Acute respiratory distress syndrome (ARDS) is a form of noncardiogenic pulmonary edema that results from acute damage to the alveoli. It is characterized by diffuse infiltrative lung lesions with resulting interstitial and alveolar edema, severe hypoxemia, and respiratory failure.^1-3 The cardinal feature of ARDS, refractory hypoxemia, is caused by formation of protein-rich alveolar edema after damage to the integrity of the lung’s alveolar-capillary barrier.

The initial definition of ARDS was based on the American-European Consensus Conference (AECC) from 1994 and included the following components:

1. The syndrome must present acutely.
2. A ratio of PaO₂ to FIO₂ ≤200 regardless of the level of positive end-expiratory pressure (PEEP).
3. The detection of bilateral pulmonary infiltrates on frontal chest x-ray examination
4. Absence of congestive heart failure (pulmonary artery wedge pressure [PAWP] ≤18 mm Hg or no clinical evidence of elevated left atrial pressure on the basis of chest x-ray examination or other clinical data)

The 2012 Berlin definition of ARDS (Table 1) addresses some of the limitations of the AECC definition and establishes the criteria for ARDS:

• Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms
• Chest imaging (chest x-ray examination or computed tomography [CT] scan): Bilateral opacities, 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 (e.g., echocardiography) to exclude hydrostatic edema if no risk factors are present
• Oxygenation (if altitude is higher than 1000 m, the correction factor should be calculated as follows: [PaO₂/FiO₂ × {barometric pressure/760}]
• Mild: 200 mm Hg <PaO₂/FiO₂≤300 mm Hg with PEEP or continuous positive airway pressure (CPAP) ≥5 cm H₂O (this may be delivered noninvasively in the mild ARDS group)
• Moderate: 100 mm Hg <PaO₂/FiO₂≤200 mm Hg with PEEP or CPAP ≥5 cm H₂O
• Severe: PaO₂/FiO₂≤100 mm Hg with PEEP or CPAP ≥5 cm H₂O

ARDS

Adult respiratory distress syndrome

Acute lung injury

• More than 150,000 ARDS cases per year in the U.S.
• 7.1% of all patients admitted to an intensive care unit (ICU) and 16.1% of all patients on mechanical ventilation develop ARDS.
• An international study in 50 countries revealed that 10% of patients admitted to an ICU fulfilled criteria for ARDS, and 93% developed it within 48 h of admission. The study reinforced that ARDS is underrecognized.⁴
• Black, Hispanic, and other patients belonging to racial minority groups in the U.S. were observed to exhibit significantly higher in-hospital sepsis-related respiratory failure and associated mortality.⁵

• Signs and symptoms:
  1. Dyspnea
  2. Chest discomfort
  3. Cough
  4. Anxiety
• Physical examination:
  1. Tachypnea
  2. Tachycardia
  3. Hypertension
  4. Paradoxic breathing and use of accessory muscles
  5. Coarse crepitations or crackles of both lungs
  6. Fever may be present if infection is the underlying etiology

• Sepsis (>40% of cases)
• Aspiration: Near-drowning, aspiration of gastric contents (>30% of cases)
• Trauma (>20% of cases)
• Pneumonia
• Multiple transfusions, blood products
• Drugs (e.g., overdose of morphine, methadone, heroin; reaction to nitrofurantoin)
• Noxious inhalation (e.g., chlorine gas, high O₂ concentration)
• Postresuscitation
• Cardiopulmonary bypass
• Burns
• Pancreatitis
• Table 3 describes risk factors associated with development of ARDS
• History of chronic alcohol abuse significantly increases the risk of developing ARDS in critically ill patients

• Cardiogenic pulmonary edema
• Interstitial lung disease (acute interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute eosinophilic pneumonia, hypersensitivity pneumonia, pulmonary alveolar proteinosis)
• Connective tissue diseases, such as polymyositis
• Diffuse alveolar hemorrhage
• Lymphangitic carcinomatosis from T-cell or B-cell lymphomas
• Drug-induced lung diseases (amiodarone, bleomycin)

The search for an underlying cause should focus on treatable causes (e.g., infections such as sepsis or pneumonia).

• Arterial blood gases (ABGs)
• Hemodynamic monitoring
• Bronchoalveolar lavage (selected patients)
• Transthoracic echocardiogram

• ABGs:
  1. Initially: Varying degrees of hypoxemia, generally resistant to supplemental oxygen
  2. Respiratory alkalosis, decreased PCO₂
  3. Widened alveolar-arterial gradient
  4. Hypercapnia as the disease progresses
• Bronchoalveolar lavage:
  1. The most prominent finding is an increased number of polymorphonucleocytes.
  2. The presence of eosinophilia has therapeutic implications because these patients respond to corticosteroids.
• Blood and urine cultures
• Blood work:
  1. Increased or reduced white blood cell count with left shift if concomitant infectious process
  2. Normal or mildly elevated B-type natriuretic peptide level
  3. Increased lactate level if concomitant sepsis or septic shock

Chest x-ray examination (Fig. 1).

• The initial chest x-ray examination might be normal in the initial hours after the precipitating event.
• Bilateral interstitial infiltrates are usually seen within 24 to 72 h; they often are more prominent in the bases and periphery.
• CT scan of chest: Bilateral diffuse, dense consolidations with air bronchograms.

Treatment of ARDS is supportive. There is no specific pharmacotherapy for ARDS. Management principles are summarized in Table 4.

Hemodynamic monitoring:

• Can be used for the initial evaluation of ARDS (in ruling out cardiogenic pulmonary edema) and its subsequent management. However, a pulmonary catheter is not indicated in the routine management of ARDS. Trials have shown that clinical management involving the early use of pulmonary artery catheters in patients with ARDS did not significantly affect mortality and morbidity rates and may result in more complications as compared with a central venous catheter.
• Although no dynamic profile is diagnostic of ARDS, the presence of pulmonary edema, a high cardiac output, and a low pulmonary capillary wedge pressure (PCWP) is characteristic of ARDS.
• It is important to remember that partially treated intravascular volume overload and flash pulmonary edema can have the hemodynamic features of ARDS; filling pressures can also be elevated by increased intrathoracic pressures or with fluid administration; cardiac function can be depressed by acidosis, hypoxemia, or other factors associated with sepsis.

Ventilatory support:

• Noninvasive positive-pressure ventilation (NIPPV) (i.e., BiPAP) should only be used in selected cases in patients with hypoxic respiratory failure.
• A randomized multicenter, open-label trial showed that high-flow oxygen by nasal cannula increased ventilator-free days and reduced 90-day mortality compared with NIPPV in patients with hypoxemic respiratory failure without hypercapnia. Either modality should not delay intubation and mechanical ventilation initiation in patients with rapidly progressing clinical deterioration.
• Mechanical ventilation is generally necessary to maintain adequate gas exchange. Ventilatory strategy for patients with ARDS as proposed by the ARDS Network is summarized in Fig. 2. A low tidal volume and low plateau pressure ventilator strategy are recommended to avoid ventilator-induced injury. Assist-control is generally preferred initially with the following ventilator settings:
  1. FiO₂ 1.0 (until a lower value can be used to achieve adequate oxygenation). When possible, minimize oxygen toxicity by maintaining FiO₂ at <60%.
  2. Tidal volume: Set initial tidal volume at 6 ml/kg of predicted body weight (PBW). Tidal volumes are reduced from 6 mL/kg of PBW to a minimum of 4 mL/kg if plateau airway pressures exceed 30 cm of water. The concept of using PBW is based on the fact that lung size depends most strongly on height and sex; PBW normalizes the tidal volume to lung size. Aim to maintain plateau pressure (P_plat) at <30 mm Hg PEEP 5 cm H₂O or greater (to increase lung volume and keep alveoli open).
  3. PEEP should be increased in small increments of 3 to 5 cm H₂O to achieve acceptable arterial saturation (>0.9) with nontoxic FiO₂ values (<0.6) and acceptable airway plateau pressures (<30 to 35 cm H₂O). It is important to remember that an increase in PEEP may lower cardiac output and, despite improvement in PaO₂, may actually have a negative effect on tissue oxygenation (the major determinants of tissue oxygenation are hemoglobin, percent saturation, and cardiac output). The optimal level of PEEP remains unestablished.⁷ Although higher levels of PEEP may help prevent life-threatening hypoxemia and be associated with lower hospital mortality in patients meeting criteria for ARDS, such benefit is unlikely in patients with less severe lung injury (PaO₂/FiO₂ >200) and a strategy of treating such patients with high PEEP levels may be harmful. A study published in 2017 demonstrated that the open lung approach increases mortality in patients with moderate to severe ARDS.⁸
  4. Inspiratory flow: 60 L/min.
  5. Ventilatory rate: High ventilatory rates of up to 35 breaths/min are often necessary in patients with ARDS to achieve the desired minute ventilation because of their increased physiologic dead space and smaller lung volumes. Patients must be monitored for excessive intrathoracic gas trapping (auto-PEEP or intrinsic PEEP) that can depress cardiac output.
• Permissive hypercapnia: To maintain a low plateau pressure, a low tidal volume is frequently required, leading to a reduced minute ventilation and hypoventilation with consequently a respiratory acidosis (elevated PCO₂ and reduced pH). Most patients (excluding patients with cerebral edema, acute coronary syndrome, seizures, cardiac arrhythmias, and so on) can tolerate a low pH without major consequences. Bicarbonate replacement is suggested when the pH falls to below 7.20.
• Sedation: Gamma-aminobutyric acid (GABA) receptor agonists (including propofol and benzodiazepines) have traditionally been the most commonly administered sedative drugs for ICU patients. Recent trials indicate that the alpha-2 agonist dexmedetomidine (Precedex) may have distinct advantages. At comparable sedation levels, dexmedetomidine-treated patients spent less time on ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia.
• Neuromuscular blockade: The benefits of early continuous neuromuscular blockade in patients with ARDS who are receiving mechanical ventilation remains unclear. In a trial among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous infusion of the neuromuscular blocking agent cisatracurium and those who were treated with a usual-care approach with lighter sedation targets.^9,10
• Discontinuing ventilation/extubation: Fig. 3 is an algorithm for assessing whether a patient is ready to be liberated from mechanical ventilation and extubated.

Identify and treat precipitating conditions:

• Blood and urine cultures and trial of antibiotics in presumed sepsis (routine administration of antibiotics in all cases of ARDS is not recommended).
• Prompt repair of bone fractures in patients with major trauma.
• Crystalloid resuscitation in pancreatitis.
• Fluid management: In most patients with ARDS, fluid restriction is associated with better outcomes than a liberal fluid policy. Optimal fluid and hemodynamic management of patients with ARDS should be patient specific; in general, administration of crystalloids is recommended if a downward trend in PCWP is associated with diminished cardiac index, resulting in prerenal azotemia, oliguria, and relative tachycardia.¹¹
• Positioning the patient: Changes in position can improve oxygenation by improving the distribution of perfusion to ventilated lung regions; repositioning (lateral decubitus positioning) should be attempted in patients with hypoxemia that is not responsive to other medical interventions. Placing patients with moderate and severe hypoxemia in a prone position may improve their oxygenation. A meta-analysis that included the recent trials by Guerin et al¹² have shown that in patients with severe ARDS, early application of prolonged (over 16 h/day) prone-positioning sessions significantly decreases 28-day and 90-day mortality.
• Corticosteroids: Routine use of corticosteroids in ARDS is not recommended; corticosteroids may be beneficial in patients with many eosinophils in the bronchoalveolar lavage fluid or in patients with severe pneumonia. Systemic infections should be ruled out or adequately treated before administration of corticosteroids. Use of methylprednisolone has not been shown to increase the rate of infectious complications but is associated with a higher rate of neuromuscular weakness. In addition, starting methylprednisolone therapy more than 2 wk after the onset of ARDS may increase the risk of death.
• Nutritional support: Nutritional support, preferably administered by the enteral route, is necessary to maintain adequate colloid oncotic pressure and intravascular volume. The use of antioxidants and dietary oil supplements is still equivocal and cannot be recommended at this time.
• Tracheostomy: Tracheostomy is warranted in patients requiring >2 wk of mechanical ventilation; discussion regarding tracheostomy should begin with patient (if alert and oriented) and/or family members/legal guardian after 5 to 7 days of ventilatory support. Early tracheostomy (within 4 days of admission to critical care) does not limit mortality and results in many unneeded procedures.¹²
• Some form of deep vein thrombosis prophylaxis is indicated in all patients with ARDS.
• Stress ulcer prophylaxis with sucralfate suspension (by nasogastric tube), or proton pump inhibitors (PO or IV) or histamine-2 blockers (PO or IV). Should be reserved for seriously ill patients who are at high risk for this complication.¹³
• The use of surfactant remains controversial. Patients who receive surfactant have a greater improvement in gas exchange in the initial 24-h period than patients who receive standard therapy alone; however, the use of exogenous surfactant does not improve survival.
• Fig. 4 illustrates the management of acute respiratory failure from acute lung injury and ARDS.
• The SARS-CoV-2 virus first identified in 2019 can lead to severe ARDS. There was debate on whether ARDS caused by the virus merited special management. There is now consensus and sufficient evidence that it should not be treated differently than other ARDS resulting from other etiologies. (See chapter on viral pneumonia.)^14,15

• Patients who survive ARDS are at risk of diminished functional capacity, mental illness, and decreased quality of life. Prognosis for ARDS varies with the underlying cause. Prognosis is worse in patients with chronic liver disease, nonpulmonary organ dysfunction, sepsis, and advanced age. ARDS survivors are at high risk for incident joblessness and substantial loss of wages, and 58% of those returning to work received disability.
• Elevated values of dead space fraction ([PaCO₂ >2 PeCO₂]/PaCO₂; normal is <0.3) is associated with an increased risk of death.
• In ARDS, the percentage of potentially recruitable lung is variable and associated with the response to PEEP.
• Overall mortality rate varies between 32% and 45%. Most deaths are attributable to sepsis or multiorgan dysfunction rather than primary respiratory causes.
• Trials have shown that as compared with the current standard of care, a ventilator strategy using esophageal measures to estimate the transpulmonary pressure significantly improves oxygenation and compliance. Further trials will determine if this approach should be widely adopted.
• Other strategies for treatment of life-threatening refractory hypoxemia (inhaled nitric acid, extracorporeal membrane oxygenation [ECMO], high-frequency oscillatory ventilation, recruitment maneuvers) may improve oxygenation, but their impact on mortality remains unproven. Use of ECMO in combination with lung-protective ventilation was found to be beneficial as a treatment strategy early in the course of ARDS related to H1N1 infection. Extracorporeal gas exchange may allow the use of low tidal volumes and lower levels of inspired oxygen and use of higher PEEP if desired. ECMO is costly and labor-intensive. The role and proper use of ECMO for patients with ARDS have not been clearly defined.^16,17
• General indications for ECMO in severe cases of ARDS are:
  1. Severe hypoxemia (e.g., ratio of PaO₂ to FiO₂ <80 despite the application of high levels of PEEP [typically 15 to 20 cm H₂O]) for at least 6 h in patients with potentially reversible respiratory failure
  2. Uncompensated hypercapnia with acidemia (pH <7.15) despite the best accepted standard of care for management with a ventilator
  3. Excessively high-end inspiratory plateau pressure (>35 to 45 cm H₂O, according to the patient’s body size) despite the best accepted standard of care for management with a ventilator

Surgical referral for tracheostomy (see “Acute General Rx”).

Referral to ECMO team or center in severe cases when indicated.

Acute Respiratory Distress Syndrome (ARDS) (Patient Information)

Pneumonia, Viral (Related Key Topic)