Chapter 9. Acute Respiratory Distress Syndrome (ARDS)

The acute respiratory distress syndrome (ARDS), first identified by Ashbaugh et al in 1967, described a constellation of findings in 12 patients who had experienced acute onset of tachypnea, hypoxemia, loss of lung compliance, cyanosis refractory to oxygen therapy, and diffuse alveolar infiltration on chest x-ray. Pathologic examination from seven of these patients found atelectasis, vascular congestion with hemorrhage, hyaline membranes, and pulmonary edema.1

Decades later, in an effort to better define the syndrome using specific and measurable criteria, Murray et al developed a lung injury scoring system. The components of the score quantified alveolar consolidation measured by chest x-ray, hypoxemia measured by Pao2/FiO2 ratios, levels of required positive end-expiratory pressure (PEEP), and pulmonary compliance.2

In 1994 the American–European Consensus Committee (AECC) on ARDS implemented new criteria, identifying two different levels of severity of lung injury. It allowed for those with less severe hypoxemia to be classified as having acute lung injury (ALI) and those with more severe hypoxemia to be defined as having ARDS.3

The AECC defined ALI as the acute onset of respiratory distress with Pao2/FiO2 <300 mm Hg, bilateral, patchy infiltrates on chest radiograph, and a pulmonary artery occlusion pressure (PAOP) <18 mm or absent clinical evidence of left atrial hypertension (indicating presumptive noncardiac etiology of pulmonary edema). ARDS was given similar diagnostic criteria, but with Pao2/FiO2 <200 mm Hg.

Achieving diagnostic accuracy using clinical definitions is imperative so as not to underdiagnose or overdiagnose the pathology and to assure that clinical trials are in fact targeting the correct disease process. However, the subjective nature of describing chest x-ray morphology, the limitations of PAOP to evaluate cardiac dysfunction, and the impact of mechanically delivered airway pressures on oxygenation are just a few of the limitations of the standard ARDS definitions.4

Pathologic examination is perhaps the gold standard for ALI/ARDS diagnosis with the key lesion identified being diffuse alveolar damage (DAD).5 While not typically performed to diagnose ARDS, one retrospective study concluded that open lung biopsy may be safely done for the diagnosis of ALI/ARDS and that in many cases (60% in their series) it produced alternative diagnoses such as pneumonia, pulmonary hemorrhage, and interstitial fibrosis, among others.6

Several studies have attempted to clarify the diagnostic accuracy of the arguably subjective clinical definitions. One such study by Ferguson et al compared the accuracy of the three different commonly used clinical definitions (Table 9-1) with autopsy results and with each other, in 138 subjects.7 They found that clinicians diagnosed ARDS in only 48% of autopsy-confirmed disease and their clinical diagnoses were 91% specific. Agreement between the Delphi and lung injury score definitions was good. Both showed significant disagreement with the AECC definition. The AECC definitions had the highest sensitivity (83%) and lowest specificity (51%), while the Delphi definition had the lowest sensitivity (69%) and highest specificity (82%). Lung injury scores had a 74% sensitivity and 77% specificity. These limited diagnostic accuracies which have been corroborated in several studies, have important implications for clinical practice, and may be problematic for subject recruitment into clinical trials.

ALI and ARDS describe a hypoxemic state caused by noncardiogenic pulmonary edema. The pathophysiology is complex, mediated by many cell types and cytokines, but ultimately culminates in diffuse damage to the alveolar capillary membrane (ACM). The ACM consists of the capillary endothelium and alveolar epithelium. The alveolar epithelium is made up of type 1 and type 2 alveolar epithelial cells. Type 1 epithelial cells are the most common and allow for gas exchange from the vascular endothelium. Type 2 cells play a role in the resorption of airspace fluid and surfactant production.8

In ALI/ARDS, the capillary endothelium is activated by cytokines. The cells swell and intercellular junctions widen that beget capillary leakage. Damaged type 1 cells impair gas exchange, and damaged type 2 alveolar epithelial cells impair fluid resorption and surfactant production. The resultant endothelial-capillary permeability leads to alveolar flooding with proteinaceous material.

Two phases are regularly described in ARDS. The acute or exudative phase is clinically characterized by rapid-onset respiratory failure and hypoxemia often refractory to supplemental oxygen. The chest x-ray during this phase typically reveals bilateral patchy infiltrates (Figure 9-1a) and computed tomography (CT) further elucidates increased density within the dependent lung zones (Figure 9-1b).9 Pathologic examination during this stage reveals DAD characterized by a disruption of the alveolar epithelium, capillary injury, microvascular thrombi, and the presence of inflammatory cells within the alveoli. The DAD results in replacement of pneumocytes with hyaline membranes and decreased surfactant production.10 These pathologic changes result in alveolar collapse and decreased lung compliance.

ALI and ARDS may completely resolve after this acute exudative phase. A subset of patients, however, progresses with persistent hypoxemia, increased alveolar dead space with continued ventilation/perfusion mismatch, and, ultimately, fibrosing alveolitis. This fibroproliferative phase occurs 5–7 days after the onset of ARDS and begins after resolution of the acute exudative phase.8 Progression to fibrosing alveolitis is also associated with a higher mortality rate.6 CT findings during this phase reveal reticular opacities, diffuse ground glass opacities, and bullae.9 Eventually, type 2 pneumocytes begin resorption of pulmonary edema and organize the hyaline membranes. They also repair the alveolar epithelium and differentiate into type 1 pneumocytes. With this repair comes interstitial pulmonary fibrosis with permanent disruption of the normal alveolar architecture.

A critical component contributing to increased pulmonary inflammation in ALI/ARDS is often iatrogenic. Ventilator-induced lung injury (VILI) is the term used to describe the microscopic and macroscopic pulmonary sequela of mechanical ventilation (MV).11 It has been long accepted that high fractions of inspired oxygen exacerbate lung injury. Additionally, it is now known that high tidal volumes (volutrauma) and pressures (barotrauma) significantly contribute to lung injury. Furthermore, the cyclic opening and closing of alveoli during tidal ventilation often translates to alveolar overdistension and complete collapse throughout the respiratory cycle. This creates shear forces on the alveoli that increase pro-inflammatory cytokines that worsens the capillary leak and alveolar edema described above. Research in this area has lead to lung-protective ventilatory strategies that seek to limit the injurious repetitive alveolar overdistension and collapse.

The incidence of ARDS was initially found to be approximately 150,000 cases per year in the United States.3 Studies now estimate the incidence at 13.5–58.7 per 105 person-years.5 ALI affects approximately 200,000 people in the United States and accounts for 10–15% of all ICU admissions.12

Risk factors for ALI and ARDS are numerous and are divided into two groups, direct (pulmonary) and indirect (extra-pulmonary), depending on their mode of injury to the lung. Examples of direct causes include aspiration, pneumonia, near drowning, toxic inhalation, lung contusion, and fat or amniotic emboli. Indirect causes or ARDS include sepsis, severe trauma, blood product transfusion, drug overdose, acute pancreatitis, cardiopulmonary bypass, and disseminated intravascular coagulation. The most common causes of ARDS include direct lung injury, sepsis, and multiple transfusions.13 Other potential predisposing conditions include renal transplant and alcoholism. One theory asserts that renal transplantation increases the risk for ARDS because immunosuppression increases the risk for pneumonia and sepsis; however, similar associations were not found for liver or pancreas transplant recipients.14 Similarly, alcoholism has been linked to increased ARDS susceptibility; however, this may be due to the fact that these patients are increasingly predisposed to trauma, sepsis, aspiration pneumonia, and transfusion from gastrointestinal bleeding. Lastly, studies suggest a possible genetic susceptibility to ARDS along with other demographic factors (age, sex, and race) further influencing the risk of developing the disease and the resultant mortality.9

Initially the mortality from ARDS was thought to be from respiratory failure. More recent studies report that respiratory failure is the cause in only 9–16% of ARDS deaths. The most common cause of death is multiple organ failure and sepsis.14 ARDS mortality was initially reported to be as high as 70% but has steadily decreased over time. Recent reports suggest that mortality has leveled off between 36% and 44% since 1994.15 Many factors are thought to increase mortality in patients with ARDS. These include old age, presence of nonpulmonary organ dysfunction, shock, hepatic failure, and blood transfusion. There does not appear to be a mortality difference between pulmonary and extrapulmonary causes of ARDS.8

Patients who survive ARDS do appear to regain pulmonary function within 12 months from ICU discharge, but with measurable functional disability. An evaluation of 109 ARDS survivors at 1 year found them to have mild restrictive lung disease on pulmonary function testing. None of these patients required the use of supplemental oxygen at 12 months and only 6% of patients had arterial oxygen saturations below 88% with exercise.16 Yet, at 1 year from ICU discharge, only 49% of patients had returned to work, and quality of life assessments were below average. Interestingly, the functional limitations experienced were largely a consequence of persistent neuromuscular weakness and muscle wasting and to a lesser extent their persistent pulmonary dysfunction.

As the etiologies and contributing factors to the development of ARDS are diverse, so too are the approaches to both the supportive care and directed treatment of the lung-injured patient. The following section reviews treatment strategies supported by varying levels of evidence. Some strategies such as protective ventilatory strategies are supported by class 1 evidence, while others such as prone position ventilation or steroid therapy are still hotly debated. Because of the heterogeneous nature of critically ill patients as well as the heterogeneity of lung injury itself, the limitations of outcome studies using mortality endpoints must be recognized. Even the most well-done studies of ventilatory and pharmacologic strategies are impacted by many variables including patient selection, etiology of lung injury, timing of therapy, and concomitant treatments, to name a few. Thus, it is important to recognize strategies that are not supported by class 1 evidence, but may play a key role in ARDS treatment if considered within the context of the individualized care of the lung-injured patient.

The importance of the many aspects of general supportive critical care in the treatment of the ARDS patient cannot be overstated. For example, a fluid-restrictive strategy (discussed later) that has been shown to improve ARDS outcome would be futile and likely harmful if this diverted attention from a targeted resuscitation to minimize the patient's degree of shock. The benefits of proven ventilatory strategies will be unrealized if appropriate treatment of infections are not delivered, and even best practices regarding MV will not limit ventilator days without judicious use of sedatives, blood product transfusions, and nutritional supplementation.

Supportive care starts with treatment of the predisposing disease process. Advances in the care of these pulmonary and extrapulmonary conditions are responsible for the decreasing ARDS mortality over the years.17 Best care practices for sepsis, trauma, and other predisposing conditions must be followed if ARDS outcomes are to be optimized. ALI/ARDS is rarely an isolated organ system failure in ICU patients and mortality is more often associated with the accompanying multiorgan dysfunction syndrome.18 Thus, it is unlikely that any lung-directed treatment on its own will impact outcome without care directed to the cardiovascular, renal, and central nervous systems, as well.

The optimization of hemodynamics and intravascular volume in the setting of ALI/ARDS is a most challenging task. Since patient survival is tied to extrapulmonary organ function, the overriding goal is to reverse any shock state and optimize organ perfusion while minimizing volume overload. Underresuscitation potentiates ongoing hypoperfusion that contributes to the inflammatory cascade and worsening lung injury. Conversely, once resuscitated, a fluid-restrictive strategy has been shown to improve pulmonary function in patients with ALI/ARDS.19,20 The ARDS Clinical Trials Network performed a prospective randomized trial of a fluid-restrictive strategy versus a liberal fluid strategy in ventilated patients with ALI. They found that targeting lower filling pressures (central venous pressure [CVP] and PAOP) and tolerating lower urine outputs in the study group significantly lowered the amount of fluids administered and in turn improved oxygenation indices and lung injury scores and minimized ventilator and ICU days as compared with control subjects.19 In this study, the fluid-restricted patients did not suffer any increased incidence of cardiovascular or renal dysfunction, although they did not realize any mortality benefit either. Similar conclusions were reached in a separate post hoc analysis of the surgical patient cohort from the larger trial.20 Hence, the paradigm of care is to first assure that patients are resuscitated to the point of optimal organ perfusion and reversal of any shock state, but to not overresuscitate them, as restricting further fluids and decreasing the overall hydrostatic pressure will lead to net negative fluid balances and improved pulmonary outcomes.

Another ALI treatment strategy with similar goals—using albumin repletion to increase colloid osmotic pressure in hypoproteinemic patients combined with furosemide diuresis to decrease hydrostatic pressure—has shown promise.21,22 Martin et al evaluated this furosemide plus albumin regimen in a randomized, placebo-controlled trial and found improved oxygenation while reducing hypotension and shock, as compared with furosemide monotherapy.22 While the exact mechanisms require further elucidation, the authors contend that the addition of albumin to a diuretic strategy stabilizes hemodynamics—presumably through the maintenance of effective circulating blood volume—while promoting egress of pulmonary edema fluid from the alveolar space.

Of course, even if one subscribes to a particular endpoint of fluid therapy (dryer vs. wetter), targeting that endpoint of intravascular fluid repletion is no easy task. Since the general parameters of intravascular volume status such as urine output, heart rate, and blood pressure do not accurately predict volume responsiveness, clinicians have advocated for other hemodynamic monitoring tools to better titrate fluid therapy. The use of pulmonary artery catheters (PAC), for example, is the source of continuous debate, and their efficacy in guiding treatment in the ALI patient has recently been evaluated. The recent ARDS network trial of 1,000 ALI patients concluded that PAC-guided therapy did not improve survival or organ function, but was associated with more complications than central venous catheter (CVC)–guided therapy.19 Others further argue that both the PAOP and the CVP are confounded by too many variables for these static filling pressures to be useful guides of volume therapy and that functional hemodynamic parameters are more accurate and preferable. A growing body of literature supports the use, during MV, of dynamic arterial waveform-derived parameters—such as stroke volume variation (SVV) or pulse pressure variation (PPV)—to more accurately predict volume responsiveness in the critically ill.23 These techniques, however, are limited to patients receiving controlled ventilation and not breathing spontaneously. Another limitation may be that tidal volumes (Vt) of 8–10 cm3/kg are required to identify the cyclic variations in stroke volume indicative of fluid responsiveness. This would be problematic in ARDS patients who benefit from low Vt ventilation. Recently, however, PPV was found to accurately predict fluid responsiveness in ARDS patients ventilated with low Vt and high PEEP, albeit in a small study.24 Further evaluation of these functional hemodynamic parameters in ALI/ARDS patients is needed. These tools may help the clinician judiciously provide volume expansion to only those who stand to increase their cardiac output without worsening pulmonary function.

The goals of nutritional support for the lung-injured patient are to meet the patient's caloric requirements and resting energy expenditure and replete deficiencies of various nutrients, while minimizing overfeeding and other complications associated with the way nutrition is delivered. Enteral feeding is preferable to parenteral nutrition as it has a beneficial impact on gastrointestinal immune function and reducing infectious complications.25 In addition to meeting the patient's metabolic needs, certain nutrients may actually modulate the inflammatory response in lung-injured patients that may have beneficial effects on pulmonary alveolar–capillary permeability, and hence lung and other organ function. The most promising dietary additives studied include fish oils rich in omega-3 polyunsaturated fatty acids (PUFA). The anti-inflammatory properties of such supplements are well studied in in-vitro and animal models. Several prospective, randomized controlled trials reported that patients receiving nutritional formulas rich in fish oil PUFAs had improved oxygenation, fewer ventilator and ICU days, and fewer nonpulmonary organ failures.26–28 A meta-analysis of the pooled data from these trials confirmed the positive outcomes correlation with use of fish oil–based formulas.29 Lastly, another meta-analysis evaluating immune-modulating diets in more heterogeneous ICU patients supported the beneficial effects of fish oil–derived omega-3 PUFAs, but only in patients with septic shock and ARDS.30 This analysis found these formulas to be of no clinical benefit to general ICU, burn, or trauma patients and further suggested that the failure of some previous studies to show a benefit from fish oil derivatives is likely due to excessive arginine supplementation. These omega-3 PUFA-enriched formulas are currently recommended for ARDS patients by the American Society of Parenteral and Enteral Nutrition (ASPEN) as well as the Society for Critical Care Medicine (SCCM).

A variety of pharmacologic agents have been investigated in ARDS including surfactant replacement, ketoconazole, nitric oxide, lisofylline, N-acetylcysteine, glucocorticoids, and β-agonist therapy. None of these therapies have emerged as accepted treatments for lung injury, but some show more promise than others. Much controversy surrounds the most studied drugs in ARDS: glucocorticoids.

Proponents assert that steroids hasten the resolution of the fibroproliferative stage of ARDS. There are many small studies using variable steroid regimens differing in therapy timing, dosage, formulation, treatment duration, and tapering regimens. A recent ARDSNet study did not support the use of methylprednisolone therapy in ARDS and cautions that steroid therapy started more than 2 weeks after ARDS onset may increase mortality.31 Conversely, the most recent meta-analysis concluded that low-dose corticosteroids were associated with improved mortality and morbidity outcomes and are an effective treatment for ARDS.32 However, they note that a well-powered randomized trial is still needed to clarify the aforementioned variables in steroid protocols.

β-Agonists in ARDS are an intriguing potential therapy that target the alveolar–capillary barrier. In vitro and animal data identified that catecholamines upregulate aquaporin channels on alveolar cells and increase alveolar water clearance. A randomized clinical trial of intravenous salbutamol for ARDS concluded that β-agonist therapy decreased extravascular lung water and improved plateau pressures.33 Further research may clarify the efficacy of β-agonist treatment in lung injury.

Strategies of mechanical ventilatory support are central to the care of the ALI/ARDS patient. The overriding goals of MV are to maintain sufficient oxygenation and ventilation and decrease the patient's work of breathing while mitigating further VILI. This last goal is paramount to understanding why the strategy of lung-protective/low Vt ventilation improved mortality in the landmark ARDSNet study known as the Respiratory Management in ALI/ARDS trial (ARMA).19 It is equally important to understand that there are many other ways to provide lung protection. While not yet supported by large randomized controlled trials like those performed by the ARDSNet investigators, some alternative strategies that will be discussed have face validity when considering the underlying pathophysiology of the disease, as well as support from prospective evaluation. In addition to the strategy touted by the ARDS Network, there are also merits of prone position ventilation and “open lung” strategies using airway pressure release ventilation (APRV) or high-frequency oscillatory ventilation (HFOV). Additionally, independent of the mode of delivering ventilatory support are the challenges of how to best target the optimal distending airway pressure as well as how to address the permissive hypercapnia that accompanies strategies of lung protection.

Understanding the importance of limiting alveolar stretch and barotrauma, the ARMA trial randomized 861 patients to either conventional Vt of 12 mL/kg or low Vt of 4–6 mL/kg of predicted ideal body weight. The low Vt group had their tidal volumes adjusted (between 4 and 6 mL/kg) to maintain plateau pressures ≤30 cm H2O. The lower Vt strategy resulted in a 9% absolute mortality reduction (from 39.8% to 31.0%) and reduced ventilator-dependent days.19 The low Vt group also had lower plasma IL-6 levels, suggesting less lung inflammation that may have contributed to the lower rate of nonpulmonary organ dysfunction. Both arms of this trial used the assist control (AC) mode of ventilation and a predetermined PEEP strategy based on the patient's required FiO2. The low Vt group required higher PEEP levels to maintain oxygenation, and some argue this contributed to the protection against cyclic alveolar opening and closing, a key component of VILI. The PEEP and FiO2 strategy used by the ARDSNet investigators in ARMA remains unvalidated and is the source of continued controversy and investigation in lung injury. Studies supporting higher versus lower PEEP strategies are conflicting.34,35 Likewise, while many clinicians have adopted the entire ARDSNet strategy from this landmark study, the AC mode of delivery has also not been proven to be the optimal ventilator mode.

Some level of PEEP is required to prevent low-volume lung injury and alveolar collapse during exhalation. Too much may lead to lung overinflation, barotrauma, and hemodynamic compromise. The challenge is to target the level of PEEP that keeps the patient breathing between the lower and upper inflection points of the pressure volume (P–V) curve (Figure 9-2). This is particularly difficult given the heterogeneous pattern of aeration and alveolar collapse in the ARDS patient so that different lung units have different P–V curves. Several techniques or guides to find the “best PEEP” exist including trending measures of pulmonary compliance along with oxygen delivery indices as one manipulates the PEEP,36 using esophageal pressure measurements to estimate transpulmonary pressures to optimize PEEP,37 CT lung morphology assessment to guide PEEP levels,38 or using the continuous flow method to measure bedside P–V relationships.39

Optimizing the PEEP during lung-protective ventilation is one challenge. Another important element is the hypercapnia resulting from a low Vt strategy. The discussed ARMA trial used increased respiratory rates and bicarbonate infusions to limit the hypercarbia and resultant acidosis. Both of these strategies are potentially problematic as high ventilatory rates may exacerbate auto-PEEP and overdistension, while bicarbonate infusions arguably increase the resultant CO2 load and may worsen intracellular acidosis. Interestingly, a growing body of literature supports that hypercapnia and moderate acidosis are not only well tolerated but may also be protective against lung and extrapulmonary organ dysfunction independent of the particular ventilator strategy. However, at this time, there are insufficient data to suggest that hypercapnia should be independently induced outside of the context of a protective ventilatory strategy.40

In ARDS patients in the supine position, alveolar aeration is greater in the anterior/nondependent lung regions. Without PEEP, the ratio of ventilated nondependent to dependent lung zones approximates 2.5:1. At higher levels of PEEP, the distribution of ventilation becomes more homogenous but at the expense of overdistending and reducing the compliance of the nondependent (anterior) lung zones.41 Ventilating a patient in the prone position may homogenize alveolar inflation and the distribution of ventilation. This is just one mechanism responsible for the favorable effects of prone position ventilation. In addition to reducing the physiologic dead space and the resulting ventilation–perfusion mismatch, the prone position has been shown to consistently improve oxygenation in many retrospective and prospective studies.42–45 Other benefits include reducing right ventricular pressures in ARDS patients with cor pulmonale,46 facilitating drainage of secretions, and improving respiratory mechanics. Yet despite significant improvements in gas exchange shown across most studies, mortality benefits have not been seen in larger evaluations.47

Various subgroup analyses, however, have revealed mortality benefits in specific patient subgroups that depend on intervention timing, the particular CT lung morphology, and/or the etiology of the lung injury. Still other trials have reported the prone position to be synergistic with other ventilatory strategies (APRV or HFOV). Many experts have accordingly called for future prospective evaluation to clarify which patients may benefit from prone positioning as well as the optimal timing, frequency, duration of the intervention, and concomitant ventilator management.

Since ongoing VILI or atelectrauma results from cyclic opening and closing of lung units, ventilatory modes designed to keep the lung opened more continuously have received considerable attention. Ventilator modes such as HFOV and APRV are two modalities that achieve “open lung ventilation” via different mechanisms.

HFOV delivers very small tidal volumes at frequencies ranging from 3 to 15 Hz that limits alveolar distension, while maintaining a continuous distending pressure throughout inspiration and expiration, preventing alveolar collapse. Thus, HFOV proponents assert that this modality achieves the goals of a lung-protective strategy while improving continuous alveolar recruitment.48 One shortcoming is that patients generally require deep sedation and neuromuscular blockade to tolerate HFOV. There are many studies evaluating HFOV in adults with ARDS, none of which reported mortality benefits. However, many of them have shown improved physiologic endpoints such as oxygenation indices and decreased ventilator days. Similar to limitations in the trials of prone position ventilation, many of the HFOV trials used this modality as a rescue therapy once conventional ventilation had failed. Proponents argue that such delays limit the efficacy of the therapy.

Another modality that can be tailored to accomplish the goals of lung protection along with the benefit of continuous alveolar recruitment is APRV. APRV essentially provides continuous positive airway pressure (CPAP) with very brief (typically <1 second) releases of this pressure to augment CO2 clearance. Maintaining CPAP above the alveolar closing pressure provides near-continuous alveolar recruitment. This improves oxygenation as well as ventilation via improved alveolar ventilation/passive gas exchange versus depending on tidal ventilation using conventional modes. Another advantage unique to APRV is maintenance of patients' spontaneous breathing. Allowing for spontaneous respiration improves the ventilation and perfusion distributions to a more physiologic pattern.49 Maintenance of spontaneous breathing also improves the overall hemodynamic profile, cardiac performance, and blood flow to end organs. Lastly, patients spontaneously breathing on APRV have been consistently shown to have lower sedative and paralytic requirements.50 But here again, the existing clinical trials have not demonstrated mortality reduction and the current successes are limited to physiologic endpoints.

In summary, the relative success of any new ventilatory strategy depends on the control ventilatory strategy with which it is compared. Larger trials in the future should test these alternatives to the well-accepted ARDSNet protocol. Nevertheless, the improved physiologic endpoints seen with these modalities, combined with sound understanding of physiology, make these alternatives viable and perhaps preferable to the conventional dogma of controlled ventilation in the supine position.