Extended Definition of Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a severe form of acute hypoxic respiratory failure caused by noncardiogenic pulmonary edema. Since it was first described 50 years ago, the definition of ARDS has been revised several times to meet the needs of patients, clinicians, and researchers. Based on the acute lung injury score proposed in 1988 and the definition from the 1994 US-European Consensus Conference, the 2012 Berlin definition of ARDS recommends that the term should include patients with an acute episode (1 week after clinical injury) requiring positive end-expiratory pressure (PEEP) of at least 5 cm H2O, with bilateral infiltrates on chest X-ray, caused by non-heart failure; it is based on the PaO2/FiO2 ratio to classify the severity. Nevertheless, since the Berlin definition was proposed and widely used in clinical practice and research, questions have occasionally been raised regarding the various criteria of the Berlin definition. It is worth noting that the definition of clinical syndrome is not universal and should be reviewed periodically. Therefore, certain new considerations have been raised regarding the definition of acute respiratory distress syndrome.

Question 1: Should patients with high-flow nasal oxygen (HFNO) be included?

HFNO is widely used as an alternative to conventional oxygen therapy and noninvasive ventilation (NIV) in patients with acute hypoxemic respiratory failure because it is associated with a lower 90-day mortality rate. Despite the lack of confirmatory evidence of benefit associated with mortality or other clinical outcomes, HFNO has recently become an integral part of noninvasive respiratory support for patients with COVID-19. HFNO offers several physiologic advantages; among them are maintenance of moderate flow-dependent PEEP levels (2-5 cm H 2O), reduction of dead space by flushing the upper airway, and reduction of respiratory workload. Although HFNO is widely used to support patients with bilateral pulmonary infiltrates and severe hypoxemia (PaO2/FiO2 <300 mmHg), these patients are not diagnosed with ARDS because they are not receiving positive pressure ventilation with a PEEP of at least 5 cm H 2O.

Because HFNO is routinely used in clinical practice, there is a growing debate about expanding the Berlin ARDS definition to include HFNO. The existing arguments in favor of expanding the definition of ARDS to include patients requiring HFNO are based on the following factors:

Non-ventilated patients who otherwise meet the Berlin criteria have clinical features, inflammatory biomarkers, and outcomes similar to those of patients with ARDS. A key study found that non-ventilated patients who met all other ARDS criteria had the same 60-day mortality as ventilated patients. Another study showed that patients with acute hypoxemia and bilateral clouding treated with HFNO had similar patterns of inflammation and injury-related biomarkers as mechanically ventilated ARDS patients. HFNO is more readily available than invasive mechanical ventilation (MV) and NIV and can produce sufficient PEEP (near 5 cm H2O) at high flow rates. Parker et al. measured nasopharyngeal pressure in patients undergoing cardiac surgery and found that HFNO at a flow rate of 50 L/min provided a mean ± standard deviation airway pressure of 3.31 ± 1.05 cm H2O (with mouth closed).

The majority of patients who met ARDS criteria during high-flow nasal cannula (HFNO) continued to meet ARDS criteria after intubation. A recent study found that patients with a PaO2 / FiO2 ratio ≤ 300 mmHg remained at 92.9% during HFNO even with invasive mechanical ventilation. A simultaneous study showed that most patients with bilateral density shadows and PaO2 / FiO2 values ≤300 mm Hg met the Berlin criteria during the first 24 hours with standard oxygen inhalation. Based on all the above evidence, positive pressure ventilation does not seem to be a prerequisite for the diagnosis of ARDS. Furthermore, the Berlin-defined criteria focus on disease state rather than treatment. The inclusion of patients treated with HFNO in the definition of ARDS may facilitate early identification and intervention. However, more stringent evidence-based parameters are needed to avoid over-expansion of the ARDS diagnosis; in this context, the lack of uniformly stringent criteria for clinical conditions and parameters of HFNO may increase the risk of over-expansion. matthay et al. suggested adding the requirement of at least 30 L/min of HFNO as a criterion for ARDS diagnosis. Further studies are needed to validate this idea.

Question 2: Should SpO2/FiO2 be a surrogate for the diagnosis of ARDS, replacing PaO2/FiO2?

ARDS has long been under-recognized by clinicians, and only 60.2% of ARDS patients can be identified by clinicians. The unavailability of the PaO2/FiO2 ratio, which is the cornerstone of ARDS diagnosis, may contribute to the underdiagnosis of the condition. Notably, the SpO2/FiO2 ratio has been found to be closely correlated with the PaO2/FiO2 ratio, which may allow for a noninvasive diagnosis of ARDS, especially in resource-limited settings; use of the latter may prevent underdiagnosis of ARDS. rice et al. concluded that in patients with ARDS, an SpO2/FiO2 ratio of 315 corresponds to a PaO2/FiO2 ratio of 300. FiO2 ratio of 300. Brown et al. found that the SpO2/FiO2 ratio could reasonably be used as a substitute for arterial blood gases to determine the level of hypoxemia in patients with ARDS. Chen et al. further demonstrated that patients with ARDS inferred from the SpO2/FiO2 ratio did not have different clinical outcomes compared to those diagnosed from the PaO2/FiO2 ratio.

Since the Berlin definition was developed with reference to resource-rich settings and is not applicable to resource-limited settings, the Kigali modification of the Berlin definition was proposed for use in the latter setting. After initial validation, the Kigali modification defined ARDS as the absence of PEEP, SpO2/FiO2 values ≤315, and bilateral pulmonary atelectasis on lung ultrasound or chest radiograph, which has been widely used in clinical practice and research. For these reasons, an SpO2/FiO2 value ≤315 may be considered in place of a PaO2/FiO2 value ≤300 in the diagnosis of ARDS. Nevertheless, SpO2 is not linearly related to PaO2 and is more susceptible to clinical factors; therefore further evidence is needed to validate this idea.

Question 3: Should the 7-day period of acute exacerbation be extended?

Given that almost all patients with acute respiratory distress syndrome are identified within 7 days of identifying potential risk factors, the Berlin definition specifies a time frame of up to 7 days. Patients with severe COVID-19 always meet criteria for ARDS other than 7 days for acute episodes. However, the emergence of COVID-19 ARDS (CARDS) has challenged our inherent understanding of ARDS. Berlin et al. reported that hypoxemia caused by COVID-19 does not usually occur within 7 days of initial symptoms, suggesting that the progression of respiratory failure in COVID-19 is slower than in other causes of ARDS. Zhou et al. found that the median time from onset in CARDS was 12 days. However, most patients with acute respiratory failure develop new or worsening respiratory symptoms within 7 days. In this case, a previous study of several AIDS-free patients found that the time from onset of respiratory symptoms to diagnosis of Pneumocystis jirovecii pneumonia was >7 days. Another study of patients with H5N1 infection found that the median time from onset to onset of ARDS was 7.5 days. These findings suggest that the time to diagnosis of ARDS may be extended to 14 days. However, available data are limited and an evidence-based evaluation is necessary.

In conclusion, the expansion of the Berlin definition is necessary to meet the needs of patients, clinicians, and researchers. Modification of the diagnostic criteria for acute respiratory distress syndrome may allow early identification of patients with less severe disease and facilitate the testing and application of new therapies for populations at high risk for poor outcomes.