generally nonspecific and are primarily indicative of underlying clinical disorders. The chest radiograph usually reveals alveolar and interstitial opacities involving at least three-quarters of the lung fields (Fig. 322-2). While characteristic for ARDS, these radiographic findings are not specific and can be indistinguishable from cardiogenic pulmonary edema (Chap. 326). Unlike the latter, however, the chest x-ray in ARDS rarely shows cardiomegaly, pleural effusions, or pulmonary vascular redistribution. Chest CT in ARDS reveals extensive heterogeneity of lung involvement (Fig. 322-4).
Because the early features of ARDS are nonspecific, alternative diagnoses must be considered. In the differential diagnosis of ARDS, the most common disorders are cardiogenic pulmonary edema, diffuse pneumonia, and alveolar hemorrhage. Less common diagnoses to consider include acute interstitial lung diseases (e.g., acute interstitial pneumonitis; Chap. 315), acute immunologic injury (e.g., hypersensitivity pneumonitis; Chap. 310), toxin injury (e.g., radiation pneumonitis; Chap. 263), and neurogenic pulmonary edema (Chap. 47e).
This phase of ARDS usually lasts from day 7 to day 21. Most patients recover rapidly and are liberated from mechanical ventilation during this phase. Despite this improvement, many patients still experience dyspnea, tachypnea, and hypoxemia. Some patients develop progressive lung injury and early changes of pulmonary fibrosis during the proliferative phase. Histologically, the first signs of resolution are often evident in this phase, with the initiation of lung repair, the organization of alveolar exudates, and a shift from a neutrophil- to a lymphocyte-predominant pulmonary infiltrate. As part of the reparative process, type II pneumocytes proliferate along alveolar basement membranes. These specialized epithelial cells synthesize new pulmonary surfactant and differentiate into type I pneumocytes.
While many patients with ARDS recover lung function 3–4 weeks after the initial pulmonary injury, some enter a fibrotic phase that may require long-term support on mechanical ventilators and/or supplemental oxygen. Histologically, the alveolar edema and inflammatory exudates of earlier phases are now converted to extensive alveolar-duct and interstitial fibrosis. Marked disruption of acinar architecture leads to emphysema-like changes, with large bullae. Intimal fibroproliferation in the pulmonary microcirculation causes progressive vascular occlusion and pulmonary hypertension. The physiologic consequences include an increased risk of pneumothorax, reductions in lung compliance, and increased pulmonary dead space. Patients in this late phase experience a substantial burden of excess morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase of ARDS is associated with increased mortality risk.
TREATMENT Acute Respiratory Distress Syndrome GENERAL PRINCIPLES
Recent reductions in ARDS mortality rates are largely the result of general advances in the care of critically ill patients (Chap. 321). Thus, caring for these patients requires close attention to (1) the recognition and treatment of underlying medical and surgical disorders (e.g., sepsis, aspiration, trauma); (2) the minimization of procedures and their complications; (3) prophylaxis against venous thromboembolism, gastrointestinal bleeding, aspiration, excessive sedation, and central venous catheter infections; (4) prompt recognition of nosocomial infections; and (5) provision of adequate nutrition. MANAGEMENT OF MECHANICAL VENTILATION
(See also Chap. 323) Patients meeting clinical criteria for ARDS frequently become fatigued from increased work of breathing and progressive hypoxemia, requiring mechanical ventilation for support. Ventilator-Induced Lung Injury
Despite its life-saving potential, mechanical ventilation can aggravate lung injury. Experimental models have demonstrated that ventilator-induced lung injury appears to require two processes: repeated alveolar overdistention and recurrent alveolar collapse. As is clearly evident from chest CT (Fig. 322-4), ARDS is a heterogeneous disorder, principally involving dependent portions of the lung with relative sparing of other regions. Because compliance differs in affected versus more “normal” areas of the lung, attempts to fully inflate the consolidated lung may lead to overdistention of and injury to the more normal areas. Ventilator-induced injury can be demonstrated in experimental models of acute lung injury, with high-tidal-volume (VT) ventilation resulting in additional, synergistic alveolar damage.
A large-scale, randomized controlled trial sponsored by the National Institutes of Health and conducted by the ARDS Network compared low VT ventilation (6 mL/kg of predicted body weight) to conventional VT ventilation (12 mL/kg predicted body weight). The mortality rate was significantly lower in the low VT patients (31%) than in the conventional VT patients (40%). This improvement in survival represents the most substantial ARDS-mortality benefit that has been demonstrated for any therapeutic intervention to date. Prevention of Alveolar Collapse
In ARDS, the presence of alveolar and interstitial fluid and the loss of surfactant can lead to a marked reduction of lung compliance. Without an increase in end-expiratory pressure, significant alveolar collapse can occur at end-expiration, with consequent impairment of oxygenation. In most clinical settings, positive end-expiratory pressure (PEEP) is empirically set to minimize Fio2 (inspired O2 percentage) and maximize Pao2 (arterial partial pressure of O2). On most modern mechanical ventilators, it is possible to construct a static pressure–volume curve for the respiratory system. The lower inflection point on the curve represents alveolar opening (or “recruitment”). The pressure at this point, usually 12–15 mmHg in ARDS, is a theoretical “optimal PEEP” for alveolar recruitment. Titration of the PEEP to the lower inflection point on the static pressure–volume curve has been hypothesized to keep the lung open, improving oxygenation and protecting against lung injury. Three large randomized trials have investigated the utility of PEEP-based strategies to keep the lung open. In all three trials, improvement in lung function was evident but overall mortality rates were not altered significantly. Until more data become available on the clinical utility of high PEEP, it is advisable to set PEEP to minimize Fio2 and optimize Pao2 (Chap. 323). Measurement of esophageal pressures to estimate transpulmonary pressure may help identify an optimal PEEP in some cases.
Oxygenation can also be improved by increasing mean airway pressure with inverse-ratio ventilation. In this technique, the inspiratory time (I) is lengthened so that it is longer than the expiratory time (E)— that is, I:E > 1:1. With diminished time to exhale, dynamic hyperinflation leads to increased end-expiratory pressure, similar to ventilator-prescribed PEEP. This mode of ventilation has the advantage of improving oxygenation with lower peak pressures than are required for conventional ventilation. Although inverse-ratio ventilation can improve oxygenation and can help reduce Fio2 to ≤0.60, thus avoiding possible oxygen toxicity, no benefit in ARDS mortality risk has been demonstrated. Recruitment maneuvers that transiently increase PEEP to “recruit” atelectatic lung can also increase oxygenation, but a mortality benefit has not been established.
In several randomized trials, mechanical ventilation in the prone position improved arterial oxygenation, but its effect on survival and other important clinical outcomes remains uncertain. Moreover, unless the critical-care team is experienced in “proning,” repositioning critically ill patients can be hazardous, leading to accidental endotracheal extubation, loss of central venous catheters, and orthopedic injury. OTHER STRATEGIES IN MECHANICAL VENTILATION
Several additional mechanical-ventilation strategies that use specialized equipment have been tested in ARDS patients; most of these approaches have had mixed or disappointing results in adults. High-frequency ventilation (HFV) entails ventilating at extremely high respiratory rates (5–20 cycles per second) and low VTs (1–2 mL/kg). Use of partial liquid ventilation (PLV) with perfluorocarbon—an inert, high-density liquid that easily solubilizes oxygen and carbon dioxide—has yielded promising preliminary results, enhancing pulmonary function in patients with ARDS, but also has provided no survival benefit. Lung-replacement therapy with extracorporeal membrane oxygenation (ECMO), which provides a clear survival benefit in neonatal respiratory distress syndrome, may also have utility in selected adult patients with ARDS.
Data supporting the efficacy of “adjunctive” ventilator therapies (e.g., high PEEP, inverse ratio ventilation, recruitment maneuvers, prone positioning, HFV, ECMO, and PLV) remain incomplete. Accordingly, these modalities are reserved for use as rescue rather than primary therapies. FLUID MANAGEMENT
(See also Chap. 321) Increased pulmonary vascular permeability leading to interstitial and alveolar edema fluid rich in protein is a central feature of ARDS. In addition, impaired vascular integrity augments the normal increase in extravascular lung water that occurs with increasing left atrial pressure. Maintaining a low left atrial filling pressure minimizes pulmonary edema and prevents further decrements in arterial oxygenation and lung compliance; improves pulmonary mechanics; shortens ICU stay and the duration of mechanical ventilation; and is associated with a lower mortality rate in both medical and surgical ICU patients. Thus, aggressive attempts to reduce left atrial filling pressures with fluid restriction and diuretics should be an important aspect of ARDS management, limited only by hypotension and hypoperfusion of critical organs such as the kidneys. NEUROMUSCULAR BLOCKADE
In severe ARDS, sedation alone can be inadequate for the patient-ventilator synchrony required for lung-protective ventilation. This clinical problem was recently addressed in a multicenter, randomized, placebo-controlled trial of early neuromuscular blockade (with cisatracurium besylate) for 48 h. In severe ARDS, early neuromuscular blockade increased the rate of survival and ventilator-free days without increasing ICU-acquired paresis. These promising findings support the early administration of neuromuscular blockade if needed to facilitate mechanical ventilation in severe ARDS; however, these results must be replicated prior to their widespread application in clinical practice. GLUCOCORTICOIDS
Many attempts have been made to treat both early and late ARDS with glucocorticoids, with the goal of reducing potentially deleterious pulmonary inflammation. Few studies have shown any benefit. Current evidence does not support the use of high-dose glucocorticoids in the care of ARDS patients. OTHER THERAPIES
Clinical trials of surfactant replacement and multiple other medical therapies have proved disappointing. Inhaled nitric oxide and inhaled epoprostenol sodium can transiently improve oxygenation but do not improve survival or decrease time on mechanical ventilation. RECOMMENDATIONS
Many clinical trials have been undertaken to improve the outcome of patients with ARDS; most have been unsuccessful in modifying the natural history. While results of large clinical trials must be judiciously applied to individual patients, evidence-based recommendations are summarized in Table 322-3, and an algorithm for the initial therapeutic goals and limits in ARDS management is provided in Fig. 322-5.