ARDS — Definition, Pathophysiology & Management

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30–40% in most studies.

Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-​rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-​resourced settings and in paediatric patients. Treatment focuses on lung-​protective ventilation; no specific pharmacotherapies have been identified. Long-​term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae.

Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

The acute respiratory distress syndrome (ARDS) was initially defined in 1967 with a case-​based report that described the clinical presentation in critically ill adults and children of acute hypoxaemia, noncardiogenic pulmonary oedema, reduced lung compliance (increased lung stiffness), increased work of breathing and the need for positive-​pressure ventilation in association with several clinical disorders including trauma, pneumonia, sepsis and aspiration1. In 1992, an American–European consensus conference established specific diagnostic criteria for the syndrome2; these criteria were updated in 2012 in the so-​called Berlin definition3 of ARDS in adults (Box 1).

Depending on the level of oxygenation, ‘mild’, ‘moderate’ and ‘severe’ descriptors can be added to the diagnosis of ARDS (Box 1). The diagnosis of ARDS depends on clinical criteria alone because it is not practical to obtain direct measurements of lung injury by pathological samples of lung tissue in most patients; furthermore, neither distal airspace nor blood samples can be used to diagnose ARDS.

ARDS develops most commonly in the setting of pneumonia (bacterial and viral; fungal is less common), nonpulmonary sepsis (with sources that include the peri­ toneum, urinary tract, soft tissue and skin), aspiration of gastric and/or oral and oesophageal contents (which may be complicated by subsequent infection) and major trauma (such as blunt or penetrating injuries or burns).

Several other less common scenarios are also associated with the development of ARDS, including acute pancreatitis; transfusion of fresh frozen plasma, red blood cells and/or platelets (that is, transfusion-​associated acute lung injury (TRALI)); drug overdose with various agents; near drowning (inhalation of fresh or salt water); haemorrhagic shock or reperfusion injury (including after cardiopulmonary bypass and lung resection); and smoke inhalation (often associated with cutaneous burn injuries).

Other causes of noncardiogenic pulmonary oedema that are often considered as additional aetiologies of ARDS include primary graft dysfunction following lung transplantation, high-​altitude pulmonary oedema, neurogenic oedema (following a central nervous system insult or injury) and drug-​induced lung injury. The frequency of the clinical disorders associated with ARDS varies depending on the geographical location, the health-​care systems that are available and whether they are resource-​rich or resource-​poor. In the past 50 years, considerable progress has been made in understanding the epidemiology, pathogenesis and pathophysiology of ARDS.

In addition, randomized trials to optimize mechanical ventilation and fluid therapy for ARDS have resulted in improved clinical outcomes. Although much progress has been made to improve supportive care for ARDS, effective pharmacological therapies for ARDS have not yet been identified. However, ARDS is increasingly being recognized as a heterogenous syndrome, generating momentum to identify clinical and biological features to classify patients into subphenotypes that might be more responsive to specific therapies. Furthermore, evidence of important long-​term effects in survivors of ARDS is growing, driving the need for research strategies to study how these effects could be mitigated.

This Primer on adult and paediatric ARDS considers the epidemiology of ARDS from a global perspective, mechanisms of lung endothelial and alveolar epithelial injury (including experimental and clinical studies) and optimal approaches to diagnosis with a focus on screening, early recognition and evaluation for infectious and non-infectious causes. We also discuss manage­ ment strategies, including mechanical ventilation, fluids and rescue therapies for severe ARDS. Finally, we describe quality of life (QOL) after recovery from ARDS. Throughout the Primer, the differences between adult and paediatric ARDS are considered.

Adults

A well-​designed, prospective analysis of the incidence of ARDS in the United States was carried out in a population-​based cohort study of 21 hospitals in King County, Washington, from April 1999 to July 2000, focused primarily on adults4. The investigators used a validated screening protocol to identify patients with ARDS (defined as a partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio (PaO2/ FiO2) of <300 mmHg and bilateral chest radiographic opacities without evidence of left-​sided heart failure). On the basis of these data, the authors estimated an annual incidence of 190,000 cases of ARDS in the United States with a hospital mortality of 38. 5%.

Subsequently, the LUNG-​SAFE study provided valuable data in a cross-​ sectional analysis of 29,144 patients in 50 countries during the winter of 2014 (ref. 5); in this study, the prevalence of ARDS in patients in intensive care was 10%, and ARDS was identified in 23% of all ventilated patients. A detailed review of ARDS incidence and time-​related changes in epidemiological factors has been recently published6. The LUNG-​SAFE study also reported that hospital mortality was 34. 9% for patients with mild ARDS, 40% for those with moderate ARDS and 46. 1% for those with severe ARDS (Berlin criteria3; Box 1).

However, it remains unclear how much of the reported mortality in ARDS can be attributed to ARDS as opposed to underlying comorbidities, such as cancer and immunosuppression, the associated nonpulmonary organ dysfunction (cardiovascular insufficiency as in septic shock, liver dysfunction and renal failure) and/or the older age of patients with the condition. For example, a follow-​ up analysis of the LUNG-​SAFE study determined that 21% of patients with ARDS in the study were immunocompromised, and hospital mortality was much higher in these patients than in non-​immunocompromised patients (52% versus 36%; P < 0. 0001)7.

Importantly, the LUNG-​SAFE study revealed that clinician recognition of ARDS was low — 51% in mild ARDS and only 79% in severe ARDS. Furthermore, fewer than two-​t hirds of patients with ARDS were treated with an optimal tidal volume (that is, for mechanical ventilation) of <8 ml per kg predicted body weight (PBW). Thus, this study confirmed that ARDS remains common in critically ill patients and that it is under-​recognized and under-​treated. Several comorbidities and exposures have been associated with increased susceptibility to ARDS, including alcohol abuse8, cigarette smoking9,10, air pollution11,12 and hypoalbuminaemia13.

Diabetes mellitus has been associated with a lower risk of ARDS development for reasons that remain unclear14,15, although data from the LUNG-​ SAFE study showed no association between diabetes and the diagnosis of ARDS, developing ARDS or outcomes of ARDS16. A two-​centre clinical study identified the major recipient risk factors for developing TRALI, including recent liver surgery, chronic alcohol abuse, current cigarette smoking, higher peak airway pressure (that is, the highest airway pressure while being ventilated) and positive fluid balance17.

Transfusion risk factors were receipt of whole blood or fresh frozen plasma from a female donor and the quantity of human leukocyte antigen (HLA) class II antibody or the volume concentration of anti-​human neutrophil antigen in the transfused blood components. There was no risk associated with the age of the stored blood. Indeed, eliminating fresh frozen plasma or whole-​blood transfusion from female donors markedly reduced the incidence of TRALI, implicating a role for allogeneic antibodies in the pathogenesis of TRALI.

In blunt and penetrating trauma, the severity and duration of shock, chest injury, the number of blood product transfusions, the presence of traumatic brain injury and the quantity of crystalloid fluids (as a volume expander) can each contribute to the risk of developing ARDS18,19. Studies of the association between ethnicity and ARDS outcomes have largely but not uniformly reported higher mortality for black and Hispanic patients with ARDS than for white patients20,21. In an analysis of patients who died with a diagnostic code for ARDS in the United States, men had higher average ARDS-related mortality than women, and black patients had higher mortality than white patients, echoing findings from similar analyses from prior decades22,23.

The aetiology of these disparities remains unknown. Studies designed to identify genetic factors that might contribute to the susceptibility for developing ARDS have been reported in the past decade. However, no specific loci with genome-​wide significance for associ­ ations with ARDS have been identified, probably in part because of the phenotypic complexity of ARDS engendered by the different risk factors24. However, other strategies, including candidate gene and pathway analyses, have revealed potentially important mechanisms of lung injury that seem to be associated with risk of developing ARDS and, in some associations, higher mortality25.

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