Respiratory Insufficiency

Jeffrey L. Johnson and James B. Haenel

The maintenance of gas exchange may be tenuous in the injured patient because of dysfunction in three key elements of the respiratory system. First, the central nervous system may be impaired, resulting in inadequate respiratory drive, or inability to maintain patent proximal airways. Second, injury to the torso can produce changes in compliance, ineffective respiratory effort, and pain that impact the patient’s ability to complete the work of breathing. Third, primary and secondary insults to the lung result in ineffective gas exchange.

In practice, it is common for patients to suffer simultaneous insults, affecting all three elements. Impaired airway patency (e.g., diminished level of consciousness), increased work of breathing (e.g., multiple rib fractures), and impaired gas exchange (e.g., pulmonary contusion, fat emboli syndrome) often coexist in the same patient. Respiratory failure that relates primarily to CNS injury is discussed at length in other chapters and will not be extensively covered here. This chapter will focus on insults that affect work of breathing and gas exchange. The syndrome of postinjury acute respiratory distress syndrome (ARDS) is a major focus.

HYPERCAPNIC PULMONARY FAILURE

The neurohormonal response to injury (Chapter 61) results in a remarkable increase in cellular metabolism. This creates a substantial increase in carbon dioxide (CO₂) production that must be matched by increased elimination from the lungs. While a resting adult eliminates 200 cm³/(kg min) of CO₂, postinjury hypermetabolism results in CO₂ production in the range of 425 cm³/(kg min).¹ Thus, the minute ventilation required to maintain eucapnia may rise from a resting rate of approximately 5 L/min to more than 10 L/min. This represents a 100% increase in the work of breathing simply to meet metabolic demands.

Additionally, injured patients typically have an increase in physiologic and anatomic dead space—ventilated regions that do not participate in gas exchange. In a normal adult, the proportion of each breath that is dead space (V_d/V_t) is approximately 0.35. In the intubated, ventilated patient, the V_d/V_t can be calculated by a number of techniques including the Bohr–Enghoff method (V_d/V_t = [{PaCO₂ – mean expired CO₂}/PaCO₂]).² For practical purposes (since mean expired CO₂ is not commonly measured), this is a reflection of the minute volume required to achieve a given PaCO₂. In ventilated patients with pulmonary failure, the V_d/V_t often exceeds 0.6. Simply put, this extra dead space is a burden because each breath is less effective at eliminating CO₂, and therefore minute ventilation requirements in the 12–20 L/min range are not uncommon in the postinjury setting.

The above increase in respiratory demand might be met by a healthy adult; however, the injured patient faces several challenges in completing this additional work. CNS dysfunction from injury impairs respiratory drive, as do many medications routinely used for sedation and analgesia. Decreased thoracic compliance from abdominal distension (e.g., as part of the abdominal compartment syndrome, Chapter 41), chest wall edema, and recumbent positioning increases the energy required to complete a respiratory cycle. Decreased pulmonary compliance from an increase in extravascular lung water and pleural collections (effusions/hemothorax) also contribute. Muscular weakness from impaired energetics (acidosis, cardiovascular failure, mitochondrial dysfunction, oxidant stress) or fatigue may be an insurmountable challenge. Finally, pain from torso injuries or operative interventions make the increased ventilatory demand a substantial burden to the patient.

The net effect of increased demand and diminished capacity to execute the work of breathing is hypercapnic respiratory failure. In the early postinjury period, patients most commonly present with a mixed acid–base picture where ventilation is inadequate to maintain physiologic pH in the face of a metabolic acidosis. This frequently occurs in the absence of major hypoxia, and therefore caution is warranted in relying on oximetry alone to assess adequacy of pulmonary function. Particularly in patients with tachypnea, blood gas analysis is optimal to quickly identify patients who are not meeting their ventilatory demands. While efforts to diminish the work of breathing should be routine, most patients with hypercapnic failure require some form of mechanical ventilation to meet their demands. Approaches to invasive and noninvasive ventilation are covered extensively in Chapter 55.

One approach to addressing the challenge of increased CO₂ production in the injured patient is to blunt the hypermetabolic response. Simple maneuvers such as maintenance of euthermia, delivery of nutrition, and minimizing pain-induced stress are warranted but may not affect the incidence or outcome of hypercapnic respiratory failure. A more novel approach is delivery of beta-adrenergic blockade, which, in a retrospective analysis, improves outcomes in injured patients. There are reasonably compelling data in the burn population and the acutely brain injured that blunting of hypermetabolism is beneficial.³ A prospective safety and efficacy evaluation of this approach in injured adults is needed before it can be recommended as routine practice.

Two injury patterns that precipitate hypercapnic respiratory failure are worthy of special mention: spinal cord injury and flail chest/pulmonary contusion. In spinal cord injury, conventional wisdom asserts that lesions below C5 should not result in pulmonary failure, because innervation to the diaphragm remains intact. In practice, however, most complete cord lesions in the cervical and upper thoracic regions routinely result in failure requiring mechanical ventilation.^4,5 The genesis is multifactorial, including delays in patient mobilization, ineffective cough due to loss of innervation of intercostal and abdominal musculature, pneumonia in the setting of multiple injuries, and aspiration at the time of the initial insult. Furthermore, unopposed vagal stimulation results in early bronchorrhea and bronchospasm. This patient population requires aggressive mobilization and pulmonary care as recurrent lobar collapse and pneumonia are the rule.

Early operative stabilization of the spine can be recommended as it has been shown to decrease the need for mechanical ventilation and ICU stay.⁶ Other adjuncts such as noninvasive ventilation, bronchodilators, mucolytics, and percussion should be considered, although most of these have not been studied in a fashion that permits a firm recommendation. Laparoscopic placement of diaphragmatic pacers is a benefit in select patients.⁷ Specifically, improvement in spirometry and some liberation from mechanical ventilation occurs in most patients evaluated thus far. Largely, this has been studied in the rehabilitation setting, and therefore a role for this approach in the acute setting remains to be defined.

Flail chest and pulmonary contusion can be thought of as a single entity. This is a challenging injury pattern, because it impacts both the patient’s ability to execute the work of breathing (from pain and mechanical instability of the thoracic) and gas exchange (from the pulmonary contusion). Isolated pulmonary contusion rarely requires mechanical ventilation. Since minor contusions are frequently identified by computed tomography (CT), it is important to realize that this tends to take a relatively benign course (see Chapter 26). It is clear that the number of rib fractures is strongly associated with pulmonary failure, ARDS, and mortality, and that this effect is more dramatic in the elderly population.⁸ This may in part be a marker of energy applied to the chest and injury to the underlying lung. Early pain control, preferably beginning in the emergency department with regional anesthesia, has been shown to be effective in reducing the impact of multiple rib fractures and should be routinely applied. Admission to a high-volume trauma center, use of patient-controlled analgesia, tracheostomy, and an algorithm-driven approach are associated with improved survival.^9,10

HYPOXIC PULMONARY FAILURE

Hypoxic pulmonary failure is a substantial co-contributor in the trauma setting. The etiologies are diverse including aspiration pneumonitis, pneumonia, pulmonary embolism, acute lung injury (ALI), and ARDS. Most of these entities are discussed elsewhere—ALI and ARDS will be the focus of this chapter. Indeed, the mechanisms at work in ALI and ARDS share many common features with these other processes that affect the alveolar–capillary interface.

ALI AND ARDS

ALI and ARDS are clinical syndromes of inflammatory lung injury that can be thought of as a common final pathway of diverse systemic processes. In the past two decades, there has been major progress in defining the underlying pathophysiology and optimal supportive care. Specific therapy for the underlying mechanisms, however, remains an elusive goal.

CURRENT DEFINITIONS AND THEIR LIMITATIONS

The recognition of ARDS as a distinct clinical entity resulted from the description by Ashbaugh et al. in 1967.¹¹ Subsequent descriptions include five principal criteria: (1) hypoxemia refractory to oxygen administration; (2) diffuse, bilateral infiltrates on chest radiograph; (3) low static lung compliance; (4) absence of congestive heart failure; and (5) presence of an appropriate at-risk diagnosis.

The current standard definitions were developed in 1994, after a Consensus Conference of American and European investigators (AECC) agreed that ARDS should be viewed as the most severe end of a spectrum of ALI. It also recommended diagnostic criteria for ALI and ARDS (Table 57-1). The diagnostic criteria for ARDS include acute onset, the PaO₂/FiO₂ 200 mm Hg or less (<300 for ALI), bilateral infiltrates on chest radiograph, and no evidence of left arterial hypertension (either clinical or with direct measurement). Moreover, the committee recognized that ARDS is most often associated with sepsis syndrome, aspiration, primary pneumonia, trauma, cardiopulmonary bypass, multiple blood transfusions, fat embolism, and pancreatitis. Although debate exists as to the usefulness of the AECC diagnostic criteria, they have promoted study of reasonably homogeneous populations, are largely accepted by clinical investigators, and are likely to be used for some time.¹²

TABLE 57-1 American–European Consensus Conference Definitions of Acute Lung Injury and Acute Respiratory Distress Syndrome

One concern about the standard definitions is substantial limitations to bedside application. For example, transient hypoxemia from mucus plugging is common in an ICU setting, and it is unclear that a patient who only transiently meets P/F criteria should be grouped with patients who have ongoing poor oxygenation. Additionally, recruitment of collapsed alveoli may result in a remarkable improvement in P/F ratio in a short period of time—does this patient no longer have ARDS? Lastly, while the AECC definition excludes patients with left atrial pressure (LAP) >18, Ferguson et al.¹³ showed that patients with no risk factors for congestive heart failure commonly had LAP >18 during a clinical course consistent with ARDS.

Whether the current definition is too broad also remains a matter of debate. For example, a 2004 study compared post-mortem analysis of lung tissue with the AECC definition. This investigation found the latter to be only 84% specific and 75% sensitive for the pathologic lung lesions characteristic of ARDS.¹⁴ It is clear, then, that the AECC definition, while useful for studies of populations, should be applied with caution to individual patients. It is also worthwhile to know its limitations and consider some alternative methods for objectively assessing lung injury.

An alternative that remains useful is the Murray lung injury score (LIS). This was proposed in 1988 and is based on four components: chest radiograph, hypoxemia, positive end-expiratory pressure (PEEP), and respiratory compliance (Table 57-2).¹⁵ Each component is scored from 0 to 4. The LIS is calculated by summing the scores of the available components and dividing by the number of components used. ARDS (or severe lung injury) is defined as an LIS greater than 2.5. Zero represents no lung injury and 0.1–2.5 represents mild to moderate lung injury.

TABLE 57-2 Lung Injury Score^a

A more recent definition makes a simple adjustment to the AECC definition and appears to approve diagnostic accuracy when compared with pathologic lesions found at autopsy. It may be more suitable for bedside evaluation of the individual patient (Table 57-3).¹⁶ Briefly, the authors include PEEP in the consideration of hypoxia and require either the absence of CHF or the presence of a recognized risk factor for ARDS. The degree of hypoxia required is a P/F less than 200 with PEEP ≥10; therefore, it excludes patients who are hypoxic purely because of derecruitment or suboptimal PEEP. By allowing patients with high filling pressures in the presence of a recognized ARDS risk factor, the definition recognizes the prevalence of high LAPs during the course of ARDS and includes patients with concomitant CHF and ARDS.

TABLE 57-3 The “Delphi” Definition of ARDS

EPIDEMIOLOGY AND RISK FACTORS

The estimated incidence of ARDS in population-based studies is on the order of 40 cases per 100,000 person-years.^17–19 In the United States, this represents about 200,000 cases per year, and about 15% of ICU admissions. With modern mortality rates (see below), one can estimate this entity is responsible for about 50,000 deaths per year in the United States.

RISK FACTORS

Several studies demonstrate that age is a risk factor for ARDS, although it is unclear whether this simply represents diminished physiologic reserve in older patients. Hudson et al. documented an increasing incidence of ARDS with increasing age. Subgroup analysis, however, showed that this was largely due to the group with postinjury ARDS who were significantly older (44 years vs. 36 years).²⁰ These authors also observed that a higher Injury Severity Score (ISS) was a risk factor for ARDS.

Genetic variability between patients may also contribute to risk for ARDS (for a discussion of genomics relevant to trauma, see Chapter 53). Polymorphisms in genes encoding cytokines, vasomotor regulators, antioxidants, and surfactant proteins have all been associated with altered risks for either the development of ALI/ARDS or the outcome. Specific candidate genes have included angiotensin-converting enzyme, mannose-binding lectin, extracellular superoxide dismutase, surfactant protein B, and interleukin (IL)-10. Many of these studies are difficult to interpret because the reported effect is modified by gender, disease process (e.g., septic vs. traumatic ARDS), or the patient population studied (e.g., Caucasian vs. Asian).

Of potential particular interest in trauma is a polymorphism in the promoter region of the NADPH:qunione oxidoreductase 1 gene (NQO1). This is an inducible gene that when activated regulates generation of oxidant species. In 2009, Reddy et al. completed an analysis demonstrating that critically injured patients (ISS >16, ICU admission) with the variant gene were about half as likely to develop ALI compared with patients homozygous for the wild-type gene. This effect was independent of race, mechanism of injury, and severity of illness score (Apache III).²¹

Clinical risk factors for ARDS can be broadly categorized into direct and indirect groups (Table 57-4). Direct factors are those primarily associated with local pulmonary parenchymal injury and include pulmonary contusion, aspiration, and pulmonary infection. Indirect factors are those thought to be associated with systemic inflammation and resultant lung injury. These include severe sepsis, transfusion of banked red cells, transfusion of FFP, and multiple long bone fractures. Unless shock is associated with significant tissue injury or other known risk factors, it has not been shown to result in ARDS.²²

TABLE 57-4 Clinical Risk Factors for ARDS

PATHOLOGY

The current paradigm of systemic inflammation leading to ALI and ARDS posits that a variety of insults, both infectious and noninfectious, can result in an unbridled hyperinflammatory response. This leads to organ injury from indiscriminate activation of effector cells that subsequently release oxidants, proteinases, and other potentially autotoxic compounds. If the initial insult is severe enough, early organ dysfunction results (“one-hit” or single insult model). More often, a less severe insult results in a systemic inflammatory response that is not by itself injurious. These patients appear, however, to be primed such that they have an exaggerated response to a second insult, which leads to an augmented/amplified systemic inflammatory response and multiple organ dysfunction (“two-hit” or sequential insult model, see Chapter 61).²³

Inflammatory models provide a unifying hypothesis for ARDS and MOF; however, the precise relationship between ARDS and MOF remains to be defined. MOF is a frequent occurrence and the most common cause of mortality in patients with ARDS.²⁴ Indeed, postinjury ARDS appears to be an obligate precursor of other organ failures.²⁵ This may be because the lung is a primary target of the inflammatory process, or because the resultant pulmonary damage impairs the lung’s ability to metabolize inflammatory mediators and control cellular effectors of injury.²⁶ It is also now clear that ventilator strategies that inadvertently promote lung injury may produce systemic inflammation, perhaps leading to other organ failures.²⁷

Inflammatory lung injury leads to the pathologic lesion of diffuse alveolar damage. This prototypic lesion of ARDS is at the alveolocapillary interface, which results in epithelial and endothelial damage as well as high-permeability pulmonary edema. The histologic appearance of this lesion can be divided into three overlapping phases: (1) the exudative phase, with edema and hemorrhage; (2) the proliferative phase, with organization and repair; and (3) the fibrotic phase.²⁸

The exudative phase generally encompasses the first 3–5 days but may last up to a week. The initial histologic changes include interstitial edema, proteinaceous alveolar edema, and intra-alveolar hemorrhage. The exudative phase is characterized by the appearance of hyaline membranes, which are composed of plasma proteins mixed with cellular debris. Electron microscopy reveals endothelial injury with cell swelling, widening intercellular junctions, and increased pinocytotic vesicles. In addition, there is disruption of the basement membrane.

The alveolar epithelium usually exhibits extensive loss of type I cells, which slough and leave a denuded basement membrane. While some loss may be from necrosis, it appears that apoptosis contributes substantially. Activation of matrix metalloproteinases, Toll-like receptors, and oxidative stress pathways initiate programmed cell death in these cells. Demonstration of soluble Fas ligand in bronchoalveolar lavage (BAL) fluid early in ARDS supports this concept.²⁹

Loss of the alveolar epithelial barrier results in alveolar edema, as the remaining cells are unable to drive sodium from the alveolar into the interstitial compartment.

During the proliferative phase, type II cells divide and cover the denuded basement membrane along the alveolar wall. This process may be seen as early as 3 days after the onset of clinical ARDS. Type II cells are also capable of differentiating into type I epithelial cells. Fibroblasts and myofibroblasts proliferate and migrate into the alveolar space in the third phase. Fibroblasts change the alveolar exudate into granulation tissue, which subsequently organizes and forms dense fibrous tissue. Eventually, epithelial cells cover the granulation tissue. This whole process is called fibrosis by accretion and is important in lung remodeling. Septal collagen deposition by fibroblasts and “collapse induration” also contribute to fibrous remodeling of the lung in ARDS.

The fibrotic stage is characterized by thickened, collagenous connective tissue in the alveolar septa and walls. Pulmonary vascular changes occur as well, with intimal thickening and medial hypertrophy of the pulmonary arterioles. Complete obliteration of portions of the pulmonary vascular bed is the end result.

PATHOGENESIS

Lung injury in ARDS involves components of inflammation, coagulation, vasomotor tone, and other systems (see Chapter 57). The pivotal cellular mediators appear to be leukocytes, with both local and humoral mediators orchestrating their function. Activation of these leukocytes results in release or activation of multiple cytokines, chemokines, oxidants, and proteases that result in the final common pathway of tissue injury in ARDS.

Neutrophils

A consistent histopathologic feature of ARDS is neutrophil infiltration of the pulmonary microvasculature, interstitium, and alveoli. Neutrophils are well equipped to cause damage through the release of reactive oxygen species and proteases.³⁰ Furthermore, neutrophils may be an important source of proinflammatory cytokines. Persistence of neutrophils in serial BAL fluid samples from patients with ARDS suggests unbridled inflammation and portends poor prognosis. In animal models, neutrophil depletion prior to an insult markedly attenuates resulting lung injury.³¹

The lung normally contains a significant number of sequestered neutrophils, and their mere presence is not sufficient to cause tissue injury. A long-standing model suggests that after a “priming” stimulus, neutrophils firmly adhere to endothelium and accumulate in the lungs; however, lung injury does not occur unless a second activating stimulus is applied. Thus, for neutrophils to cause tissue damage, there must be adherence to the endothelium, transmigration to the interstitium, and subsequent activation. Adherence and transmigration create a toxic microenvironment that is protected from endogenous antioxidants and antiproteases normally present in the plasma.

Both cellular biomechanical and adhesive mechanisms are operative in the process of neutrophil sequestration. The initial phase is thought to result from a change in the cytoskeleton of the neutrophil that increases rigidity. This change impedes flow through the pulmonary microvasculature.³² A second, more prolonged phase is related to increased adhesive forces between neutrophils and endothelial cells. Initially, neutrophils “roll” and then “tether” to the endothelium as a result of the interaction of selections (L, E, and P) on the neutrophil and endothelial surfaces. This is followed by firm adhesion or “capture” of the PMN on the endothelial surface, which is mediated by β₂ integrins on the neutrophil. These adhere to intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and MADCAM. Once adherent, PMNS can transmigrate into the subendothelial space via paracellular or transcellular routes, again via surface integrins, adhering to platelet–endothelial cell adhesion molecule-1 (PECAM-1) or junctional adhesion molecules.³³

MACROPHAGES

The lung contains large numbers of fixed tissue macrophages that are a critical component of the inflammatory response in ALI. Activated macrophages can cause tissue injury by releasing the same toxic mediators as neutrophils (reactive oxygen species and proteases). Probably more important is the macrophage capability to synthesize multiple proinflammatory mediators, such as complement fragments, cytokines, and chemokines. Thus, macrophages are thought to have a major role in amplifying and perpetuating the inflammatory response. This is exacerbated by the long half-life of the macrophage, which is measured in days rather than hours as in the neutrophil. The alveolar macrophage has two additional key functions: control of local infection and modulation of fibrosis.³⁴ Alveolar macrophage from ARDS patients demonstrates defective phagocytosis and bacterial killing, reflecting an increased risk for infection in these patients.

ENDOTHELIUM

The pulmonary endothelium is not a passive bystander in the pathogenesis of ARDS, but actively participates in initiating and perpetuating the inflammatory response. Endothelial cells increase the expression of adhesion molecules (ICAM-1, ICAM-3, and E-selectin) following exposure to an activating stimulus. These ligands serve as tethering and signaling molecules by binding to their cognate leukocyte membrane proteins. Thus, the endothelial cell actively coordinates trafficking, firm adhesion, and transmigration. In the setting of systemic inflammation, inappropriate endothelial cell activation may lead to indiscriminate leukocyte recruitment and parenchymal inflammation. Moreover, endothelial cells produce and release vasoactive substances, such as prostacyclin, nitric oxide (NO), and endothelins. These substances may mediate much of the pulmonary vascular dysfunction characteristic of ARDS. Activated endothelium also expresses procoagulant activity, which contributes to intravascular coagulation and microvascular dysfunction.³⁵ Thrombin, in turn, has proinflammatory effects on leukocytes. Endothelial injury, then, may be both a proximate cause and a marker for ALI.

THE GUT LYMPH HYPOTHESIS

It has long been understood that reperfusion of the ischemic gut can lead to lung injury.³⁶ Because gut ischemia/reperfusion is an established phenomenon in the injured patient with hemorrhagic shock, this remains a tantalizing hypothesis for the development of inflammatory injury to the lung. Curiously, however, convincing evidence of inflammatory mediators leaving the gut into the portal circulation has been lacking in humans. This led Deitch³⁷ to hypothesize that the egress of proinflammatory substances from the gut may be via lymph, not venous blood. This intriguing hypothesis has substantial support in animal models, including the finding that diversion of gut lymph abrogates lung injury. While the precise mediators of this phenomenon are as yet unknown, changes in posthemorrhagic shock lymph flow, lipid content, and protein content are an active area of investigation.^38,39

Mediators and Markers of Acute Respiratory Distress Syndrome

Complement

Systemic complement activation secondary to trauma or sepsis is considered a major early factor in ARDS.⁴⁰ C5a, a product of complement activation, is a powerful neutrophil chemoattractant. Moreover, C5a induces neutrophil aggregation and activation leading to pulmonary neutrophil sequestration and lung injury. Clinically, plasma and bronchoalveolar C3a levels correlate with the development of ARDS.⁴¹

Lipid Mediators

Phospholipids are potent inflammatory mediators that are formed by the action of phospholipase A₂ (PLA₂) on membrane phospholipids. PLA₂ contributes to the inflammatory response by two separate pathways, catalyzing the production of both platelet-activating factor (PAF) and arachidonic acid. Arachidonic acid metabolism results in release of eicosanoids such as leukotrienes, thromboxane, and prostaglandins. Each of these is a pivotal mediator in the inflammatory cascade and has been implicated in the pathogenesis of ARDS.⁴²

PAF is a phospholipid with potent vasoactive and inflammatory properties. It is produced by a number of cell types including macrophages, neutrophils, endothelial cells, and type II pneumocytes. PAF production is stimulated by endotoxin, tumor necrosis factor (TNF), and leukotrienes, and exerts diverse biologic actions, including neutrophil activation and adherence, platelet aggregation and degranulation, and macrophage production of inflammatory mediators. Infusion of PAF in animals results in increased vascular permeability and neutrophil-mediated ALI.⁴³

Lysophosphatidyl cholines are another class of bioactive lipids that may play a significant role in lung injury after trauma. These compounds accumulate during routine storage of packed red blood cells and have been shown to cause lung injury in isolated perfused rodent lungs.⁴⁴ These or related compounds from transfusion of banked red cells may provide a second insult leading to inflammatory organ injury in the injured patient.

As mentioned above, the pulmonary endothelium is recognized as an active participant in the development of ALI. As such, markers of endothelial activation or injury have been investigated as predictors of the development of ARDS. von Willebrand factor antigen (vWF:Ag) has been studied fairly extensively as a marker of endothelial dysfunction. vWF:Ag is synthesized largely by vascular endothelial cells and has been shown to be a sensitive marker of endothelial injury or activation.⁴⁵ This antigen was studied prospectively in 45 patients to determine whether elevated levels of vWF:Ag are predictive for the development of ALI.⁴⁶ Only patients with nonpulmonary sepsis were included, and one third developed ALI. Elevated plasma levels of vWF:AG (>45% above controls) were 87% sensitive and 77% specific for development of ALI. Positive predictive value was 65%.

Following activation, endothelial expression of adhesion molecules, including ICAM-1, VCAM-1, E-selectin, and P-selectin, is upregulated. These compounds are susceptible to proteolytic cleavage and may exist in the circulation in a soluble form. Therefore, these molecules represent a measure of endothelial activation or damage. We and others have demonstrated elevated ICAM-1 levels in severely injured patients who subsequently developed MOF.^47,48 In contrast, plasma levels of soluble E- and P-selectins measured at admission were not useful in predicting ALI.

The maintenance of a functioning alveolar epithelium is important for recovery from ALI.⁴⁹ Unlike the endothelium, there is a lack of specific histologic markers of alveolar epithelial injury. Surfactant abnormalities have been noted in the earliest reports of ARDS. Surfactant lipids and proteins are synthesized and released by alveolar epithelial type II cells. The surfactant-associated proteins SP-A and SP-B are decreased in BAL fluid from patients with ARDS and at risk for ARDS.⁵⁰

Markers of leukocyte activation have also been measured in plasma and BAL fluid of patients in an attempt to predict development of ARDS. Gordon et al. noted markedly elevated plasma elastase levels very early after multisystem trauma.⁵¹ Subsequent studies supported a causative role for neutrophil elastase in ARDS,⁵² and have led to the clinical development of human elastase inhibitor.⁵³ Increased expression of β₂ integrins has been observed on the surface of circulating pulmonary artery neutrophils in patients at risk for postinjury ARDS.⁵⁴

Circulating and BAL fluid levels of cytokines are also inherently attractive as predictors of ARDS; whether they are markers or mediators remains an important question. TNF-α, IL-1β, IL-6, and IL-8 have been the most intensely investigated in relation to the development of ARDS. Studies examining the predictive value of cytokines central to sepsis (TNF-α, IL-1β) levels in ARDS have had negative or mixed results.⁵⁵ IL-8 is a neutrophil chemoattractant that has been studied in both plasma and BAL fluid. It is elevated in the plasma following injury but does not appear to consistently predict development of ARDS. Donnelly et al. studied 29 patients at risk for developing ARDS and observed that IL-8 levels in BAL fluid were significantly higher in patients who later progressed to ARDS.⁵⁶

PATHOPHYSIOLOGY

ARDS is characterized by diffuse, patchy, panlobular pulmonary infiltrates on plain chest radiograph (Fig. 57-1

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