Respiratory System

Acute respiratory distress syndrome (ARDS)

Acute disorder characterized by bilateral lung infiltrates and severe progressive hypoxemia in the absence of any evidence of cardiogenic pulmonary edema within 7 days of an inciting event.

Acute disorder characterized by bilateral lung infiltrates and severe progressive hypoxemia in the absence of any evidence of cardiogenic pulmonary edema within 7 days of an inciting event.


ARDS represents a stereotypic response to various etiologies.

  • Sepsis (M/C cause)
  • Inhalation of harmful substances: High concentrations of smoke or chemical fumes, aspiration of vomit or near-drowning episodes.
  • Severe pneumonia. 
  • Head, chest or other major injury. 
  • Coronavirus disease 2019 (COVID-19). 
  • Others: Pancreatitis (inflammation of the pancreas), massive blood transfusions and burns
Common respiratory pathogens in ARDS and associated demographic features and comorbidities.
Common community-acquired and hospital-acquired pathogens that cause pneumonia should always be considered in patients with suspected acute respiratory distress syndrome (ARDS). Some organisms such as Streptococcus pneumoniae are more common as community-acquired infections whereas Pseudomonas aeruginosa is more common as a hospital-acquired infection in ARDS. Enterobacteriaceae include Klebsiella pneumoniae, Escherichia coli and Enterobacter species. The group ‘other respiratory viruses’ includes parainfluenza virus, human metapneumovirus virus, respiratory syncytial virus, rhinovirus, coronaviruses and adenovirus. | Matthay, M.A., Zemans, R.L., Zimmerman, G.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 18 (2019).


Disease phases:

  1. Exudative phase: Alveolar-capillary damage characterized by inflammation, apoptosis, necrosis, and increased alveolar-capillary permeability, which leads to the development of alveolar edema and proteinosis. Alveolar edema, in turn, reduces gas exchange, leading to hypoxemia.
  2. Proliferative phase: Improved lung function and healing
  3. Fibrotic phase: End of the acute disease process
Progression of disease in ARDS
Progression of disease in ARDS: The clinically challenging problem of acute respiratory distress syndrome (ARDS) is illustrated by the diversity in the underlying etiologies and the complex time course of the disease. Approximately 40% of patients with severe sepsis will develop ARDS. Patients who do not recover during the proliferative phase may go on to develop emphysematous regions in the lungs and ultimately fibrosis. While it is reasonable to expect that each of these phases will have a distinct metabolomics phenotype, these have yet to be realized. | “Lungs diagram simple” by Patrick J. Lynch, medical illustrator. Licensed under CC BY 2.5 via Wikimedia Commons – wiki/File:Lungs_diagram_simple.svg#mediaviewer/File:Lungs_diagram_simple.svg.
Injured alveolus in ARDS
Injured alveolus in ARDS: A variety of insults (such as acid, viruses, ventilator-associated lung injury, hyperoxia or bacteria) can injure the epithelium, either directly or by inducing inflammation, which in turn injures the epithelium. Direct injury is inevitably exacerbated by a secondary wave of inflammatory injury. Activation of Toll-like receptors (not shown) on alveolar type II (ATII) cells and resident macrophages induces the secretion of chemokines, which recruit circulating immune cells into the airspaces. As neutrophils migrate across the epithelium, they release toxic mediators, including proteases, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which have an important role in host defence but cause endothelial and epithelial injury. Monocytes also migrate into the lung and can cause injury, including epithelial cell apoptosis via IFNβ-dependent release of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which activates death receptors. Activated platelets form aggregates with polymorphonuclear (PMN) leukocytes, which are involved in NET formation, and monocyte–platelet aggregates. Red blood cells (RBCs) release cell-free haemoglobin, which exacerbates injury via oxidant-dependent mechanisms. Angiopoietin 2 inhibits TIE2-stabilization of vascular endothelial cadherin (VE-cadherin); vascular endothelial growth factor and other permeability-promoting agonists also destabilize VE-cadherin via dissociation from p120-catenin, resulting in its internalization and enhanced paracellular permeability. Additionally, loss of cell–cell adhesion in the setting of actomyosin contraction results in the formation of occasional gaps between endothelial cells. Epithelial injury also includes wounding of the plasma membrane, which can be induced by bacterial pore-forming toxins or mechanical stretch, and mitochondrial dysfunction. Together, these effects result in endothelial and epithelial permeability, which further facilitate the transmigration of leukocytes and lead to the influx of oedematous fluid and RBCs. Airspace filling with oedematous fluid causes hypoxaemia, resulting in the need for mechanical ventilation. The vascular injury and alveolar oedema contribute to the decreased ability to excrete CO2 (hypercapnia), accounting for the elevated pulmonary dead space in acute respiratory distress syndrome. In turn, hypoxaemia and hypercapnia impair vectorial sodium transport, reducing alveolar oedema clearance. | ATI, alveolar type I cell; BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel. | Matthay, M.A., Zemans, R.L., Zimmerman, G.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 18 (2019).


The syndrome is characterized by the development of dyspnea and hypoxemia, which progressively worsens within 6 to 72 hours of inciting event, frequently requiring mechanical ventilation and intensive care unit-level care.

Acute Respiratory Distress Syndrome Pathogenesis and clinical findings


Berlin criteria:

Berlin definition of acute respiratory distress syndrome.
Berlin definition of acute respiratory distress syndrome. | doi:
Identifying patients with early acute lung injury before progression to ARDS by the Berlin criteria
Identifying patients with early acute lung injury before progression to ARDS by the Berlin criteria: Anterior–posterior chest radiographs in a critically ill 48-year-old man who presented to the emergency department with worsening dyspnoea, hypoxaemia (oxygen saturation of 70% on room air) and a 3-day history of fever, chills and a productive cough. He also had acute kidney failure with severe oliguria and a serum creatinine of 6.2 mg per dl. His systemic blood pressure was low, at 105/50 mmHg. He was diagnosed with acute pneumonia, acute renal failure and sepsis. a | Chest radiograph showing right lower lobe consolidation consistent with pneumonia. At this time, the patient was breathing spontaneously with 6 litres nasal oxygen that increased his oxygen saturation to 91%. b | Chest radiograph taken 24 hours later showing an endotracheal tube in place (arrows) for positive-pressure ventilation with bilateral opacities, consistent with the Berlin radiographic criteria. At this time, the patient had a partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio of 125 mmHg on positive-pressure ventilation with a tidal volume of 6 ml per kg predicted body weight and a positive end-expiratory airway pressure of 15 cmH2O. The patient also had a central line (arrowhead) inserted for administration of fluids and vasopressors as he progressed to developing septic shock. Time elapsed between the images demonstrates the potential window for early acute respiratory distress syndrome (ARDS) detection and early administration of therapies designed to prevent progression. | Matthay, M.A., Zemans, R.L., Zimmerman, G.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 18 (2019).


Distinguishing ARDS on radiography
Distinguishing ARDS on radiography: Similarities in the chest radiographs from a patient with acute respiratory distress syndrome (ARDS) from influenza pneumonia (panel a) and a patient with pulmonary oedema due to cardiac failure (panel b) reflect the difficulty in identifying ARDS. In both cases, diffuse bilateral parenchymal opacities are consistent with alveolar filling. The cardiac silhouette (panel b) is slightly more globular, consistent with heart failure; however, this feature is not reliable for distinguishing ARDS from cardiogenic pulmonary oedema. | Matthay, M.A., Zemans, R.L., Zimmerman, G.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 18 (2019).


Ventillatory support:

Chief treatment strategy is supportive care and focuses on 1) reducing shunt fraction, 2) increasing oxygen delivery, 3) decreasing oxygen consumption, and 4) avoiding further injury.
  • Mild-moderate ARDS:
    • Non-invasive ventillation: Continuous positive airway pressure (CPAP), bi-level airway pressure (BiPAP), proportional-assist ventilation, and a high-flow nasal cannula
  • Severe ARDS:
    • Endotracheal intubation
    • Invasive mechanical ventilation
Aligning Therapeutic Options with The Berlin Definition
Aligning Therapeutic Options with The Berlin Definition: This figure depicts potential therapeutic options according to the severity of ARDS. Boxes in yellow represent therapies that in the opinion of the panel still require confirmation in prospective clinical trials. This figure is just a model based on currently available information. In the coming years, various aspects of the figure will likely change; proposed cut-offs may move, and some therapies may be found to not be useful, while others may be added | Froese AB, Ferguson ND (2012) High-Frequency Ventilation. In: Tobin MJ (ed) Mechanical Ventilation (3rd edn). McGraw-Hill, New York, In Press

Medical management:

  • Diuretics: Protection against fluid overload
  • Nutritional support: High-fat, low-carbohydrate diet containing gamma-linolenic acid and eicosapentaenoic acid

Non-ventilatory strategies:

  • Prone positioning (8 hours/day): Recruitment of dependent lung zones, improved diaphragmatic excursion, and increased functional residual capacity
  • Conservative fluid management


Acute respiratory distress syndrome (ARDS)
Acute respiratory distress syndrome (ARDS) is the rapid onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation in hospitalized patients. | Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 19 (2019).

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