ARDS is an acute, diffuse, inflammatory lung injury that causes increased pulmonary vascular permeability or “leaky capillaries” within the lung, impairing ventilation. Clinical hallmarks of ARDS are hypoxemia and bilateral opacities on chest radiograph.1 Many clinicians use the terms acute respiratory distress syndrome and acute lung injury (ALI) interchangeably; however, the updated definition of ARDS classifies ALI as mild ARDS.1 This article provides a review of ARDS, including epidemiology, pathophysiology, clinical presentation, diagnostic criteria, a brief overview of treatment focusing on mechanical ventilation, and alternative treatments such as recruitment maneuvers and prone positioning.
Each year, about 190,000 patients in the United States develop ARDS.2 In the ICU, 7% to 10% of admitted patients and 5% to 8% of mechanically ventilated patients meet the criteria for ARDS.3 According to a comprehensive systematic review published in 2009, mortality from ARDS has remained stable at 44% in observation studies and 36.2% in random controlled trials.4 The most common cause of mortality in patients with ARDS is multiorgan failure secondary to sepsis. Severe irreversible hypoxemia only accounts for 9% to 19% of deaths.3
Understanding normal lung physiology is key to understanding the mechanism of ARDS and ALI. Normal healthy lungs regulate the movement of fluid within the pulmonary vasculature, maintaining a small amount of interstitial fluid and keeping the alveoli dry. The wall of the pulmonary capillaries is selectively permeable. This semi-permeable membrane lets fluid cross under the control of hydrostatic and oncotic pressures and keeps serum proteins in the vessels.5 Three mechanisms prevent alveolar edema or fluid overload in the lung:
* retained intravascular proteins maintain an oncotic pressure gradient that allows fluid reabsorption
* the interstitial lymphatic system returns large amounts of fluid back into circulation
* tight junctions between alveolar epithelial cells prevent fluid from leaking into the air spaces of the lung.
Lung injury causes excess fluid to leak into both the interstitium and alveoli; this fluid overload causes impaired gas exchange, pulmonary hypertension, and compromised lung compliance.6
ARDS is caused by damage to the alveoli and acute inflammation of the alveolar walls and hyaline membranes.1 The injury causes the release of proinflammatory cytokines, which recruit neutrophils to the lungs (Figure 1). The activated neutrophils release toxic mediators that damage the pulmonary capillary endothelium and alveolar epithelium.7,8 Damage to the capillary endothelium and alveolar epithelium lets oncotic proteins escape from the intravascular space, causing pulmonary edema (Figure 2). The oncotic gradient that normally favors resorption of fluid is destroyed, leading to the release of fluid into the interstitium.9 The normal physiologic ability to regulate the fluid clearance is also either damaged or lost. This results in aerated tissue filling with bloody, proteinaceous edema fluid and other debris. Functional surfactant is also lost, resulting in alveolar collapse.10
Ventilation-perfusion mismatching, commonly known as a V/Q mismatch, causes impaired gas exchange. Physiologic shunting (normal perfusion with no ventilation) causes hypoxemia. Increased physiologic dead space (normal ventilation with no perfusion) impairs the elimination of carbon dioxide, leading to severe respiratory acidosis, hypotension, and lethargy.11
Impaired pulmonary compliance, another hallmark of ARDS, is caused by the stiffness of a poorly or completely non-aerated lung. This stiffness prevents the lung from fully expanding on inhalation, compromising the normal pressure-volume characteristics of functioning lung tissue. Decreased compliance limits inspiratory capacity even with small tidal volumes and causes increased airway pressures.12
Pulmonary hypertension is a consequence caused by the treatment of ARDS with mechanical ventilation, and occurs in up to 25% of patients. Pulmonary hypertension is caused by hypoxic vasoconstriction, vascular compression with the use of positive airway pressure, airway collapse, hypercarbia, and pulmonary vasoconstrictors.13
CAUSES OF ARDS
Sepsis is the most common cause of ARDS, although more than 60 other causes have been identified.14 About one-third of hospitalized patients who have a witnessed episode of aspiration of gastric contents will develop ARDS. Gastric enzymes and food particles are believed to contribute to alveolar damage.14 Nosocomial pneumonias can also develop into ARDS. Common pathogens include Streptococcus pneumonia, Legionella pneumophila, Pneumocystis jiroveci, Staphylococcus aureus, and Pseudomonas aeruginosa.15
ARDS can be a complication of severe trauma including bilateral lung contusion after blunt trauma, fat embolism resulting from long-bone fractures, and sepsis secondary to burns and massive tissue injury.16 Massive transfusion of blood products can cause transfusion-related acute lung injury (TRALI) and ARDS. Transfusion of more than 15 units of packed red blood cells is a risk factor, as well as transfusion of fresh frozen plasma and platelets. The symptoms of ARDS develop within 6 hours of transfusion; however, the mechanism of the alveolar injury is not completely understood. The volume-expansion quality of blood products may contribute to fluid overload, leading to the development of pulmonary edema and potentially TRALI and ARDS.17
In patients who are not hospitalized, community-acquired pneumonia is the most common cause of ARDS.
Clinical features of ARDS appear within 6 to 72 hours after the causative event. Patients present with dyspnea, cyanosis, and diffuse crackles on auscultation. Other signs include tachypnea, tachycardia, diaphoresis, use of accessory muscles of respiration, cough, and chest pain. The hallmark radiographic presentation is bilateral “fluffy” infiltrates (Figure 3).
Clinical findings also will represent the inciting event or cause of ARDS in individual patients. For example, if the cause is sepsis, the patient may have fever, leukocytosis, lactic acidosis, hypotension, and disseminated intravascular coagulation.1
Clinical course During the first few days of symptom onset, patients require moderate to high concentrations of oxygen. This initial period is associated with the highest mortality rate due to severe hypoxemia and significant bilateral infiltrates on chest radiograph. After this initial period, the infiltrates will begin to dissipate and the patient's oxygenation will improve. Improved oxygenation will allow the clinician to start weaning ventilator support and prevent prolonged use of toxic oxygen levels (greater than 60% FiO2).
Patients who do not exhibit improved oxygenation secondary to persistent severe hypoxemia become ventilator-dependent. Prolonged respiratory failure and alveolar damage leads to pulmonary proliferative changes and fibrosis. Radiographically, fibroproliferative changes appear as a coarse reticular pattern as opposed to bilateral opacification seen in classic ARDS. These fibrotic changes are associated with persistent hypoxemia, increased dead space, further impaired lung compliance, and progressive pulmonary hypertension. Patients who survive the initial phase of ARDS and the potential fibroproliferative phase will enter the subsequent phase of resolution and restoration. This phase can take weeks to months as the hypoxemia and infiltrates improve.1
Common complications Major complications of ARDS include barotrauma, delirium, and nosocomial infection. Patients with ARDS are predisposed to pulmonary barotrauma due to impaired lung compliance and the physical stress of positive pressure mechanical ventilation on damaged alveolar membranes. As stated, poor lung compliance prevents full expansion of the lung with inhalation. With large tidal volumes (8 to 10 mL/kg), pressure can build within the lung, increasing the risk of barotrauma. This can cause a simple to a potentially life-threatening tension pneumothorax. Clinically, this complication is less common now that low tidal volume ventilation is widely accepted. Low tidal volume ventilation reduces plateau airway pressure, which is associated with a lower incidence of pulmonary barotrauma.18
Delirium is commonly associated with ICU patients because of their prolonged hospital stay and increased risk of infection. Nosocomial infections, particularly pneumonia, are a major cause of morbidity and mortality in patients with ARDS. Intubation and endotracheal tube care increases the risk of pneumonia in all patients requiring mechanical ventilation. Note pneumonia and ARDS are difficult to distinguish radiographically because of the type of infiltrates seen in both conditions. Many of these patients also require invasive procedures such as arterial and central line placement; these procedures increase the risk of infection.19
The diagnosis of ARDS is determined with symptom onset, arterial blood gas (ABG) analysis, chest radiograph, and CT scan. The cause of the syndrome cannot be associated with a cardiac cause such as heart failure (infiltrates associated with ARDS and severe pulmonary edema caused by heart failure are difficult to differentiate on radiographs). Once this has been determined (primarily with echocardiogram), the specific criteria created by the Berlin Definition of ARDS (Table 1) are used to determine the severity of ARDS.
The updated 2012 Berlin Definition of ARDS does not include pulmonary artery occlusion pressure as part of the diagnostic criteria, because the use of high-risk invasive pulmonary artery catheters has declined greatly in the last decade.
Treatment for ARDS should focus on hemodynamic monitoring, oxygenation, fluid management, infection prevention, prophylaxis for gastrointestinal ulcers and deep vein thrombosis (DVT), and nutritional support.
Fluid management depends on the cause of ARDS. Patients with ARDS caused by pneumonia or inhalation injury can be treated with fluid restriction with a negative fluid balance. When ARDS is secondary to infection or inflammation, the patient may need initial aggressive fluid resuscitation and may need vasopressor therapy for hemodynamic stabilization. Closely monitor daily fluid intake and output and overall fluid balance.
Critically ill patients are at risk for stress-induced ulcers; prescribe proton pump inhibitors, histamine2 receptor antagonists, or sucralfate for patients with ARDS. Use caution when prescribing PPIs because of the increased risk for healthcare-associated pneumonia.20 Patients who are intubated and immobile can develop DVT and pulmonary embolism. Unfractionated or low-molecular-weight heparin is recommended for these patients, along with graduated compression stockings and intermittent pneumatic compression devices. After 48 to 72 hours of mechanical ventilation, patients should be started on nutritional support, using a high-fat, low-carbohydrate formula administered via feeding tube.
Mechanical ventilation is the cornerstone of treatment for patients with ARDS. In these patients, a small portion of the lung remains healthy with normal aerated tissue. This area is especially susceptible to over-distention and barotrauma because it has normal compliance. Protect this area by using low tidal volumes and increasing perfusion.3 Low tidal volume ventilation is a lung protective form of ventilation; the definition is 5 to 8 mL/kg and a plateau pressure maintained at less than 30 cm H2O.
The ARDS network developed a landmark trial that determined that low tidal volume ventilation significantly reduced mortality in patients with ARDS.21 The ARMA trial (originally a trial known as KARMA, the Ketoconazole and Respiratory Management in Acute lung injury/ARDS) determined that the low tidal volume ventilation group had a lower mortality rate and more ventilator-free days.22 Two meta-analyses of randomized trials found that low tidal volume ventilation significantly improved 28-day mortality and hospital mortality when compared to conventional mechanical ventilation.23,24
Another aspect of ventilation that reduces lung injury is delivering a high level of positive end-expiratory pressure (PEEP). High PEEP opens collapsed alveoli and decreases alveolar distention. Keeping the alveoli open throughout the respiratory cycle reduces cyclic atelectasis, one of the main causes of lung injury.25 Therefore higher PEEP improves oxygenation.3
Treatment should also be focused on the cause of the lung injury. As stated, sepsis is the most common cause of ARDS. The treatment of sepsis includes broad-spectrum antibiotics particularly with coverage for pneumonia, and IV fluid resuscitation to maintain a central venous pressure (CVP) above 12 to 14 mm Hg in mechanically ventilated patients. Maintain a mean arterial pressure (MAP) above 65 mm Hg, prescribing vasopressors if indicated. If the clinical picture permits, diuretics can reduce pulmonary edema. Laboratory results such as complete blood cell count, comprehensive metabolic panel, ABGs, venous blood gas, lactic acid, blood cultures, and respiratory cultures also are helpful in focusing the treatment towards a specific cause.3
Alternative treatments for ARDS include recruitment maneuvers, sigh breaths, and prone positioning.
A recruitment maneuver is the use of a high level of CPAP for a brief period of time (for example, 35 to 40 cm H2O for about 40 seconds). This application of high pressure is thought to open collapsed alveoli.26 Sigh breaths are a type of recruitment maneuver involving cyclic administration of high-level CPAP for brief periods of time (typically 3 breaths of CPAP at 45 cm H2O per minute for 1 hour). Studies suggest that sigh breaths are most beneficial for patients who are in a prone position and for patients with extrapulmonary causes of ARDS.27
The prone position was first proposed for treating ARDS in 1974, when it was suggested that this position would better-expand the dorsal lung regions and improve oxygenation. Prone positioning improves oxygenation by recruiting alveoli, redistributing ventilation toward dorsal areas of the lung, improving V• /Q• matching, and eliminating compression of the lung by the heart. Prone ventilation may also reduce ventilator-induced lung injury by reducing lung stress and strain.28 A prospective randomized study also demonstrated that the combination of the prone position with the upright position leads to further improvement of oxygenation in patients.29
The key to preventing ARDS is to manage the predisposing factors, such as sepsis, aspiration pneumonia, trauma, and massive transfusions/TRALI. Another way to prevent lung injury is to use lung-protective tidal volumes on all mechanically ventilated patients. A preventive randomized controlled trial sought to determine whether the low tidal volume ventilation used to reduce barotrauma in patients with ARDS would be beneficial for preventing ALI and ARDS in all mechanically ventilated patients. The data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury at the onset of mechanical ventilation. The use of low tidal volume ventilation leads to a significant decrease in the incidence of ALI, ARDS, and mortality in ventilated patients.30
The many advances in the management of ARDS have led to a reduction in morbidity and mortality. However, the prognosis of these patients remains poor. Future efforts in clinical research should continue to focus on the use of mechanical ventilation and strategies to prevent further lung injury. Research also should address the use of alternative treatments, such as noninvasive maneuvers, novel drug therapies, and early diagnostic markers. These developments may lead us to improve the management of this serious condition.
1. The ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin Definition. JAMA. 2012;5:1-13.
2. Ruberfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685.
3. Cortes I, Penuelas O, Esteban A. Acute respiratory distress syndrome: evaluation and management. Minerva Anestesiologica. 2011;78(3):343–357.
4. Phua J, Badia JR, Adhikari NK, et al. Has mortality from acute respiratory distress syndrome decreased over time. Am J Respir Crit Care Med. 2009;179:220–227.
5. George RB, Chesson AL, Rennard SI. Functional anatomy of the respiratory system. In George RB, Light RW, Matthay MA, et al (eds). Chest Medicine Essentials of Pulmonary and Critical Care Medicine, 3rd edition. Lippincott Williams & Wilkins, Baltimore, MD, 1995.
6. Matthay MA. Acute hypoxemia respiratory failure: pulmonary edema and ARDS. In George RB, Light RW, Matthay MA, et al (eds). Chest Medicine Essentials of Pulmonary and Critical Care Medicine, 3rd edition. Lippincott Williams & Wilkins, Baltimore, MD, 1995.
7. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med. 2004;141:460.
8. Martin TR. Lung cytokines and ARDS: Roger S. Mitchell Lecture. Chest. 1999;116(1 Suppl):2S-8S.
9. Calandrino FS Jr, Anderson DJ, Mintun MA, Schuster DP. Pulmonary vascular permeability during the adult respiratory distress syndrome: a positron emission tomographic study. Am Rev Respir Dis. 1988;138:421.
10. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1376.
11. Dantzker DR, Brook CJ, Dehart P, et al. Ventilation-perfusion distributions in the adult respiratory distress syndrome. Am Rev Respir Dis. 1979;120:1039.
12. Roupie E, Dambrosio M, Servillo G, et al. Titration of tidal volume and induced hypercapnia in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995;152:121.
13. Morelli A, Teboul JL, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med. 2006;34:2287.
14. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995;151:293.
15. Mannes GP, Boersma WG, Baur CH, Postmus PE. Adult respiratory distress syndrome due to bacteremic pneumococcal pneumonia. Eur Respir J. 1991;4:503.
16. Treggiari MM, Hudson LD, Martin DP, et al. Effect of acute lung injury and acute respiratory distress syndrome on outcome in critically ill trauma patients. Crit Care Med. 2004;32:327.
17. Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol. 2007; 136:788.
18. Boussarsar M, Thierry G, Jaber S, et al. Relationship between ventilator settings and barotraumas in the acute relationship distress syndrome. Intens Care Med. 2002;28:406.
19. Chastre J, Trouillet JL, Vuagnat A, et al.. Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998;157:1165.
20. Barkun AN, Bardou M, Pham CQ, Martel M. Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis. Am J Gastroenterol. 2012;107(4):507.
21. Burns K, Adhikari N, Slutsky A, et al. Pressure and volume limited ventilation for the ventilator management of patients with acute lung injury: a systematic review and meta-analysis. PLoS ONE. 2011;6(1):e14623.
22. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301.
23. Pertucci N, Iacovelli W. Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and acute respiratory distress syndrome. Cochrane Database Sys Rev. 2004;CD003844.
24. Putensen C, Theuerkauf N, Zinserling J, et al. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009;151:566.
25. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilator strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med. 2006;34:1311.
26. Hodgson C, Keating JL, Holland AE, et al. Recruitment maneuvers for adults with acute lung injury receiving mechanical ventilation. Cochrane Database Sys Rev. 2009;CD006667.
27. Pelosi P, Cadringher P, Bottino N, et al. Sigh in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;159:872.
28. Girard T, Bernard G. Mechanical ventilation in ARDS: a state-of-the-art review. Chest. 2007;131:921–929.
29. Robak O, Schellongowski P, Bojic A, et al. Short-term effects of combining upright and prone positions in patients with ARDS: a prospective randomized study. Crit Care. 2011;15:R230.
30. Determann R, Royakkers A, Wolthuis EK, et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010;14(1):R1.
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