Chapter 57: Respiratory Insufficiency

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. 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 acute respiratory distress syndrome (ARDS) and current management is a major focus.

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, post-injury 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 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 accurately determined using Fowler’s nitrogen washout technique² or more commonly calculated by a number of techniques including the Bohr–Enghoff method (V_d/V_t = [{Paco₂ – mean expired CO₂}/Paco₂]).³ 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 post-injury 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 (eg, as part of the abdominal compartment syndrome, Chapter 38), chest wall edema, and recumbent positioning increase 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 (hypothermia, acidosis, coagulopathy, cardiovascular failure, mitochondrial dysfunction, and 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 post-injury period, patients most commonly present with a mixed acid-base disorder 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.

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 The genesis is multifactorial, including loss of vital capacity, ineffective cough with retention of secretions 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, vagal nerve autonomic dysfunction results in increased secretions, bronchospasms, and pulmonary edema. This patient population requires aggressive mobilization and pulmonary care, as recurrent lobar collapse and pneumonia are certain and lethal if not aggressively prevented.

Early operative stabilization of the spine is advocated as it has been shown to decrease the need for mechanical ventilation and ICU stay.⁵ Other adjuncts such as noninvasive ventilation, bronchodilators, mucolytics, and percussion should be considered. Laparoscopic placement of diaphragmatic pacers is a benefit in select patients with a recent report by Onders and colleagues showing that 96% of SCI were able to use diaphragm pacing stimulation to provide ventilation replacing their mechanical ventilator.⁶ Largely, this has been studied in the rehabilitation setting, and therefore a role for this approach in the acute setting remains undefined.

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 25). It is clear that the number of rib fractures is strongly associated with the development of pulmonary failure, ARDS, and mortality, that profoundly impact the elderly population.⁷ 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 especially in those patients over the age of 65 that have more than three continuous ribs fractured.⁸ Admission to a high-volume trauma center, use of patient-controlled analgesia, epidural or paravertebral catheter administered analgesia, routine tracheostomy, and an algorithm-driven approach are associated with improved survival.^9,10

Hypoxic pulmonary failure is a substantial cocontributor to respiratory failure in the trauma setting. The etiologies are diverse including aspiration pneumonitis, pneumonia, pulmonary embolism, congestive heart failure, blunt thoracic trauma, and ARDS. Most of these entities are discussed elsewhere; however, ARDS will be the focus of this chapter. Indeed, the mechanisms at work in ARDS share many common features with these other processes that affect the alveolar–capillary interface.

ARDS is a clinical syndrome of inflammatory lung injury that can be thought of as the final common pathway of diverse systemic processes. In the past two decades major progress has been achieved in defining the underlying ARDS pathophysiology and optimal supportive care. Specific therapies that address the underlying mechanisms responsible for ARDS development remain elusive at present.

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.

Since the initial description of ARDS 50 years ago, the optimal definition of ARDS remains a controversial subject. The lung injury score (LIS), proposed by Murray and colleagues in 1988 has been a commonly used measure of lung injury severity in previous clinical studies. The LIS is based on four components: chest radiograph, hypoxemia, positive end-expiratory pressure (PEEP), and respiratory compliance (Table 57-1).¹² 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.

The first standard definitions were developed in 1994, by the Consensus Conference of American and European investigators (AECC). Acute lung injury (ALI) was defined as respiratory failure of acute onset with a Pao₂/Fio₂ ratio less than or equal to 300 mm Hg (regardless of the level of positive end-expiratory pressure, PEEP), bilateral infiltrates on frontal chest radiograph, and a pulmonary capillary wedge pressure less than or equal to 18 mm Hg (if measured) or no evidence of left atrial hypertension. ARDS was defined identically except for a lower limiting value of less than 200 mm Hg for Pao₂/ Fio₂ (Table 57-2).¹³ The AECC definition of ALI/ARDS has been used in many of the ARDS Network clinical trials; however, debate still exists as to the usefulness of the AECC diagnostic criteria. Criticism of the AECC definition includes lack of account of the mode of ventilation and the level of PEEP, which can significantly affect oxygenation. Furthermore, with the decreased use of Swan–Ganz catheters, the wedge pressure is not commonly measured.¹⁴

An alternative definition of ARDS developed by a consensus panel of senior investigators using the Delphi method appears to be more specific than AECC critiera.¹⁵ 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 greater than or equal to 10; therefore, it excludes patients who are hypoxic purely because of de-recruitment or suboptimal PEEP (Table 57-3). 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.

The definition of ARDS was most recently revised by a panel of specialists in a joint effort of the European Society of Intensive Care Medicine, the American Thoracic Society, and the Society of Critical Care Medicine. Their collective aim was to address the current limitations of the AECC definition and explore other defining ARDS variables. The panel agreed to maintain the previous conceptual model, which defined ARDS as a syndrome of acute, diffuse lung inflammation, with edema because of increased permeability of the alveolar–capillary membrane, and clinically characterized by decreased oxygenation because of increased venous admixture, decreased lung compliance, increased physiological dead space, and bilateral radiographic opacities. The newest and most widely accepted ARDS criteria, also referred to as the Berlin definition of ARDS, are as follows in Table 57-4.¹⁶ In a large, multi-ICU cohort of patients with ARDS, both LIS and the Berlin definition severity stages were associated with increased in-hospital morbidity and mortality; however, the predictive validity of both scores is only marginally better than chance alone.¹⁷

The estimated incidence of ARDS in population-based studies is on the order of 40 cases per 100,000 person-years.^18,19,20 In the United States, this represents about 200,000 cases per year, and about 15% of ICU admissions. With modern mortality rates (see further), one can estimate this entity is responsible for about 50,000 deaths per year in the United States.

Clinical Risk Factors

Clinical risk factors for ARDS can be broadly categorized into direct and indirect pulmonary factors (Table 57-5). Direct pulmonary factors are those primarily associated with local pulmonary parenchymal injury and include inhalation injury, pulmonary contusion, aspiration, and pulmonary infection. Indirect pulmonary factors are those thought to be associated with systemic inflammation and resultant lung injury. These include trauma, shock, burn injury, extrapulmonary sepsis, transfusion of blood products, multiple long bone fractures, pancreatitis, and others.^18,21

The King County Lung Injury Project (KCLIP) identified pulmonary and extrapulmonary sepsis as the most common risk factor with 46% and 33% of ARDS cases, respectively. Following sepsis in descending order of frequency were aspiration (11%), trauma (7%), transfusion (3%), drug overdose (3%), and pancreatitis (3%). Cases with another or no risk factor identified constituted 14% of the total. The highest mortality rates were noted in aspiration-associated (44%) and pulmonary-sepsis–associated lung injury groups (41%) with the lowest rate in trauma-associated lung injury (24%).²⁰

Demographic Risk Factors

Several demographic factors have been identified as risk modifiers for development of ARDS. The incidence of ARDS increases with age and older patients have consistently higher mortality rates, although it is unclear whether this simply represents diminished physiologic reserve in older patients.^22,23 Alcohol abuse, active cigarette smoking, and exposure to second-hand smoke have also been linked to ARDS incidence.^24,25 Higher BMIs have been associated with increased incidence of ARDS²⁶ with data suggesting a decrease in mortality.²⁷

Treatment Risk Factors

It is well established that high tidal volume ventilation increases mortality for patients with established ARDS.²⁸ Several studies have shown that increased tidal volume is an independent risk factor for the subsequent development of ARDS in a dose-responsive manner.^29,30 This phenomenon, termed ventilator-induced lung injury (VILI), has been an area of increasing scrutiny.

Transfusion of blood products is a major iatrogenic risk factor for ARDS. Multiple studies have shown increased risk of ARDS in ICU patients receiving packed red blood cells, fresh frozen plasma, and/or platelet transfusions,^31,32 a phenomenon, termed transfusion-related acute lung injury (TRALI). The National Heart, Lung, and Blood Institute established a consensus definition to promote research in TRALI. In addition to the standard criteria for ARDS, TRALI requires additional criteria (Table 57-6). A patient must (1) develop ARDS during or within 6 hours of transfusion and (2) no ARDS may be present before transfusion. (3) Alternative ARDS risk factors may be present, but the patients’ clinical course should determine whether the ARDS is mechanistically related to the transfusion.³³

The current paradigm of systemic inflammation leading to 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).³⁴

Inflammatory models provide a unifying hypothesis for ARDS and MOF; however, the precise relationship between ARDS and MOF remains to be further refined. MOF is a frequent occurrence and the most common cause of mortality in patients with ARDS.³⁵ Indeed, post-injury ARDS appears to be an obligate precursor of other organ failures.³⁶ 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.³⁷ It is also now clear that ventilator strategies that inadvertently promote lung injury may produce systemic inflammation, perhaps leading to other organ failures.³⁸

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.³⁹

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 intraalveolar hemorrhage. The exudative phase is characterized by the appearance of hyaline membranes, which are composed of fibrin, immunoglobulin, and complement. 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.⁴⁰ 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, typically occupying the second 2 weeks after the onset of respiratory failure, 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.

Many patients with ARDS recover lung function 3–4 weeks after initial injury; however, some enter a fibrotic phase 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. Clinical sequelas include an increased risk of pneumothorax, decreased lung compliance, and increased pulmonary dead space. This may lead increased long-term support on mechanical ventilators and/or need for supplemental oxygen.

Lung injury in ARDS involves components of inflammation, coagulation, vasomotor tone, and other systems (see Chapter 55). 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 infiltration may result in lung injury due to neutrophil-mediated release of reactive oxidant species (ROS) and resulting oxidant stress. Furthermore, neutrophils are 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.⁴¹ Evidence from clinical studies supporting excess ROS in ARDS include findings of increased hydrogen peroxide in exhaled breath,⁴² decreased levels of glutathione in lung lavage fluids,⁴³ and increased lipid peroxidation products in plasma.⁴⁴

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 (ROS 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.⁴⁵ Alveolar macrophage from ARDS patients demonstrate 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. The activated endothelium expresses procoagulant activity, which also contributes to intravascular coagulation and microvascular dysfunction.⁴⁶ 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. Deitch et al have shown that injured intestine releases danger signals, transported via lymph, that induce inflammatory pathways resulting in organ injury.⁴⁷ As the lung is the first organ exposed to mesenteric lymph (via the thoracic duct), it might explain the clinical observation that the lung is often the first organ to fail. In animal models, diversion of gut lymph appears to abrogate lung injury.⁴⁸ 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.⁴⁹

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.⁵⁰ 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.⁵¹

Endothelial Injury

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 activation⁵² and predictive for the development of ALI.⁵³

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. Elevated ICAM-1 levels have been found in severely injured patients who subsequently developed MOF.⁵⁴ In contrast, plasma levels of soluble E- and P-selectins measured at admission were not useful in predicting lung injury.

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.⁵⁵ Subsequent studies supported a causative role for neutrophil elastase in ARDS and have led to the clinical development of human elastase inhibitor (see the section “Pharmacologic Therapy”).⁵⁶

Cytokines

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. Direct measurement BAL or pulmonary edema fluid in ARDS patients has shown that both fluids consistently contain elevated levels of TNF-α and IL-1; additionally, high levels of TNF-α and IL-1 in plasma and in BAL have been associated with an increased risk of death in patients with ALI and ARDS.^57,58 Persistently elevated IL-6 levels have also been associated with an increased risk of death in ARDS patients. In the ARDSNet trial, there was a significantly steeper fall in IL-6 levels over the initial 72 hours in the lung protective treatment group with decreased mortality compared to the higher-tidal-volume treatment group.⁵⁹ IL-10 is a potent inhibitor of proinflammatory molecules including TNF-α and IL-1. Lower levels of IL-10 in blood and lung lavage fluid have been in association with development of ARDS and associated with mortality.⁶⁰

ARDS is characterized by diffuse, patchy, panlobular pulmonary infiltrates on plain chest radiograph (Fig. 57-1). CT of the chest will demonstrate that the parenchymal changes are inhomogeneous with the dependent lung regions most affected (Fig. 57-2). The inhomogeneous distribution of parenchymal densities led to the concept of a three-compartment model of the lung in ARDS.⁶¹ One compartment is substantially normal (healthy zone), one is fully diseased without any possibility of recruitment (diseased zone), and, finally, the third compartment is composed of collapsed alveoli potentially recruitable with increasing pressure (recruitable zone). Increased airway pressure is necessary to recruit collapsed alveoli. In the 1990s, however, it was already recognized that in the heterogeneously injured lung, VILI may be damaging to the healthy zone. This injury is thought to be responsible for severe protracted ARDS, as well as perpetuation of systemic inflammation and MOF.^29,30

A standard method used to describe the mechanical properties of the lung is to determine the static pressure–volume (PV) curve during inflation and deflation (Fig. 57-3). In early ARDS, the lower inflection point represents the airway pressure at which considerable alveolar recruitment occurs. The upper inflection point is where near maximal inflation occurs such that further increases in airway pressure result in alveolar overdistension and little change in volume. In practice, however, inflection points in individual patients have been difficult to consistently measure.

Pulmonary Edema

Increased pulmonary capillary permeability is a consistent feature. Increased permeability promotes alveolar flooding with protein-rich edema fluid, as well as release of proteins generally confined to the lung into the systemic circulation. In ARDS, the pulmonary epithelium is injured, leading to altered fluid transport. Multiple studies have documented elevated total protein concentrations in BAL fluid from patients with established ARDS.⁶⁰ One study observed higher BAL fluid protein concentrations in nonsurvivors, suggesting that more severe lung injury is associated with greater endothelial and epithelial permeability.⁶¹

Gas Exchange

Hypoxemia in ARDS results from ventilation–perfusion mismatching and intrapulmonary shunting of blood flow. Shunting results from blood that passes through the systemic venous to pulmonary arterial system without going through the normal gas exchange units in the lung (ie, right–left shunt). Normally, the shunt fraction is less than 5%; however, in ARDS, it may exceed 25%. Because blood flowing through a shunt is not exposed to alveoli participating in gas exchange, supplemental oxygen is ineffective in increasing arterial oxygen concentration. Other techniques designed to restore ventilation to diseased lung regions, such as PEEP or continuous positive airway pressure (CPAP), are thus necessary to improve oxygenation. Hypoxic pulmonary vasoconstriction is a protective mechanism that limits perfusion to poorly ventilated alveoli and minimizes shunting. In ARDS, hypoxic pulmonary constriction is impaired, resulting in greater intrapulmonary shunt. Multiple factors may contribute to loss of hypoxic pulmonary vasoconstriction in lung injury, including local prostaglandin or NO production.⁶²

In early ARDS, most patients are tachypneic from hypoxemia and are secondarily hypocapneic. With disease progression, hypercapnia may become a prominent feature because of physiologic dead space and CO₂ production. Increased dead space ventilation is invariably present. As discussed earlier, the normal dead space to tidal volume ratio is approximately 35%, but in ARDS, it can approach 60%.

Pulmonary Mechanics

Lung compliance is defined as the change in lung volume per change in transpulmonary pressure. Normal lung compliance in a mechanically ventilated patient ranges from 60 to 80 mL/cm H₂O. With ARDS, it is not unusual to see greatly diminished lung compliance on the order of 10–30 mL/cm H₂O. Initially, reduced compliance is the result of interstitial and alveolar edema with alveolar flooding. Surfactant dysfunction and terminal bronchiolar spasm contribute to loss of ventilated alveoli. In later ARDS, interstitial fibrosis and parenchymal loss further reduce pulmonary compliance.

Hemodynamics

Pulmonary hypertension is a frequent finding in patients with ARDS and can lead to increased interstitial pulmonary edema, right ventricular dysfunction, and impaired cardiac output. When severe, pulmonary hypertension has been observed to be a marker of poor outcome. The etiology of pulmonary hypertension in ARDS is multifactorial. Early in ARDS, the predominant mechanism is most likely impaired vasorelaxation related to hypoxemia, acidosis, and vasoactive mediators, in concert with obstruction from microvascular coagulation. In late ARDS, fibrosis and obliteration of the pulmonary vascular bed are most likely responsible. Steltzer et al noted markedly depressed right ventricular function in nonsurvivors of ARDS.⁶³ The authors related this to reduced myocardial contractility and not to pulmonary hypertension. They also noted that oxygen delivery was more related to cardiac performance than to pulmonary gas exchange.

The diagnosis of ARDS is based on the criteria used to define the syndrome and has historically been divided into four clinical phases with radiographic, clinical, physiologic, and pathologic correlates. In the initial phase, dyspnea and tachypnea are evident, with a remarkably normal chest examination (radiographically and clinically). Arterial oxygen saturation is preserved, and hypocapnia from hyperventilation is frequently noted.

The second phase quickly follows (12–24 hours), with physiologic and pathologic evidence of lung injury. The chest x-ray now shows bilateral patchy alveolar infiltrates with hypoxemia evident on arterial blood gas (ABG) determination. If ARDS persists and progresses, the third clinical phase becomes evident. Acute respiratory failure necessitates mechanical ventilation with increasing inspired oxygen concentrations. There is an increase in physiologic dead space and rising minute ventilation. Patients at this point may develop sepsis syndrome with a hyperdynamic hemodynamic pattern. The radiographic picture worsens with more diffuse infiltrates, consolidation, and air bronchograms.

Without resolution, progressive pulmonary failure and fibrosis characterize the fourth phase. Pneumonia, often recurrent, is frequent (see Chapter 18). Hypercapnia may worsen and become more difficult to control. MOF commonly develops and is the most common cause of death (see Chapter 61).

Because there is no proven specific treatment for ARDS, therapy primarily involves supportive measures to maintain life while the lung injury resolves. Such measures include identifying and treating predisposing conditions, mechanical ventilatory support with oxygen, nutritional support, nonpulmonary organ support, and hemodynamic monitoring as necessary. Attention to detail is necessary to avoid nosocomial infection and iatrogenic complications.

Fluid Management and Hemodynamic Support

One of the hallmark pathological changes in ARDS is increased endothelial and epithelial permeability, resulting in extravasation of fluid and plasma elements, including albumin, in the interstitium and alveolar space. This leads to hypoxemia, atelectasis, decreased lung compliance, and increased pulmonary artery pressures.⁶² Fluid management is one of the most important measures shown to impact ARDS. On the basis of the known pathophysiologic mechanisms, current management is in favor of limiting the forces that favor fluid filtration from the capillaries or augmenting those factors implicated in fluid reabsorption can limit fluid accumulation in the lung.

One of the most important trials in the treatment of ARDS has been the fluid and catheter treatment (FACT) trial.⁶³ This study randomized 1000 patients to liberal versus conservative fluid management, based on targeted central venous pressure or PCWP. There was no significant 60-day mortality difference between the groups but patients in the conservative strategy group had significantly more days alive and free of mechanical ventilation and ICU. Importantly, there was no increase in organ failures in these patients at 7 and 28 days. However, a recent analysis using a validated telephone-based neuropsychological test battery suggests that conservative fluid management may be a risk factor for the development cognitive impairment in long term⁶⁴—this observation requires further investigation.

As ARDS is a common complication in patients with severe sepsis or septic shock, proper fluid management is essential for optimal outcomes. The correct assessment, however, of fluid status in ICU patients is still a challenge. An important tool in estimating lung fluid balance is extravascular lung water (EVLW), calculated using the single thermodilution method.⁶⁵ Traditionally, EVLW has been indexed to actual body weight (mL/kg); however, a recent observational cohort study of patients with ARDS has shown that baseline EVLW when indexed to predicted body weight is a better prognostic indicator of mortality, after adjusting for severity of illness and other important factors, than EVLW indexed to actual body weight.⁶⁶ Indexes of pulmonary permeability obtained derived from thermodilution methods such as the global end-diastolic volume index and pulmonary vascular permeability index, have also shown utility in differentiating ARDS from hydrostatic pulmonary edema.⁶⁷

With respect to colloids, there is no evidence that their use for acute resuscitation improves outcome. A study in hypoproteinemic patients suggests that gas exchange can be improved in late ALI by using colloid in concert with diuretics to mobilize interstitial fluid and promote diuresis.⁶⁶ A 2006 randomized clinical study (RCT) study suggested that critically ill patients with profound hypoproteinemia have fewer organ failures (by SOFA score) when given colloid therapy.⁶⁷ Short-term improvement in physiology is not, however, accompanied by an improved outcome in these investigations. The very large Australian SAFE study revealed no difference in mortality and other significant clinical endpoints for patients resuscitated with albumin, as compared to those resuscitated with normal saline.⁶⁸ However, the patient population in this study was heterogeneous. Further large randomized studies of albumin use only in ARDS patients are needed.

Mechanical Ventilation

Most patients with ARDS require endotracheal intubation for mechanical ventilation. This technique reduces shunt physiology and administers high concentrations of oxygen. Emergent intubation is associated with significantly higher morbidity and mortality. Accordingly, early elective intubation should be considered in all patients with deteriorating gas exchange or mental status. The use of noninvasive positive pressure mask ventilation should be used very cautiously, if at all, for hypoxemic respiratory failure as several studies have shown a higher mortality and increased risk of intubation related complications.^69,70

Respiratory support with a mechanical ventilator is a cornerstone in the supportive management of patients with or at risk for ARDS. The goals of mechanical ventilation in ARDS are to maintain oxygenation while avoiding oxygen toxicity. Typically, this involves maintaining oxygen saturation in the range of 85–90%, and decreasing Fio₂ to less than 65% in the first 24–48 hours. It has long been recognized that the ventilator settings can contribute to VILI by worsening lung injury, and causing barotrauma (mediastinal emphysema, pneumothorax, etc). This recognition supported many early experimental studies in animals showing that high-tidal volume (V_T) ventilation caused injury morphologically similar to ARDS in humans, and even multiorgan system failure in otherwise healthy animals, which was associated with release of inflammatory cells and proinflammatory cytokines.^71,72 Early RCTs examining low V_T strategies were inconclusive with limited sample size and lack of statistical power. The hallmark clinical study by the ARDS Network (ARDSNet) was the first to conclusively show the benefit of low V_T ventilation compared to traditional strategies.⁷³ In this trial, volume-controlled, continuous mandatory ventilation was used and V_T was set based on ideal body weight (IBW). In the group treated with traditional V_T, the target V_T was 12 mL/kg IBW. In the group treated with lower V_T, the target V_T was 6 mL/kg IBW if the plateau pressure (Pplat) did not exceed 30 cm H₂O and 4 mL/kg if Pplat was greater than or equal to 30 cm H₂O. For patients with severe dyspnea, the V_T could be increased to 8 mL/kg IBW. The trial was stopped after the enrollment of 861 patients because mortality was significantly lower in the group treated with lower V_T than in the group treated with traditional V_T (31% vs 39.8%). Importantly, plasma IL-6 plasma levels and the number of organ-failure-free days were lower among the low V_T group.

Whereas previous studies employing low V_T allowed permissive hypercapnia and acidosis to achieve the protective ventilation goals of low V_T and inspiratory airway pressure, the ARDSNet study allowed increases in respiratory rate as the V_T was decreased and administration of bicarbonate to correct acidosis. This may explain the positive outcome in this study compared to earlier studies that had failed to demonstrate a benefit. The ARDSNet trial was also criticized for relying on strict ventilator protocols for the higher-tidal-volume group.

With the results of the ARDSNet trial and two subsequent concordant meta-analyses,^74,75 current standard of care now includes lower-tidal-volume ventilatory strategy (“ARDSNet lung-protective strategy”) and the use of incremental Fio₂-PEEP combinations to achieve oxygenation goals.

Permissive Hypercapnia

Controlled hypoventilation (relative to CO₂ production) with increased Paco₂ is referred to as permissive hypercapnia. The widespread acceptance of the ARDSNet lung protective strategies, has led to a shift in clinical paradigms regarding hypercapnic acidosis (HCA)—from intolerance to acceptance. In fact, not only is it accepted that permissive HCA is well tolerated, there is emerging data regarding the benefits of permissive hypercapnia in experimental models of lung injury.

HCA has multiple physiologic effects on different organs, particularly the pulmonary, cardiovascular and cerebrovascular systems. Because CO₂ diffuses freely across cell membranes, an increase in extracellular Pco₂ will result in intracellular acidosis. Cytosolic pH is normally tightly regulated between 6.9 and 7.2.⁷⁶ Gradual increases in Paco₂ are usually well tolerated, provided renal compensation is adequate (see Chapter 59) and severe acidosis (pH <7.1) usually does not occur. Three mechanisms are responsible for this regulation: (1) physiochemical buffering, mainly due to proteins and phosphates; (2) reduced intracellular generation of protons; and (3) changes in transmembrane ion exchange. Physiochemical buffering is immediate, while the other mechanisms require 1–3 hours. These regulatory mechanisms are remarkably powerful and efficient. As a result, normoxic HCA has only limited potential for resulting in intracellular acidosis, and is generally well tolerated.

Moderate HCA enhances tissue perfusion and oxygenation, through multiple mechanisms. In both normal and diseased lungs, there is evidence that HCA reduces ventilation–perfusion heterogeneity, likely through increasing compliance and directing ventilation to underventilated lung regions with higher alveolar Pco₂.^77,78,79 The overall hemodynamic response to acute HCA in human experiments is increased cardiac output, heart rate, and stroke volume, with decreased systemic vascular resistance. Although HCA can result in reversible impairment of myocardial contractility due to intracellular acidosis, which interferes with myofilament responsiveness to activator calcium,⁸⁰ the net increase in cardiac output, appears to be mediated through increased sympathoadrenal activity.⁸¹ For each 10 mm Hg increase in Paco₂, cardiac index rises by 10–15%.⁸²

HCA has multiple effects on the central nervous system. CO₂ is an important regulator of cerebrovascular tone. It has long been recognized that hypercarbia increases cerebral blood flow and intracranial pressure secondary to diminished vascular tone and enlargement of cerebral blood volume.⁸³ Indeed, traditional management of traumatic brain injury (TBI) historically included hypocapnia to reduce cerebral blood volume and intracranial pressure. Accumulating evidence, however, has shown that sustained hypocapnia reduces cerebral O₂ supply, and increases brain ischemia, vasospasm risk, and seizures.⁸⁴ In fact, recent studies have shown that prehospital hypocapnia worsens outcomes after severe TBI.^85,86

The direct contribution of HCA to the protective effects observed with lung protective ventilator strategies remains an area of debate. A secondary analysis of ARDSNet data, using multivariate logistic regression and controlling for comorbidities and severity of lung injury, showed that HCA on day 1 was associated with reduced mortality in patients ventilated with 12 mL/kg but not in patients ventilated with 6 mL/kg.⁸⁷ Recent studies have introduced the concept of therapeutic hypercapnia, whereby deliberately elevated Paco₂ can lessen lung and systemic organ injury. Substantial evidence demonstrates that moderate HCA directly reduces VILI through several mechanisms including prevention of stretch-induced lung inflammation.^88,89 HCA has been shown to directly attenuate indices of ALI in in-vivo and ex-vivo models of primary and secondary ischemia-reperfusion lung injury.^90,91 These effects appear to be mediated in part through inhibition of the NF-κB.⁹² In contrast to the observed beneficial effects of HCA described above, there is data to suggest that HCA can be deleterious in prolonged, untreated pneumonia, through reduction of neutrophil- and macrophage-mediated bacterial killing.⁹³ Also, HCA appears to impair pulmonary epithelial wound healing by diminishing cellular migration through inhibition of NF-κB.⁹⁴ Despite these concerns, the potential for therapeutic HCA in attenuating lung injury is promising.

A major area of controversy in regards to HCA is the role of buffering with sodium bicarbonate infusion, a common practice in many ICUs. While bicarbonate may correct arterial pH, it may actually worsen intracellular acidosis because the CO₂ produced from reaction of metabolic acids with bicarbonate diffuses readily across cell membranes.⁹⁵ Accumulating evidence also suggests that the protective effects of HCA are attenuated by pH buffering,^95,96,97 suggesting that these benefits are a function of pH, rather than elevated CO₂.

There has been a lack of human trials to establish guidelines for the use of buffering during therapeutic hypercapnia. In most institutions, sodium bicarbonate would not be administered unless the pH was less than 7.2. With increased experience, however, many centers reserve bicarbonate infusion for pH less than 7.0. An alternative is to use, trishydroxymethyl aminomethane (THAM), which does not increase CO₂ production but is not specifically labeled for this use.⁹⁸ Sedation is mandatory with permissive hypercapnia in mechanically ventilated patients in order to control respiratory drive and prevent discomfort. Even with heavy sedation, however, respiratory drive may be insufficiently suppressed, resulting in patient–ventilator dyssynchrony. Neuromuscular blockade is often necessary in these patients.

Positive End-Expiratory Pressure

PEEP is one of several methods of increasing mean airway pressure and improving oxygenation. It improves oxygenation by enhancing lung volume, and increasing functional residual capacity (FRC) through recruitment of collapsed alveoli. Lung compliance may also be improved. The use of PEEP in patients with ARDS has two primary goals: adequate tissue oxygen delivery and the reduction of Fio₂ to nontoxic (generally below 0.6) levels. Increasing PEEP above a certain level, however, may have significant adverse effects. By raising intrathoracic pressure, PEEP may significantly reduce venous return and cardiac output.⁷⁰ This may result in decreased tissue oxygen delivery despite improvement in arterial oxygen saturation. This effect is accentuated in the hypovolemic patient, and can usually be reversed with intravascular volume expansion. Cardiac depression is rarely seen with PEEP levels less than or equal to 10 cm H₂O. If PEEP greater than 10 cm H₂O is required, assessment of intravascular volume status and cardiac function is warranted.

PEEP may also result in alveolar overdistention with compression and obliteration of surrounding pulmonary capillaries. This alveolar overdistention may actually worsen oxygenation by increasing the shunt fraction. Moreover, dead space ventilation may be increased, resulting in a higher minute ventilation requirement. Finally, PEEP may cause a maldistribution of tidal volumes and pressures, creating overdistension of normally aerated lung regions. This hyperinflated form of lung injury may result in barotrauma referred to as “volutrauma.”

The optimal approach to PEEP for ARDS remains a matter of debate. In the ARDSNet study, patients ventilated with lower V_T required higher levels of PEEP (9.4 vs 8.6 cm water) to maintain oxygen saturation at 85% or morel leading some to speculate that the improved survival rates were due to higher levels of PEEP. However, three subsequent RCTs, including the ARDSNet trial of higher versus lower PEEP levels in patients with ARDS, have failed to demonstrate additional benefit of higher PEEP in patient outcomes.^99,100,101 It is likely, however, that these trials enrolled patients who had both a lower and a greater potential for alveolar recruitment. Gattinoni et al found that in patients with ARDS, the percentage of potentially recruitable lung differs widely.¹⁰² With the use of higher levels of PEEP, there can be an associated increase in Pplat in patients who have regions of lung that are nonrecruitable with a higher risk of overdistention. Patients with recruitable lungs have proportionally less increase in Pplat when higher levels of PEEP are used, and may benefit from PEEP with less risk of overdistention.¹⁰³

In the individual patient, the application of PEEP needs to be balanced between providing a sufficient inspiratory plateau pressure (peak alveolar pressure) to maintain adequate oxygenation and at the same time avoiding derecruitment of the alveoli during exhalation. Today, many centers have adopted the algorithm-driven approach adopted by the ARDSNet investigators where PEEP was individually titrated with combinations of PEEP and Fio₂ selected for a target level of arterial oxygenation. The advantage of a ratio approach is that it can be done without measurement of pulmonary compliance curves or invasive hemodynamic monitoring. One disadvantage is that it is not necessarily applicable to an individual patient with individual physiology. Despite this criticism, this approach has been used in all of the trials conducted by ARDSNet and carries validity.

The pressure–volume curve has also been used to select optimal PEEP. In this approach, static PV curves are used to select a PEEP level above the lower inflection point to prevent alveolar end-expiratory collapse. Although this approach is intriguing, static pressure–volume curves can be difficult to obtain as well as to implement. Measurement of the PV also requires sedation and often paralysis as patient effort may confound measurements of inflection points. Further evidence is needed before the PV curve can used routinely to determine optimal PEEP. Other methods for selecting PEEP include use of the stress index tress (the shape of the pressure–time curve during constant flow volume controlled ventilation), use of esophageal pressure monitoring to maintain positive transpulmonary pressure, and use of imaging techniques such as CT, electrical impedance tomography, and ultrasound to evaluate PEEP settings.¹⁰³

Recruitment Maneuvers

A recruitment maneuver is a transient increase in transpulmonary pressure to promote reopening of collapsed alveoli. The use of recruitment maneuvers in ARDS for the symptomatic treatment of hypoxemia is still a matter of debate. Complications in secondary to recruitment maneuvers such as desaturation or hypotension are common, but serious complications, such as a new air leak through an existing chest tube, are infrequent.¹⁰⁴ A systematic review and meta-analysis¹⁰⁵ including 10 RCTs reported a decrease in hospital mortality with the use of recruitment maneuvers; however, there is concern about the risk of bias in the included studies and the use of concomitant therapeutic strategies. Some groups advocate use of recruitment maneuvers as rescue therapy in patients with ARDS who have life-threatening hypoxemia.

Prone Ventilation

Prone positioning has been used for more than 30 years in patients with acute hypoxemic respiratory failure and ARDS. Initially, prone positioning in ARDS patients was found to be an efficient technique to improve oxygenation as a rescue treatment in case of life-threatening hypoxemia; however, it is now evident that prone positioning is able to prevent VILI. Therefore, prone positioning is a strategy that covers the two major goals of ventilator support in ARDS patients, maintaining safe oxygenation, and preventing VILI.

Since the initial description by Bryan¹⁰⁶ of the beneficial effects of the prone position on arterial oxygenation more than 30 years ago, it is remarkable that it took 20 years for the first RCT to be performed. The trial, reported by Gattinoni et al,¹⁰⁷ consisted of 152 patients randomized to a prone group and 152 patients to a supine group and showed no differences in mortality rates were noted between the two groups after a 10-day period (21.1% vs 25%), but the study was underpowered to detect a statistical difference. Several follow-up RCTs after this trial also failed to strongly show an improvement in survival with prone positioning.^{107,108,109,110} However, several meta-analyses^111,112 have since shown that survival in severely hypoxemic ARDS patients is significantly improved with prone positioning as compared with supine positioning. A recently published RCT by the Proning Severe ARDS Patients (PROSEVA) study investigators¹¹³ assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (p <0.001). Furthermore, unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (p <0.001), with a hazard ratio of 0.44 (95% CI, 0.29–0.67). Importantly, there was no significant difference in the incidence of complications between the groups, except for the incidence of cardiac arrests, which was higher in the supine group.

There mechanisms by which prone positioning improves survival in patients with severe ARDS are multifactorial.¹¹⁴ Pappert et al used the multiple inert gas elimination technique and showed that the improvement in oxygenation was the result of decreased intrapulmonary shunt fraction.¹¹⁵ Albert and coworkers have investigated the mechanism of prone ventilation in a canine oleic acid model of ARDS. The prone position consistently reduced shunt fraction compared with the supine position. The improvement in gas exchange was independent of changes in cardiac output or FRC between the two positions. Subsequently, pulmonary blood flow was shown to be distributed preferentially to dorsal lung regions in the supine and prone positions.¹¹⁶ In supine animals, pleural pressure increases from nondependent to dependent regions. This may lead to dependent atelectasis in the highly perfused dorsal lung regions, resulting in intrapulmonary shunt and hypoxemia. In the prone position, the pleural pressure gradient is less, and the dorsal (now nondependent) regions are exposed to a lower pleural pressure. This results in opening of previously atelectatic alveoli. Intrapulmonary shunting is reduced because perfusion of the dorsal lung regions is maintained.¹¹⁷ Using chest CT, Gattinoni et al showed that in the supine position, gasless lung was found predominantly in the dorsal regions.⁸⁷ With prone positioning, densities redistributed to the ventral areas and dorsal regions were well aerated. Thus, prone positioning results in recruitment of previously atelectatic dorsal lung regions.

In addition to improvement in oxygenation, there is increasing evidence regarding the effects of prone position on respiratory mechanics and lung volume. In adult humans with ARDS, chest wall elastance, which contributes to set the end expiratory lung volume (EELV), has consistently been found to be higher in the prone than in the supine position.¹¹⁴ Pelosi et al found that sighs superimposed on the prone position further increased EELV and oxygenation only in the prone position, suggesting that the prone position either extends the potential for recruitment.¹¹⁸ Lung CT scan studies have also shown that the prone position promotes lung recruitment as compared to the supine position regardless of whether PEEP was low or high in the supine position.¹⁰²

As vascular dysfunction is a major independent factor associated with ARDS mortality, the beneficial effects of prone positioning on hemodynamics have been shown to be important. These effects include the reduction of the transpulmonary gradient (the difference of mean pulmonary arterial pressure relative to pulmonary artery occlusion pressure).¹¹⁹ Also, the increase in pulmonary arterial occlusion pressure induced by prone positioning is thought to result in pulmonary vascular recruitment thus decreasing dead space, another factor independently related to ARDS mortality.¹¹⁹ There is also evidence that prone positioning unloads the right ventricle in severe ARDS,¹²⁰ which may play a role in patient outcome.

Another important benefit of prone positioning appears to be prevention of VILI. Broccard et al showed that prone positioning attenuates and redistributes ventilator-induced lung injury in dogs.¹²¹ Papazian et al also found lower concentrations of proinflammatory cytokines in BAL fluid in ARDS patients after 12 hours the in prone position compared to supine position in similar settings.¹²²

The technical aspects of prone positioning require a coordinated team effort. Prone positioning must be performed with care to avoid inadvertent extubation or loss of intravenous lines or chest tubes. Transient hemodynamic instability and desaturation also may occur during repositioning. Cardiopulmonary resuscitation is difficult, if not impossible, in the prone position. Placement of multifunction electrode pads, which allow defibrillation, cardioversion, and pacing, has been recommended to facilitate cardiopulmonary resuscitation in the prone position. Other areas of concern that accompany prone positioning include facial and eyelid edema, peripheral nerve injury, tongue injuries, and skin necrosis. Multiply injured patients may present unique problems due to the presence of incisions, drainage tubes, extremity fractures, cervical spine, or facial fractures, and the like.

High Frequency Ventilation

Recognition of the impact of mechanical ventilation on VILI naturally led to an interest in the use of high frequency oscillatory ventilation (HFOV); after all, this might be considered the ultimate in “low tidal volume ventilation.” High frequency ventilation techniques such as HFOV use very small tidal volumes (1–5 mL/kg) delivered at rates of 60–3600 cycles/min. Although peak airway pressures are reduced compared with conventional modes, mean airway pressures, barotrauma, and hemodynamic compromise appear unchanged. The recently published OSCILLATE (OSCillation in ARDS Treated Early)¹²³ showed that HFOV did not reduce, and may increase, in-hospital mortality. HFOV was also associated with higher mean airway pressures, greater use of sedatives, neuromuscular blockers, and vasoactive drugs. The OSCAR (high-frequency oscillation in ARDS)¹²⁴ trial also showed that HFOV failed to reduce 30-day mortality in patients undergoing mechanical ventilation for ARDS. The disappointing results of these two major trials have casted doubt on the benefits of HFOV in ARDS. A number of potential mechanisms to explain the results have been proposed include, including the negative effects of increased sedation in patients treated with HFOV—this was also associated with the administration of an additional liter of fluid over the first 72 hours to maintain hemodynamic stability in the OSCILLATE trial. Also, the increased mean airway pressure in these patients may increase pulmonary vascular resistance and right ventricular afterload due to passive compression of alveolar vessels. Others have also argued the inclusion of patients receiving mechanical ventilation for up to 1 week and the high prevalence of direct lung injury in the OSCILLTE trial may have contributed to the lack of benefit.¹²⁵ Finally, as it has been reported that a profound heterogeneity exists in the extent of alveolar recruitment in response to increases in airway pressure,¹⁰² patients lacking “recruitable lung,” may suffer increased mean airway pressures and worsening alveolar strain and increased right ventricular afterload.¹²⁶

In light of the available evidence and until further trials address the above issues, HFOV should likely be reserved for a subset patients with refractory hypoxemia. When using HFOV, monitoring lung recruitment and right ventricular function to ensure achievement of appropriate physiological goals is crucial.

Extracorporeal Life Support

Extracorporeal life support (ECLS), also called extracorporeal membrane oxygenation (ECMO), has been in clinical use since 1972. The most common type of ECLS used in ARDS patients is “venovenous” ECLS, where blood is both withdrawn from and returned to the venous system. Most centers have shifted to the use of a single (dual lumen) large (~31 F) cannula placed under fluoroscopic guidance as the preferred approach for adults requiring VV-ECLS.¹²⁷ Blood is withdrawn into an extracorporeal circuit by a mechanical pump before entering an oxygenator. A membrane within the oxygenator provides a blood–gas interface for diffusion of gases. The oxygenated extracorporeal blood can be warmed or cooled as needed and then returned to the body.

The results of two early RCTS in patients with ARDS (published in 1979¹²⁸ and 1994¹²⁹) did not show a survival benefit with ECLS, including extracorporeal carbon dioxide removal (a related technique). The old ECLS circuits were difficult to manage and potentially hazardous, with a relatively high complication rate. Recently, technological advancements in circuitry including introduction of dual lumen percutaneous catheters, better pumps and oxygenators, has been instrumental in improvement in patient outcomes and wider adaptation of this therapy. Recent observational studies have suggested a benefit in severe cases of ARDS, with survival rates ranging from 47% to 66%.^130,131,132 Widespread interest in use of ECLS intensified with the H1N1 influenza epidemic in 2008–2009 that resulted in thousands of cases of severe respiratory failure, often with concomitant septic shock generated. The use of ECLS in these critically ill patients was associated with an impressive 70% survival rate.^133,134,135

The conventional ventilator support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR)¹³⁶ trial has been the only controlled clinical trial using modern ECMO technology. In this trial, 180 were allocated to either continued conventional management or referral to a specialized center with a standardized management protocol that included consideration for treatment with ECLS—75% of those allocated patients eventually received ECLS. Of the patients randomized to ECLS, 63% survived to 6 months without disability compared to 47% of those assigned to conventional management. However, this study was not a randomized trial of ECLS compared with standard lung-protective ventilation. In fact, only 70% of patients in the conventional management group received lung-protective ventilation. Despite these limitations, this trial provides support for transferring patients with severe ARDS to a tertiary care center that is capable of advanced ventilator management techniques and not necessarily the ability to carry out ECMO.

There is still uncertainty regarding which patients with ARDS are the best candidates for this treatment and what the optimal timing for initiation of therapy. In general, indications for ECLS in patients with ARDS include one or more of the following: severe hypoxemia, uncompensated hypercapnia, and the presence of excessively high end-inspiratory plateau pressures (Table 57-7).¹³⁷ According to the Extracorporeal Life Support Organization (ELSO) guidelines,¹³⁸ the use of ECMO should be considered when the ratio of Pao₂ to Fio₂ is less than 150, and ECMO is indicated when the ratio is less than 80. A Paco₂ greater than 80 mm Hg or an end-inspiratory plateau pressure greater than 30 cm of water is also considered an indication for ECMO in patients with ARDS.

The most appropriate strategy for weaning patients with ARDS from ECMO is a matter of debate. Typically, weaning from ECMO starts when improvement is noted in oxygenation, chest radiography findings, or lung compliance. At that time, the flow rate of sweep gas is decreased to compensate for increase in lung ventilation. Lung-resting ventilation is then transitioned to standard lung-protective settings or pressure-support ventilation. When ECLS support is less than 30% of total, native lung function may be adequate and a trial off is indicated.¹³⁹

The usual duration of ECLS in patients with ARDS is 7–10 days; however, survival rates of 50–70% with native lung recovery are increasingly reported in cases of prolonged duration ECLS (>14 days).^131,140 With advances in component technology and the techniques used to perform ECLS, serious complications have been reduced significantly. In the CESAR trial, only one serious adverse event related to ECLS was reported (a death related to vessel perforation during cannulation). In the largest single institutional review, the most common complication was nonintracranial bleeding, usually associated with cannula insertion sites (39% of the patients). The second most common complication was renal failure, defined as the need for dialysis or hemofiltration (31%). The least common complications were pump malfunction (2%), air entry into the circuit (8%), and intracranial bleeding or infarction (8%).¹⁴¹

The diversity of approaches to pharmacologic therapy for ARDS reflects the complex pathophysiology. Many therapies have been tested in randomized trials in humans including nitric oxide, corticosteroids, immunomodulating agents, pulmonary vasodilators, antioxidants, and surfactants.

Inhaled Nitric Oxide and Prostacyclin

NO is responsible for regulation of basal vascular tone. Inhaled NO (iNO) is a selective pulmonary vasodilator with no systemic side effects. Moreover, delivery of iNO exposes only ventilated alveoli to its vasodilatory effects. Selective vasodilation of pulmonary vessels in ventilated areas diverts blood away from nonventilated areas, improving ventilation–perfusion matching and hypoxemia. Inhaled NO decreases mean pulmonary artery pressure, and in doing so, lessens the hydrostatic pressure for pulmonary edema.¹⁴² For all of these reasons, iNO has seemed very attractive for use in severely hypoxemic patients. However, data from clinical trials in humans have been disappointing. The largest multicenter RCT of iNO for treatment of ARDS assigned 385 patients to placebo (nitrogen gas) or iNO at 5 ppm until 28 days, discontinuation of assisted breathing, or death. iNO at a dose of 5 ppm resulted in short-term oxygenation improvements in patients with ALI not due to sepsis and without evidence of nonpulmonary organ system dysfunction; however, there was no substantial impact on the duration of ventilatory support or mortality.¹⁴³ A cochrane review of 14 prospective RCTs of iNO versus placebo or standard therapy showed a statistically significant but transient improvement in oxygenation in the first 24 hours, but no statistically significant effect on overall mortality. Concerningly, iNO appeared to increase the risk of renal impairment among adults.

Currently, the role of iNO should be limited to short durations, (24–96 hours) in patients with severe, refractory hypoxemia, or pulmonary hypertension in whom iNO may act as a “bridge” allowing short-term physiologic support. Application of iNO in these situations may allow for possible patient survival until other therapies may be employed such as pronation or alternative modes of ventilation.

Aerosolized prostacyclins are potent vasodilators with similar effects as iNO including reduction of pulmonary arterial hypertension, improvement in right-heart function, and improvements in ventilation–perfusion matching. There has been an interest in use of aerosolized prostacyclins as an alternative to iNO due to various advantages (cost, setup, and administration). Similar to iNO, trials of aerosolized prostacyclin have shown transient improvement in oxygenation but no significant differences in mortality, ventilator-free days, or reduction in disease severity.¹⁴⁴ These trials have been limited by small sample sizes, lack of appropriate control subjects, and varying doses, timing, and modes of delivery of the drugs.

Corticosteroids

The ability of corticosteroids to attenuate the inflammatory response would seem to make them ideal treatment for ARDS. From the first description of ARDS, corticosteroids were suggested as possible therapeutic agents. Controversy remains as to whether low-dose corticosteroids can reduce the mortality and morbidity ARDS without increasing the risk of adverse reactions. Early RCTs to assess the use of corticosteroids in patients with respiratory failure at risk of developing ARDS showed no role for steroids in the prevention of ARDS.¹⁴⁵ Large prospective clinical trials have also failed to show any survival benefit with high-dose steroids in early ARDS. The earliest trial, by Bernad and colleagues tested 30 mg/kg of intravenous methylprednisolone every 6 hours for a total of 4 doses, with the hypothesis that this treatment would reduce 45-day mortality. However, the study was stopped early after enrolling 99 patients, with 60% mortality in the methylprednisolone group and 63% in the control group.¹⁴⁶ Another RCT by Meduri et al in 2007 examined the effect of low-dose methylprednisolone given during the first 72 hours of onset of ARDS showed improvement in pulmonary outcomes, including lung injury score and ventilator-free days but no significant difference in mortality.¹⁴⁷

With evidence mounting against treatment with corticosteroids for prevention and early treatment of ARDS, trials have shifted towards evaluating the utility for treatment of the late, proliferative phase of ARDS, with the understanding that the pathogenetic mechanisms initiating early ARDS differ from the late stages. A number of anecdotal reports and small series have suggested that high-dose corticosteroids may be of some benefit during the late ARDS.^148,149 The ARDSNet conducted a multicenter RCT of 180 patients with ARDS of at least 7-day duration assigned to either methylprednisolone or placebo. Methylprednisolone treatment did increase the number of ventilator-free days, improved oxygenation and respiratory compliance, and resulted in less vasopressor use without a difference in ICU length of stay. There was no overall difference in 60-day mortality; however, among patients enrolled after day 13 of ARDS, mortality was 12% in the placebo group compared with 44% in steroid group, suggesting that steroids may be harmful if administered too late in the course of ARDS. Interestingly, the rate of infectious complications was no different between the groups, but the methylprednisolone group had a higher incidence of neuromuscular weakness and hyperglycemia. Given the challenges of this patient group, any use of steroids for late ARDS must be individualized and, optimally, delivered before disease day 14. Several meta-analyses have failed to conclusively support routine use of corticosteroids for treatment of early or late ARDS.^{145,150,151,152} Well-designed randomized controlled trials are needed to understand the potential benefits of steroid treatment in the face of short- and long-term risks, including delayed recovery and impairments in physical function and health-related quality of life.

Exogenous Surfactant

Surfactant dysfunction with quantitative and qualitative abnormalities of phospholipids and proteins is a pathological feature of ARDS. Results for surfactant therapy in infants with the respiratory distress syndrome of prematurity were dramatic with improvement in gas exchange and lung mechanics, and decrease in CPAP requirement and barotrauma. Unfortunately, results in adult ARDS patients have not been consistent. This is likely due to differences in death pathology as ARDS is characterized by surfactant inhibition by plasma constituents and increased breakdown by activated oxidative and hydrolytic pathways whereas the deficiency of surfactant as the primary pathology in premature infants.¹⁵³ Several RCTs of surfactant replacement in adults with ARDS have shown improvements in oxygenation indices but have failed to produce any demonstrable survival benefits, as noted by a recent meta-analysis of 9 RCTs.¹⁵⁴ Further understanding of which patients may benefit the most from this type of therapy as well as refinement of surfactant preparation may offer hope in the future for use of this therapy.

Antioxidants

It is well known that indices of oxidative damage including neutrophil recruitment, lipid peroxidation, and protein degradation are higher in patients that die of ARDS. Natural antioxidants such as glutathione, have been shown to be depleted in the lungs of ARDS patients. This has been the rationale behind using agents that increase glutathione levels such as N-acetylcysteine (NAC) and procysteine. A cochrane analysis of 5 studies using NAC which randomized 239 patients, showed no statistically significant effect of NAC on early mortality and inconclusive results regarding duration of mechanical ventilation, or ventilator-free days to day 28.¹⁵² Currently, no clear evidence exists for use of NAC or procysteine in the treatment of ARDS patients.

Anti-Inflammatory Therapies

Neutrophil elastase (NE), a serine protease with antimicrobial and anti-inflammatory actions has been implicated in the pathogenesis of ARDS. Silvelestat, a neutrophil elastase inhibitor, was investigated in the STRIVE trial, an international, multicenter RCT.¹⁵⁵ The study was stopped prematurely due to an increase in 180-day all-cause mortality. A recent meta-analysis of eight clinical trials (including STRIVE) has shown no benefit in short-term mortality, and a worse outcome for 180-day mortality.¹⁵⁶ Other agents currently in testing include anti-TNF-α, anti-IL-1, and anti-IL-10 antibodies as well as monoclonal anti-CD40L antibody. In experimental models of acid aspiration and endotoxemia, early treatment with anti-IL-8 antibodies has been found to reduce lung injury and mortality in animal models.¹⁵⁷ There have been no clinical trials yet in patients with ARDS.

Nutritional Support

Nutrition support in critically ill patients with ALI and ARDS is a vital aspect of treatment. The proinflammatory and hypercatabolic response seen with ALI/ARDS can lead to significant nutrition deficits. Proper nutrition support is necessary to prevent cumulative caloric deficits, malnutrition, loss of lean body mass, and deterioration of respiratory muscle strength. Early enteral nutrition has been shown to attenuate disease severity and immune response to injury. The optimal dosage, composition of fatty acids, and the ratio of individual immune-modulating nutrients in specialized enteral formulations remain controversial; however, a meta-analysis of 3 trials showed that a diet enriched with eicosapentaenoic acid (EPA) and γ-linolenic acid (GLA), and antioxidants resulted in reduction in mortality, increase in ventilator- and ICU-free days, improvement in oxygenation, and reduction in the risk of developing new organ failures.¹⁵⁸ Data from the ARDSNet EDEN-Omega study regarding utility of specialized nutrition support have not been published yet. However, based on existing data, ASPNE/SCCM guidelines, as well as the Canadian clinical practice guidelines, an enteral diet enriched with omega-3 fatty acid, GLA, and antioxidant supplementation, should be considered in patients with ALI/ARDS.¹⁵⁹

Careful monitoring of nutritional support may be necessary in patients with tenuous respiratory status. An indirect calorimeter can be helpful in providing estimates of CO₂ production and the respiratory quotient. The respiratory quotient should be kept below 0.9 by appropriate adjustment of the proportion of lipid and total calories administered. Overfeeding patients or administering excess carbohydrates can lead to excess production of CO₂. In the setting of marginal ability to execute work of breathing, this may, in theory, precipitate or prolong hypercapnic pulmonary failure. Our goals for nutritional support are to deliver 21–25 nonprotein cal/kg/d and 0.25–0.30 g of nitrogen/kg/d. The primary goal of carbohydrate administration should be a rate of less than 5 mg/kg min.

Mortality associated with ARDS has historically been reported from 30% to 60% with significant variation owing to age and risk factors (see the section “Risk Factors”). The majority of deaths are related to sepsis and MOF (see Chapter 61). Respiratory failure is a cause of death in only 15% of patients. There has been a gradual improvement in overall incidence and mortality of ARDS patients across several RCTs in the past two decades suggests, with the most recent rates as low as 20–25%.¹⁶⁰ The principal therapy that improves outcome in patients with ARDS appears to be low tidal volume ventilation¹⁶¹ but other improvements in critical care delivery and goal directed care reduce ARDS incidence are at work as well (Fig. 57-4).

Acknowledgment

We thank Jeffrey L. Johnson and James B. Haenel for their contribution to the previous edition chapter, portions of which have been retained in this chapter.