May 11, 2021
Dr. Gautam Rawal, Sankalp Yadav and Raj Kumar
Acute respiratory distress syndrome (ARDS) is an acute life threatening inflammatory lung injury manifested by hypoxia and stiff lungs due to increased pulmonary vascular permeability and almost always requiring mechanical ventilation support.
ARDS was first described by Ashbaugh et al. in 1967, and since then, there have been multiple studies addressing the various clinical aspects of the syndrome, its pathogenesis, risk factors, and treatment. However, despite the intense research, only few effective therapies for ARDS have been postulated, including the lung protection strategies.
ARDS was first defined in 1994 by the American-European Consensus Conference (AECC) as the acute onset of hypoxemia (arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FIO2] ≤ 200 mm Hg) with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension.
Acute lung injury (ALI) was defined using similar criteria, but having PaO2/FIO2 ≤ 300 mm Hg.A panel of experts assembled in 2011 and developed the Berlin Definition of ARDS using a consensus process.
The Berlin definition require all four criteria to be present for diagnosis of ARDS:
(1) Timing: Respiratory symptoms must have begun within one week of a known clinical insult, or the patient must have new or worsening symptoms during the past week.
(2) Chest imaging: Bilateral opacities consistent with pulmonary edema must be present on a chest radiograph or computed tomographic scan, which is not fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules.
(3) Origin of edema: The patient’s respiratory failure must not be fully explained by cardiac failure or fluid overload. An objective assessment (e.g., echocardiography) to exclude hydrostatic pulmonary edema is required if no risk factors for ARDS are present.
(4) Oxygenation: A moderate to severe impairment of oxygenation must be present, as defined by the PaO2/ FiO2 ratio.
The severity of the hypoxemia defines the severity of the ARDS:
(1) Mild ARDS—The PaO2/FiO2 is > 200 mmHg, but ≤ 300 mmHg, on a ventilator with a positive end-expiratory pressure (PEEP) or continuous positive airway pressure ≥ 5 cm H2O.
(2) Moderate ARDS—The PaO2/ FiO2 is > 100 mmHg, but ≤ 200 mmHg, on a ventilator with a PEEP ≥ 5 cm H2O.
(3) Severe ARDS—The PaO2/ FiO2 is ≤ 100 mmHg on a ventilator with a PEEP ≥ 5 cm H2O.
Compared with the AECC definition, the Berlin Definition had a better prediction for mortality with increased percentage of mortality associated with increasing stages of ARDS with mild ARDS having 27% mortality, moderate with 32%, and severe with 45%, with a 95% Confidence Interval.
Current Therapies for ARDS
Various trials have demonstrated that mechanical ventilation with lower tidal volumes (LTV) and airway pressures (tidal volume of 4–6 ml/kg predicted body weight and maintenance of plateau pressure between 25 and 30 cm H2O) reduces mortality in ALI and ARDS.
This lung-protective ventilation preserves barrier properties of the alveolar endothelium and alveolar epithelium by preventing alveolar overdistension, which is one of the major causes of ventilator-induced lung injury.
The concept of open lung ventilation uses low tidal volume with high PEEP with the rationale that LTV will minimize the damage due to overdistension while the high PEEP will minimize the cyclic atelectasis.
Lung-protective ventilation also down regulates mechanosensitive pro-inflammatory pathways, resulting in reduced neutrophil accumulation in the alveoli and lower plasma levels of IL-6, IL-8, and TNF.
Prone ventilation showed improvement in the level of oxygenation and thus improved the outcome in patients with ARDS having severe hypoxia.
This effect is due to the reduction in the trans-pulmonary pressure gradient on making the patient prone, which helps in recruiting the collapsed areas of the lung without causing significant increase in the airway pressures.
In the study by De Jong et al. (2013), prone ventilation was found to be a significantly effective in obese patients with ARDS than in non-obese patients.
Extracorporeal Membrane Oxygenation(ECMO)
ECMO is an advanced circulatory and ventilatory support system, which is used to salvage the patients with refractory hypoxemia when the conventional treatment fails.
The evidence to support the use of ECMO as a primary treatment in ARDS is lacking and needs further research.
High-Frequency Oscillatory Ventilation
High-frequency oscillatory ventilation (HFOV) seemed ideal for lung protection in ARDS, but the OSCAR study concluded with no 30-day survival benefit or cost benefit in patients in whom HFOV was used.
The meta-analysis of randomized control trials (RCT) by Gu et al. (2014) also concluded that with use of HFOV, there was no improvement in survival in ARDS patients, although it had no increase the risk of barotrauma or hypotension and also reduced the risk of oxygenation failure.
Neuromuscular blocking agents (NMBAs) are commonly used in ARDS, but their use remains controversial. In recent meta-analysis and review, the use of short term NMBAs in ARDS patients have shown a beneficial outcome mainly by decreasing the barotrauma and ventilator-induced lung injury.
The conservative approach of fluid management in ARDS has been proven to be beneficial in reducing ventilator days but doesnot improve survival.
Intravenous β-2 agonist in ARDS
The BALTI trial (2006) was a single center RCT, which showed the benefit of intravenous infusion of Salbutamol for 7 days in patients with ARDS, by causing significant reductions in extravascular lung water and plateau airway pressures.
Despite this, the recent evidence from the BALTI 2 trial, which is a multicenter RCT, showed no benefit of intravenous β-2 agonist (Salbutamol) in patients with ARDS and concluded that this may have significant detrimental effects with increase in mortality.
Corticosteroids in ARDS
ARDS, despite being an acute lung inflammatory disease with involvement of diverse inflammatory cells and mediators, the use of anti-inflammatory corticosteroids has not shown improved survival.
A systematic review and meta-analysis by Ruan et al. (2014), which included 8 RCTs and 10 cohort studies concluded that corticosteroids may be harmful in some patients and not to be routinely used in ARDS.
In experimental models of ARDS in rats, bone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of ventilator-induced lung injury by enhancing the regeneration of lung tissue and its repair.
Studies have shown that MSCs could be of benefit by their property to reduce the production of inflammatory mediators, leukocyte infiltration, tissue injury, and pulmonary failure.
There has been considerable research on ARDS in the past decade and better understanding of its pathogenesis. Despite this, the effective therapeutic measures to decrease mortality in ARDS seem to be low-tidal volume mechanical ventilation, prone ventilation for severe ARDS cases; and in life-threatening cases not responding to the conventional therapies, ECMO rescue technology serves as a bridge to recovery