Acute Hypoxemic Respiratory Failure and ARDS

Pathology

The pathologic features of ARDS have classically been described using three overlapping and sequential stages.³⁴ In the first or exudative phase of lung injury, the pathologic findings have been termed diffuse alveolar damage. There are hyaline membranes lining the alveolar walls and protein-rich edema fluid in the alveolar spaces, as well as epithelial disruption and infiltration of the interstitium and air spaces with neutrophils. Areas of hemorrhage and macrophages can also be found in the alveoli. This phase, which is thought to last for approximately 5 to 7 days, is followed in some patients by the so-called proliferative phase. At this point, hyaline membranes are reorganized and fibrosis begins to be observed. Obliteration of pulmonary capillaries and deposition of interstitial and alveolar collagen may be observed, along with a decrease in the number of neutrophils and the extent of pulmonary edema. This proliferative stage has traditionally been described as being followed by a fibrotic phase, essentially emphasizing the appearance of pulmonary fibrosis in a subset of patients with persistent (i.e., >2 weeks) ARDS. More recently, it has been realized that areas of fibrosis may actually develop sooner than usually appreciated: elevated levels of N-terminal procollagen peptide III, thought to represent collagen synthesis, can be detected in bronchoalveolar lavage fluid of patients with ARDS as early as 24 hours into the course of the illness. In addition, the bronchoalveolar lavage fluid from these patients has been shown to stimulate cultured fibroblasts to proliferate.³⁵ These and other observations have led some investigators to hypothesize that fibroproliferation may be initiated simultaneously with (rather than after) inflammatory lung injury.³⁶

Alveolar-Capillary Membrane

If ARDS is a disorder of increased alveolar-capillary permeability, it stands to reason that the pulmonary microvascular endothelium or the alveolar epithelium (or both) must be involved in its pathophysiology. Damage to the alveolar epithelium is thought to be a key event.³⁷ Once ARDS has begun, the importance of the alveolar epithelium is also clear: Type II pneumocytes must differentiate into type I cells to help cover the denuded epithelial surface, while both type I and II cells express the Na⁺,K⁺-ATPase, which is thought to be important in clearance of edema fluid (discussed later). Injury to type II pneumocytes impairs the production and metabolism of surfactant. In addition to damage to the alveolar epithelium, loss of lung endothelial barrier integrity is both necessary and sufficient for the development of ARDS.^38,39 How the alveolar-capillary membrane is damaged is not known for certain, although mediators of epithelial and endothelial apoptosis⁴⁰ and neutrophils are suspected of playing a role (see later).

Neutrophils and Other Inflammatory Mediators

Histologically, one of the hallmarks of ARDS is the accumulation of neutrophils in the microvasculature of the lung.⁴⁷ As key players in innate immunity, neutrophils can generate an impressive array of cytotoxic compounds. These include reactive oxygen species, cationic peptides (e.g., defensins), eicosanoids, and proteolytic enzymes such as leukocyte elastase. In addition, once activated, neutrophils release growth factors and cytokines (e.g., tumor necrosis factor [TNF]-α and interleukin [IL]-1β) that may enhance the inflammatory response. Given this destructive potential, it has long been theorized that neutrophils may be central to the pathogenesis of ARDS⁴⁸ (Fig. 100-3). There is an abundance of clinical and preclinical data to support this hypothesis. For example, in humans with ARDS following sepsis, bronchoalveolar lavage neutrophilia is associated with a poor prognosis.⁴⁹ Neutrophil-depleted mice exposed to hyperoxia develop less lung injury than normal mice.⁵⁰ Similarly, in a hamster model of ARDS induced by endotoxin inhalation, the administration of a specific inhibitor of neutrophil elastase (even hours after administration of endotoxin) prevented the development of lung injury.⁵¹

If neutrophils are involved in the pathogenesis of ARDS, some defect in their regulation must be invoked. For example, in an uncomplicated bacterial pneumonia, the pulmonary inflammatory response is limited by counter-regulatory processes that prevent tissue damage. Whether this regulation is ineffective or insufficient in ARDS is a fascinating and unanswered question.⁵²

One of the earliest manifestations of ARDS, even before hypoxemia, is a transient leukopenia due to sequestration of neutrophils in the lung microvasculature.⁵³ The average pulmonary capillary is smaller than the average neutrophil, and neutrophils therefore have to deform to pass through the microvasculature. Activated neutrophils “stiffen” and cannot negotiate narrow capillary segments.⁵⁴ Inhibitors of actin polymerization can abrogate this stiffening, implicating a change in the actin cytoskeleton in neutrophil sequestration in the lung.⁵⁵ Neutrophil sequestration also involves interactions between molecules on the surface of the neutrophil and the lung capillary endothelium. For example, in rabbits, blocking the adhesion molecule L-selectin on the surface of the neutrophil prevented neutrophil sequestration in alveolar capillaries induced by exposure to endotoxin.⁵⁶

After the initial sequestration, neutrophils must translocate (via diapedesis) across the alveolar-capillary barrier to the alveolar space. The determinants of this seemingly simple movement remain incompletely understood. Integrins on the surface of the neutrophil are thought to mediate emigration of neutrophils from the pulmonary circulation in response to some, but not all, inflammatory stimuli.⁵⁷ Proteases secreted by the alveolar epithelium, in concert with regional cytokine production and glycosaminoglycans on the epithelial surface, may act together to form a chemotactic gradient for neutrophils to follow.⁵⁸

Many studies are focusing on the mechanisms of neutrophil activation whereas others are focusing on the interaction between platelets and neutrophils and how mutual activation may contribute to ARDS or sepsis.^59-62 Other studies have looked at various components of intracellular signal transduction pathways, such as kinases (enzymes that phosphorylate substrates) and transcription factors. For example, one such kinase is the p38 mitogen-activated protein kinase, which is activated when cells are stimulated with lipopolysaccharide (LPS).⁶³ Activation of this kinase stimulates TNF-α production and macrophage inflammatory protein-2 release (a chemotactic factor for macrophages).⁶⁴ Interestingly, inhibition of p38 mitogen-activated protein kinase in mice, even hours after the mice are exposed to aerosolized LPS, attenuates neutrophil chemotaxis and migration from the lung microvasculature into alveoli.⁶⁵ Another kinase often discussed in the context of inflammation is phosphatidylinositol 3-kinase. This enzyme phosphorylates phosphatidylinositol, a lipid-derived second messenger whose phosphorylated forms have been implicated in a myriad of intracellular signaling events. Phosphatidylinositol 3-kinase γ is preferentially activated in neutrophils exposed to IL-8 or fMLP (a bacterial-derived peptide).⁶⁶ Despite exposure to intraperitoneal endotoxin, phosphatidylinositol 3-kinase γ knockout mice displayed decreased neutrophil accumulation, cytokine production, and lung injury compared to control mice. The neutrophils in the lung of the knockout mice also demonstrated diminished activation of NF-κB, an important transcription factor known to mediate the up-regulation of numerous cytokines and proinflammatory mediators.⁶⁷

There are many potential mechanisms by which activated neutrophils might mediate ALI. In addition to secreting cytokines and growth factors that might stimulate the local and systemic inflammatory response, neutrophils release defensins⁶⁸ and generate reactive oxygen species that can mediate tissue damage.⁶⁹ In animal studies, inhibition of the assembly of NADPH oxidase (the major source of reactive oxygen species) by apocynin has been shown to attenuate sepsis-induced lung injury.⁷⁰ The nitric oxide synthase (NOS) pathway has also been implicated in mediating lung injury; knockout mice lacking the gene for inducible NOS developed less severe lung injury than wild-type animals upon injection with LPS.⁷¹

In addition, neutrophils contain proteolytic enzymes that may be involved in the pathogenesis of ALI. In particular, both neutrophil elastase and metalloproteinases have been extensively studied.⁵² Because of its ability to degrade multiple substrates including growth factors and cytokines, neutrophil elastase may be involved in regulation of the inflammatory response. It has also been shown to degrade epithelial and endothelial cadherins, proteins that are major components of adherens junctions, which hold cells together. It is possible that elastase-mediated destruction of cadherin could predispose to alveolar flooding. Despite its potential to cause unwanted tissue damage, neutrophil elastase (NE) is likely crucial to host defense. In NE-deficient mice, the administration of intraperitoneal Klebsiella pneumoniae causes 100% mortality within 48 hours, whereas mortality in normal mice was only 50%.⁷² However, NE-deficient mice are paradoxically resistant to normally lethal doses of LPS. Furthermore, mice that lack both NE and another neutrophil protease (cathepsin G) are protected against alveolar damage induced by endotoxic shock.⁷³ These apparently contradictory results suggest that NE, while important in a regulated inflammatory response, may nonetheless participate in inflammatory injury under certain circumstances. In numerous studies of multiple different experimental models in multiple species of animals, NE has been shown to play an important role in the pathogenesis of ALI. Whether it is as important in the development of ARDS in humans remains unanswered. A clinical trial of a leukocyte elastase inhibitor in ARDS was halted because preliminary analysis suggested lack of efficacy.⁷⁴

Metalloproteinases may also be important mediators of leukocyte-mediated lung injury. Elevated concentrations of the matrix metalloproteinases gelatinase A and B have been found in the epithelial lining fluid of patients with ARDS.⁷⁵ Mice lacking the genes for gelatinase B or stromelysin 1 had less severe injury in an animal model of ALI.⁷⁶ As mentioned earlier, matrilysin (matrix metalloproteinase 7) has been shown to regulate the formation of a chemotactic gradient and the transmigration of neutrophils across the alveolar epithelium in a mouse model of ALI.⁵⁸ Finally, administration of an inhibitor of elastase and metalloproteinases (chemically modified tetracycline-3) attenuated ALI after cardiopulmonary bypass in pigs.⁷⁷

Despite the emphasis on neutrophils as potentially causative for lung injury, it is important to note that ARDS has certainly been described in patients with profound neutropenia.^78,79 Indeed, it is possible that the neutrophil infiltration observed in some cases of ARDS is adaptive (i.e., a physiologic response to a primary injury) rather than destructive. At present, however, it is generally believed that neutrophils are a causative factor in the development of most cases of ARDS. Comparatively little is known about the mechanisms of neutrophil-independent ARDS and this must be a goal of future investigations.

Inflammation and Coagulation

Because one of the most common precipitants for ARDS is sepsis, it is hoped that therapies for sepsis may either prevent or improve the outcome of ARDS. Our current concept of sepsis is that there is an initial inflammatory state, with up-regulation of inflammatory cytokines such as TNF-α and IL1β and recruitment and activation of inflammatory cells such as neutrophils. This early stage of inflammation is followed by a relatively depressed immunity, in which the patient is vulnerable to nosocomial infections.⁸⁰ The theory that dysregulation of the inflammatory response is responsible for sepsis has led to the search for agents that would selectively block components of the inflammatory pathway. It has also been appreciated that there are important connections between the molecular cascades that regulate both inflammation and coagulation; for example, TNF-α causes an increase in thrombin and fibrin formation, while fibrin fragments themselves are known to be chemotactic for neutrophils.⁸¹ TNF-α increases tissue factor expression on endothelium and inhibits fibrinolysis, both of which favor fibrin formation. Activated protein C (APC), an endogenous anticoagulant, has direct and indirect anti-inflammatory effects, which include reducing levels of IL-6 and attenuating neutrophil activation in sepsis.^82,83 Because sepsis is the most common cause of ARDS and because abnormalities of coagulation are very common in sepsis, investigators have wondered whether altered coagulation is involved in the genesis of ARDS. How this might happen is largely speculative, but intraalveolar, interstitial, and intravascular fibrin deposition have all been observed in patients with ARDS. Indeed, fibrin is a major component of hyaline membranes. Intraalveolar fibrin has been postulated to serve as a nidus for fibroblast proliferation and potentially, as ALI resolves, as a stimulus for pulmonary fibrosis. Fibrin might contribute as well to ongoing lung injury through its chemotactic properties, and intravascular fibrin deposition, as in microthrombi, might contribute to the elevated pulmonary vascular pressures observed in ARDS.

Interest in the role of coagulation in the pathogenesis of ARDS was buttressed in part by observations in animal studies that anticoagulation can attenuate the severity of sepsis-induced lung injury,⁸⁴ although studies in humans have been disappointing. Indeed, a small randomized controlled trial of APC in patients with ALI was stopped prematurely due to lack of efficacy,⁸⁵ and APC was pulled from the market after a large multicenter trial showed it provided no mortality benefit in patients with septic shock.⁸⁶

Other molecular determinants of inflammation continue to be elucidated. Some data have implicated transforming growth factor-β in an animal model of ALI.⁸⁷ In one study, transforming growth factor-β was postulated to cause increased alveolar epithelial cell permeability by depleting intracellular glutathione levels.⁸⁸ Other investigators have attempted to improve the endogenous counter-inflammatory response; in one study, the gene for heat shock protein 70 was ligated to an adenoviral promoter, and the resultant recombinant construct was administered into the lungs of rats in which ARDS had been induced by cecal ligation and perforation. Administration of the heat shock protein 70 construct increased heat shock protein 70 expression specifically in the lung; remarkably, this increased expression was associated with a significant reduction in pulmonary edema and inflammation and even mortality.⁸⁹ Indeed, mice deficient in heat shock protein 70 showed increased mortality and lung injury after cecal ligation and perforation.⁹⁰ The mechanisms underlying this effect are not clear, but may involve suppression of the proinflammatory transcription factor NF-κB or decreased lung parenchymal apoptosis.⁹¹

Ventilator-Induced Lung Injury

Although mechanical ventilation for ARDS may be lifesaving, there is abundant preclinical and clinical evidence that it can also be harmful.^106,106a While it was quickly recognized that excessive airway pressure could lead to barotrauma (Fig. 100-4), including pneumothorax, pneumomediastinum and subcutaneous emphysema, attention has since turned to subtler but more common manifestations of lung injury related to mechanical ventilation. Mechanical ventilation can induce pulmonary edema by causing increases in both epithelial and endothelial permeability.¹⁰⁶ Indeed 40 years ago Webb and Tierney demonstrated that ventilation of rats with high peak airway pressures could lead to severe pulmonary edema,¹⁰⁷ and more than 20 years ago, investigators noted that mechanical ventilation could produce a form of increased permeability pulmonary edema remarkably similar to ARDS.¹⁰⁸ Now, the accumulated evidence suggests that certain mechanical ventilation strategies may aggravate if not induce ARDS in some patients.¹⁰⁹

A major mechanism causing VILI is overdistention of lung units, rather than the absolute airway pressure per se. Normal rats ventilated with high airway pressure due to a high tidal volume developed increased permeability, whereas rats ventilated with smaller tidal volumes, but with the same end-inspiratory pressure (obtained by strapping the chest walls of the rats) did not develop increased permeability.¹⁰⁶ Rats were also ventilated with low airway pressure using negative inspiratory pressure (applied at the chest wall) and high tidal volumes. Their results demonstrated that the rats ventilated with high tidal volumes had significantly more edema than others. In particular, the negative (low) pressure and high tidal volume group had the worst edema. These important observations, confirmed in other species,¹¹⁰ led to the appreciation that large tidal volumes, rather than high airway pressures per se, are an important determinant of ventilator-induced pulmonary edema. The term volutrauma was created to recognize this fact.

The repetitive opening and closing of terminal lung units associated with mechanical ventilation is also considered to be detrimental. The mechanism of this injury, which has been termed atelectrauma,¹¹¹ is thought to be the high shear stresses generated at the interface of collapsed and aerated tissue when a collapsed airway is reopened.¹¹² Theoretically, PEEP should be helpful in minimizing this injury by keeping the lung recruited and promoting greater lung homogeneity; any such advantage of PEEP would have to be balanced against the potential harm caused by a potentially greater overdistention of lung units due to the higher PEEP levels (see Video 100-1).

It is important to point out that patients with ARDS may be especially vulnerable to VILI because of the heterogeneous nature of the pulmonary parenchymal injury. On computed tomography scans of the lungs, normal-appearing lung and densely consolidated injured lung are both seen; as a consequence, there are marked regional differences in lung compliance¹¹³ (Fig. 100-5). A tidal volume designed to inflate an entire lung would preferentially inflate the normal-appearing areas, potentially leading to overdistention and volutrauma. Patients with ARDS may similarly be more vulnerable to atelectrauma. Although some evidence suggests that normal lungs can tolerate at least short periods of cyclic opening and closing of airways from mechanical ventilation,¹¹⁴ injured lungs, such as in ARDS, would be exposed to much higher shear stresses and would not be expected to fare as well.¹¹⁵

Over the past 15 years, there has been a growing appreciation that VILI is not only a mechanical injury, but also reflects an underlying complex cellular and molecular response. The term biotrauma has been coined to emphasize this change in thinking.¹¹⁶ In our understanding of VILI, one of the most significant advances made is that mechanical ventilation per se can induce both a local and systemic inflammatory response. In animal studies of ex vivo lungs, it has been shown that, compared to a control ventilation strategy with moderate tidal volumes and PEEP, ventilation either with high tidal volumes or with zero PEEP causes elevations in lung lavage levels of inflammatory cytokines. Lungs ventilated both with high tidal volumes and with zero PEEP had a synergistic elevation in cytokine levels.¹¹⁷ This inflammatory response to an injurious ventilation strategy has also been shown to extend beyond the lung. In an acid aspiration rat model of lung injury, a ventilatory strategy using high tidal volumes and zero PEEP was associated with an increase in blood levels of various cytokines; this was not observed in groups ventilated with a small tidal volume or in the group ventilated with the large tidal volume but higher PEEP levels.¹¹⁸

Most importantly, similar observations have been made in humans with ARDS. In one study, patients were randomized to “lung-protective” ventilation, in which the tidal volume was set to avoid overdistention and PEEP was set above the lower inflection point of the pressure volume curve.¹¹⁹ The control group received a strategy that would have been considered conventional ventilation at the time. While alveolar-lavage and plasma cytokine levels declined in the lung-protective group, they rose significantly in the control group. Post hoc analyses revealed a significantly higher number of ventilator-free days in the lung-protective group than in controls and significant correlations between the development of multisystem organ failure and plasma cytokines. The impact of ventilator strategy on the development of biotrauma can be remarkably quick. Within 1 hour after switching patients from a protective ventilatory strategy, Stuber and colleagues found an increase in a number of proinflammatory cytokines in the lungs and plasma of patients with ARDS.¹²⁰

Mortality and Complications

As discussed in the section on outcomes, patients with ARDS often die of the systemic inflammatory response syndrome and multiorgan dysfunction. Hence, the observation that mechanical ventilation can influence pulmonary and systemic cytokine levels is intriguing. Taken together, these findings suggest that mechanical ventilation has the potential not only to injure the lungs, but also to lead to a loss of compartmentalization of the pulmonary inflammatory response. Systemic dissemination of this response could be associated with the development of systemic inflammatory response syndrome and potentially with multisystem organ failure (Fig. 100-6).¹²¹ In one study, injurious mechanical ventilation in rats not only caused elevated plasma and lung cytokine levels, but also caused increased renal epithelial cell apoptosis and associated renal dysfunction.¹²² Furthermore, pretreatment with either IL-10 (an anti-inflammatory cytokine) or IL-22 (a member of the IL-10 family that has immunoregulatory and tissue protective properties) reduced lung injury and reduced mortality in animal models of VILI.¹²³

Finally, patients with ARDS often require very high inspired fractions of oxygen. The toxic effects of hyperoxia on the lung have been well described,¹²⁴ and the histologic appearance mirrors that of human ARDS. Oxygen toxicity is thought to be mediated by the formation of both reactive oxygen and nitrogen species, which can damage tissues by a multitude of mechanisms,⁶⁹ and hyperoxia appears to worsen VILI.¹²⁵ Antioxidants have been considered as a potential therapeutic strategy for preventing and treating ARDS, although clinical trials have so far been disappointing (see Therapy).

Genetic Determinants

To date, relatively little is known about which genes might affect the development or prognosis of ARDS. Genome-wide association studies have suggested a number of candidate genes,^126-129 including those coding for angiopoietin 2 and the angiotensin-converting enzyme,¹³⁰ that might affect the incidence and/or outcome of ARDS. Subsequent studies have reported conflicting results.^131,132 The heterogeneity of patients with ARDS is likely to make it difficult to identify clinically important genetic associations except in clearly defined subsets of patients.

Predictors of Poor Prognosis

Despite the prominence of hypoxemia among the clinical manifestations of ARDS, early trials did not find that the severity of hypoxemia early in the course of the illness was a good predictor of subsequent mortality.¹³⁷ Pulmonary injury scoring systems, such as the Lung Injury Score and the ARDS score, have been shown to predict a prolonged (>2 weeks) requirement for intubation and ventilation,¹³⁸ while scoring systems that measure the overall severity of illness, such as the Simplified Acute Physiology Score, correlate better with survival.¹³⁹ The classic teaching is that patients with ARDS do not usually die of refractory hypoxemia, which may seem paradoxical given that hypoxemia is frequently the focus of resuscitative efforts. In fact, most patients with fatal ARDS die of sepsis and multiorgan failure.^140,141 The explanation for this apparent paradox is unknown, although it has been hypothesized that injurious mechanical ventilation during the course of ARDS may be involved.¹²¹ As discussed earlier, ventilation using excessive tidal volumes has been shown to cause elevations in pulmonary and systemic cytokine levels, and has been linked in an animal model to apoptosis of renal cells and renal dysfunction.¹²²

The mortality rate from ARDS varies depending on the precipitant. The highest risk of death has consistently been reported in sepsis, while ARDS in the setting of major trauma has a much better prognosis.¹⁴² In addition, it is known that chronic liver disease,¹³⁷ older age,¹⁴³ chronic alcoholism,²⁹ and nonpulmonary organ dysfunction¹³⁷ are associated with higher mortality from ARDS. Other predictors of death from ARDS have included a history of organ transplantation and infection with human immunodeficiency virus,¹⁴⁴ while one study described a higher mortality rate in men and also in African-Americans compared to non–African-Americans.¹⁴⁵

As mentioned earlier, risk factors for ARDS have been classified as being pulmonary or nonpulmonary in origin, thereby leading to an injury to the lung by direct or indirect means. It remains unclear whether this distinction has prognostic importance. In one prospective cohort study of ARDS patients, investigators found a trend toward higher mortality in patients with a pulmonary precipitant, although the difference was not statistically significant.¹⁴⁶ In contrast, the ARDS Network investigators retrospectively analyzed the data from their large randomized study of low tidal volume ventilation versus traditional tidal volume ventilation. While confirming that the mortality rate for ARDS was highest in patients with sepsis and lowest in patients with trauma, there was no difference in mortality, days off the mechanical ventilator, or the development of organ failure between patients with pulmonary or nonpulmonary risk factors. In addition, there was no statistically significant evidence that the low tidal volume strategy was less efficacious in any subgroup.¹⁴² A meta-analysis came to a similar conclusion.³³ The consensus group that developed the Berlin definition of ARDS decided not to include pulmonary versus nonpulmonary ARDS as distinct categories.

Because hypoxemia is not a reliable predictor of mortality from ARDS, investigators have searched for other lung-specific markers of prognosis. In one prospective study of 179 patients with ARDS, a multiple logistic regression was performed to identify which clinical and physiologic variables predicted mortality.¹⁴⁷ The analysis found that the dead space fraction (as calculated by the Bohr equation) was elevated in ARDS and was an independent predictor of mortality. For every increase of 0.05 in the dead space fraction, the odds of death from ARDS increased by 45%. The mechanism of this association is not known: it is possible that the pulmonary vascular injury in ARDS that accounts for the increase in dead space may be important to overall outcome.

The development of pulmonary fibrosis is also thought to connote a worse prognosis. Elevated procollagen III levels, thought to be indicative of collagen synthesis, have been found in the pulmonary edema fluid of patients with ARDS and have been shown to correlate with increased mortality.^148,149 In another study, 22 of 25 consecutive patients with ARDS underwent transbronchial biopsies of the most abnormally appearing areas on the chest radiographs. In those whose biopsies showed any fibrosis, the mortality rate was significantly higher than in patients whose biopsies showed no fibrosis.¹⁵⁰ Of note, there is evidence in animal models that the stress induced by mechanical ventilation may lead to lung fibrosis via epithelial-mesenchymal transition.¹⁵¹

Finally, there is extensive interest in the identification of biomarkers to predict outcome from ARDS. For instance, associations have been reported between elevated levels of cytokines such as IL-6 and IL-8¹⁵² and growth factors such as angiopoietin 2¹⁰⁰ and a poor prognosis from ARDS. However, even a combination of biomarkers when used together with clinical predictors is only slightly more predictive for mortality than the clinical predictors alone.¹⁵³

Complications

ARDS is complicated by ventilator-associated pneumonia in about 30% to 65% of cases (see also Chapter 34). In this setting, ventilator-associated pneumonia usually develops more than 5 to 7 days after the onset of mechanical ventilation and is often preceded by colonization of the lower respiratory tract by potential pathogens.¹⁵⁴ The likely organisms include nonfermenting gram-negative rods, methicillin-resistant Staphylococcus aureus, and Enterobacteriaceae.¹⁵⁵ Although the development of VAP prolongs the duration of mechanical ventilation in ARDS, it does not appear to increase mortality.^154,156,157 Making a definitive diagnosis of VAP in patients with ARDS can be challenging, because patients with ARDS already have radiographic abnormalities, and not uncommonly have leukocytosis and fever. If diagnostic techniques such as bronchoalveolar lavage or protected specimen brushes are used, the yield is higher when the lung is sampled bilaterally and when the patient is off antibiotics.^157,158

Another feared complication of ARDS is barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema, eFig. 100-1) due to the effect of positive pressure ventilation in heterogeneous lungs with diminished compliance. Because most patients with ARDS will be supine (rather than erect), diagnosing a pneumothorax requires vigilance; the radiographic appearance of a pneumothorax is different and can be subtler in the supine patient (e.g., air in the costophrenic angle, the “deep sulcus” sign). Data from a number of prospective studies suggest that the incidence of barotrauma in ARDS currently is about 10% or less.^109,159,160

Hemodynamic Management

The optimal approach to hemodynamic management in ARDS has become less controversial with the publication of studies comparing different strategies. Before these studies, it had been unclear whether clinicians should attempt to diurese to decrease pulmonary edema at the expense of potentially causing hypovolemia and shock or to liberalize fluids to maintain perfusion.

This issue was addressed by a large multicenter randomized controlled trial from the ARDS Network, made up of investigators at multiple American hospitals. The trial randomized 1000 patients with ARDS to one of two highly protocolized fluid strategies: through the administration of fluids, diuretics, or vasoactive agents, the two protocols targeted either a higher or lower intravascular pressure (as measured by a pulmonary artery or central venous catheter) for 7 days. Patients randomized to the conservative fluid strategy (targeting a lower intravascular pressure) had significant improvements in oxygenation and more ventilator-free and intensive care unit–free days than the patients in the liberal strategy. Importantly, patients in the conservative arm did not have a higher incidence of dialysis or shock than those in the liberal arm; in addition, mortality rates in the two arms were similar. Thus, the results of this study suggest that conservative administration of fluids is safe and beneficial to patients with ARDS.

At first, this recommendation may seem at odds with the principle of early goal-directed therapy, whereby patients with sepsis are aggressively resuscitated with fluid in accordance with the randomized controlled trial reported by Rivers and coworkers.¹⁶¹ However, the apparently disparate results of these clinical trials are not difficult to reconcile. First, it is important to note that patients in the ARDSNet study were enrolled an average of 24 hours after meeting the criteria for ALI, much later than the 6-hour window in the study by Rivers. In addition, the study protocol of the ARDSNet trial was strictly designed to avoid aggravating or inciting shock or pulmonary edema.

One last caveat is that the ARDSNet study used a very complex algorithm for fluid administration that may not be widely adopted. A simplified protocol has since been proposed but has not been validated.¹⁶² In the meantime, we recommend that clinicians manage fluids conservatively in patients who are not in shock, nonetheless taking care to avoid overdiuresis and hypovolemia.

Clinicians had historically inserted a pulmonary artery catheter into patients with pulmonary edema to help establish the diagnosis and to guide therapy. The consensus from numerous clinical trials is that, for most patients, the information from a pulmonary artery catheter does not improve outcome.¹⁶ For this reason, we do not recommend the routine use of these catheters in patients with ARDS.

Which fluid to use in patients with ARDS remains an open question. The use of starch-based colloids has fallen out of favor in patients with severe sepsis, because of a randomized trial that found a higher incidence of renal failure in patients with severe sepsis receiving 10% pentastarch compared to patients receiving Ringer lactate.¹⁶³ Whether pentastarch has the same detrimental effect in patients with ARDS without severe sepsis is unknown. On a theoretical basis, the use of albumin is appealing, because it would increase intravascular oncotic pressure and predispose to less pulmonary edema. A small placebo-controlled study in ARDS demonstrated that a regimen of albumin and furosemide infusions over 5 days caused a substantial and statistically significant improvement in oxygenation accompanied by a decrease in heart rate. However, most of the patients had ARDS as a result of trauma, with less than 5% having sepsis. There were no differences in important clinical outcomes (e.g., mortality), although the study was not powered to address these issues.¹⁶⁴ A follow-up study established that the beneficial effect on oxygenation was due to the albumin, not the furosemide.¹⁶⁵ Although a large clinical trial of patients admitted to the intensive care unit has concluded that albumin was as safe as crystalloid,¹⁶⁶ the study did not specifically enroll patients with ARDS and only looked at short-term outcomes. It is also important to remember that as a blood product, the administration of albumin is associated with a very small but finite risk of transmissible diseases. Thus, pending further trials, the role of albumin in the management of patients with ARDS is unclear.

Nutrition

It has been hypothesized that manipulations in diet could enhance the immune system and improve the outcome of inflammatory diseases such as sepsis and ARDS. Such strategies have involved supplementing enteral feeds with one or more of arginine, glutamine, omega-3 fatty acids, and antioxidants.

One small randomized study examined the effect of a modified enteral feed containing eicosapentaenoic acid, gamma-linolenic acid, and various antioxidants compared to a control enteral feed in patients with ARDS.¹⁶⁷ The authors found that the modified feed improved oxygenation, reduced the number of neutrophils in alveolar lavage fluid, decreased length of stay, and decreased the requirement for mechanical ventilation. In a more recent study, modified enteral feeds (containing eicosapentaenoic acid, gamma-linolenic acid, and various antioxidants) also improved oxygenation, although clinically important outcomes were unchanged.¹⁶⁸ Many other studies of modified enteral feeds (often called immunonutrition) have been conducted in less well-defined populations of critically ill patients, with conflicting results. A meta-analysis on the topic highlighted the heterogeneity of the studies and suggested that the effect of immunonutrition varied depending on the group of patients being studied.¹⁶⁹ At this point, the role of immunonutrition in the management of ARDS remains unclear.

A related issue in this area has been how much enteral nutrition should be given. In a recent randomized controlled trial, the rate of enteral feeding (e.g., at a regular rate versus a low, so-called trophic rate that delivered one third as many calories) did not affect the outcome of ALI.¹⁷⁰

Pharmacotherapy

Attempts to develop pharmacologic therapies for ARDS have been frustrating and largely unsuccessful, with no pharmacotherapies that unequivocally reduce mortality from ARDS, despite a multitude of randomized controlled trials of dozens of potential agents.¹⁷¹ Despite the heterogeneity of the agents that have been evaluated, three generalizations can be made:

The following section reviews the biologic rationale for various potential therapies for ARDS, with an emphasis on evidence from clinical trials when available.

Novel Therapies.

As discussed earlier in the section on Pathogenesis, alveolar fluid clearance can be augmented by catecholamines. A small trial randomized 40 patients with ARDS to intravenous salbutamol or placebo for 7 days.²⁰¹ Patients receiving salbutamol had a decrease in extravascular lung water but a higher incidence of arrhythmias. A follow-up study was performed in almost 50 intensive care units in the United Kingdom and enrolled more than 300 patients with ARDS. However, the trial was halted earlier than planned because of an increase in mortality in the group receiving intravenous salbutamol.⁹⁸ A similar-sized trial of aerosolized albuterol (given every 4 hours for up to 10 days) for ARDS found no benefit.²⁰² Thus, routine use of β₂-agonists cannot be recommended in ARDS.

Stem cell therapy for ARDS is being explored.²⁰³ Beneficial effects have been noted in animals with endotracheal and intravenous delivery of stem cells²⁰⁴ and may be augmented by using stem cells transfected with ANGPT1.²⁰⁵ A schematic of novel potential therapeutic approaches is shown in Figure 100-7.

Neuromuscular Blockade

Mechanical ventilation of patients with ARDS is often complicated by patient-ventilator dyssynchrony, which can worsen oxygenation and ventilation. To overcome this, clinicians have traditionally sedated patients and even paralyzed them using neuromuscular blocking agents. Many clinicians have since become reluctant to use neuromuscular blocking agents because of concerns of inducing myopathy and prolonging the duration of mechanical ventilation. However, a multicenter randomized controlled trial of more than 300 patients with early (<48 hours) and severe ARDS compared a 48-hour infusion of cisatracurium to placebo.²¹³ Both groups received lung-protective ventilation based on the ARDSNet trial, discussed earlier. The authors reported a significant reduction in 90-day mortality (the primary end point) as well as a number of secondary end points, including barotrauma and organ failure. There was no increase in intensive care unit–acquired weakness. The mechanism of benefit from neuromuscular blocking agents is unknown, but may involve decreased ventilator-induced lung injury.²¹⁴ These provocative data, while promising, await replication before being widely adopted.

The Role of PEEP and Recruitment Maneuvers

As mentioned earlier, the first description of ARDS commented on the apparent utility of PEEP in improving oxygenation. From a theoretical standpoint, PEEP may be beneficial in avoiding damage from cyclic opening and closing of terminal lung units (atelectrauma, see Pathogenesis), and in allowing for a reduction in tidal volume (and hence volutrauma). In addition, PEEP, by improving oxygenation, may allow for lowering of the Fio₂, thereby decreasing the risk for oxygen toxicity. On the other hand, PEEP that is too high can itself cause excessive end-inspiratory lung volume and volutrauma. Many clinicians are also familiar with the potential effect of PEEP to depress cardiac output and blood pressure. The optimal level of PEEP to use in patients with ARDS has therefore been a source of controversy.^215-217

Along the same lines, the low tidal volumes and pressures advocated for lung-protective ventilation can lead to progressive de-recruitment of the lung, which can worsen hypoxemia and potentially aggravate atelectrauma. To counteract de-recruitment, so-called recruitment maneuvers have been proposed. These maneuvers involve an increase in airway pressure for a certain duration, although the pressure to be applied and its duration have not been standardized. One example of a recruitment maneuver would be 40 cm H₂O of continuous positive airway pressure for 40 seconds. Similar to the problems with setting the level of PEEP, however, it is difficult to predict which patients might benefit from recruitment maneuvers and which might be harmed by overdistention. Overdistention of well-perfused lung units could result in diversion of blood to poorly perfused alveoli, with consequent worsening of right-to-left shunt and hypoxemia.²¹⁸

A number of randomized controlled trials have addressed the issue of PEEP and recruitment maneuvers in the management of ARDS.

The ARDS Network investigators randomized 549 patients with ARDS to lower or higher PEEP levels, according to preset combinations of PEEP and Fio₂. The patients in the lower PEEP arm received the PEEP/Fio₂ levels used in the original ARDSNet trial of lung-protective ventilation (see earlier). The precise level of PEEP used in the higher arm varied with the Fio₂, but was on average 5 cm H₂O higher than the control arm (mean of 13 to 15 cm H₂O over the first 7 days). Recruitment maneuvers were initially used in the higher PEEP group but were discontinued after the first 80 patients because they were not very effective.²¹⁹ The study was stopped early due to perceived futility and the mortality rate in both arms was about 25%, significantly lower than had been reported in other trials of ARDS.²²⁰

A second large trial randomized almost 1000 patients with ALI to what was described as an “open lung” strategy versus the ventilation protocol used in the original ARDSNet trial.²²¹ The “open lung” strategy consisted of pressure control ventilation with plateau pressure (P_plat) less than 40, recruitment maneuvers, and high PEEP, together with the low tidal volumes (6 mL/kg) used in the control group. On average, on day 1 of the study, PEEP in the open lung arm was 16 cm H₂O, compared with 10 cm H₂O in the control group. This trial also found no difference in the mortality rates between the two groups (about 40%), although the open lung group had improvements in secondary end points related to hypoxemia.

Finally, a large French trial randomized 767 patients with ALI to PEEP of 5 to 9 cm H₂O or PEEP maximized as long as P_plat was less than 28 to30.²²² On day 1 of the study, the mean applied PEEP level in the control arm was about 7 cm H₂O, or marginally lower than that of patients in the original ARDSNet trial of lung-protective ventilation, while the higher PEEP arm had an average applied PEEP of 15 cm H₂O. The study demonstrated no difference in mortality, but the higher PEEP arm had improved compliance, oxygenation, and a decreased duration of mechanical ventilation and organ failure.²²²

Taken together, the data from these trials suggest that higher PEEP levels than used in the original ARDSNet trial are safe and may improve oxygenation, but there are insufficient data to argue that higher PEEP improves survival. Why these clinical studies are generally negative despite very strong animal data demonstrating the benefits of higher PEEP levels is somewhat of a puzzle. One possibility is the yin-yang of PEEP. To the extent that PEEP recruits lung units, it may be beneficial; to the extent that it leads to greater overdistention of lung units, it may be harmful. In all studies to date, PEEP has been applied to all patients whether or not their lungs are recruitable. As such, one reasonable approach to be tested in future studies of PEEP is to randomize only patients to a high/low PEEP strategy if they have lungs that are potentially recruitable.^217,223 Indeed, a meta-analysis that included these trials found that while higher PEEP was associated with a lower mortality in patients with arterial Po₂/Fio₂ < 200 mm Hg (i.e., ARDS), there was less benefit and a trend to harm in patients with a higher arterial Po₂/Fio₂ and hence less severe lung injury.²²⁴

The data also suggest that the role of recruitment maneuvers in the management of ARDS is only supportive, and the data currently available do not demonstrate improvement in clinically important outcomes. The major putative benefit of recruitment maneuvers is to decrease ventilator-induced lung injury. Many studies report a variable and transient improvement in oxygenation after some form of recruitment,²¹⁹ which can be better maintained with a higher level of PEEP after recruitment. It is also possible that the same degree of recruitment could be achieved by simply raising the level of PEEP.^225,226 Although recruitment maneuvers are generally safe, the patient must be closely monitored for any adverse effects on hemodynamics or oxygenation.

Permissive Hypercapnia and Tracheal Gas Insufflation

The use of lower tidal volumes (to avoid VILI) often results in respiratory acidemia, an effect that has been termed permissive hypercapnia. The theoretical detrimental effects of hypercapnia include myocardial depression, increased pulmonary vascular resistance, and decreased renal blood flow. Hypercapnia may have an injurious effect on alveolar epithelial cells.²²⁷ Perhaps the most clinically important adverse effect of hypercapnia is elevated intracranial pressure from increased cerebral blood flow. However, data also suggest that hypercapnia has protective effects, including attenuation of free radical–mediated lung injury and pulmonary inflammation.^228,229

Given the uncertainty about permissive hypercapnia, it is worth remembering that the only large randomized controlled trial to show a reduction in mortality in ARDS treated respiratory acidosis fairly aggressively (discussed earlier).¹⁰⁹ In the absence of other data, following the protocol used in that study seems prudent.

One approach that has been used to decrease high levels of arterial Pco₂ is tracheal gas insufflation, a technique whereby a gas flow is introduced via a small catheter placed in the endotracheal tube, with its tip near the carina. Tracheal gas insufflation has been proposed as an adjunct to permissive hypercapnia, because the insufflated gas improves CO₂ clearance from the anatomic dead space and ventilator tubing. However, the gas flow has the potential to increase alveolar volume and pressure, and may increase PEEP.²³⁰ Although there are many case reports describing the use of tracheal gas insufflation,²³¹ there have been no randomized studies in ARDS. Because of technical and monitoring issues, we do not recommend its routine use of tracheal gas insufflation in ARDS.

Mechanical Ventilation of Patients in the Prone Position (Proning)

Placing patients with ARDS in the prone position (proning) was described almost 30 years ago as a means of improving oxygenation. The mechanisms by which the prone position improves oxygenation are multiple, but probably the most important factor is the effect that proning has on chest wall and lung compliance.²³² In the supine position, the most dorsal and caudal regions of lung (along the spine and diaphragm) are the worst affected in many patients with ARDS. Some of this is due to gravity, but the weight of the heart and of the abdominal organs on the lungs also contributes. When a patient is placed in the prone position, the anterior chest wall is fixed (by the bed) and becomes less compliant, thus increasing the proportion of ventilation directed to the dorsal lung. In addition, the volume of lung that is being compressed by the heart due to gravity is substantially decreased. The net result is more homogenous ventilation of the lung and presumably improved matching. Data from a study in dogs suggest that ventilation in the prone position can attenuate the severity of VILI.²³³

A number of multicenter randomized controlled trials have now examined the efficacy of proning in patients with ARDS. One study enrolled more than 300 patients with ALI and randomized them to conventional treatment (supine) or treatment in the prone position for 6 or more hours for 10 days. The study found that oxygenation improved in approximately 70% of proning procedures and that most of the improvement was evident within 1 hour of proning. However, although oxygenation improved significantly in prone patients, there was no difference in mortality between the groups. Retrospective analyses of the quartile of patients with the poorest oxygenation or the highest acuity of illness (or the highest tidal volume) showed a lower mortality rate at 10 days in the patients who were prone, but this difference did not persist beyond discharge from the intensive care unit.²³⁴ The study has been criticized for the relative short duration of the intervention, as well as the fact that most patients spent the majority of the day supine.²³⁵

A subsequent study randomized more than 700 patients with acute hypoxemic respiratory failure (which included but was not limited to patients with ARDS) to ventilation in the prone or supine position; patients were prone an average of 50 hours after intubation for a median of 8 hours per day, for a median of 4 days.²³⁶ Prone patients exhibited improved oxygenation but no improvement in mortality or duration of ventilation. These patients also suffered from a higher incidence of complications, including pressure sores, selective intubation, and endotracheal tube obstruction.

A pediatric study (median age 2 years) of proning in ARDS was similarly negative,²³⁷ and two Spanish trials of proning for adults with ARDS were inconclusive but suggestive of benefit.^238,239

In 2013, a multicenter randomized trial of prolonged (>16 hours) proning was reported in more than 400 patients with early (<36 hours) and severe ARDS.²⁴⁰ ARDS was defined according to the AECC criteria, with severe ARDS denoting arterial Po₂/Fio₂ < 150 mm Hg with Fio₂ ≥ 0.6, PEEP ≥ 5 cm H₂O and tidal volume of about 6 mL/kg predicted body weight. Patients were proned within the first hour after randomization and kept prone for at least 16 consecutive hours; proning was performed every day up to day 28. Remarkably, the 28-day survival rate was 16% in the prone group and 33% in the supine group.

These results are very impressive and are likely to increase the adoption of proning by intensivists. While proning in that trial was not associated with any complications, it is important to note that it was conducted in centers with significant expertise in prone-position ventilation, which requires some attention to detail, and that it did not involve use of a rotating bed. Lines and tubes are vulnerable to dislodgement during the process, and sufficient staff should be on hand to assist with the move. Personnel should be ready and capable of immediate reintubation in case the endotracheal tube is displaced. Prone patients are more susceptible to development of pressure sores, and exquisite care must be taken to ensure that no stray objects (e.g., syringes, electrocardiogram leads) are left under the patient, because these leave impressions and even scars on the body. An unstable spinal injury is an absolute contraindication to proning. In addition, if cardiopulmonary resuscitation is required, the patient must be returned to the supine position emergently. Finally, in the most recent trial, there were a number of exclusion criteria, including elevated intracranial pressure, massive hemoptysis, recent tracheal or facial surgery, and low mean arterial pressure (<65 mm Hg).²⁴⁰

Volume-Control Versus Pressure-Control Ventilation

The volume and pressure-limited protocol used in the ARDS Network study employed volume-assist control as the mode of ventilation. The Lung Open Ventilation study (described earlier) demonstrated that pressure-control ventilation could be used with equivalent outcomes.²²¹ Other studies that have examined this issue have also found little difference in physiologic parameters or outcome between the two modes of ventilation.^241,242

High-Frequency Jet Ventilation and High-Frequency Oscillation

In high-frequency jet ventilation, a small gauge catheter is used to introduce gas under high pressure into the endotracheal tube. The high velocity of the gas entrains additional oxygen and humidified air from side ports in the system. This form of mechanical ventilation achieves a tidal volume of 2 to 5 mL/kg and involves frequencies of 100 to 200 breaths per minute.²⁴³ Exhalation is passive, requiring recoil of the lungs and chest wall. There is little evidence that high-frequency jet ventilation is superior to conventional mechanical ventilation for ARDS. An early randomized trial of over 300 oncology patients with ARDS compared conventional ventilation (using volume-cycled ventilation) with high-frequency jet ventilation. Because the end points of the study differed between the two groups of patients, it is difficult to interpret the data. Nonetheless, the authors found no significant difference in any clinically important outcome.²⁴⁴

In high-frequency oscillatory ventilation (HFO), lung recruitment is maintained using a constant mean airway pressure generated by an inspiratory bias flow and limitation of gas outflow from the circuit. Ventilation is achieved through rapid (e.g., 5 Hz) regular oscillations of a piston or diaphragm. The push and pull action of the piston causes oscillations in pressure in the endotracheal tube and proximal airways, creating peak and trough pressures around the set mean airway pressure. The tidal volumes achieved through HFO are small, on the order of 1 to 5 mL/kg. In theory, HFO seems ideally suited for avoiding VILI. Atelectrauma is minimized because of the relatively high mean airway pressure, which along with small tidal volumes limits derecruitment of the lung, and volutrauma is minimized because the small tidal volumes limit end-inspiratory stretch.²⁴⁵ With HFO, loss of pressure from the circuit can lead to de-recruitment, thus recruitment maneuvers (e.g., application of continuous positive airway pressure for approximately 30 to 40 seconds) should be applied after each patient disconnect from the ventilator (e.g., open suctioning).

In an early randomized trial of HFO in adults, 148 patients with ARDS were randomized to conventional ventilation using pressure-control mode or to HFO.²⁴⁶ The specific ventilatory parameters for both the conventional group and the HFO group were adjusted to achieve adequate oxygenation at a minimum Fio₂ (i.e., 88% at Fio₂ ≤ 0.60), as well as an arterial pH greater than 7.15. Because the study was begun before the publication of the ARDS Network trial on tidal volume limitation, the conventional ventilation arm of this study targeted tidal volumes of 6 to 10 mL/kg. The trial was not powered to detect a mortality difference, and there was no significant difference in 30- or 90-day mortality, or in any other outcome. The authors performed a retrospective analysis of predictors of mortality, and discovered that being on conventional ventilation for more than 5 days correlated with a poor outcome.

More recently, two large randomized trials of HFO were published and showed no benefit in terms of survival or the duration of mechanical ventilation^247,248 compared with conventional lung-protective ventilation. Indeed, one of the studies suggested that HFO might be harmful due to the amount of sedation required or due to impairment of hemodynamics. Because of these findings, the routine use of HFO for ARDS cannot be recommended, although its role as “rescue” therapy is not clear.

Liquid Ventilation

Liquid ventilation relies on the oxygen and carbon dioxide carrying capacity of organic liquids such as perfluorocarbons. Perfluorocarbons are modified hydrocarbons in which hydrogen atoms are replaced with fluorine, generating inert liquids that are nontoxic and minimally absorbed through the respiratory epithelium. The most widely studied perfluorocarbon, perflubron (perfluorooctyl bromide, eFig. 100-2), can dissolve about 17 times more O₂ than saline solution and almost 4 times more CO₂.²⁴⁹ Total liquid ventilation is a technique in which the lungs are completely filled with liquid and an extracorporeal exchanger is used to add O₂ and remove CO₂ from the liquid. Partial liquid ventilation, which is much easier to use clinically, involves partially filling the lung with liquid and then using a traditional ventilator to deliver gas tidal volumes.²⁵⁰

The theoretical benefits of liquid ventilation stem largely from improved lung recruitment, due to the lower surface tension of the perfluorocarbons and because the liquid tends to distribute to the dependent regions of the lung. Deposition of liquid with low surface tension in these areas may enhance alveolar recruitment; in addition, the weight of the liquid is thought to cause diversion of pulmonary blood flow to the nondependent (better ventilated) areas, improving matching. Clearance of secretions (due to their displacement by the liquid) is also improved. Anti-inflammatory effects of perflubron have been described, although the clinical relevance of these effects is not well understood. To date, two randomized controlled trials of partial liquid ventilation in adults with ARDS have been published.²⁵¹ The first enrolled 90 patients with ARDS to partial liquid ventilation with perflubron or to conventional mechanical ventilation. Other than very general guidelines (e.g., target arterial So₂ > 90%), neither of the two ventilation strategies was protocolized. In addition, the inclusion and exclusion criteria were modified slightly during the course of the study. There was no significant difference in the number of ventilator-free days (the primary outcome measure) or in any other predefined outcome. More patients in the liquid ventilation arm experienced hypoxia, bradycardia, and respiratory acidosis, although the increase in the incidence of these adverse events was not statistically significant.

In 2006 a multicenter randomized trial of partial liquid ventilation with perfluorocarbon compared with conventional mechanical ventilation (Vt 10 mL/kg) enrolled more than 300 patients with ARDS. The study found a trend toward higher mortality in the groups receiving perfluorocarbon in addition to a higher incidence of barotrauma, hypoxia, and hypotension.²⁵² Based on these data, partial liquid ventilation cannot be recommended for patients with ARDS.

Extracorporeal Membrane Oxygenation (see Chapter 103)

Extracorporeal membrane oxygenation (ECMO), also referred to as extracorporeal life support or extracorporeal lung assist, refers to the process by which the patient's blood is circulated to an external machine that provides oxygenation and/or carbon dioxide removal.²⁵³ In theory, ECMO could be used to oxygenate patients with ARDS while minimizing VILI and oxygen toxicity and allowing the lungs time to heal. There are multiple case reports of ECMO being used in ARDS, and it is used routinely in neonates with severe respiratory failure. A randomized controlled trial of ECMO in ARDS was completed almost 30 years ago and did not show any benefit.²⁵⁴ It is worth pointing out that the mortality rate in that study was approximately 90% in both the ECMO and the control arm. Subsequently, a variant of ECMO dedicated to carbon dioxide removal (extracorporeal CO₂ removal, or ECco₂R) was developed and showed promise in a case series when compared with a historical control group.²⁵⁵ This was followed by a randomized controlled trial using pressure-controlled inverse-ratio ventilation (IRV) and ECco₂R in ARDS that failed to find any improvement in survival.²⁵⁶ This study illustrates the importance of using concurrent controls when assessing a novel therapy.

One of the complications of ECMO is bleeding; in an early randomized trial, patients randomized to the device were transfused an average of 1.7 L of blood per day. More recent data suggest that, because of many technological improvements, ECMO can be relatively safely performed by specialized centers. In 2009, a randomized controlled trial of conventional ventilation versus ECMO for acute respiratory failure was reported.²⁵⁷ The vast majority of patients in each arm had ARDS; referral to an ECMO center conferred a statistically significant survival benefit (relative risk of death at 6 months, 0.69; confidence interval, 0.05–0.97). However, patients in the conventional ventilation arm were cared for in multiple hospitals, did not have a standardized ventilation protocol, and experienced a mortality rate of 53%. In contrast, of the patients referred to the ECMO center, 75% actually received ECMO and a significantly higher percentage of patients in this group received lung-protective ventilation. Thus, it is unclear whether the improvement in survival was attributable to ECMO or to better care in a specialized hospital. A cohort study by the same authors examining ECMO for H1N1 influenza-induced ALI also suggested lower mortality from the treatment.²⁵⁸

There is also growing interest in using extracorporeal life support as an adjunctive therapy to maximize the benefit of lung-protective ventilation. Even at the recommended tidal volume of 6 mg/kg, the lungs of patients with ARDS may be damaged by overdistention and VILI. Thus, the promise of ECMO is that tidal volumes of less than 6 mL/kg predicted body weight can be used and the resultant respiratory acidosis can be managed by extracorporeal removal of CO₂.²⁵⁹ Because of ongoing technological improvements that have reduced the requirement for anticoagulation and the invasiveness of the devices,^260,261 this is likely to be a fertile area of research in coming years.

Summary

The modern approach to mechanical ventilation of patients with ARDS is based on two facts: first, that the diffuse lung injury of ARDS affects the lung heterogeneously; second, that mechanical ventilation itself can cause ALI. Thus, until new data emerge, the lung-protective ventilatory strategy adopted by the ARDS Network study¹⁰⁹ is the standard of care and is associated with both short-term and long-term improvement²⁶² in survival. Plateau pressure should be maintained at less than 30 cm H₂O, and tidal volume should be limited to 6 mL/kg predicted body weight as much as possible. The prone position should be seriously considered in patients with P/F less than approximately 150 mm Hg in centers with medical staff experienced in proning patients. Given the dangers inherent in this approach, proning must be performed with caution and following published protocols.

The optimal level of PEEP in ARDS remains unclear, although randomized trial data indicate that using higher PEEP levels than the original ARDS Network study is safe and may improve oxygenation. We favor high levels of PEEP in order to prevent atelectrauma, reduce Fio₂ and prevent hyperoxic lung injury in patients with greater hypoxemia (i.e., P/F < approximately 150 mm Hg), as long as the patient's hemodynamic status remains stable. We use the lowest possible Fio₂ that maintains oxygen saturation above 90%, and we empirically adopt a target Fio₂ of less than 0.6.

The use of neuromuscular blocking agents may also improve outcome by reducing ventilator-induced lung injury when used early in the clinical course of patients with relatively severe ARDS. Finally, despite the theoretical appeal of HFO ventilation, randomized controlled trials have shown that it does not improve survival over conventional lung-protective ventilation.