Critical Care Medicine

Acute Respiratory Distress Syndrome; Acute Hypoxemic Respiratory Failure, Non-Cardiogenic Pulmonary Edema, High-Permeability Pulmonary Edema

Acute Respiratory Distress Syndrome (ARDS)

Synonyms

Acute Hypoxemic Respiratory Failure, Non-Cardiogenic Pulmonary Edema, High-Permeability Pulmonary Edema

Related Conditions

Sepsis, Trauma, Multiorgan Failure, Acute Respiratory Failure, Ventilator-Associated Lung Injury, Pulmonary Edema

1. Description of the problem

What every clinician needs to know

Acute respiratory distress syndrome (ARDS) is a form of acute-onset hypoxemic respiratory failure caused by acute inflammatory edema of the lungs and not primarily due to left heart failure. Histologically, ARDS is characterized by diffuse alveolar damage (DAD) and extravasation of protein-rich edema (Figure 1) with frequent evolution to pulmonary fibrosis.

Figure 1.

Schematic representation of alveolar damage in ARDS, with interstitial and alveolar edema, hyaline membranes, neutrophil migration, epithelial cell death, and initial fibroblast activation. From: Matthay MA, Zimmerman GA. Am J Respir Cell Mol Biol. 2005;33:319-27

Any pulmonary or extrapulmonary process that generates uncontrolled inflammation can lead to ARDS, including pneumonia, sepsis, aspiration of gastric contents, and trauma. ARDS requires invasive respiratory support in the majority of cases and is associated with a high mortality.

Mechanical ventilation affects the natural history of ARDS by promoting ventilator associated lung injury (VALI). Low tidal volume (TV) ventilation has been shown to decrease mortality.

Clinical features

  • Acute onset of dyspnea and hypoxemia, not adequately responsive to oxygen therapy.

  • Low lung compliance.

  • Difficulty in excreting CO2.

  • Need for higher PEEP.

  • Pulmonary hypertension.

  • Late evolution to pulmonary fibrosis.

  • Prolonged mechanical ventilation.

  • Protracted disability.

Key management points

Airway management: Most ARDS patients will require endotracheal intubation. Certain subpopulations of patients may respond to noninvasive ventilation (NIV). A recent study showed reduced mortality and no change in intubation rates in patients with non-hypercapnic, acute hypoxemic respiratory failure who received high-flow oxygen therapy, compared with NIV via facemask. Also, a study looking at NIV using a helmet showed a significant reduction in intubation rates and mortality in patients with ARDS, compared with traditional facemask NIV.

Mechanical ventilation: Set small TV (<6.5 ml/kg) relative to PBW. This is usually accomplished in VC mode, but PC ventilation is probably equivalent providing tidal volumes are appropriate. Maintain inspiratory plateau pressures (Pplat) (Figure 2) lower than 30 cmH2O to prevent VALI. Maintain respiratory rate less than 30-35 breaths/min. Unless a major contraindication to hypercapnia or acidemia exists, normalization of arterial PCO2 is not a primary goal of ventilatory support. Arterial pH values as low as 7.2 may be tolerable by most patients. Use PEEP and FiO2 to obtain PaO2 between 55 and 80 mmHg (SpO2 88-95%). The use of full ventilatory support and muscle relaxation may be desirable in the early stages of moderate – severe ARDS to ensure constant small TV. However, early use of partial ventilatory support with close monitoring of TV’s, particularly in mild-moderate disease may be preferred in patients who can tolerate it to minimize ventilator-induced diaphragm dysfunction (VIDD).

Figure 2.

Measuring plateau airway pressure (Pplat) during an inspiratory hold provides an estimate of alveolar pressure (Palv). However, actual alveolar distension is also a function of transpulmonary pressure (Pl), which is heavily affected by the chest wall.

Hemodynamic management: Early on, if associated with shock or hypovolemia, may require aggressive fluid resuscitation. Later, consider high risk for pulmonary hypertension and right ventricular dysfunction.

Fluid management: If perfusion is adequate, minimize fluid administration as fluid overload is associated with worse outcomes; consider diuretic administration and negative fluid balance. Aggressively identify and address underlying causes of ARDS when possible; treat infections.

General management: Maintain standard ICU practices to minimize complications. In patients who do not respond to standard management, expertise in advanced modes of ventilation and rescue therapies is required. Consider transfer to regional centers of expertise.

2. Emergency Management

  1. Secure the airway. Intubation is a high-risk procedure in these patients due to the risk of rapid deterioration of oxygenation and hemodynamics. An airway management expert should be present.

  2. Prepare for resuscitation with fluids and vasopressors/inotropes if needed. Central vessel and arterial cannulation will be required in most cases.

  3. Consider alveolar recruitment maneuvers immediately after intubation to restore acceptable oxygenation.

  4. Start mechanical ventilation with AC. Set high initial FiO2 and a moderate to high (~10 cmH2O) level of PEEP for initial stabilization. Assess patient response and wean FiO2 quickly when possible to less than 0.7.

  5. If FiO2 remains high despite elimination of respiratory effort, ↑ PEEP to enable reductions in FiO2.

3. Diagnosis

Diagnostic criteria and tests

The previous American-European Consensus Conference (AECC) criteria defined acute lung injury (ALI) as a broader class of lung injury with ARDS as its higher-severity subcategory. ALI is no longer a diagnostic category under the current Berlin Definition of ARDS, which include the following clinical and radiological criteria:

  • Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms.

  • Chest imaging: Bilateral opacities on CXR or chest computerized tomography (CT) not fully explained by effusions, lobar/lung collapse, or nodules.

  • Origin of edema: Respiratory failure not fully explained by cardiac failure or fluid overload (need objective assessment - such as echocardiography - to exclude hydrostatic edema if no risk factor present).

  • Oxygenation:

    • Mild: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg with PEEP or CPAP ≥ 5 cmH2O

    • Moderate: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP ≥ 5 cmH2O

    • Severe: PaO2/FiO2 ≤ 100 mmHg with PEEP ≥ 5 cmH2O

Similar to the AECC criteria, the Berlin criteria have limitations that reduce their ability to identify patients with diffuse alveolar damage (DAD), the pathologic correlate of ARDS, as shown by autopsy studies. However, all the studies that provide the evidence for our best care practices in ARDS used the clinical definition to enroll patients. In addition, clinical criteria do not account for the etiology of the injury and they do not distinguish between the main phenotypes of direct versus indirect injury of the lungs. Although the Berlin criteria introduced a requirement for a minimum PEEP of 5 cmH2O, response to predefined PEEP and FiO2 and to recruitment maneuvers identify patients at a higher versus lower risk of death. For these reasons, clinical criteria for ARDS diagnosis select populations of patients who are exceedingly heterogenous in their outcomes and responses to treatment, which renders problematic informed enrollment into trials and individualized clinical decision making.

Normal lab values

Bilateral alveolar infiltrates on chest radiograph (Figure 3). Heterogeneous distribution of chest CT densities, which are mainly dorsally localized and coexist with normally or near-normally aerated lung regions (Figure 4). Low compliance of the respiratory system, measured with an inspiratory hold maneuver (Figure 2). Elevated alveolar dead space ratio (VD/VT).

Figure 3.

Chest x-ray showing diffuse alveolar infiltrates.

Figure 4.

CT scan appearance of a patient with ARDS following trauma and gastric aspiration.

Establishing the diagnosis

The patient fulfills Berlin criteria and the PaO2/FiO2 ratio does not improve after simple interventions such as diuresis, alveolar recruitment maneuvers, or use of moderate PEEP for a limited period of time. The patient has a low respiratory system compliance.

Other possible diagnoses

Unrecognized cardiogenic pulmonary edema and fluid overload: The differentiation between hydrostatic pulmonary edema and ARDS can be difficult, since the hypoxemia and radiological appearance are similar in the two conditions. Although the Berlin criteria require left heart failure to be ruled out to diagnose ARDS, the two conditions often coexist. Pure hydrostatic pulmonary edema usually responds quickly to diuretics and other cardiac-specific therapies.

Atelectasis: Bilateral infiltrates and hypoxemia due to alveolar collapse can be confused with ARDS but usually respond dramatically to alveolar recruitment strategies. Bilateral radiological infiltrates caused by pneumonia or traumatic lung contusions in the absence of widespread pulmonary inflammation can be difficult to distinguish from ARDS, as the latter may be patchy. The clinical course, the response to mechanical ventilation and PEEP settings and the appearance on CT scan can help establish the diagnosis. However, these patient populations should be treated in an identical fashion with lung-protective ventilation.

Interstitial lung diseases such as idiopathic pulmonary fibrosis can present with acute clinical deterioration together with radiological (new-onset diffuse infiltrates) and physiological (hypoxemia, low lung compliance) signs that are similar to ARDS. The history of chronic illness and previous radiographs/pulmonary function tests may help in the diagnosis. Acute interstitial pneumonia (Hamman Rich) can present with subacute evolution of respiratory functional impairment and diffuse radiological infiltrates with no known predisposing factors to ARDS. When the differential diagnosis is uncertain, open lung biopsy should be considered prior to initiation of immunosuppressant therapy.

Acute eosinophilic pneumonia presents with bilateral infiltrates. The diagnosis is confirmed by abundance of eosinophils in the bronchoalveolar lavage. Occasionally, a radiological infiltrative pattern can be caused by malignancy.

Diffuse Alveolar hemorrhage due to vasculitic processes such as Goodpasture's syndrome and Wegener's granulomatosis presents with hypoxemia, diffuse radiological infiltrates and hemoptysis (although this symptom can be absent). The presence of acute anemia and hemorrhagic sputum by fiberoptic bronchoscopy and bronchoalveolar lavage usually confirm the diagnosis of alveolar hemorrhage. Serologic testing and lung and kidney biopsies are used to narrow the differential diagnosis.

Confirmatory tests

There are no specific confirmatory tests that can be performed for ARDS. However, in cases where no predisposing factors are evident (e.g. trauma, aspiration, sepsis), diagnostic testing should include fiberoptic bronchoscopy and bronchoalveolar lavage fluid sampling to rule out infection, alveolar hemorrhage, eosinophilia and cancer. Serologic testing for autoimmune diseases and viral infections should be obtained when appropriate. If the diagnosis remains uncertain after bronchoscopy, open lung biopsy should be considered if clinical conditions allow, especially in cases where immunosuppressant therapy is contemplated.

Chest CT can help confirm the presence of bilateral ground-glass opacities suggestive of DAD. CT can give some indication of the amount of fibrosis, the presence of coexisting processes (i.e. pleural effusions, pulmonary abscess) and the extent of atelectasis.

Pulmonary artery catheterization is not required to confirm the diagnosis of ARDS. Heart failure can be ruled out by clinical assessment or by echocardiography.

Measuring respiratory mechanics helps identify low compliance as a cofactor in causing respiratory failure and is usually present; however, this is not required for diagnosis.

4. Specific Treatment

There is no specific therapy for ARDS, other than treatment of the precipitating causes. The treatment of ARDS is mainly supportive and is centered on evidence-based respiratory care, thoughtful management of hemodynamics and judicious administration of fluids or diuretics. The only approaches that have been shown to affect ARDS outcomes are the manipulation of ventilator settings with the goal of protecting the lungs from VALI and the use of prone positioning for extended duration in high severity patients.

Lung-protective strategies

When low-TV ventilation was compared to higher TV, the former resulted in lower mortality and better secondary outcomes. The strategy used in this study included setting TV to 6 ml/kg PBW, limiting Pplat to less than 30 cmH2O and using a nomogram to set PEEP and FiO2. This is currently considered the standard ventilatory management for ARDS. Although Pplat limitation to less than 30 cmH2O and TV limitation to 6 ml/kg IBW is recommended, there is no evidence that this constitutes a safety limit.

Radiological evidence suggests overdistension and inflammatory activation at Pplat values between 25 and 30. Of note, if the plateau pressure is less than 30 cmH2O while receiving a high TV above 6 ml/kg IBW, the TV should still be reduced to approximately 6 ml/kg, as evidence suggests that the mortality benefit associated with low tidal volumes is independent of the compliance and Pplat.

The use of higher levels of PEEP (with or without recruitment maneuvers) to enhance alveolar opening and minimize atelectrauma has been advocated based on animal studies. In the two clinical trials that showed a benefit from this “open lung approach,” high PEEP/low TV was tested against lower PEEP/high TV. However, in studies where only the effect of higher PEEP was tested in ARDS, the open lung approach did not result in improved survival.

At the same time, these studies showed that high PEEP was not unsafe. Furthermore, a recent meta-analysis using 2,299 patients from three studies detected a 10% relative mortality reduction (NNT 25) in those patients who met ARDS criteria at study entry and were randomized to high PEEP. This mortality reduction in the high PEEP group was associated with a smaller number of patients who needed rescue therapies for refractory hypoxemia, suggesting a benefit from high PEEP in a select ARDS subpopulation. Furthermore, the survival benefit of high PEEP was concentrated in the more severely ill patients who responded to this treatment with improvement in oxygenation. Since the radiological response to alveolar recruitment is variable among patients and is related to survival, CT studies - albeit a cumbersome approach - can have a role in identifying patients who are at high risk of death and who may benefit from high PEEP strategies.

Although the rationale for using a fixed small (6 ml/kg PBW) Tidal Volume in ARDS was based on the concept that the ARDS lung is essentially small (“baby lung”), a one size fits all approach of using a tidal volume normalized to PBW doesn’t account for the wide variability in the degree of lung aeration between patients. To account for these differences, it was recently proposed that since respiratory system compliance correlates with the volume of aerated lung, TV should be normalized to compliance to estimate the tidal lung “stress” in a given patient. The TV/compliance is equal to the Plateau Pressure – PEEP a.k.a. the driving pressure. Data to support this concept is accumulating. Recently, a complex statistical analysis (meta-analysis of individual patient data from over 3,500 subjects from ARDS trials) revealed that, in fact, mortality correlated best with the lowest driving pressure, and not the TV/PBW, Plateau Pressure, or PEEP level. Although this was a retrospective analysis, it makes sense physiologically and justifies future controlled trials targeting driving pressure minimization as a goal. To achieve this goal either TV or PEEP can be manipulated, however, all the patients enrolled in the driving pressure study had their driving pressure reduced by either a change in PEEP or through a TV reduction to 6 ml/kg PBW. Thus, until we have prospective data to inform this best, we advocate setting the TV to < 6.5 ml/kg PBW and then titrating PEEP upward to minimize the driving pressure to ≤ 14. Interestingly, this approach to PEEP titration is very similar to PEEP titration practices prevalent in the late 70’s and 80’s, which was driven by data published by Peter Suter in 1975 showing that PEEP titrated to the highest compliance (lowest DP) correlated best with oxygen delivery. Although O2 delivery was the wrong outcome variable he delineated this approach using sound physiologic principles.

Ventilatory management during the first 12 hours

Early ventilatory management after intubation should be focused on lung protection and characterization of pulmonary mechanics.

  1. Set initial PEEP at 10 cmH2O and FiO2 of 1.0 and repeat blood gases to verify patient severity after intubation.

  2. Maintain deep sedation and muscle relaxation: paralysis can be considered in the early stage to facilitate respiratory mechanics measurements and maximize lung protection in what is possibly the most crucial stage of the disease. Additionally, muscle relaxation during the first 48 hours may have outcome benefits.

  3. Identify potential for alveolar recruitment by performing recruitment maneuvers or trials at different PEEP levels. Recruitment response can be evaluated using changes in oxygenation, compliance and PaCO2 together with hemodynamic tolerance. The benefit of alveolar recruitment versus hemodynamic impairment at high PEEP should be critically weighed. Choose the lowest PEEP that allows FiO2 below 0.6 and Pplat below 30 cmH2O. If driving pressure remains > 14-16, titrate PEEP up and down to achieve a driving pressure goal of < 14.

  4. Identify optimal tidal volume. Gradually reduce TV to 6 ml/kg PBW and reduce further if Pplat is above 30 cmH2O. Increase respiratory rate (RR) up to 35 (closely monitor for autoPEEP). Tolerate hypercapnia until pH is below 7.10-7.15. At that point consider chemical buffering. If RR = 35 with intolerable acidemia, consider decreasing PEEP and increasing TV to 8 ml/kg if Pplat is below 30.

  5. Prone positioning: Patients may respond to this maneuver with dramatic improvement in gas exchange. Three previous clinical trials did not document a mortality benefit, however a more recent study that employed prone positioning for an extended period of time (> 16 hours) in patients with more severe ARDS (PaO2/FiOS2 < 150 mmHg) showed a dramatic improvement in survival. Prone positioning should no longer be considered a rescue therapy and instead should be included in the initial management of moderate to severe ARDS unresponsive the aforementioned maneuvers.

  6. Based on response to ventilator settings and severity of functional compromise, the use of adjunctive and non-conventional therapies should be considered early.

  7. Respiratory mechanics should be intermittently assessed and at minimum compliance, plateau pressures, and driving pressure should be measured. While these ventilator goals should be achieved in all patients, for the individual patient the combination of TV < 6.5 ml/kg PBW and PEEP that minimizes driving pressure and maximizes lung protection and recruitment should be identified along with the minimum acceptable FiO2.

Refractory cases

Refractory ARDS cases are those that present with critical hypoxemia that does not respond to standard respiratory care including prone positioning. The limits of acceptable PaO2 have not been established since most deaths from ARDS are not directly due to hypoxemia. However, patients with refractory hypoxemia tend to have a higher mortality. Depending on the institutional experience and clinicians' preferences, these patients can be treated with:

  • Super-recruitment maneuvers: They may improve oxygenation but they also can have hemodynamic effects and potentially worsen alveolar strain and VALI.

  • In severe, refractory cases, heavy sedation and paralysis can be used to decrease O2 consumption and, by thus increasing venous saturation, indirectly increase arterial oxygenation. Muscle paralysis also eliminates expiratory muscle activity (i.e. forced exhalation), which can counteract the effect of PEEP on lung volumes and decrease intra-abdominal pressure.

  • Inhaled nitric oxide or epoprostenol: It often has significant gas exchange benefits but also has no documented outcome effects and high costs. Inhaled prostacyclin is a relatively less expensive alternative that is more widely available and has comparable effects. Enhanced sitting position and/or reverse Trendelenburg can have beneficial effects on oxygenation by decreasing abdominal pressure and increasing FRC.

  • Advanced modes of ventilation that may have physiological appeal include airway pressure release ventilation (APRV) and Bi-Level ventilation. In spite of their physiological appeal and effectiveness in improving gas exchange and in preserving diaphragm activity and strength, these ventilatory modes are not supported by clinical outcome data. They should be considered as rescue strategies in refractory hypoxemia until further studies are done. High frequency oscillatory ventilation (HFOV) has been shown to significantly increase mortality in moderate to severe ARDS and should be avoided.

  • ECLA: Although typically considered a rescue therapy, a recent study showed better outcomes in ARDS patients who were randomized to receive consideration for ECLA in a specialized medical center, as opposed to those who remained in their original location. However, the results of this study are clouded by the likely presence of a mixed effect of the treatment and of the transfer to the ECLA center. ECLA remains a rescue therapy pending results of ongoing clinical trials.

  • A higher number of patients can be considered refractory due to the inability to control respiratory acidosis within the boundaries of the lung-protective strategy. Buffer infusions can be considered to tolerate extreme acidemia. If its efficacy is confirmed in clinical trials, veno-venous ECLA can be considered as a means to remove CO2 while protecting the lungs from VALI with very low stretch ventilation.

  • Exogenous surfactant administration: Although its positive outcome effects have been documented in preterm newborns and in pediatric ARDS, multiple studies have failed to show outcome effects from surfactant therapy in adults.

  • Steroids: Preliminary studies showed beneficial effects of low- to medium-dose steroids in late-stage ARDS with no documented ongoing infection. However, a recent ARDSnet trial could not detect positive outcome effects in the general population.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Mortality from ARDS is high. Among surviving patients, prolonged duration of mechanical ventilation and ICU stay is expected. Transfer to a long-term weaning facility should be considered during the resolution stage. Patients who are discharged from the hospital will have significant disability and weakness years following discharge.

Follow-up

Patients who survive ARDS will have mild impairment in lung function with little clinical impact; therefore pulmonary follow-up is generally not required. However, survivors are affected by long-term disability, delayed recovery of function and reduced quality of life. These complications seem to be related to neuromuscular, cognitive and psychological impairments, including PTSD and depression. The high prevalence of critical illness neuromyopathy and the high usage of sedatives in this population during the ICU stay may explain these disabilities. Extensive rehabilitation starting in the ICU and continuing after discharge from the hospital could benefit ARDS survivors.

Pathophysiology

The main pathophysiological abnormalities that are observed in ARDS include hypoxemia, impaired CO2 excretion, low lung volumes and low respiratory system compliance. These alterations are the direct consequence of alveolar epithelial and endothelial injury with high-permeability edema due to inflammatory cell activation. Alveolar spaces are either obliterated by cell debris and edema or they are collapsed due to atelectasis. Pulmonary vessels may be narrowed or obliterated. Genetic and microbiological virulence factors seem to have a key role in the pathogenesis of ARDS.

  • The presence of non-ventilated alveolar units in ARDS generates gas exchange impairment by causing intrapulmonary shunt, which is the main reason for hypoxemia in this condition. Multiple studies showed that shunt is prevalent in ARDS, which also explains why these patients have a poor response to oxygen therapy. Hypoxic vasoconstriction appears to be blunted in ARDS, contributing to low arterial oxygenation.

  • Regional decreases in pulmonary blood flow due to mechanical and biochemical factors cause high alveolar dead space, which impairs CO2 excretion. In addition, these mechanisms predispose to pulmonary hypertension.

  • Atelectasis is a consistent finding in ARDS and is promoted by alveolar collapse due to increased lung tissue weight, lower lobe compression by abdominal contents and the heart and decreased inspiratory excursion of the posterior portion of the diaphragm. These factors are partly relieved by PEEP prone positioning, explaining their beneficial effects on gas exchange.

  • Respiratory system compliance can be low due to a reduction in the compliance of the lungs, the chest wall, or both. Lung compliance reduction is mostly due to a decrease in the amount of ventilated airspaces, a phenomenon that is described by the "baby lung" model of pulmonary mechanics. Chest wall compliance can be decreased due to intraabdominal processes and thoracic wall edema. The effect of chest wall mechanics on respiratory mechanics is variable among patients and can be assessed using esophageal manometry. This technique, which allows estimation of transpulmonary pressure, may be important in assessing alveolar stress and strain during mechanical ventilation.

  • As a consequence of their smaller number in the “baby lung” (Figure 5), ventilated airspaces reach abnormally large volumes and higher recoil pressures at end inspiration. This mechanism generates high pulmonary tissue stress, thus promoting VALI. Ideally, lung stress should be monitored during mechanical ventilation but, in the absence of this measurement, inspiratory plateau pressures are typically used. However, the relation between plateau pressure and lung stress is loose, mainly due to the variable effects of chest wall compliance on respiratory mechanics.

  • The combination of low compliance and high dead space causes dramatically elevated work of breathing in ARDS. Once intubated, these patients will require high minute volumes and high inspiratory pressures to exchange CO2, which increase their predisposition to VALI. These mechanisms may help explain why dead space and compliance are independent predictors of mortality in ARDS.

Figure 5.

Schematic representation of the “baby lung” model of ARDS. As the consequence of the loss of viable airspaces, ventilated alveoli reach higher inspiratory distension than normal. This causes excessive alveolar wall stress and strain, ultimately leading to VALI.

Epidemiology

In a 2005 study, the incidence of ARDS was 78.9 per 100,000 patient-years, which suggests an estimate of approximately 200,000 cases per year in the United States alone. A 2016 study found a 10.4% incidence of ARDS among patients admitted to ICU’s. Approximately 25% of patients who receive mechanical ventilation for longer than 48 hours are identified as having ARDS. Pneumonia, sepsis, and advanced age are the most frequently encountered predisposing factors for ARDS. Genetic factors may have an important role in determining individual patients' propensity of acquiring ARDS.

Prognosis

The reported mortality from ARDS is variable. Over the years, a progressively decreasing death rate has been observed among patients recruited for clinical trials. However, this observation may be explained by selection bias and by the relatively recent introduction of the standardized criteria. Previous studies estimated the mortality rate of ALI at 38.5% (41% for ARDS), but higher rates have also been reported with a recent report finding a 46.1% hospital mortality in patients with severe ARDS. Racial factors seem to have an effect on mortality from ARDS. In a recent retrospective study, the death rate was higher in the Black and Hispanic population compared to Caucasians.

Although hypoxemia is the key inclusion criterion for ARDS and is considered an index of severity, there is an ambiguous correlation between level of hypoxemia and death rate. Indeed, mortality is more likely to be associated with the extent of non-pulmonary organ failure. Other pathophysiological abnormalities, such as high alveolar dead space and low compliance, may have a significant impact on outcome. Hypoxemia seems to be the direct cause of death only in a select subgroup of patients who may benefit from rescue therapies and higher PEEP. The extent of alveolar recruitability as measured by CT scan and response to high PEEP is also a predictor of mortality in ARDS.

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

Diagnosis

Goligher, EC, Laghi, F, Detsky, ME. "Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity". Int Care Med.. vol. 41. 2015. pp. 642-49.

(In this study the feasibility and reproducibility of diaphragm thickness measurements using a linear array ultrasound probe was assessed in mechanically ventilated patients and the validity of diaphragm thickening measurements in estimating intrinsic respiratory effort was evaluated. Enrollment included 96 mechanically ventilated patients and 9 healthy subjects. Diaphragmatic measurements were reproducible with greater success on when evaluating the right diaphragm. Regarding validity, in cases of partial ventilatory support [< 50% of inspiratory capacity], inspiratory thickening does reflect contractility of the muscle and thus can be used as a surrogate for diaphragmatic function.)

Calfee, CS, Janz, DR, Bernard, GR. "Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies". Chest. vol. 147. 2015. pp. 1539-48.

(This study evaluated plasma biomarkers of ARDS to evaluate whether direct ARDS [pneumonia, aspiration] caused more lung injury than indirect ARDS [nonpulmonary sepsis]. Two cohorts of patients were included in the study totalling 953 patients. The study found lung epithelial injury was more consistent with ARDS from direct lung injury while endothelial injury was more common in indirect lung injury. These findings raise the possibility of specific therapies for ARDS aimed at unique phenotypes of disease.)

Thille, AW, Esteban, A, Fernández-Segoviano. "Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy". Am J Respir Crit Care Med.. vol. 187. 2012. pp. 761-67.

(This study evaluated the accuracy of the Berlin definition of mild, moderate, and severe ARDS by identifying at autopsy the presence or absence of DAD in patients who had been clinically diagnosed with ARDS. Fewer than half of patients with a clinical diagnosis of ARDS were found to have DAD however 69% of patients with severe ARDS exhibited the finding. The results showed that severity and duration of ARDS [> 72 hours] correlated with DAD.)

Ranieri, VM, Rubenfield, GD. "Acute respiratory distress syndrome: the Berlin Definition". JAMA. vol. 307. 2012. pp. 2526-33.

(Given concerns over the reliability and validity of the AECC ARDS definition, a consensus panel developed new criteria for diagnosing and classifying the severity of ARDS in order to simplify the diagnosis and improve prognostication. Three exclusive categories [mild, moderate, severe] were proposed based on degree of hypoxemia and ALI was removed as a category. The authors evaluated the new criteria by applying it to a cohort of 4,457 patients from previous randomized trials or prospective studies with the results showing an improved ability to predict mortality compared to the AECC criteria.)

Bernard, GR, Artigas, A, Brigham, KL. "The American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination". Am J Respir Crit Care Med.. vol. 149. 1994. pp. 818-24.

(The previous criteria for defining ALI and ARDS are outlined in this consensus statement. These criteria placed emphasis on the degree of hypoxemia as a predictor of outcome and heavily rely on radiological characteristics to diagnose ALI. ARDS is a high-severity subcategory of ALI, based on oxygenation impairment. However, it is not entirely clear if ALI patients without ARDS have better outcomes.)

Esteban, A, Fernandez-Segoviano, P, Frutos-Vivar, F. "Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings". Ann Intern Med.. vol. 141. 2004. pp. 440-5.

(This article questions the validity and reliability of the AECC criteria in identifying patients with diffuse alveolar damage.)

Meade, MO, Cook, RJ, Guyatt, GH. "Interobserver variation in interpreting chest radiographs for the diagnosis of acute respiratory distress syndrome". Am J Respir Crit Care Med.. vol. 161. 2000. pp. 85-90.

(Poor interobserver agreement has been documented in the radiological interpretation of pulmonary infiltrates.)

Whiteley, JP, Gavaghan, DJ, Hahn, CE.. "Variation of venous admixture, SF6 shunt, PaO2, and the PaO2/FIO2 ratio with FIO2". Br J Anaesth.. vol. 88. 2002. pp. 771-8.

(This article illustrates how PaO2/FiO2 is affected by changes in FiO2 and is not a stable indicator of oxygenation impairment.)

Ferguson, ND, Kacmarek, RM, Chiche, JD. "Screening of ARDS patients using standardized ventilator settings: Influence on enrollment in a clinical trial". Intensive Care Med.. vol. 30. 2004. pp. 1111-6.

(The application of uniform PEEP and FIO2 settings for a predetermined duration of time allows one to differentiate a subgroup of patients who continue to have low PaO2/FiO2 from those whose hypoxemia improves. The former patients have a markedly higher mortality.)

Villar, J, Mendez-Perez, L, Lopez, J. "An early PEEP/FiO2 trial identifies different degrees of lung injury in ARDS patients". Am J Respir Crit Care Med.. vol. 176. 2007. pp. 795-804.

(Based on the results of this study, the introduction of a trial of standardized ventilator settings is advocated as a preliminary step prior to diagnosing ALI and ARDS. This approach may help identify more homogenous populations of patients in future clinical trials on ALI/ARDS.)

Epidemiology and prognosis

Bellani, G, Laffey, JG, Pham, T. "Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries". JAMA. vol. 315. 2016. pp. 788-800.

(In this prospective cohort study across 459 ICU’s in 50 countries ARDS epidemiology, recognition, management, and outcomes were investigated. Among over 29,000 patients evaluated a 10.4% incidence of ARDS was noted with 23.4% requiring mechanical ventilation. Overall hospital mortality was 34.9%, 40.3%, and 46.1% for mild, moderate, and severe ARDS respectively. ARDS was underrecognized with 60.2% of all cases being diagnosed by the clinician. In those patients diagnosed, 35.1% received a tidal volume greater than 8mL/kg PBW and 82.6% received a PEEP less than 12 cmH2O. The diagnosis of ARDS was not independently associated with the use of lower TV’s but was significantly associated with higher PEEP, prone positioning, and neuromuscular blockage. The study showed significant underrecognition of ARDS, infrequent use of evidence based treatment adjuncts, and confirmed the high mortality from the disease.)

Rubenfeld, GD, Caldwell, E, Peabody, E. "Incidence and outcomes of acute lung injury". N Engl J Med.. vol. 353. 2005. pp. 1685-93.

(An epidemiological study performed in King's County, Wash. provided national estimates on the epidemiology of ALI. According to this study, the incidence and death burden of ALI may be higher than previously thought, nearing those of breast cancer.)

Brun-Buisson, C, Minelli, C, Bertolini, G. "Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study". Intensive Care Med.. vol. 30. 2004. pp. 51-61.

(In this European 78-ICUs cohort study, 7.1% of all admissions had or developed ALI. The overall mortality of ALI was 55%. Age and SAPS were among the independent predictors of mortality, while arterial oxygenation was not. However, meeting oxygenation criteria for ARDS conferred an increased risk of death.)

Luhr, OR, Antonsen, K, Karlsson, M. "Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF study group". Am J Respir Crit Care Med.. vol. 159. 1999. pp. 1849-61.

(Among the patients who are diagnosed with ALI, 75% also have ARDS. In this study, it was not clear whether or not patients who have ALI but not ARDS constitute a subgroup with distinct characteristics and outcomes.)

Esteban, A, Anzueto, A, Frutos, F. "Characteristics and outcomes in adult patients receiving mechanical ventilation: A 28-day international study". JAMA. vol. 287. 2002. pp. 345-55.

(A large international epidemiological study on ventilated patients in ICU. Mortality of ventilated patients was overall high. ARDS was independently associated with higher death rate and with prolonged durations of ventilation and ICU stay.)

Phua, J, Badia, JR, Adhikari, NK. "Has mortality from acute respiratory distress syndrome decreased over time? A systematic review". Am J Respir Crit Care Med.. vol. 179. 2009. pp. 220-7.

(The evolution of ARDS mortality was assessed by reviewing studies performed between 1984 and 2006 with a total of 18,900 patients. Pooled mortality was 44%, but it was lower in randomized controlled trials (36%) than in observational studies, suggesting a selection bias. Death rate did not decrease after the introduction of the AECC criteria.)

Herridge, MS, Cheung, AM, Tansey, CM. "One-year outcomes in survivors of the acute respiratory distress syndrome". N Engl J Med.. vol. 348. 2003. pp. 683-93.

(In this prospective study on ARDS survivors, patients continued to have significant weakness and muscle wasting at one year after discharge. However, no patient required oxygen therapy.)

Herridge, MS, Tansey, CM, Matte, A. "Functional disability 5 years after acute respiratory distress syndrome". N Engl J Med.. vol. 364. 2011. pp. 1293-304.

(In this follow-up to their 2003 study, the authors found that functional, psychomotor and psychological impairment was still significant 5 years after discharge in spite of the fact that the patients were relatively young and had few comorbidities. The costs of health care were related to coexisting diseases at the time of admission.)

Nuckton, TJ, Alonso, JA, Kallet, RH. "Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome". N Engl J Med.. vol. 346. 2002. pp. 1281-6.

(In a prospective study of 179 patients with early ARDS, dead space fraction was an independent predictor of mortality, together with the Simplified Acute Physiology score II and with respiratory system compliance, while oxygenation was not. These results could be due to an association between dead space and microvascular injury. An alternative explanation could be that CO2 retention, prompting the use of higher tidal volumes, could lead to higher exposure to VALI.)

Specific treatment

Patel, BK, Wolfe, KS, Pohlman, AS. "Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: A randomize clinical trial". JAMA. 2016.

(This single-center randomized trial of 83 patients with ARDS diagnosed by Berlin criteria randomized patients who required NIV for at least 8 hours via facemask to either continue facemask therapy or switch to helmet. The trial was terminated early due to results meeting criteria for early stoppage given the superiority of helmet therapy. The trial found that among patients randomized to helmet therapy there was a significant reduction in intubation rates (18.2% vs 61.5%), increase in ventilator-free days, and reduction in 90-day mortality.)

Frat, JP, Thille, AW, Mercat, A. "High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure". N Engl J Med.. vol. 372. 2015. pp. 2185-96.

(In this randomized controlled multicenter trial 310 patients with nonhypercapnic acute hypoxemic respiratory failure (PaO2/FiO2 ratio ≤ 300 mmHg) were randomized to high-flow oxygen therapy, standard oxygen therapy via facemask, or noninvasive positive-pressure ventilation. High flow oxygen was delivered for at least 2 days at 50 liters per minute with an SpO2 titrate to > 92%. There was no significant difference in intubation rates however there was a significant difference in 90-day mortality that favoured high-flow oxygen.)

Amato, MB, Meade, MO, Slutsky, AS. "Driving pressure and survival in the acute respiratory distress syndrome". N Engl J Med.. vol. 372. 2015. pp. 747-55.

(Using data from nine previous randomized trials totalling 3562 patients with ARDS multilevel mediation analysis was used to examine whether driving pressure was an independent predictor of survival. Driving pressure was defined as tidal volume divided by compliance or more simply plateau pressure minus PEEP. Driving pressure was independently predictive of survival and more strongly associated with outcome versus other ventilatory variables. Tidal volume and PEEP were not independently associated with survival unless their adjustments led to a decrease in driving pressure.)

Goligher, EC, Kavanagh, BP, Rubenfeld, GD. "Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials". Am J Respir Crit Care Med.. vol. 190. 2014. pp. 70-6.

(In this secondary analysis of the Lung Open Ventilation Study (LOVS) and the Expiratory Pressure (ExPress) Study Group trials, the relationship between physiologic response to trials of higher PEEP and mortality was examined. The results showed that an increase in the P/F ratio following increases in PEEP correlated with reduced mortality.)

Guérin, C, Reignier, J, Richard, JC. "Prone positioning in severe acute respiratory distress syndrome". N Engl J Med.. vol. 368. 2013. pp. 2159-68.

(In this randomized controlled trial 466 patients across 27 European ICU’s with severe ARDS were assigned to undergo prone positioning for at least 16 hours or remain in a supine position. Severe ARDS was defined as a PaO2/FiO2 ratio < 150 mmHg. Patients who underwent prone positioning had statistically significant decreases in 28-day mortality (16.0% in prone versus 32.8% in supine) and 90-day mortality (23.6% in prone versus 41% in supine) with no increased incidence of complications.)

Alhazzani, W, Alshahrani, M, Jaeschke, R. "Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials". Crit Care. vol. 17. 2013. pp. R43.

(This systematic review and meta-analysis of three large randomized controlled trials investigating neuromuscular blockade in ARDS found short-term cisatricurium besylate was associated with lower hospital mortality, lower risk of barotrauma, and no effect on the risk of ICU-acquired weakness. The analysis also showed that among survivors there was no effect on the duration of mechanical ventilation.)

Ferguson, ND, Cook, DJ, Guyatt, GH. "High-frequency oscillation in early acute respiratory distress syndrome". N Engl J Med.. vol. 368. 2013. pp. 795-05.

(In this randomized controlled trial of a planned 1200 patients with moderate-to-severe ARDS at 39 ICU’s across 5 countries patients were randomized to HFOV or conventional ventilation. HFOV protocols targeted a mean airway pressure of 30 cmH2O using the highest possible frequency to maintain a blood pH of 7.25. The conventional protocol called for either pressure or volume control modes with target TV of 6 ml/kg and initial PEEP’s of 20 cmH2O. The trial was stopped following recruitment of 548 patients due to higher in-hospital mortality. It was also noted that patients in the HFOV arm required higher doses of sedatives and more frequently required neuromuscular blockade and vasopressors.)

Amato, MB, Barbas, CS, Medeiros, DM. "Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome". N Engl J Med.. vol. 338. 1998. pp. 347-54.

(In the first study to demonstrate that mechanical ventilation settings affect outcomes, ARDS patients who were randomized to receive 6 ml/kg TV and high PEEP (based on the pressure-volume curve) had better survival and shorter duration of ventilation than control patients who received VT 12 ml/kg and minimal PEEP. Due to the concomitant use of low TV and high PEEP in the treatment group, the separate effects of these two strategies cannot be distinguished in this study.)

"Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome". N Engl J Med.. vol. 342. 2000. pp. 1301-8.

(861 patients with ALI were randomized to receive initial TV of either 6 ml/kg IBW, with Pplat limitation to 30 cmH2O, or 12 ml/kg IBW, with maximum Pplat of 50 cmH2O. PEEP and FiO2 management algorithm was identical in the two groups. Patients in the low-TV arm had a 22% reduction in mortality, shorter duration of ventilation and lower plasma interleukin-6, a marker of pulmonary and systemic inflammation. The results of this study confirmed that VALI is a relevant clinical entity and that its limitation improves outcomes.)

Briel, M, Meade, M, Mercat, A. "Higher vs. lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: Systematic review and meta-analysis". JAMA. vol. 303. 2010. pp. 865-73.

(In this meta-analysis on 2,299 patients from the three main studies on high vs. low PEEP (with low tidal volume) in ALI, a beneficial effect on survival from the high-PEEP approach was observed only in patients who met ARDS criteria. However, this result had marginal statistical significance. The fact that most patients who died had needed rescue therapy for refractory hypoxemia may suggest that the choice of high PEEP should be very selective.)

Gattinoni, L, Caironi, P, Cressoni, M. "Lung recruitment in patients with the acute respiratory distress syndrome". N Engl J Med.. vol. 354. 2006. pp. 1775-86.

(A cohort of ALI patients were stratified according to their response to an alveolar recruitment maneuver, based on CT analysis. Patients with high recruitability were more likely to have ARDS and had a higher mortality rate. This study suggested that CT response to recruitment attempts is variable and identifies higher-risk patients who may potentially benefit from a high-PEEP approach.)

Papazian, L, Forel, JM, Gacouin, A. "Neuromuscular blockers in early acute respiratory distress syndrome". N Engl J Med.. vol. 363. 2010. pp. 1107-16.

(In this randomized controlled study of 340 patients with early severe ARDS, patients who received muscle relaxation for 48 hours had lower mortality and higher number of ventilator-free days compared to the control group. This result was not associated with an increased rate of muscle weakness in the muscle relaxant group and could be explained by better lung protection.)

Peek, GJ, Mugford, M, Tiruvoipati, R. "Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre randomised controlled trial". Lancet. vol. 374. 2009. pp. 1351-63.

(In this study of 180 patients with severe acute respiratory failure, subjects who were randomized to be transferred to a dedicated center for consideration for ECLA (75% of whom did receive this treatment) had higher survival without disability and improved quality-adjusted life-years than patients who were treated at their original institution. This study is relevant since it suggests transfer to a specialized ECLA center is safe, likely beneficial and financially feasible. The results are likely related to the use of ECLA, although their interpretation is clouded by the fact that control patients were treated in different centers and with loose management protocols.)

Sud, S, Friedrich, JO, Taccone, P. "Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: Systematic review and meta-analysis". Intensive Care Med.. vol. 36. 2010. pp. 585-99.

(A meta-analysis of 10 trials on prone positioning with a total of 1,867 patients was performed. In severely hypoxemic ARDS patients (PaO2/FiO2 under 100), mortality was improved by the use of the prone position, as opposed to conventional management. However, the rate of complications from prone positioning was also increased. This study suggests that prone positioning can be considered in the most severely ill patients, although its routine use cannot be recommended until dedicated trials are performed in this specific population.)

Talmor, D, Sarge, T, Malhotra, A. "Mechanical ventilation guided by esophageal pressure in acute lung injury". N Engl J Med.. vol. 359. 2008. pp. 2095-104.

(61 patients were randomized to receive either PEEP/ FiO2 adjustment based on ARDSnet recommendations or transpulmonary pressure-guided adjustments, using esophageal pressure catheters. Patients in the treatment group had better oxygenation and lung mechanics, and a trend towards improved mortality. Although there are perplexities concerning the physiological meaning of esophageal pressures in the supine position, this hypothesis-generating study could guide larger clinical outcome trials.)

**The original Author(s) for this chapter was (were) Drs. Maurizio Cereda and Luciano Gattinoni. The chapter was revised by Drs. Maurizio Cereda and Alexander Fort.

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