Acute respiratory distress syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

Acute respiratory distress syndrome (ARDS), originally known as adult respiratory distress syndrome (to contrast with neonatal respiratory distress syndrome) is a serious and potentially life-threatening inflammatory lung condition that develops rapidly (usually within 24 to 48 hours) in the setting of sepsis, toxic exposures, adverse drug reactions, trauma, or other critical illnesses. ARDS is characterized by inflammation of the lung parenchyma resulting in increased permeability of the alveolar-capillary membrane, non-cardiogenic pulmonary edema, impaired gas exchange, and decreased lung compliance.

The vast majority of patients with ARDS are managed in an intensive care unit (ICU), where many will require mechanical ventilation at some point during the course of their illness and recovery. ARDS may be categorized as mild, moderate, or severe based on the degree to which oxygenation is impaired; however, all levels of severity carry a high mortality rate if appropriate measures to improve oxygenation and minimize the risk of further lung injury are not taken.^[1]

Although the pathologic features of ARDS were first documented in the 19th century, the modern definition of ARDS did not arise until the 1960s. In 2012, the Berlin Definition of ARDS became the standard diagnostic criteria and definition of the syndrome.

ARDS may be classified according to 2012 Berlin Definition into three subtypes: mild, moderate, and severe. These levels of severity are based on the degree to which oxygenation relative to the amount of supplemental oxygen is being delivered to the patient via positive pressure ventilation.^[1]

ARDS is a syndrome of inflammation and increased permeability with the lung parenchyma that leads to loss of type I pneumocytes, impaired gas exchange, inappropriate cell proliferation within alveoli, and, in survivors, fibrosis.

ARDS may be caused by either direct or indirect insults to the lung. Common causes of ARDS include sepsis, aspiration pneumonitis, and transfusion-related acute lung injury (TRALI).^[2]

ARDS must be differentiated from other diseases that cause hypoxemia and pulmonary infiltrates, such as pneumonia, pulmonary contusion, pulmonary edema, and pulmonary hemorrhage. Prior to the development of the Berlin Definition in 2012, a greater emphasis was placed on excluding other potential illnesses prior to making a diagnosis of ARDS. While it is important to recognize and treat and underlying cause of the patient’s impaired ventilation and hypoxemia, this search for potential etiologies should not delay any focused efforts to improve oxygenation and ventilation.

The incidence of ARDS in the United States is estimated at approximately 75 cases per 100,000 individuals, which amounts to roughly 150,000 new cases annually.^[3] There is substantial variance in the rates of ARDS between different countries and geographic regions due to factors such as mean life expectancy, prevalence of different risk factors and comorbidities, and access to healthcare.

The most potent risk factor in the development of ARDS is chronic alcoholism.^[4][5] Other risk factors include advanced age, cigarette smoke exposure, and chronic liver disease.

There are no screening tools for ARDS. The best way to make an early diagnosis of ARDS is to apply the diagnostic criteria to any patient with bilateral pulmonary infiltrates on chest x ray, and new/worsening hypoxemia with an increasing supplemental oxygen requirement in whom a potential cause or risk factor for ARDS exists.

If left untreated, 70% of patients with ARDS may progress to mortality.^[6] Common complications to ARDS include weakness, impaired lung function, and brain death. Prognosis for patients with ARDS is generally poor and varies based on the severity of illness, the precipitating insult, and medical comorbidities.

Established by the ARDS Definition Task Force in 2012, the Berlin Definition is the most current set of diagnostic criteria for ARDS.

The history of a patient with ARDS varies according to the underlying cause. The symptoms of ARDS are fairly nonspecific and typically include rapid breathing, shortness of breath, and rapid heartbeat.

There are no physical exam findings specific to or pathognomonic of ARDS. The most notable physical exam findings tend to be those of the underlying illness or injury, as well as those of respiratory distress, critical illness, shock, and end organ damage.

Laboratory findings consistent with the diagnosis of ARDS include an arterial partial pressure of oxygen (PaO₂) that is inappropriately low relative to the fraction of inspired oxygen (FIO₂) that is being breathed by the patient. This is referred to as the PaO₂/FIO₂ ratio (sometimes abbreviated as P/F ratio) and is calculated by dividing the PaO₂ (in mmHg) by the FIO₂ (as a decimal rather than a percentage).

There are no EKG findings associated with ARDS.

X ray is the imaging modality of choice for ARDS. By definition, findings of ARDS on x ray include bilateral airspace opacities.

There are no findings on computed tomography (CT) that are diagnostic of ARDS. CT scan may be used to better define the extent of lung injury or identify potential underlying causes of ARDS.

Echocardiography is not especially useful in the diagnosis of ARDS, except under circumstances where cardiogenic pulmonary edema has not yet been excluded.

There are no additional diagnostic studies that are especially useful in the diagnosis and management of ARDS.

The majority of medical therapies for ARDS are aimed at treating its underlying cause (e.g., antimicrobials for infection).

Most patients with ARDS will require endotracheal intubation and mechanical ventilation at some point during the course of their illness and recovery. A mechanical ventilation strategy using lower tidal volumes of 6 mL/kg predicted body weight and higher levels of positive end-expiratory pressure (PEEP) has been shown to be most effective at improving oxygenation and minimizing volutrauma (injury to stiff lungs resulting from overdistention).

Surgical intervention is not recommended for the management of ARDS, except when a procedure might be recommended to treat the underlying cause.

There are no primary preventive measures available for ARDS. The only prevention strategy for ARDS is early recognition and treatment of medical conditions that have the potential to cause ARDS.

Secondary prevention strategies for ARDS include aggressive treatment of the underlying cause and the early application of noninvasive methods of oxygenation to slow or prevent the worsening of ARDS and potentially reduce the need for intubation and mechanical ventilation.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

Although the pathologic features of acute respiratory distress syndrome (ARDS) were first documented in the 19^th century, characterization of its clinical features did not arise until the 1960s. The most recently updated definition is the Berlin definition devised by the European Society of Intensive Care Medicine in 2012.

Although the first pathologic description of ARDS dates back to 1821,^[1] our understanding of the distinct pathophysiologic features of ARDS has volved alongside the development of medical technologies that facilitated a more in-depth study of the syndrome. The advent of radiography permitted visualization of the bilateral pulmonary infiltrates (originally termed double pneumonia), while the development of arterial blood gas measurement and positive-pressure mechanical ventilation allowed for identification of the impaired oxygenation and reduced lung compliance that are now recognized as central features of ARDS.^[2]

In 1967, Ashbaugh and colleagues first described the clinical entity “acute respiratory distress in adults” characterized by a clinical and pathological course of events remarkably similar to the infantile respiratory distress syndrome.^[3] In the case series, 12 patients developed severe dyspnea, tachypnea, cyanosis refractory to oxygen therapy, decreased pulmonary compliance, and diffuse alveolar infiltration following trauma, viral infection, or acute pancreatitis. Autopsy findings of the lungs include atelectasis, vascular congestion, hemorrhage, pulmonary edema, and hyaline membrane formation.

In 1988, Murray et al. proposed an expanded definition of ARDS that utilized a four-point lung injury scoring system to assess the physiologic respiratory impairment based on oxygenation status, level of positive end-expiratory pressure, static pulmonary compliance, and chest radiograph involvement.^[4] Although the scoring system may be used to quantify the extent of lung injury in the research setting, the lack of survival predictability has limited its clinical usefulness.^[5][6]

In 1994, a standardized definition of ARDS was devised by the American European Consensus Conference (AECC).^[7] The AECC committee defined acute lung injury (ALI) as “a syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiologic, and physiologic abnormalities that cannot be explained by, but may coexist with, left atrial or pulmonary capillary hypertension” that “is associated most often with sepsis syndrome, aspiration, primary pneumonia, or multiple trauma“. The term ARDS was reserved for the end of this spectrum with the most severe oxygenation deficit. ALI and ARDS are acute in onset and persistent, are associated with one or more known risk factors, and are characterized by arterial hypoxemia resistant to oxygen therapy alone and diffuse radiologic infiltrates. Despite the wide acceptance of the AECC definition, there are limitations across all four diagnostic criteria such as unspecified timing of acute onset, no minimum requirement of PEEP which can influence oxygenation status, and poor inter-observer agreement on interpretation of chest radiographs or pulmonary artery catheter tracings.^[8]

In 2012, the AECC definition was superseded by the Berlin definition from the European Society of Intensive Care Medicine.^[9] The major changes to the Berlin definition of ARDS include: the term ALI was removed, pulmonary artery wedge pressure requirement was removed, subgroups by severity of oxygenation deficit were added, minimal PEEP or CPAP levels across subgroups were added, and chest CT was incorporated as an alternative imaging modality for determination of lung infiltrates. Data from the pooled cohorts suggested that each stage is associated with a progressive increase in the mortality as well as the duration of mechanical ventilation among survivors. Compared with the AECC definition, the Berlin definition was deemed to be a better predictor of mortality among patients with ARDS.^[10]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

According to the Berlin definition, ARDS may be classified by the severity of oxygenation deficit into three subtypes: mild, moderate, and severe.

ARDS may be classified according to the Berlin Definition into three mutually exclusive subtypes: mild, moderate, and severe. These levels of severity are based on the PF ratio, the degree of oxygenation relative to the fraction of oxygen participating in gas exchange. Data from the pooled cohorts demonstrated that mild, moderate, and severe ARDS were associated with increased 90-day mortality (27%, 32%, and 45%, respectively) and increased median duration of mechanical ventilation among survivors (5 days, 7 days, and 9 days, respectively).^[1]

The Berlin definitions of mild, moderate, and severe ARDS are as follows:

The Berlin Definition of Acute Respiratory Distress Syndrome
Oxygenation †
Mild	200 mm Hg < PaO2/FiO2 ≤ 300 mm Hg with PEEP or CPAP ≥ 5 cm H2O ‡
Moderate	100 mm Hg < PaO2/FiO2 ≤ 200 mm Hg with PEEP ≥ 5 cm H2O
Severe	PaO2/FiO2 ≤ 100 mm Hg with PEEP ≥ 5 cm H2O
† If altitude is higher than 1000 m, the correction factor should be calculated as follows: [PaO2/FIO2 × (barometric pressure/760)]. ‡ This may be delivered noninvasively in the mild ARDS group.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

ARDS is a syndrome of inflammation and increased permeability with the lung parenchyma that leads to loss of type I pneumocytes, impaired gas exchange, inappropriate cell proliferation within alveoli, and, in survivors, fibrosis.

ARDS typically develops within 24 to 48 hours of the provoking illness or injury and is classically divided into three phases:^[1][2][3]

• Exudative phase (within 5 to 7 days): Systemic inflammation results in increased permeability of the alveolar-capillary barrier and leads to the formation of hyaline membranes along alveolar walls, accumulation of proteinaceous exudate within the alveolar air spaces (non-cardiogenic pulmonary edema), and extravasation of inflammatory cells (predominantly neutrophils) into the lung parenchyma, leading to extensive alveolar damage and, occasionally, diffuse alveolar hemorrhage
• Proliferative phase (within 7 to 21 days): Fibroblast proliferation, collagen deposition, and early fibrotic changes are observed within the pulmonary interstitium as alveolar exudate and hyaline membranes begin to be absorbed
• Fibrotic phase (within several weeks): Many patients with ARDS will develop some degree of pulmonary fibrosis, of which at least one-quarter will go on to develop clinically apparent fibrotic lung disease with a restrictive ventilatory defect on pulmonary function tests;^[4] the development and extent of pulmonary fibrosis in ARDS correlates with an increased mortality risk^[5]

The role of genetics in the development of ARDS is an ongoing area of research. While studies have demonstrated associations between certain genetic factors (including single nucleotide polymorphisms and allelic variants of angiotensin-converting enzyme) and increased susceptibility to the development of ARDS, the nature and implications of these relationships remain uncertain.^[6][7][8]

On gross pathology, the following are characteristic findings of ARDS:

• Firm, boggy, and dusky lungs
• Generally increased weight compared to healthy lungs due to edema

On microscopic histopathological analysis, the following are characteristic findings of ARDS:

• Lung parenchyma demonstrates:
  • Hyaline membranes lining the alveolar air spaces
  • Edema fluid within alveoli and the interstitium
  • Shedding of type I pneumocytes and proliferation of type II pneumocytes
  • Infiltration of polymorphonuclear and other inflammatory cells into the interstitial and alveolar compartments,
  • Thrombosis and obliteration of pulmonary capillaries
  • Hemorrhage into alveoli
• Features specific to the underlying disease process (e.g., pneumonia or aspiration pneumonitis)
• With progression, alveolar infiltrates are reabsorbed and the inflammatory milieu is replaced by increased collagen deposition and proliferating fibroblasts, culminating in interstitial fibrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2], Brian Shaller, M.D. [3]

ARDS may be caused by either direct or indirect insults to the lung. Common causes of ARDS include pneumonia, sepsis, aspiration of gastric contents, and transfusion-related acute lung injury (TRALI).

ARDS is a life-threatening condition and must be treated as such irrespective of the causes. Life-threatening conditions may result in death or permanent disability within 24 hours if left untreated.

ARDS may occur as the result of either a direct or indirect insult to the lungs:^{[1][2][3][4][5]}

• Direct insult

• Pneumonia (bacterial, viral, fungal, or parasitic)
• Aspiration of of gastric contents
• Inhalational injury (e.g., smoke inhalation, toxic gas inhalation)
• Fat embolism
• Amniotic fluid embolism
• Drowning
• Pulmonary contusion
• Alveolar hemorrhage
• Reperfusion (pleural effusion drainage, embolectomy)
• Lung transplantation
• Ventilator-associated lung injury

• Indirect insult:

• Severe sepsis
• Major trauma (e.g., head trauma, polytrauma)
• Multiple transfusions or transfusion-associated acute lung injury (TRALI)
• Drug overdose (e.g., acetylsalicylic acid overdose, heroin overdose)
• Pancreatitis
• Severe burns
• Shock
• Cardiopulmonary bypass
• Disseminated intravascular coagulation

Cardiovascular	No underlying causes
Chemical/Poisoning	Mercury inhalation
Dental	No underlying causes
Dermatologic	Stevens-Johnson syndrome, toxic epidermal necrolysis[6]
Drug Side Effect	Acetylsalicylic acid, ado-trastuzumab emtansine, afatinib, amiodarone, crizotinib, cytarabine, cytomegalovirus immune globulin, docetaxel, filgrastim, follitropin, gemcitabine, mitomycin, nitrofurantoin, sorafenib, tbo-filgrastim, urofollitropin
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	Acute eosinophilic pneumonia, inhalation injury, near-drowning, surface burns
Gastroenterologic	Aspiration of gastric contents, pancreatitis
Genetic	No underlying causes
Hematologic	Bone marrow transplantation, massive blood transfusion
Iatrogenic	Bone marrow transplantation, cardiopulmonary bypass, massive blood transfusion, oxygen toxicity
Infectious Disease	Acute eosinophilic pneumonia, ehrlichiosis, leptospirosis, malaria, miliary tuberculosis, pneumonia (bacterial, viral, fungal, or parasitic), sepsis, severe acute respiratory syndrome (SARS)
Musculoskeletal/Orthopedic	Fat embolism, polytrauma
Neurologic	Traumatic brain injury (TBI)
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	Amniotic fluid embolism
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	Acetylsalicylic acid, heroin, naloxone
Psychiatric	No underlying causes
Pulmonary	Acute eosinophilic pneumonia, aspiration of gastric contents, Cryptogenic organizing pneumonia (COP), decompression sickness, fat embolism, lung transplantation, pneumonia
Renal/Electrolyte	Uremia
Rheumatology/Immunology/Allergy	Anaphylaxis, bone marrow transplantation, leukoagglutin reactions
Sexual	No underlying causes
Trauma	Pulmonary contusion, polytrauma, severe trauma, traumatic brain injury (TBI)
Urologic	No underlying causes
Miscellaneous	No underlying causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

ARDS must be differentiated from other diseases that cause hypoxemia and pulmonary infiltrates, such as pulmonary edema, diffuse pneumonia, pulmonary hemorrhage, interstitial lung disease, and radiation pneumonitis.

Prior to the development of the Berlin definition, a greater emphasis was placed on excluding other potential illnesses before establishing the diagnosis of ARDS. While it is important to recognize and treat and underlying cause, this search for potential etiologies should not delay any focused efforts to improve oxygenation and ventilation.

ARDS must be differentiated from other diseases that cause hypoxemia and pulmonary infiltrates, such as:^[1]

• Infectious pneumonia (bacterial, fungal, viral, or parasitic)
• Aspiration pneumonitis (chemical pneumonia)
• Acute eosinophilic pneumonia
• Pulmonary contusion
• Cardiogenic pulmonary edema
• Neurogenic pulmonary edema
• Hypersensitivity pneumonitis
• Pulmonary hemorrhage

On chest x ray, the bilateral, non-cardiogenic pulmonary infiltrates of ARDS may appear similar to those of cardiogenic (hydrostatic) pulmonary edema. Therefore, it is necessary to formally assess cardiac function and volume status if ARDS is suspected but no clear precipitating insult (e.g., sepsis, trauma, toxic inhalation) can be identified. The preferred methods for making this assessment in the ICU are:

• Echocardiography to assess heart function
• Central venous catheterization to measure central venous pressure
• Pulmonary artery (Swan-Ganz) catheterization to measure right-sided heart pressures and pulmonary capillary wedge pressure (a surrogate of left atrial pressure)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

The incidence of ARDS is estimated to be 1.5 to 75 cases per 100,000 individuals per year worldwide. The reported incidence varies geographically and is higher in the United States than in other countries.

No reliable comparative epidemiological data of ARDS are available due to the evolution of the diagnostic criteria.^[1] The exact incidence of ARDS as defined by the Berlin definition remains unclear.

Worldwide, the incidence of ARDS ranges from 1.5 to 75 cases per 100,000 person-years.^[2] Most studies report the incidence rate of approximately 2 to 8 cases per 100,000 person-years.^[3]

In the United States, the National Heart and Lung Institute (NHLI) suggested an estimated incidence at 150,000 new cases annually, which translates to a population-based figure of 71 cases per 100,000 person-years.^[4] Data from a population-based study reported the crude and age-adjusted incidence of 58.7 and 64.0 cases per 100,000 person-years.^[5]

In the United Kingdom, the incidence of ARDS is 4.5 cases per 100,000 person-years.^[6]

In Europe, the incidence of ARDS ranges from 4.9 to 13.5 cases per 100,000 person-years.^{[7][8][9][10][11]}

According to the NHLI Task Force Report, the mortality rate of ARDS varies from 25% with optimal care to 70% in the absence of treatment.^[12] Report from the American-European Consensus Conference quoted a range of mortality from 10% to as high as 90%.^[13] Data from population-based studies suggest that the mortality rate ranges from 34.0% to 57.9%.^{[14][15][16][17]}

The incidence of ARDS increases with age. Data from a population-based study indicated that the groups with the lowest and highest age-specific incidence are 15 through 19 years of age and 75 through 84 years of age, respectively. Mortality also increases with age from a minimum of 24% among those 15 through 19 years old to 60% among those 85 years or older.^[18]

Women are slightly more commonly affected with ARDS than men. However, the mortality rate is slightly higher among men than women.^[19][20]

There is no racial predilection for the development of ARDS. However, African-American race is associated with an increased mortality among patients with ARDS.^[19]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

Common risk factors for the development of ARDS include advanced age, chronic alcoholism, and acidosis.

Common risk factors for ARDS include:^[1][2][3][4]

• Advanced age
• Chronic alcoholism (including alcoholic liver disease and hepatic cirrhosis)
• Acidemia with pH < 7.25
• Metabolic acidosis with bicarbonate < 20 mEq/L
• High anion gap
• Hypoproteinemia
• Increased severity of critical illness (as measured by APACHE II score or Injury Severity Score)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

Several screening tools have been devised to aid in the early detection of acute respiratory distress syndrome including Early Acute Lung Injury (EALI), ALI sniffer, and Lung Injury Prediction Study (LIPS) score.

Several screening tools have been proposed and validated for early recognition of progression to ARDS. However, no single biomarker is currently specific or sensitive enough to be incorporated into routine clinical practice.

Levitt et al. proposed the criteria for “Early Acute Lung Injury (EALI)” which include: (1) hospital admission with bilateral opacities on chest radiograph; (2) the absence of isolated left atrial hypertension; and (3) the need for > 2 L/min of supplemental oxygen.^[1] The EALI was 73% sensitive and 79% specific for progression to ALI.

Thakur et al. developed and validated an ALI screening tool (“ALI sniffer”) based on the American-European Consensus Conference definition using an electronic medical record that facilitates early recognition of specific criteria.^[2] The tool demonstrated a sensitivity of 96.3% and a specificity of 89.4%, with a positive predictive value of 46.0% and a negative predictive value of 99.6%.

Trillo-Alvarez et al. devised the Lung Injury Prediction Study (LIPS) score to identify patients at high risk for ALI or ARDS before ICU admission by utilizing parameters that are clearly defined and routinely available in the medical record.^[3] Covariates used in model derivation include predisposing conditions (trauma, high-risk surgery, sepsis, shock, pneumonia, aspiration, and pancreatitis) and risk-modifiers (tachypnea, alcohol abuse, hypoalbuminemia, oxygen supplementation, chemotherapy, diabetes mellitus, and smoking history). The LIPS score efficiently discriminated patients who developed ALI from those who did not, with an area under the ROC curve (AUC) of 0.84. The performance of the LIPS score was consistent in a multicenter cohort study with an AUC of 0.80 while maintaining an appropriate negative predictive value of 97% for a screening tool.^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Brian Shaller, M.D. [2]

If left untreated, 70% of patients with ARDS may progress to mortality. Common complications to ARDS include weakness, impaired lung function, and brain death. Prognosis for patients with ARDS is generally poor and varies based on the severity of illness, the precipitating insult, and medical comorbidities.

The natural history of ARDS is hallmarked by three histopathological phases—exudative, proliferative, and fibrotic phase—each correlated to distinctive clinical manifestations.^[1]

The exudative phase typically encompasses the first 5 to 7 days of illness after exposure to one or more precipitation factors. Histopathologically, loss of integrity of the alveolar barrier results in influx of proteinaceous fluid into the air place and formation of hyaline membrane. Pulmonary edema and atelectasis with reduced pulmonary compliance ensue, leading to the development of pulmonary shunt and hypoxemia. In this phase, patients experience respiratory symptoms including dyspnea, tachypnea, and increased work of breathing that eventually result in respiratory failure requiring ventilator support. If left untreated, approximately 70% of patients with ARDS may progress to mortality.^[2] Among non-survivors, approximately 50% patients die within a week of the onset with exudative change as the predominant histopathological feature.^[3]

The proliferative phase generally lasts from day 7 to day 21. Histopathologically, reparative processes take place in the injured alveoli, including organization of exudates, a shift to lymphocyte-predominant infiltrates, and proliferation of type II pneumocytes. In this phase, patients may recover from acute respiratory distress despite the persistence of residual symptoms. Patients who do not recover during this phase develop progressive lung injury and early changes of fibrosis.

The fibrotic phase occurs 3 to 4 weeks following the initial pulmonary insult. Histopathologically, extensive fibrosis is prominent in the alveolar interstitium and duct, with disruption of acinar architecture and emphysema-like changes. The evidence for pulmonary fibrosis on biopsy is associated with increased mortality.

Complications of ARDS are more likely to develop among patients who do not receive early or adequate treatment.

Common complications include:

• Ventilator-associated pneumonia (VAP)

• ARDS is complicated by VAP in approximately 37% to 60% of cases.^[4][5][6][7]
• VAP usually develops 5 to 7 days after the initial exposure to the precipitating factor.^[8]
• The most likely microorganisms of VAP include non-fermenting Gram-negative bacilli, methicillin-resistant Staphylococcus aureus, and Enterobacteriaceae.^[9]

• Barotrauma (e.g., pneumothorax, pneumomediastinum, and subcutaneous emphysema)

• Barotrauma occurs as a consequence of inappropriate positive airway pressure in regions with reduced pulmonary compliance and may complicate ARDS in approximately 10% of cases.^[10][11][12]

Other complications include:

• Significant weakness due to critical illness myoneuropathy and muscle atrophy as a result of long-term immobilization
• Impaired lung function
• Chronic ventilator dependency due to advanced weakness and atrophy of the muscles of respiration
• Pulmonary fibrosis and restrictive lung disease
• Psychiatric illness, including post-traumatic stress disorder (PTSD), anxiety, and depression
• Impaired cognition
• Persistent vegetative state or brain death due to prolonged hypoxemia

Complications associated with a prolonged ICU stay include:

• Secondary or nosocomial infections (e.g., ventilator-associated pneumonia [VAP] or central line-associated blood stream infection [CLABSI])
• Venous thromboembolic events (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE])
• Gastrointestinal bleeding (often secondary to stress ulcers)
• Pressure ulcers and poor wound healing
• Muscle wasting and atrophy

Prognosis for patients with ARDS is generally poor and varies based on the severity of illness, the precipitating insult, and medical comorbidities:^{[13][14][15][16][17][18]}

• The 90-day morality rates for mild, moderate, and severe ARDS are 27%, 32%, and 45%, respectively.
• The 1-year mortality rate for patients with ARDS who survive to hospital discharge varies widely and is estimated at 11% to over 40%.
• Between 1992 and 1995, in-hospital mortality rate ranges from 36% to 52%.
• ARDS among trauma patients have a lower mortality as compared with sepsis patients.