Epidemiology

The exact incidence of ALI/ARDS has been difficult to estimate for a variety of reasons. In the past, variable definitions of the syndrome were used.⁵ The wide variety of causes and coexisting disease processes has also made identification of cases difficult, both at the clinical and administrative coding level.⁶ The National Institutes of Health first estimated the incidence at 75 per 100,000 population in 1977,⁷ but a number of studies since then have reported lower incidences.⁶ Two prospective studies confirmed the higher original National Institutes of Health Estimate. The first utilized enrollment logs from the National Heart, Lung and Blood Institute–sponsored ARDS Network of 20 hospitals and estimated that the incidence could be as high as 64 cases per 100,000 population. This dataset has the advantage of being prospectively collected from a large number of academic medical centers. The second was a large prospective study of residents of King County, Washington. In that study, the crude incidence of ALI/ARDS in adults was 78.9 per 100,000 patient years.⁸ A large prospective European study of the incidence of ARDS found that ALI occurred in 7.1% of all hospital admissions.⁹ A third of these patients presented with only mild ALI, but of these, half progressed rapidly to ARDS. Some studies suggest a decline in the incidence of ARDS over time. A large prospective cohort of trauma patients at risk for ARDS and multisystem organ failure collected over time showed that the incidence of ARDS decreased from 43% in 1997 to 12% in 2004, a finding that may reflect advances in posttrauma critical care.¹⁰ Regardless of the exact incidence, it is clear that ALI/ARDS is a major public health problem that will be encountered frequently by all physicians who care for critically ill patients.

Risk Factors

ALI/ARDS can occur as a result of either direct or indirect injury to the lungs (Table 58-1) in patients with a predisposing risk factor. The commonly associated clinical disorders can be separated into those that directly injure the lung and those that indirectly injure the lung. Although it is not always feasible to determine the exact cause of ALI/ARDS in a given patient, direct causes appear to account for approximately half of all cases of ALI/ARDS.¹¹ It is not clear whether the distinction between direct and indirect lung injury is clinically useful.¹² Some investigators have demonstrated reduced respiratory system compliance in patients with ARDS due to direct pulmonary injury compared to indirect causes,¹³ although total respiratory system compliance (including the chest wall) is similar.¹⁴ Patients with direct lung injury may be more likely to have improved lung mechanics with the application of PEEP. However, in the largest cohort of patients studied to date, there was no difference in mortality between those with direct (pulmonary) and indirect (extrapulmonary) causes of lung injury.¹¹ Regardless of the underlying cause of ALI/ARDS, most patients with ALI/ARDS appear to have a systemic illness with inflammation and organ dysfunction not confined to the lung.¹⁵

TABLE 58-1 Risk Factors Associated with Development of Acute Lung Injury and Acute Respiratory Distress Syndrome

Sepsis is the most common cause of indirect lung injury, with an overall risk of progression to ALI or ARDS of approximately 30% to 40%.^16–19 In a more recent prospective study of hospitalized patients with a risk factor for acute lung injury (e.g., sepsis, pneumonia) 6.5% of patients developed ALI, and 4% met criteria for ARDS; the risk was higher with multiple risk factors.²⁰ In addition to sepsis itself being a risk factor for development of ARDS, the site of infection may also influence the risk of lung injury. In patients with sepsis admitted to an ICU, patients who had pneumonia as the source of sepsis had an increased risk of ARDS compared to those with infections at other sites such as the abdomen, skin, or soft tissue.²¹ Severe trauma with shock and multiple transfusions also can cause indirect lung injury. Although the other causes of indirect lung injury are less common, many, such as blood transfusions, are commonplace events in the ICU setting. The most common cause of direct lung injury is pneumonia, which may be of bacterial, viral, or fungal origin. The risk of developing ALI/ARDS increases substantially in the presence of multiple predisposing disorders.¹⁹ Secondary factors may also increase the risk. Such factors include chronic lung disease,¹⁸ chronic or acute alcohol abuse,^22,23 increasing age,²⁴ transfusion of blood products,^25–27 lung resection,²⁸ and obesity.²⁴ Emerging evidence has suggested that some at-risk patients may actually be protected from the development of ARDS. Several studies have shown that patients with diabetes are less likely to develop ARDS.^29–31 To some extent, every patient in the ICU is at risk for developing ALI/ARDS, and vigilance is required to recognize the diagnosis and treat appropriately.

Pathophysiology

The pathophysiology of ALI/ARDS is complex and remains incompletely understood. Microscopically, lungs from afflicted individuals in the early stages show diffuse alveolar damage with alveolar flooding by proteinaceous fluid, neutrophil influx into the alveolar space, loss of alveolar epithelial cells, deposition of hyaline membranes on the denuded basement membrane, and formation of microthrombi (Figure 58-1).³² Alveolar flooding occurs as a result of injury to the alveolar-capillary barrier and is a major determinant of the hypoxemia and altered lung mechanics that characterize early ALI/ARDS.

Figure 58-1 Histology. A, Lung biopsy specimen obtained from a patient 2 days after onset of acute respiratory distress syndrome (ARDS) as a result of aspiration of gastric contents. Characteristic hyaline membranes are evident (arrow), with associated intraalveolar red cells and neutrophils, findings consistent with pathologic diagnosis of diffuse alveolar damage (hematoxylin and eosin, ×90). B and C, Lung biopsy specimens obtained 14 days after onset of sepsis-associated acute lung injury (ALI) and ARDS; B shows granulation tissue in distal air spaces, with chronic inflammatory-cell infiltrate (hematoxylin and eosin, ×60). Trichrome staining in C reveals collagen deposition (dark blue areas) in granulation tissue, a finding consistent with deposition of extracellular matrix in the alveolar compartment (×60). D, Specimen of lung tissue from a patient who died 4 days after onset of ALI/ARDS. There is injury to both capillary endothelium and alveolar epithelium. Note intravascular neutrophil (LC) in the capillary (C). Vacuolization and swelling of endothelium (EN) are apparent. Loss of alveolar epithelial cells is also apparent, with formation of hyaline membranes on epithelial side of basement membrane (BM^*). E, Specimen of lung tissue obtained from a patient during fibrosing alveolitis phase; there is evidence of reepithelialization of epithelial barrier with alveolar epithelial type II cells. Arrow indicates a typical type II cell with microvilli and lamellar bodies containing surfactant. Epithelial cell immediately adjacent to this cell is in the process of changing to a type I cell, with flattening, loss of lamellar bodies, and microvilli. Interstitium is thickened, with deposition of collagen (C).

(With permission from Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342[18]:1334-1349.)

The alveolar-capillary barrier is formed of two separate cell layers, the microvascular endothelium and the alveolar epithelium. Injury to the alveolar epithelium is a prominent histologic feature, with loss of alveolar epithelial barrier integrity and sloughing of alveolar epithelial type I cells. Alveolar epithelial apoptosis is widespread and likely contributes to the loss of epithelium seen ultrastructurally.^33,34 Although endothelial injury is less obvious at the microscopic level, ultrastructural studies reveal that it is widespread.^35,36 Endothelial injury allows leakage of plasma from the capillaries into the interstitium and airspaces. Alveolar flooding in ALI/ARDS is characteristically with a protein-rich edema fluid, owing to the increased permeability of the alveolar capillary barrier, in contrast to the low-protein pulmonary edema that results from hydrostatic causes such as congestive heart failure or acute myocardial infarction.^37–40

Neutrophils play an important role⁴¹ in the initial inflammatory response in ARDS. Early ALI/ARDS is characterized by migration of neutrophils into the alveolar compartment.^35,36 Neutrophils can release a variety of injurious substances, including proteases such as neutrophil elastase, collagenase, and gelatinases A and B, as well as reactive nitrogen and oxygen species. In addition, they can elaborate proinflammatory cytokines and chemokines which amplify the inflammatory response in the lung. Resident alveolar macrophages are also involved in initiating and sustaining a proinflammatory cytokine cascade that leads to recruitment of neutrophils into the lung.

In addition to acute neutrophilic inflammation and elaboration of a proinflammatory cytokine cascade, a variety of other abnormalities contribute to the pathogenesis of ALI/ARDS. Surfactant dysfunction is characteristic, with abnormalities in both the protein and lipid components.^42–45 This likely results from disruption of normal surfactant activity secondary to the influx of plasma proteins into the airspaces, intraalveolar proteolysis, and injury to the alveolar epithelial type II cells. Surfactant dysfunction may have important implications both for lung mechanics and host defense.⁴⁶ Activation of the coagulation cascade and impaired fibrinolysis are also apparent in patients with ALI/ARDS,^47,48 both in the lung^49–51 and systemically.^52,53 Alteration in the balance of endogenous oxidants and antioxidants, with a decrease in endogenous antioxidants⁵⁴ despite the increased oxidant production, has also been observed.⁵⁵

The contribution of ventilator-associated lung injury to the pathogenesis of ALI/ARDS has been recognized. There are several mechanisms by which mechanical ventilation can injure the lung. Ventilation at very high volumes and pressures can injure even the normal lung, leading to increased permeability pulmonary edema due to capillary stress failure⁵⁶ and sustained elevations of circulating plasma cytokines.⁵⁷ In the injured lung, even tidal volumes that are well tolerated in the normal lung can lead to alveolar overdistension in relatively uninjured areas because the lung available for distribution of the administered tidal volume is greatly reduced and because of uneven distribution of inspired gas.^58,59 In addition to alveolar overdistension, cyclic opening and closing of atelectatic alveoli can cause lung injury even in the absence of alveolar overdistension. The combination of alveolar overdistension with cyclic opening and closing of alveoli is particularly harmful and can initiate a proinflammatory cascade.⁶⁰

A ventilatory strategy that was designed to minimize alveolar overdistension and maximize alveolar recruitment ameliorated proinflammatory cytokine release.⁶¹ This fundamental insight into the pathogenesis of clinical ALI/ARDS has led to multiple clinical trials of novel ventilatory strategies for patients with ALI/ARDS, including the landmark ARDS Network trial of 6 mL/kg versus 12 mL/kg tidal volume ventilation⁶² (see Treatment section).

Diagnosis

In 1994, the American-European Consensus Conference published new clinical definitions for ALI and ARDS.⁵ Prior to this time, a variety of definitions were used clinically, including the Murray Lung Injury Score.⁶³ To meet the Consensus diagnostic criteria for either ALI/ARDS, the acute onset of bilateral radiographic infiltrates is required. There should be no clinical evidence of left atrial hypertension, with a pulmonary artery occlusion pressure (PAOP) ≤ 18 mm Hg if measured. Although not strictly part of these definitions, an underlying cause of lung injury should be sought. In the absence of an identifiable underlying cause (see Table 58-1), particular attention should be given to the possibility of other causes of pulmonary infiltrates and hypoxemia, such as hydrostatic pulmonary edema. One potential limitation of the consensus definition is the need for arterial blood gas sampling to calculate a PaO₂/FIO₂ ratio. Recent work has shown good correlation between the SpO₂/FIO₂ ratio (measured by pulse oximetry) and the PaO₂/FIO₂ ratio,^64,65 with an SpO₂/FIO₂ ratio of 235 corresponding to a PaO₂/FIO₂ ratio of 200, and an SpO₂/FIO₂ ratio of 315 correlating to a PaO₂/FIO₂ ratio of 300. These calculations are valid only when the SpO₂ is less than 98%, because the oxyhemoglobin dissociation curve is flat above this level. Oxygen saturation is a noninvasive, continuously available measurement; use of the SpO₂/FIO₂ ratio may improve the ability of clinicians to diagnose ARDS.

Differentiating ARDS from hydrostatic edema can be difficult, and there may be significant overlap in the syndromes (Figure 58-2).⁶⁶ A recent multicenter trial on intravenous catheter directed fluid management strategies in patients with ARDS showed that 29% of patients with clinically defined ARDS had a PAOP greater than 18 mm Hg at the time of pulmonary artery catheter insertion, but that 97% of patients had a normal or elevated cardiac index, suggesting they did not have clinical heart failure.⁶⁷ Other studies have shown similar rates of elevated PAOP in patients with ARDS.⁶⁸

Figure 58-2 Algorithm for differentiating between cardiogenic and noncardiogenic pulmonary edema.

(With permission from Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med. 2005;353[26]:2788-2796.)

There are no specific clinical or laboratory studies that can reliably distinguish between ARDS and hydrostatic edema. A study examining the diagnostic utility of serum levels of B-type natriuretic peptide (BNP) showed that BNP measured at admission could not reliably differentiate between hydrostatic edema and ARDS. Furthermore, BNP levels in these patients did not correlate with invasive hemodynamic measurements.⁶⁹

The standardization of definitions for ALI and ARDS has been helpful from several perspectives. For clinical research, it has been valuable in allowing the comparison of different studies and the rapid identification of patients for enrollment in clinical trials. Clinically, the new definitions are easy to apply and facilitate rapid identification and appropriate treatment of patients with ALI/ARDS. However, it should be noted the nature of ALI/ARDS is such that any definition will have significant shortcomings. First, the definitions must be based solely on clinical criteria, because currently there is no laboratory test that allows clinical assessment of the presence or absence of ALI/ARDS. Second, there is no reference to pathogenesis or underlying cause. This is because the list of potential causes of ALI/ARDS is so long, diverse, and common in the critically ill. Third, the presence or absence of multiorgan dysfunction, an important determinant of outcome, is not specified. Finally, though the presence of bilateral infiltrates has major prognostic significance and is clearly a hallmark of the syndrome, the radiographic findings are not specific for ALI/ARDS.^4,70 Diagnostic uncertainty in ALI/ARDS is a major barrier to initiation of appropriate therapy and one of the main reasons why clinicians fail to initiate lung-protective ventilation in clinically appropriate patients.⁷¹

Recent work has focused on alternative methods to increase sensitivity and specificity of the clinical definitions for ALI/ARDS. The pulmonary edema fluid–to–plasma protein ratio can reliably distinguish between low-permeability (hydrostatic edema) and high-permeability (ARDS) pulmonary edema if measured early after endotracheal intubation,⁷² but prospective validation is still needed. Alternatively, circulating biomarkers may prove useful for the diagnosis of ALI/ARDS.⁷³ Despite its shortcomings, the current clinical definition of ALI/ARDS based on consensus criteria should be used to rapidly identify patients with ALI/ARDS so appropriate therapy can be initiated promptly.

In the majority of patients, the initial diagnosis of ALI/ARDS is made clinically. Invasive techniques for diagnosis are of limited clinical utility, and the benefits rarely outweigh the risks. Bronchoscopy may be indicated in the early phases of ALI/ARDS in patients in whom there is no identifiable predisposing risk factor. Rarely, an alternate treatable diagnosis is found, such as acute eosinophilic pneumonia, pulmonary alveolar proteinosis, diffuse alveolar hemorrhage, or unsuspected infection. Bronchoalveolar lavage for cultures and cytologic examination can identify the cause of pneumonia, and is particularly useful in the diagnosis of opportunistic infections. Lavage fluid usually has a predominance of neutrophils, and there may be evidence of diffuse alveolar hemorrhage. Cytologic examination can be used to confirm the presence of diffuse alveolar damage.⁷⁴

In the past, open lung biopsy was obtained more frequently for diagnosis in patients with suspected ARDS. Interestingly, the degree of histologic abnormality on lung biopsy does not correlate with ultimate outcome as measured by pulmonary function.⁷⁵ Open or thoracoscopic lung biopsy may still be useful in some cases where the diagnosis is uncertain and the underlying cause is not apparent. Although open lung biopsy can provide findings that lead to a change in treatment, postoperative complications can occur in 20% of patients.⁷⁶ Several pathologic studies have shown that biopsy or autopsy can identify unsuspected diagnoses requiring specific therapy (e.g., miliary tuberculosis, pulmonary blastomycosis, aspergillosis, bronchiolitis obliterans organizing pneumonia) in 40% to 60% of cases,^76–78 although the general applicability of these studies may be limited by the fact that they were retrospective case series.

In addition to familiarity with the Consensus definitions of ALI and ARDS, the critical care clinician should be aware that ALI and ARDS also have been called by a variety of other terms, some of which are seen mainly in older literature, but some that remain in clinical use. Some of the more common of these terms include adult hyaline membrane disease, postperfusion lung or pump lung, shock lung, ventilator-associated lung injury, and adult respiratory insufficiency syndrome. The terms primary graft dysfunction, primary graft failure, or transplant lung have been used to describe ALI/ARDS from reperfusion pulmonary edema occurring immediately after lung transplantation.

Regardless of the name applied, ALI/ARDS is a clinical syndrome that has prognostic and therapeutic implications above and apart from the underlying cause (i.e., infections, aspiration, trauma, etc.). This fact should not take away the imperative to identify these underlying causes if present and treat them aggressively.

Clinical Course

Early Ali/Ards

The Consensus definitions are designed to identify ALI/ARDS patients early in their course, in the acute or exudative phase. Clinically, the acute phase is manifested by the acute onset of radiographic infiltrates consistent with pulmonary edema, hypoxemia, and increased work of breathing. Radiographic infiltrates are bilateral (by definition), but may be patchy or diffuse, fluffy or dense (Figure 58-3), and pleural effusions may occur.⁷⁹ Chest computed tomographic (CT) imaging, though rarely of use clinically, has been employed extensively as an investigative tool to better define the nature of the infiltrates in patients with ALI/ARDS. The distribution of infiltrates by CT is surprisingly patchy; areas of alveolar filling and consolidation occur predominantly in dependent zones, while non-dependent regions can appear relatively spared.^80–82 Even areas that appear spared in conventional radiographic images may have substantial inflammation when sampled using bronchoalveolar lavage⁸³ or using FDG-PET scanning.⁸⁴

Figure 58-3 Chest radiograph.

The hypoxemia that characterizes early ALI/ARDS is usually relatively refractory to supplemental oxygen. The increased work of breathing in the acute phase of ALI/ARDS is due to decreased lung compliance as a result of alveolar and interstitial edema combined with increased airflow resistance⁸⁵ and increased respiratory drive.⁸⁶ The combination of hypoxemia and increased work of breathing usually necessitates endotracheal intubation and mechanical ventilation, although occasionally patients can be managed with noninvasive ventilation (see Treatment section).

In addition to hypoxemia and increased work of breathing, many patients with ARDS also develop evidence of increased pulmonary vascular resistance leading to pulmonary hypertension and RV failure. The prevalence of pulmonary hypertension in patients presenting to the hospital with ARDS may be as high as 92%,⁸⁷ and as many as 10% of patients with ARDS may have right ventricular (RV) failure defined by hemodynamic measurements.⁸⁸ Nevertheless, the presence of RV failure does not impact mortality. Attempts to reverse pulmonary hypertension and RV failure with pulmonary vasodilators such as sildenafil have led to decreased pulmonary artery pressure with treatment, as well as concomitant increases in shunt fraction and decreases in oxygenation.⁸⁹ These findings suggest that although patients with ARDS have evidence of pulmonary hypertension, it may in some cases be a beneficial physiologic response to reduce blood flow to areas of severely compromised lung.

Treatment

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