Chapter 28: Acute Lung Injury and the Acute Respiratory Distress Syndrome: Pathophysiology and Treatment

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) represent a spectrum of respiratory failure of rapid onset characterized by diffuse, bilateral lung injury and severe hypoxemia that are caused by noncardiogenic pulmonary edema. ALI/ARDS can affect patients of any age or preexisting condition, although both predispose to worse outcomes. Respiratory failure may be initiated by pulmonary or extrapulmonary insults that increase alveolar epithelial and endothelial permeability, flood alveoli, and reduce lung compliance in a pattern reflecting an acute restrictive lung disease. Despite numerous prospective, double-blind clinical trials in patients with ALI/ARDS, the only treatment that improves survival is mechanical ventilation using a lung protective strategy in which tidal volume V_T is carefully titrated to ~6 mL/kg of predicted body weight. Positive end-expiratory pressure (PEEP) ventilation is useful for alveolar recruitment in lungs that will be prone to atelectasis. Clinical vigilance must be comprehensive and anticipatory to guard against development of ventilator-associated pneumonia or worsened ALI. Although mortality can exceed 50%, survivors have a good prognosis for recovery of lung function.

ALI and ARDS affect over 190,000 patients annually in the United States and cause 75,000 deaths. They occur rapidly and show diffuse, bilateral lung injury readily evident by x-ray or CT. Patients exhibit severe hypoxemia despite use of supplemental O₂, and are considered emblematic of a noncardiogenic pulmonary edema with low alveolar ventilation/perfusion ratios (V̇_A/ Q̇) and abnormal physiological shunting of O₂. Such acute respiratory failure usually occurs with neutrophil (PMN)-mediated lung inflammation. Pathological increases in the permeability of alveolar epithelial and endothelial cells lead to dyspnea, tachypnea, and arterial hypoxemia. These permeability defects increase efflux of proteins and fluids from blood into the alveolar interstitium and airspaces, while alveolar liquid clearance mechanisms are impaired that normally would resolve the edema. Consequently, alveolar O₂ exchange deteriorates.

ALI/ARDS is complex and multiphasic. The initiating factors that may cause early lung dysfunction may differ from those that perpetuate, complicate, or delay its resolution. ALI/ARDS can be caused by pulmonary-specific mechanisms, notably severe pneumonia, aspiration of gastric contents, embolism of fat, air, or amniotic fluid, chest trauma, near-drowning, and inhalation of noxious gases. ALI/ARDS can also occur due to systemic conditions, notably bacteremic sepsis, peritonitis, pancreatitis, hemorrhagic shock, burns, massive transfusions, and drug overdoses. Such indirect factors reflect pulmonary manifestations of acute systemic inflammation and generalized endothelial injury that may involve many organ systems. Approximately 15% of deaths from ALI/ARDS are due to progressive respiratory failure with intractable hypoxemia, increased dead space ventilation, and hypercarbia. The main cause underlying death in ALI/ARDS (~75% patients) is the multiple organ dysfunction syndrome (MODS) involving the heart, kidneys, coagulation system, and liver as well as lung.

In 1994, the American-European Consensus Conference on ARDS issued definitions that have been widely adopted by clinicians and researchers. These include:

1. Acute lung injury. A syndrome of acute and persistent lung inflammation with increased vascular permeability characterized by:

   1. acute onset (within days of exposure to predisposing direct or indirect causes);

   2. diffuse bilateral infiltrates on x-ray consistent with noncardiogenic edema;

   3. P_ao₂/F_Io₂ ≤ 300 mm Hg, regardless of the level of PEEP during mechanical ventilation. The ratio P_ao₂/F_Io₂ estimates lung oxygenation efficiency across the range of supplemental O₂ provided to patients. P_ao₂ is measured in mm Hg and F_Io₂ is a decimal between 0.00 and 1.00. For example, in a subject with P_ao₂ = 100 mm Hg on room air (F_Io₂ = 0.21), the P_ao₂/F_Io₂ = 100/0.21 = 476 mm Hg;

   4. no clinical evidence of left-sided heart failure or elevated left atrial pressure, that is, an elevated P_PW if a pulmonary artery catheter (PAC) had been placed, as in congestive heart failure (Fig. 28.1). A relatively normal heart size by x-ray supports the clinical absence of left ventricular failure as the explanation for pulmonary edema. If a PAC is in use, the wedge pressure is ≤18 mm Hg. Clinical evidence of left heart failure includes systolic left ventricular (LV) dysfunction, plus appropriate physical findings, such as LV S₃ gallop and peripheral edema, especially when supported by LV dilation or reduced ejection fraction by echocardiography or catheterization, or enlarged cardiac silhouette plus pleural effusions.

2. Acute respiratory distress syndrome. A more severe physiological expression of ALI, at the further end of a spectrum of evolving lung injury characterized by:

   1. acute onset;

   2. diffuse bilateral infiltrates on x-ray consistent with pulmonary edema;

   3. P_ao₂/F_Io₂ ≤200 mm Hg;

   4. no evidence of left-sided heart failure, including normal heart size on x-ray (Fig. 28.2). If a PAC is used, the measured P_PW is ≤18 mm Hg.

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.

1. Increased microvascular permeability (noncardiogenic pulmonary edema)

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:

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:

1. Decreased σ during sepsis, causing larger proteins like albumin to enter the interstitium, so that protein-rich edema floods alveoli.

2. Reduced π_MV from excessive IV infusions and/or reduced acute phase protein synthesis, favoring increased transvascular fluid flux into distal airspaces.

3. Increased P_MV from IV fluids to treat hypovolemia, or decreased venous return due to increased intrathoracic pressures during positive-pressure ventilation.

4. Increased π_PMV from plasma proteins entering alveolar interstitium, or from loss of alveolar epithelial Na⁺ transport, both retarding alveolar liquid clearance.

These cause gravitationally dependent alveolar edema, first evident in inferior lung zones of supine patients (Fig. 28.3), worsening V̇_A/ Q̇ mismatch and reducing P_aO₂.

2. Alveolar instability and de-recruitment with decreased lung compliance: pathophysiology and potential for ventilator-associated lung injury

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:

1. Alveolar edema inactivates surfactant as plasma proteins leak into airspaces.

2. 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).

3. Functional residual capacity (FRC) declines in ALI/ARDS patients, who often breathe rapidly and shallowly to maximize their V̇_E while minimizing the work of breathing that would be required to expand their noncompliant or "stiff" lungs.

4. Superimposed mechanical ventilation-associated lung injury (VALI) may occur, especially at V_T's exceeding 10 mL/kg of predicted body weight (PBW) that were historically used to ventilate adults with ALI/ARDS.

When previously normal alveoli become atelectatic due to alveolar flooding and inflammatory exudates, mechanical ventilation of patients with high V_T's to sustain V̇_E 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:

1. barotrauma: pressure-related lung injury

2. volutrauma: alveolar over-distention injury

3. cyclical shear stress from excessive tidal swings in alveolar diameters

3. Dysregulated and excessive acute lung inflammatory responses

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:

1. cytokines, notably TNF-α, IL-1β, IL-6, IL-8, IL-10, G-CSF, and GM-CSF;

2. chemokines, such as macrophage inhibitory factor and chemoattractant protein;

3. arachidonic acid metabolites, including prostanoids and leukotrienes;

4. oxyradicals/oxidants, including superoxide anion and peroxynitrite;

5. proteases that degrade alveolar structures and enhance inflammation;

6. fibrin, following activation of tissue factor and the coagulation system.

Together, these processes cause acute lung dysfunction, tachypnea with distress, declining P_aO₂ by blood gases or declining S_aO₂ 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 V̇_A/ Q̇ mismatch and physiological shunt causing hypoxemia. Additionally, physiological dead space may increase despite a constant V̇_E, 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 P_aCO₂ rises.

Despite these diverse precipitating factors, most ALI/ARDS patients follow similar clinical courses that are characterized initially by severe hypoxemia requiring prolonged mechanical ventilatory support (days to weeks). Patients generally progress through three pathologic stages (see Chap. 26). An initial exudative stage with diffuse alveolar damage gives way over the first week to a proliferative stage with resolving pulmonary edema, proliferating type II cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and deposition of collagen. For unclear reasons, some patients progress to a third fibrotic stage with accelerated collagen deposition, obliteration of normal lung architecture, diffuse fibrosis, and parenchymal cyst formation. This last subgroup accounts for most patients who die "of " ALI/ARDS with intractable hypoxemia and increasing dead space ventilation that require progressively higher F_IO₂ and the associated risk of lung O₂ toxicity. Prolonged ventilation with F_IO₂ ≥0.60 is associated with increased inflammation and fibrosis.

The bedside physical exam usually reveals tachycardia, tachypnea, diffuse crackles over the chest, increased work of breathing, and frequent dependence on the accessory respiratory muscles (trapezius, scalene, sternocleidomastoid, and pectoralis). Typical laboratory findings in ALI/ARDS are nonspecific and may include leukocytosis, evidence of disseminated intravascular coagulation (DIC), and lactic acidosis. Arterial blood gases usually show acute respiratory alkalosis, reduced S_aO₂ (<90%), decreased P_aO₂/ F_IO₂ ratio, and severe hypoxemia that collectively reflect right-to-left shunt physiology. Chest radiographic findings, while distinctive, are also seen in diffuse lung hemorrhage and acute interstitial edema. Importantly, ALI/ARDS is a clinical syndrome, not a specific disease. It is always caused by underlying conditions that must be diagnosed and treated, in addition to the respiratory failure.

As to the subsequent course in such patients, oxygenation may improve over the first few days as edema resolves. Nevertheless, patients can remain ventilator-dependent due to continued hypoxemia, high V̇_E requirements, and poor lung compliance. Lung radiographic densities become less opaque as edema resolves, but interstitial infiltrates may persist. In the exudative and proliferative phases, lung flooding may resolve but patients continue to exhibit increased dead space ventilation seen as an increased V̇_E with normal or elevated P_aco₂. Oxygenation may respond favorably to PEEP by reversing atelectasis (Fig. 28.4), or remain problematic because of surfactant dysfunction. Organizing fibrosis may occur in the proliferative phase, causing increased airway pressures, pulmonary hypertension, and honeycomb appearances on x-ray.

Serious complications can occur daily in ICU patients, and those with ALI/ARDS and coexisting MODS are particularly prone to deep venous thrombosis, pulmonary thromboembolism, gastrointestinal bleeding, malnutrition, untoward effects from sedative and neuromuscular blocking medications, and superimposed catheter-related infections. In addition, several lung-specific complications may develop, most especially ventilation-related trauma, shear stress injury, and VALI already described.

In addition, nosocomial ventilator-associated pneumonia (VAP) in mechanically ventilated patients is a feared complication, with mortality rates of up to 50%. The "attributable mortality" for VAP is 33%-50%, despite aggressive supportive care and targeted antimicrobial therapy in affected patients. VAP develops in 9%-27% of ventilated patients, and the risk of VAP increases 1%-3% per day of intubation. Late-onset VAP, developing after ≥5 days of intubation and ventilation, is frequently caused by multiple drug resistant (MDR) organisms such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, or Acinetobacter baumannii. VAP is clinically diagnosed by the development of new fever, increased purulent secretions from the endotracheal tube, and new or worsening infiltrates seen on chest x-rays.

The manner in which ALI/ARDS patients are mechanically ventilated has immediate consequences on oxygenation, but also impacts acute inflammatory responses within alveoli. Thus, how such diffusely injured lungs are ventilated by positive-pressure ventilation may: (1) augment inflammatory injury by superimposing additive pressure- or volume-related trauma; (2) delay resolution of lung injury; or (3) enhance recovery of pulmonary gas exchange, lung cell function, and non-pulmonary organ homeostasis.

The first priority in patients with ALI/ARDS is to stabilize their abnormal gas exchange and hemodynamics, ideally to prevent hypoxic organ damage, respiratory muscle fatigue, increased work of breathing, and cardiopulmonary arrest. Rapid clinical assessment followed by transfer to an ICU is important. Most patients will require intubation and mechanical ventilation with a high initial F_IO₂ (commonly 1.00) to relieve hypoxemia, and application of PEEP to increase their FRC. Diagnosing the underlying causes of ALI/ARDS also is critically important. For septic patients, aggressively seeking the cause is indicated (eg, pneumonia, catheter-related bacteremic sepsis, postsurgical abdominal abscess), since infections and purulence within closed spaces must be drained, and empiric broad-spectrum antimicrobial therapy begun quickly.

Given the increased vascular permeability in ALI/ARDS, the appropriate goals for fluid administration, volume status, and hemodynamic management will differ across patient categories. Administering sufficient IV fluids to perfuse non-pulmonary organs may aggravate alveolar edema and cause life-threatening hypoxemia. Similarly, aggressive diuresis may improve pulmonary gas exchange by lowering left atrial pressure and thus the gradient for alveolar flooding from leaky capillaries. Early initiation of supplemental nutrition within 72 hours of ICU admission, preferably by enteral route, is indicated and has been associated with improved outcomes in limited trials.

Historically, a tidal volume (V_T) of 12-15 mL/kg PBW was recommended in ALI/ARDS. However, it is now clear that a low V_T lung protective strategy reduces mortality and is the single most important evidence-based therapy that should be initiated in mechanically ventilated patients with ALI/ARDS. In 2000, the NIH ARDS Network published results of a randomized, controlled multicenter clinical trial in 861 patients. The trial compared a low V_T strategy (6 mL/kg and a plateau pressure <30 cm H₂O) with a higher V_T cohort (12 mL/kg, plateau pressure <50 cm H₂O). Plateau pressure, P_PLAT in vivo is that airway pressure during the brief pause after a mechanical inspiration ends and before the subsequent expiration begins (see Chap. 30). Measured P_PLAT in ventilated patients reflects the static distending pressure in the lungs when airflow (and thus, frictional resistance to airflow) is zero. As such, P_PLAT reflects lung compliance measured during a 0.5 second inspiratory hold in a relaxed, sedated patient. The chief therapeutic goal of minimizing VALI is achieved when P_PLAT is <30 cm H₂O.

In this ARDS Net Trial, in-hospital mortality was 40% among the 12 mL/kg group versus 31% in the 6 mL/kg group. This highly significant 22% reduction in mortality necessitated stopping the trial early for ethical reasons. With an absolute risk reduction of 9% using low V_T ventilation, one life is saved for every eleven ALI/ARDS patients treated by this modality. There were also more ventilator-free days, thereby decreasing the likelihood of VAP, as well as more organ failure-free days in patients in the low V_T group. The prescribed steps in the lung protective strategy to establish initial ventilator V_T and frequency (f) adjustments are the following:

1. Calculate the patient's predicted body weight (PBW);

2. Set initial V_T to 8 mL/kg PBW and ventilator mode to "Volume Assist-Control";

3. Decrease V_T to 7 mL/kg after 1-2 hours, then to 6 mL/kg PBW after another 1-2 hours;

4. Set f to maintain adequate V_E but <35 breaths/min to reduce VALI even if P_aCO₂ increases slightly reflecting mild hypoventilation (permissive hypercapnia);

5. Establish a P_PLAT goal of <30 cm H₂O;

6. Check P_PLAT with a 0.5 second inspiratory pause every 4 hours and after each change in PEEP or V_T.

Survival has improved for patients with ALI/ARDS, particularly since widespread institution of the lung protective strategy for mechanical ventilation. Overall mortality from ARDS uncomplicated by MODS remains 25%-35% despite improved ICU management, availability of new antimicrobial therapies, nutritional support, and other factors. However, mortality in patients with ALI/ARDS and MODS increases proportionately with the number of dysfunctional nonpulmonary organs, reaching 50%-75% with concurrent septic shock plus MODS. Thus, severe sepsis, septic shock, and MODS are more powerful predictors of survival than respiratory parameters per se. Advanced age and preexisting liver dysfunction also connote a poor outcome.

It is difficult to predict outcome in a specific patient with ALI/ARDS based on initial severity of physiological impairments including oxygenation. Such findings do not reliably distinguish survivors from nonsurvivors, nor do the patient's initial respiratory compliance, radiographic findings, or required PEEP. However, failure to improve clinically over the first several days, particularly regarding oxygenation, predicts a complicated course and greater mortality risk. Long-term prognosis for recovery of lung function following ALI/ARDS is reasonably good with respect to lung function. Within six months after hospital discharge, spirometric lung volumes largely return to premorbid or predicted values, except in patients with preexisting lung disease. At one year after discharge, the commonest pulmonary physiological finding is mild to moderate reduction in the single-breath diffusion capacity for carbon monoxide, DL_CO (see Chap. 16). Exertional O₂ deoxygenation remains in perhaps 6% of survivors, reflecting persistent fibrotic remodeling that retards diffusive gas exchange in the distal airways and alveoli.