Chapter 19: The Acute Respiratory Distress Syndrome

The acute respiratory distress syndrome (ARDS) was first described in 1967 by Dr David Ashbaugh and colleagues.¹ ARDS is a life-threatening lung condition characterized by acute onset and rapidly progressive dyspnea, tachypnea, and hypoxemia. Several clinical precipitants are associated with the development of ARDS, including sepsis, pneumonia, aspiration, and transfusion of blood products. Pathogenesis is through a severe inflammatory process, which causes diffuse alveolar damage and alveolar capillary leakage, resulting in a ventilation-perfusion mismatch and poor lung compliance. A significant amount of basic and clinical research has resulted in a greater understanding of ARDS and subsequent improvement in outcomes through improved ventilatory strategies and supportive care of other organ systems. Morbidity and mortality, however, remain high. This chapter discusses the current understanding of the epidemiology, pathophysiology, management approaches, and prevention of ARDS.

Epidemiology

Accurate estimation of the incidence of ARDS is limited due to variations in diagnostic criteria over the last two decades. In 2005, a prospective cohort study estimated the incidence of acute lung injury (ALI) and ARDS to be approximately 190,600 cases annually in the United States.² Additional cross-sectional studies demonstrated that patients with ARDS represent approximately 5% of hospitalized, mechanically ventilated patients.³ Over the last decade, there has been a decrease in the incidence of hospital-acquired ARDS, which has been attributed to overall improvements in the care of critically ill patients. However, it appears the incidence of community-acquired ARDS is unchanged.⁴

Prior literature has suggested that mortality from ARDS differs by sex and race, with males and African Americans suffering disproportionately lower survival rates.⁵ This sex-related mortality difference may be partially explained by recent data suggesting sex differences exist in patient presentation and likelihood of development of ALI with males more likely than females to develop ALI. The same explanation was not true for race-related differences, as White patients were found more likely than Black patients to develop ALI.⁶

Predisposing Conditions

A number of medical and surgical conditions have been associated with the development of ARDS. Traditionally, these disorders have been categorized into direct (pulmonary) lung injury or indirect (extrapulmonary) lung injury resulting from inflammatory disease states. Direct/pulmonary injuries account for the majority of cases, while pneumonia and sepsis are the two most common causes overall.⁷ Table 19–1 summarizes pulmonary and extrapulmonary predisposing conditions.

Mechanism of Injury

ARDS is characterized by a severe inflammatory process, which causes diffuse alveolar epithelial and capillary damage, resulting in three distinct pathologic stages. During the acute exudative stage, increased alveolar capillary permeability leads to alveolar flooding with protein-rich fluid. A release of proinflammatory cytokines coupled with neutrophil extravasation into the alveoli leads to diffuse alveolar injury. Damage to type I and II alveolar cells results in exposition of the underlying basement membrane and impaired surfactant synthesis, respectively. Alveolar collapse ensues and is accompanied by alveolar hemorrhage and hyaline membrane formation. Approximately 7 to 14 days following the initial insult the second fibroproliferative stage begins, represented by varying degrees of neovascularization and fibrosis. From here, most patients enter into a subsequent resolution and repair phase. Few individuals, however, progress to a fibrotic stage resulting in obliteration of the normal lung architecture.⁸

Clinical Presentation

The clinical features of ARDS typically manifest within 72 hours of the predisposing event and worsen rapidly. In addition to clinical findings related to the precipitating condition, patients typically present in respiratory distress with tachypnea, dyspnea, and hypoxemia. Laboratory evaluation reveals hypoxemia with an elevated alveolar-arterial gradient. Supplemental oxygenation is generally inadequate, and endotracheal intubation is often required. Imaging exhibits bilateral alveolar infiltrates on chest radiograph (CXR; Figure 19–1) and generalized airspace opacities on computed tomography (CT) with predominance in the dependent lung zones (Figure 19–2).

Diagnosis

In 1994, the American-European Consensus Conference (AECC) defined diagnostic criteria for ALI and ARDS which included four components: appropriate clinical setting, acute severe hypoxemia (defined as a ratio of P_aO₂/F_iO₂ ≤ 200 mm Hg for ARDS), bilateral infiltrates on CXR, and unelevated pulmonary capillary wedge pressure (PCWP ≤ 18 mm Hg) or no clinical evidence of left atrial hypertension. The AECC used a P_aO₂/F_iO₂ threshold of 200 to differentiate ALI (P_aO₂/F_iO₂ 201-300 mm Hg) from ARDS (P_aO₂/F_iO₂ ≤ 200 mm Hg).⁹

Due to AECC definition limitations in sensitivity and reproducibility,¹⁰ these criteria were reevaluated and eventually superseded by the Berlin definition of ARDS in 2012. Important modifications to the AECC definition include (1) specification of “acute” as 7 days or less from the predisposing event, (2) elimination of the use of PCWP to rule out cardiogenic edema, and (3) elimination of ALI as a diagnostic category and instead implementing a mild, moderate, and severe grading system.¹¹ Table 19–2 outlines the Berlin definition, which is the current standard for diagnosis.

There is ongoing research into the predictive value of plasma biomarkers for the diagnosis of ARDS. Several ARDS-associated biomarkers have been identified, such as Krebs von den Lungen-6, lactate dehydrogenase, receptor for advanced glycation end products, von Willebrand factor, and interleukin-8.¹² Definitive validation of the use of these biomarkers for diagnosis has not been accomplished, however, and the diagnosis of ARDS remains a clinical one.

Management strategies for ARDS are centered on treatment of the underlying clinical disorder while providing supportive care that minimizes ventilator-induced lung injury (VILI).

Mechanical Ventilation

The majority of patients with ARDS develop respiratory failure severe enough to necessitate mechanical ventilation. While positive-pressure ventilation helps to ensure adequate oxygenation, our understanding of the potential harms of mechanical ventilation has evolved over the last decade. There are four potential mechanisms of alveolar damage in ventilated patients with ARDS: (1) barotrauma caused by excessive airway pressures, (2) volutrauma caused by over distension of alveoli from high tidal-volume ventilation, (3) atelectrauma caused by shearing forces on alveoli from inspiratory opening and expiratory collapse, and (4) biotrauma caused by the release of proinflammatory cytokines from excessive mechanical forces on the lung.¹³

A substantial amount of basic and clinical research has been devoted to understanding optimal ventilator strategies to reduce VILI, which are summarized as follows.

Low Tidal-Volume Ventilation

One strategy for reducing lung injury during mechanical ventilation is the use of low tidal-volume (V_t) ventilation. This became the standard of care following the landmark National Heart, Lung, and Blood Institute's ARDS Network (ARDSNet) trial in 2000, in which a lower V_t (goal 6 mL/kg ideal body weight) with lower plateau-pressure (< 30 cm H₂O) was compared to a higher V_t and plateau-pressure (12 mL/kg ideal body weight and < 50 cm H₂O). Patients randomized to the low V_t/low plateau-pressure group had a reduced 28-day mortality and developed fewer instances of organ failure.¹⁴ These findings have been confirmed by additional work showing increased intensive care unit and hospital mortality in patients ventilated with higher V_t.¹⁵

Positive End-Expiratory Pressure

Another strategy used to reduce injury during mechanical ventilation is the application of positive end-expiratory pressure (PEEP) to reduce cyclical alveolar opening/collapse. However, the optimal level of PEEP in ventilated patients with ARDS remains controversial given the opposing risks of alveolar overdistension and hemodynamic compromise. In a meta-analysis of trials comparing high-PEEP and low-PEEP strategies (14 cm H₂O vs ~8 cm H₂O), patients with moderate to severe ARDS (P_aO₂/F_iO₂ ≤ 200) showed a small but significant improvement in survival among the higher PEEP group. However, this mortality benefit did not exist when all ARDS patients (P_aO₂/F_iO₂ ≤ 300) were included in the analysis.¹⁶ One possible explanation for these findings is that patients with moderate to severe ARDS (with more significant edema and potentially recruitable lung) may respond favorably to higher PEEP, whereas patients with mild ARDS (and less proportion of recruitable lung) may experience alveolar distension of their healthy, already-aerated lung tissue. At this time, clinical practice guidelines recommends titrating PEEP to maintain an oxygen saturation of 88% to 95% and a plateau pressure of 30 cm H₂O or less to avoid barotrauma.

Fraction of Inspired Oxygen

While the use of high concentrations of inspired oxygen (FiO₂) is commonly necessary, at least temporarily, for patients with severe ARDS, excessive use of high FiO₂ can cause a spectrum of lung injury. Cellular injury appears to be related to increased production of reactive oxygen species, which impair intracellular molecule function and cause cell death.¹⁷ This can lead to damage of the airways and pulmonary parenchyma. Reducing the FiO₂ to the lowest tolerable level is desirable for all critically ill patients and particularly in patients with ARDS who have already sustained some form of lung injury.

Novel Ventilation Strategies

Transpulmonary pressure-guided ventilation—Transpulmonary pressure-guided ventilation uses an esophageal balloon-catheter to estimate pleural pressure and titrate PEEP to each individual's lung and chest wall mechanics. This approach targets a positive transpulmonary pressure (P_TP) to deliver enough PEEP to prevent repetitive airspace collapse yet avoiding alveolar overdistension. A preliminary single-centered trial showed that optimizing P_TP significantly improved oxygenation and lung mechanics compared to a conventional ventilation strategy.¹⁸ Further investigations are being conducted to examine potential survival benefit.

High-frequency oscillation ventilation—High-frequency oscillation ventilation (HFOV) delivers very small tidal volumes at a high frequency (180-1800 per minute) in an effort to maintain a high mean airway pressure. The supporting theory is that sustaining a constant mean airway pressure during inspiration and expiration will prevent end-expiratory collapse. An initial randomized, controlled trial showed an early, transient improvement in oxygenation among patients ventilated with HFOV versus conventional ventilation.¹⁹ However, a subsequent trial showed no significant differences between both groups and was stopped prematurely due to low inclusion.²⁰

Airway pressure release ventilation—Airway pressure release ventilation is a mode of pressure-controlled mechanical ventilation, which applies continuous positive airway pressure for a prolonged time, followed by a release phase to a lower pressure for a shorter period of time. The prolonged high-pressure phase allows for maintenance of adequate lung volume and alveolar recruitment while the shorter low-pressure phase provides the majority of ventilation and carbon dioxide removal.²¹ APRV was developed to provide lung recruitment while minimizing VILI. Several studies have shown APRV to improve clinical outcomes, such as oxygenation, lung recruitment, respiratory mechanics, and sedation requirement. However, thus far it has not been shown to improve mortality as compared to other lung protective ventilation strategies.²²

Supportive Care

Patients with ARDS require diligent supportive care, including judicious use of sedatives, appropriate fluid management, and adequate nutritional support.

Sedation

The use of sedatives and analgesia in patients with ARDS improves ventilator tolerance²³ and decreases oxygen consumption.²⁴ However, given the significant morbidity associated with excessive sedation, judicious use of agents is recommended. Moreover, improved outcomes have been demonstrated through the application of strategies for frequent sedation liberation and awakening as well as early mobilization.²⁵

Fluid Management

Although the ARDS definition excludes patients with pulmonary edema exclusively due to volume overload or cardiogenic etiologies, an estimated 30% of patients with ARDS have an elevated pulmonary artery occlusion pressure less than 18 mm Hg. Even in patients without elevated filling pressures, a positive fluid balance is associated with poorer outcomes.²⁶ Thus, conservative fluid management for patients with hemodynamic stability and adequate urine output may be beneficial in patients with ARDS.

Nutritional Support

Given the tremendously catabolic state present among patients with ARDS, nutritional support is advantageous. Enteral feedings are preferable if the gastrointestinal tract is acceptable for intake. Theoretically, enteral feeds with increased fat and decreased carbohydrates should result in less carbon dioxide production, thereby decreasing the degree of respiratory acidosis. The ARDSNet EDEN trial showed no difference in physical function, survival, or cognitive performance among patients receiving trophic versus full enteral feedings.²⁷

Novel Therapies

Paralysis

Neuromuscular blocking agents are used to achieve paralysis and decrease ventilator dyssynchrony. Improved patient–ventilator synchrony is thought to reduce VILI by improving control of low tidal-volume ventilation and decreasing the inflammatory response.²⁸ In patients with ARDS, early, short-term paralysis has been shown to improve mortality without a significant increase in development of muscle weakness.²⁹

Prone Positioning

Prone positioning results in improved oxygenation through three primary mechanisms. First, redistribution of blood flow to healthier lung regions results in a decreased ventilation perfusion mismatch and recruitment of dependent lung units.³⁰ Mechanically, lung tissue relieved of compression from anterior mediastinal and abdominal structures. Lastly, clearance of respiratory secretions is improved with an associated reduction in ventilator-associated pneumonia.³¹ For patients with severe ARDS (P_aO₂/F_iO₂ ≤ 100 mm Hg), early application of prone positioning has been shown to confer a survival benefit at 28 and 90 days.³²

Extracorporeal Membrane Oxygenation

During extracorporeal membrane oxygenation (ECMO) blood is rerouted outside the body to an external membrane oxygenator, which acts as an artificial lung to facilitate adequate gas exchange. Major risks include bleeding due to anticoagulation (in particular, intracranial hemorrhage) and complications of large bore vascular access. While initial studies showed no improvement in mortality, a more recent trial suggested a potential survival benefit for patients put on ECMO,³³ though other studies have not reproduced this benefit. Currently, ECMO is reserved as an option for rescue therapy for patients with severe ARDS and refractory hypoxemia.

Pulmonary Vasodilator Pharmacotherapy

Inhaled vasodilators, such as nitric oxide (NO) have been used in ARDS to improve oxygenation by selectively dilating pulmonary arterial vasculature and decreasing ventilation/perfusion mismatching. While inhaled NO has been shown to improve oxygenation in some ARDS patients with refractory hypoxemia, it has not shown a reduction in mortality.³⁴ Thus, inhaled NO has not used routinely and is instead reserved for patients with intractable hypoxemia.

Despite significant advancements in the diagnosis and management of ARDS over the last two decades, recent mortality estimates remain more than 40%.³⁵ Recent studies have suggested an improvement in survival over time; however, this appears to instead reflect a shift in clinical trials to enroll patients with less severe ARDS.³⁷

Among patients who survive ARDS, there is frequently appreciable morbidity that persists years later. Decreased functionality, impaired exercise intolerance, negative psychosocial sequelae, and decreased quality of life have been shown to persist up to 5 years following discharge.³⁸