Show Summary Details
Page of

Pathophysiology of acute respiratory distress syndrome 

Pathophysiology of acute respiratory distress syndrome
Chapter:
Pathophysiology of acute respiratory distress syndrome
Author(s):

Lorraine B. Ware

DOI:
10.1093/med/9780199600830.003.0108
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2020. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

date: 30 November 2020

Key points

  • ARDS can occur in disparate clinical settings including both children and adults, both medical and surgical patients, and in both the immunocompetent and the immunocompromised.

  • Common aetiologies of ARDS include sepsis, pneumonia, severe traumatic injury and aspiration of gastric contents.

  • Clinical identification of cases of ARDS is based on the acute onset of both radiographic infiltrates and significant hypoxaemia.

  • Alveolar flooding causes decreased lung compliance, ventilation perfusion mismatch, and shunt leading to increased work of breathing and hypoxaemia.

  • The pathophysiology of ARDS is complex and involves acute lung inflammation, increased permeability of the lung endothelial and epithelial barriers, inhibition of surfactant function, impairment of alveolar fluid clearance mechanisms and systemic inflammation.

Clinical presentation

The acute respiratory distress syndrome (ARDS) is a common clinical syndrome with an estimated incidence in the United States of 180,000 cases per year [1]‌. ARDS can occur in disparate clinical settings, and is seen in both children and adults, in medical and surgical patients, and in both the immunocompetent and the immunocompromised. Common aetiologies of ARDS include sepsis, pneumonia, severe traumatic injury, and aspiration of gastric contents [2]. Less common aetiologies include acute pancreatitis, transfusion-associated acute lung injury (TRALI), ischaemia reperfusion injury, drug overdose, fat embolism, and near drowning. Environmental factors, such as alcohol abuse and cigarette smoke exposure may increase the risk of developing ARDS in at risk patients.

Regardless of the underlying cause, ARDS is characterized by the acute onset of non-cardiogenic pulmonary oedema leading to increased work of breathing and acute hypoxaemic respiratory failure. The majority of patients require invasive mechanical ventilation. Although ARDS is defined by its pulmonary manifestations, multi-organ system failure is common and contributes to morbidity and mortality. Current mortality rates in unselected patients are in the 30–50% range. Mortality rates in clinical trials tend to be lower due to exclusion of patients with severe comorbidities. Morbidity is likewise high; survivors have both short- and long-term sequelae, including pulmonary function abnormalities, cognitive impairment, and other neurologic problems [3]‌.

Diagnosis and clinical definitions

The diagnosis of ARDS should be considered in any patient presenting with acute respiratory failure, and an appropriate risk factor for ARDS, such as sepsis, pneumonia, or severe trauma. Although recent efforts have been aimed at identifying patients at risk for ARDS [4]‌ or with early ARDS [5], the clinical definitions of ARDS, established by expert consensus, are intended for diagnosis of established ARDS. The Berlin definitions [6], the most recent, are a minor modification of the 1994 American European Consensus Conference definitions [7]. Diagnosis is based on the acute onset (within 1 week) of radiographic infiltrates consistent with acute pulmonary oedema (Fig. 108.1) accompanied by hypoxaemia as assessed by the arterial to inspired oxygen fraction. In addition, there should be no clinical evidence of a cardiogenic cause of pulmonary oedema. Echocardiography to exclude a cardiac cause should be considered in patients without a risk factor for ARDS [6]. Despite the simplicity of the definitions, they are under-utilized and the diagnosis of ARDS is often missed leading to under-treatment. The need for arterial blood gas measurement may be one factor that limits uniform application of ARDS definitions, particularly in children. Several investigators have studied the use of the oxygenation saturation (as measured by pulse oximetry) to inspired oxygen ratio [SpO2/FiO2] as a substitute for the PaO2/FiO2 ratio in determining the severity of hypoxemia across various patient populations [8].

Fig. 108.1 Frontal chest radiograph of a patient with ARDS.

Fig. 108.1 Frontal chest radiograph of a patient with ARDS.

Pathologically, ARDS is characterized by diffuse alveolar damage (Fig. 108.2) [2]‌. This injury pattern is consistent regardless of the underlying cause of ARDS. Invasive diagnosis of ARDS by lung biopsy is not commonly undertaken due to the morbidity and mortality associated with lung biopsy in the critically ill. Of note, in autopsy studies, neither the American European Consensus Conference [9] nor the Berlin ARDS definitions [10] have high specificity for diffuse alveolar damage. Other pathological diagnoses that were made at autopsy in patients who met the Berlin definition of ARDS include pneumonia, abscess, tuberculosis, cancer, pulmonary embolism, acute pulmonary oedema, pulmonary haemorrhage, interstitial pneumonia/fibrosis, and severe emphysema, underscoring the fact that a variety of clinical conditions can present with clinical features consistent with ARDS [10].

Fig. 108.2 Photomicrograph (×400) of lung tissue from a patient with ARDS showing diffuse alveolar damage with hyaline membrane formation, and intra-alveolar and interstitial neutrophilic inflammation.

Fig. 108.2 Photomicrograph (×400) of lung tissue from a patient with ARDS showing diffuse alveolar damage with hyaline membrane formation, and intra-alveolar and interstitial neutrophilic inflammation.

Physiological mechanisms of impaired gas exchange and alterations in pulmonary mechanics in ARDS

Acute non-cardiogenic pulmonary oedema is a prominent clinical feature of ARDS. Pulmonary oedema formation in ARDS is caused by increased lung endothelial and alveolar epithelial permeability. Increased endothelial permeability leads to increased rates of filtration of fluid and solute from the lung microvasculature into the lung interstitium. In the absence of increased epithelial permeability, oedema fluid accumulates in the peribronchial interstitial space, and is drained from the peribronchial interstitium by the lung lymphatics that arise in this space. The early interstitial phase of non-cardiogenic pulmonary oedema may not be recognized clinically since interstitial oedema alone does not typically cause significant hypoxaemia and pulmonary oedema may not be visible on chest radiograph until lung water content increases by over 30%.

Although some patients with very mild lung injury may have only interstitial oedema, increased alveolar epithelial permeability due to injury to the epithelial barrier combined with fluid filtration rates that exceed the capacity of the lung lymphatics for fluid removal leads to frank alveolar flooding. Alveolar flooding is a major cause of hypoxaemia in ARDS. Lung units that are flooded contribute to ventilation–perfusion mismatch and intrapulmonary shunt. Inactivation of surfactant by alveolar fluid accumulation may also cause atelectasis of alveolar units, contributing to ventilation–perfusion mismatch and shunt.

Both interstitial and alveolar oedema decrease lung compliance contributing to the increased work of breathing, as well as to the need for ventilation with relatively high distending pressures to deliver sufficient tidal volumes to maintain alveolar ventilation. Accumulation of pulmonary oedema fluid in the peribronchial interstitial space can increase airway resistance, further contributing to increased work of breathing.

Although increased permeability is the primary cause of pulmonary oedema in ARDS, any increases in pulmonary microvascular hydrostatic pressure will raise the driving force for oedema fluid formation across the permeable alveolar–capillary barrier. Increased pulmonary microvascular hydrostatic pressure is common in patients with ARDS [11]. As is discussed in more detail in the chapter on treatment of ARDS, treatment to lower pulmonary microvascular hydrostatic pressure can reduce duration of mechanical ventilation in ARDS likely due to diminished pulmonary oedema formation [11].

Although plain chest radiographs may suggest that pulmonary oedema is diffusely distributed throughout the lung in ARDS, computed tomography demonstrates substantial heterogeneity in oedema distribution [12]. In some patients, particularly those with an extra-pulmonary cause of ARDS [13], pulmonary oedema is indeed diffuse, while others have more focal oedema which tends to be concentrated in dependent regions with less dependent regions appearing more normal.

Molecular mechanisms of acute lung injury and ARDS

A variety of cellular and molecular mechanisms contribute to the pathophysiology of ARDS [14]. Although our understanding of the pathophysiological pathways has improved substantially in the past two decades, therapies targeted at specific mechanisms of injury have largely been ineffective, perhaps due to the complexity and redundancy of injury pathways. In addition, many of these pathways are critically important in host defence.

Inflammation

Dysregulated inflammation is a pathophysiological hallmark of ARDS. Innate immune response pathways are activated in ARDS by pattern recognition receptor binding by either pathogen-derived or cell injury-derived molecules that serve as danger signals. Pattern recognition receptors, such as the Toll-like receptors are highly expressed on the lung epithelium and alveolar macrophages. Activation of these receptors leads to pro-inflammatory signalling, and robust cytokine and chemokine production, activating alveolar macrophages and recruiting neutrophils from the vasculature into the alveolar space. Intracellular pattern recognition receptors such as the Nod-like receptors can also be activated leading to inflammasome activation, caspase-1 cleavage, and release of the pro-inflammatory cytokines interleukin-1 and interleukin-18. Activated neutrophils can release a variety of potentially injurious products, including proteases, oxidants, lipid mediators, histones, and neutrophil extracellular traps, networks of extracellular antimicrobial factors, and chromatin that can cause endothelial injury. Although these neutrophil-derived mediators are important for host defence against pathogens, excessive, rather than controlled production can contribute to lung injury.

Molecular mechanisms of increased endothelial permeability

The integrity of the lung endothelial barrier is maintained by adherens junctions that are formed by structural proteins, including endothelial-specific VE-cadherin. Factors that stabilize and destabilize the adherens junctions regulate endothelial permeability [15]. Destabilizing factors that may increase permeability in ARDS include pro-inflammatory agonists, such as thrombin, vascular endothelial growth factor, TNF, interleukin-1, microbial products such as lipopolysccharide and leukocyte signals. These factors can disrupt the adherens junction by disrupting homophilic bonds between VE-cadherin molecules. Stabilizing factors include sphingosine-1 phosphate, a glycosphingolipid, and the Robo/Slit signalling pathway. Other endothelial stabilizing agonists include angiopoietin-1, atrial natriuretic peptide, activated protein C, and ATP. Although targeting endothelial stabilization pathways is an attractive avenue for development of potential therapies for ARDS and sepsis, increased endothelial permeability also facilitates leukocyte margination, a process that is critically important for host defence.

Molecular mechanisms of epithelial injury and permeability

The alveolar epithelium is an important site of injury in ARDS that contributes to increased alveolar–capillary barrier permeability and pulmonary oedema formation. In ultrastructural studies of patients dying with ARDS, epithelial lesions range from mild injury with cytoplasmic swelling, vacuolization, and bleb formation to frank necrosis and complete loss of the epithelial layer [16].

In addition to impairing barrier function, injury to the lung epithelium facilitates leukocyte migration, reduces surfactant production and inhibits the clearance of pulmonary oedema fluid from the airspace. Alveolar fluid clearance is normally driven by transcellular active transport of sodium and chloride across the lung epithelial layer from the airspace into the interstitium, which creates a mini-osmotic gradient for resorption of water. In patients with ARDS, intact lung epithelial fluid transport function is associated with better clinical outcomes suggesting that the degree of alveolar epithelial injury is an important determinant of clinical severity of lung injury. In addition to simple loss of barrier function, a variety of other mechanisms have been identified that impair alveolar fluid clearance in ARDS including deleterious effects of pro-inflammatory cytokines, oxidants, and hypoxia.

Regulation of lung epithelial permeability has not been as well studied as endothelial permeability. In general, the lung epithelial barrier is much tighter than the endothelial barrier. Like the endothelium, the epithelial barrier is maintained by cadherin-mediated adherens junction bonds and tight junctions, but contains epithelial specific E-cadherin, rather than VE-cadherin. Recent evidence suggests that the tight junction proteins claudins may be critical regulators of lung epithelial permeability in ARDS.

Ventilator-induced lung injury

Although mechanical ventilation is an important supportive therapy for patients with ARDS, ventilation with high volumes, and high pressures can injure the normal lung and exacerbate injury and oedema formation in the injured lung. There are several mechanisms by which mechanical ventilation is injurious. Because of heterogeneity in the distribution of alveolar consolidation, tidal volumes are delivered predominantly to alveoli that are relatively uninjured, leading to over distension. Alveolar over distension can cause capillary stress failure with endothelial and epithelial injury and initiation of a pro-inflammatory cascade, as well as release or metalloproteinases and oxidative stress. Clinical trials aimed at reducing alveolar over distension by reducing tidal volume have improved clinical outcomes in ARDS [17]. In addition to alveolar over distension, the repeated collapse and re-opening of atelectatic alveoli in areas where surfactant function is impaired can be pro-inflammatory. However, therapies targeted at maintaining alveolar recruitment have not yet had a major impact on clinical outcomes, perhaps because it is difficult in an individual patient to improve alveolar recruitment without causing alveolar over distension.

Dysregulated coagulation and fibrinolysis

In patients with ARDS, both intra- and extravascular coagulation and fibrinolytic pathways are dysregulated [18]. Intra-alveolar fibrin deposition, as evidenced by hyaline membrane formation, is promoted by increased procoagulant, and decreased anticoagulant and fibrinolytic mediators in the airspace. Tissue factor, a potent activator of the extrinsic coagulation cascade, is elevated in the airspace in ARDS, and is associated with increased procoagulant activity. Active tissue factor is also shed into the airspace on membrane-bound microvesicles. Levels of the endogenous anticoagulant protein C are decreased and high levels of plasminogen activator inhibitor-1 impair fibrinolysis.

The systemic procoagulant antifibrinolytic state in ARDS is characterized by increased circulating levels of tissue factor, and PAI-1 and decreased levels of protein C. Microvascular thrombosis occurs both systemically and in the lung in ARDS. Systemic microvascular thrombosis probably contributes to the frequent occurrence of multi-organ system failure in patients with ALI/ARDS. Microvascular thrombosis in the lung capillary bed contributes to ventilation–perfusion mismatch and elevated pulmonary dead space fraction.

Initiation of coagulation is a potent pro-inflammatory stimulus that has been postulated to amplify lung inflammation in ARDS. Thrombin generation induces neutrophil adhesion to the endothelium, expression of selectin, and activation of platelet receptors. Fibrin generation also increases vascular permeability, activates endothelial cells, and induces neutrophil adhesion and margination. However, anticoagulant therapies have not been effective at reducing mortality in clinical ARDS or sepsis. Several recent experimental studies suggest that procoagulant pathways are critically important in regulating barrier permeability and host defence in ARDS, findings that could explain the lack of clinical benefit of anticoagulant strategies.

Resolution of ARDS

Although patients with ARDS continue to die from refractory respiratory failure and multi-organ system failure, with improvements in supportive care and ventilator management, the majority of patients (>50%) with ARDS now survive to hospital discharge. Although ARDS survivors may have chronic neurological and cognitive impairments related to critical illness, lung function in survivors of ARDS gradually returns to normal or near normal. By 1 year, only modest decrements in diffusing capacity for carbon monoxide may persist. In order for normal lung function to be restored, a variety of resolution pathways need to be activated.

In order for lung epithelial integrity to be restored, the alveolar epithelium must be repopulated to replace injured and necrotic cells. Alveolar epithelial type I cells, which cover the majority of the alveolar surface are regenerated through proliferation and differentiation of the more injury-resistant alveolar epithelial type II cells. Recent evidence also suggests a role for broncho-alveolar stem cells that reside in the broncho-alveolar junction. Therapies that accelerate alveolar epithelial regeneration, such as keratinocyte growth factor can improve experimental lung injury suggesting that epithelial regeneration is a key determinant of outcome of ARDS. Endothelial integrity must also be restored, but this process is less well understood.

Resolution of pulmonary oedema is mediated by alveolar epithelial fluid transport, which requires an intact alveolar epithelium. Although various mediators such as beta-adrenergic agonists have been identified that accelerate the rate of alveolar fluid clearance in animal and human lungs, clinical trials have been disappointing [19,20].

Resolution of inflammation is a coordinated process that involves termination of pro-inflammatory signalling, elaboration of anti-inflammatory signals such as lipoxin A4, resolvin E1, and clearance of apoptotic neutrophils by alveolar macrophages. Recent experimental evidence suggests that T-regulatory lymphocytes are important regulators of resolution of lung inflammation, enhancing neutrophil apoptosis, and suppressing cytokine secretion, in part by release of TGF-beta.

References

1. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. (2005). Incidence and outcomes of acute lung injury. New England Journal of Medicine, 353(16), 1685–93.Find this resource:

2. Ware LB and Matthay MA. (2000). Medical progress: the acute respiratory distress syndrome. New England Journal of Medicine, 342, 1334–49.Find this resource:

3. Herridge MS, Tansey CM, Matte A, et al. (2011). Functional disability 5 years after acute respiratory distress syndrome. New England Journal of Medicine, 364(14), 1293–304.Find this resource:

4. Gajic O, Dabbagh O, Park PK, et al. (2011). Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. American Journal of Respiratory and Critical Care Medicine, 183(4), 462–70.Find this resource:

5. Levitt JE, Bedi H, Calfee CS, Gould MK, and Matthay MA. (2009). Identification of early acute lung injury at initial evaluation in an acute care setting prior to the onset of respiratory failure. Chest, 135(4), 936–43.Find this resource:

6. Ranieri VM, Rubenfeld GD, Thompson BT, et al. (2012). Acute respiratory distress syndrome: the Berlin Definition. Journal of the American Medical Association, 307(23), 2526–33.Find this resource:

7. Bernard GR, Artigas A, Brigham KL, et al. (1994). The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. American Journal of Respiratory and Critical Care Medicine, 149, 818–24.Find this resource:

8. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, and Ware LB. (2007). Comparison of the SpO2/FiO2 ratio and the PaO2/FiO2 ratio in patients with acute lung injury or acute respiratory distress syndrome. Chest, 132(2), 410–17.Find this resource:

9. Esteban A, Fernandez-Segoviano P, Frutos-Vivar F, et al. (2004). Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings. Annals of Internal Medicine, 141, 440–5.Find this resource:

10. Thille AW, Esteban A, Fernandez-Segoviano P, et al. (2013). Comparison of the Berlin Definition for Acute Respiratory Distress Syndrome with Autopsy. American Journal of Respiratory and Critical Care Medicine, 187(7), 761–7.Find this resource:

11. Wheeler AP, Bernard GR, Thompson BT, et al. (2006). Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. New England Journal of Medicine, 354(21), 2213–24.Find this resource:

*12. Gattinoni L, Bombino M, Pelosi P, et al. (1994). Lung structure and function in different stages of severe adult respiratory distress syndrome. Journal of the American Medical Association, 271, 1772–9.Find this resource:

13. Pelosi P, D’Onofrio D, Chiumello D, et al. (2003). Pulmonary and extrapulmonary acute respiratory distress syndrome are different. European Respiratory Journal, 42(Suppl.), 48s–56s.Find this resource:

14. Matthay MA, Ware LB, and Zimmerman GA. (2012). The acute respiratory distress syndrome. Journal of Clinical Investigation, 122(8), 2731–40.Find this resource:

15. Vandenbroucke E, Mehta D, Minshall R, and Malik AB. (2008). Regulation of endothelial junctional permeability. Annals of the New York Academy of Sciences, 1123, 134–45.Find this resource:

16. Bachofen M and Weibel ER. (1977). Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. American Review of Respiratory Diseases, 116, 589–615.Find this resource:

17. The Acute Respiratory Distress Syndrome Network. (2000). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine, 342, 1301–8.Find this resource:

18. Ware LB, Bastarache JA, and Wang L. (2005). Coagulation and fibrinolysis in human acute lung injury—new therapeutic targets? Keio Journal of Medicine, 4, 142–9.Find this resource:

19. Matthay MA, Brower RG, Carson S, et al. (2011). Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. American Journal of Respiratory and Critical Care Medicine, 184(5), 561–8.Find this resource:

20. Gao Smith F, Perkins GD, Gates S, et al. (2012). Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet, 379(9812), 229–35.Find this resource: