The acute respiratory distress syndrome

Abstract

The acute respiratory distress syndrome (ARDS) is a major cause of acute respiratory failure. Its development leads to high rates of mortality, as well as short- and long-term complications, such as physical and cognitive impairment. Therefore, early recognition of this syndrome and application of demonstrated therapeutic interventions are essential to change the natural course of this devastating entity. In this review article, we describe updated concepts in ARDS. Specifically, we discuss the new definition of ARDS, its risk factors and pathophysiology, and current evidence regarding ventilation management, adjunctive therapies, and intervention required in refractory hypoxemia.

During the Vietnam War in 1960s, military physicians encountered a distinctive form of hypoxemic respiratory failure involving both lungs simultaneously. During the same period, civilian physicians who came across this form of lung injury called it adult respiratory distress syndrome (1). This term was later modified to acute respiratory distress syndrome (ARDS), when similar cases were reported across all age groups. In the United States, the most recent population-based data estimated an incidence of 190,000 cases per year (2). Mortality from ARDS has been estimated at 26% to 58% (3–6). Advances in supportive care have led to improvements in patient outcomes (7, 8). Nevertheless, the mortality associated with this syndrome remains unacceptably high.

DEFINITION AND DIAGNOSIS

ARDS and what was previously called acute lung injury (ALI) are both characterized by rapid onset of respiratory failure following a variety of direct and indirect lung insults. Since these entities were originally described, multiple definitions or diagnostic criteria have been proposed. In 1988, Murray et al introduced the lung injury score, which included chest radiograph, the ratio of the partial pressure of arterial oxygen and the fraction of inspired oxygen (PaO₂/FiO₂), total respiratory system compliance, and positive end-expiratory pressure (PEEP). Despite its clinical utility, the score was unable to differentiate between cardiogenic and noncardiogenic edema (9). In 1994, the American and European Consensus Conference established specific clinical criteria for ARDS and ALI (10). There were three diagnostic criteria: 1) PaO₂/FiO₂ ≤ 200, 2) bilateral infiltrates on chest radiograph, and 3) pulmonary artery occlusion pressure < 18 mm Hg when measured by pulmonary artery catheterization, or no clinical evidence of left atrial hypertension. The term ALI was adopted from the lung injury score to include patients with less severe forms of the same pathological entity. Therefore, patients with a PaO₂/FiO₂ of 200 to 300 were included within this group.

Since its description, the American and European Consensus Conference definition has been widely used for enrollment of ARDS patients in therapeutic clinical trials (11–15). Nevertheless, the aforementioned definition also presented several shortcomings. First, the reliability in reading chest radiographs was questionable. Second, the definition did not explicitly define the time interval for “acute.” Third, the level of PEEP utilized during ventilation was not incorporated in the definition. Last, the use of pulmonary artery catheters has been decreasing over the last few years, precluding measurements of pulmonary artery occlusion pressures.

Based on the aforementioned limitations, and after reviewing current epidemiologic evidence and results of clinical trials, in 2011 the European Society of Intensive Care Medicine proposed the Berlin ARDS definition (16), which considered the factors of timing, chest imaging, origin of edema, and oxygenation:

• Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms

• Imaging: A chest radiograph or computed tomography scan showing bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules

• Origin of edema: Respiratory failure not fully explained by cardiac failure or fluid overload; objective assessment (e.g., echocardiography) needed to exclude hydrostatic edema if no risk factor present

• Oxygenation: Divided into mild (PaO₂/FIO₂ >200 to ≤ 300 mm Hg with PEEP or continuous positive airway pressure ≥ 5 cm H₂O), moderate (PaO₂/FIO₂ >100 to ≤ 200 mm Hg with PEEP ≥ 5 cm H₂O) or severe (PaO₂/FIO₂ ≤ 100 mm Hg with PEEP ≥ 5 cm H₂O)

Of note, the term ALI has been eliminated. The categories of mild, moderate, and severe correlate with mortalities of 27%, 32%, and 45%, respectively (16).

RISK FACTORS

Multiple conditions may cause ARDS (Table 1). Sepsis remains the most common cause of ARDS, with 46% of the cases triggered by pulmonary entities (2). Mortality also varies according to the cause. Particularly, mortality in patients with ARDS due to severe trauma (injury severity score > 15) is 24.1%, whereas mortality in patients with severe sepsis with a pulmonary source is 40.6% (2). Notably, certain patient-related variables have been associated with the risk of developing ARDS and with mortality. Among these risk factors, age (2, 17–19), male gender, African American race (20), and history of alcoholism are associated with a higher incidence and mortality (21–23). Active and passive smoking exposure increases the incidence of ARDS as well (24, 25). Patients with a higher body-mass index have an increased incidence of ARDS, but its association with mortality is not clearly defined (26–28). Both diabetes mellitus and prehospital antiplatelet therapy seem to have a protective effect on development of ARDS (29–31).

Table 1.

Common risk factors for acute respiratory distress syndrome/acute lung injury

Direct	Indirect
Pneumonia Aspiration of gastric contents Inhalation injury Pulmonary contusion Pulmonary vasculitis Drowning Fat embolism Reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy	Nonpulmonary sepsis Major trauma Pancreatitis Severe burns Noncardiogenic shock Drug overdose Multiple transfusions (>15 units blood in 24 h) or transfusion-related acute lung injury Neurogenic pulmonary edema Amniotic fluid embolism Following bone marrow transplantation

Interestingly, the Acute Lung Injury Verification of Epidemiology (ALIVE) study (32) reported that ALI occurred in 16.1% of patients who were mechanically ventilated for other reasons. Hence, several groups have investigated a variety of methods to predict ARDS. Particularly, Gajic et al described the Lung Injury Prediction Score (LIPS, Table 2) using a prospective cohort study of 5584 patients (33). A LIPS score higher than 4 was associated with risk of developing ARDS within a median time of 2 days. The score has a sensitivity of 69% and a specificity of 78%, with a positive predictive value of 18% and a negative predictive value of 97%.

Table 2.

Lung Injury Prediction Score calculation worksheet

	LIPS points
Predisposing conditions
Shock	2
Aspiration	2
Sepsis	1
Pneumonia	1.5
High-risk surgerya
Orthopedic spine	1
Acute abdomen	2
Cardiac	2.5
Aortic vascular	3.5
High-risk trauma
Traumatic brain injury	2
Smoke inhalation	2
Near drowning	2
Lung contusion	1.5
Multiple fractures	1.5
Risk modifiers
Alcohol abuse	1
Obesity (body mass index >30)	1
Hypoalbuminemia	1
Chemotherapy	1
Fraction of inspired oxygen > 0.35 (>4 L/min)	2
Tachypnea (respiratory rate >30/min)	1.5
Oxygen saturation < 95%	1
Acidosis (pH <7.35)	1.5
Diabetes mellitusb	–1

^aAdd 1.5 points if emergency surgery.

^bOnly if sepsis.

Reprinted from Gajic et al, 2011 (33) with permission of the American Thoracic Society. Copyright © American Thoracic Society.

The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

PATHOPHYSIOLOGY OF VENTILATOR-INDUCED LUNG INJURY

Gattinoni et al (34) described three general regions of the lung: normal lung tissue, a region densely consolidated, and a region that collapses during expiration and is recruitable during inspiration. When these heterogeneous lungs are ventilated at low tidal volumes, in the absence of PEEP they present a repetitive opening and closing of airways and lung units (35). This type of injury is called “atelectrauma” (35). Conversely, when heterogeneous lungs are ventilated with high tidal volumes, overdistension of alveoli is produced, leading to “barotrauma,” which involves complications such as pneumothorax (36). A third form of ventilator-induced lung injury is called “biotrauma,” which is a systemic inflammatory response syndrome as a consequence of a release of lung cytokines (tumor necrosis factor–alpha, interleukin-6, interleukin-8, matrix metallopeptidase 9, nuclear factor kappa-light-chain-enhancer of activated B cells) (37).

TREATMENT

Standard treatment

Low-tidal volume strategy. The aim of mechanical ventilation in ARDS is to provide oxygenation and ventilation, while reducing the risk of ventilator-induced lung injury. A multicenter National Heart, Lung, and Blood Institute ARDSnet trial randomly assigned 861 patients with ARDS to receive low-tidal volume ventilation (initial tidal volume of 6 mL/kg) or conventional mechanical ventilation (initial tidal volume of 12 mL/kg) (11). Tidal volumes were titrated to keep plateau pressures (alveolar pressure at the end of a paused inspiration) lower than 50 cm H₂O in the conventional ventilation group, and lower than 30 cm H₂O in the low-tidal volume group. Results showed that the intervention group (low-tidal volume) had a lower mortality rate (31% vs. 40%) and more ventilator-free days (12 days vs. 10 days). A recent meta-analysis of four randomized trials, which included 1149 patients, confirmed these findings with a reduction of hospital mortality from 41% to 34.2% (38). Since the publication of this landmark study, a low-tidal volume strategy, which involves a tidal volume of 6 mL/kg predicted body weight, is considered the standard of care. In certain circumstances, tidal volumes may be further decreased to 4 mL/kg in order to limit inspiratory plateau pressures to levels lower than 30 cm H₂O (11).

Positive end-expiratory pressure. The utilization of PEEP improves gas exchange and lung function in a number of ways. PEEP recruits collapsed alveoli, improving oxygenation and lung compliance, and reduces cyclic atelectasis, decreasing atelectrauma and biotrauma. Despite these benefits, the appropriate dose of PEEP is still a matter of controversy. In the ARDSnet trial (11), patients using tidal volumes of 4 mL/kg required significantly higher levels of PEEP. Therefore, some have argued that this could have been the reason for the positive outcomes of the study. However, the subsequent Higher vs. Low PEEP in Patients with ARDS (ALVEOLI) study (4), which was a prospective, multicenter trial with 549 patients randomized to either lower or higher levels of PEEP, set according to predefined tables, showed no differences in outcomes among groups. Importantly, the study design of the ALVEOLI trial was highly criticized, as many providers believe that PEEP levels cannot universally be set for all patients, but rather must be individualized based on lung mechanics.

The analysis of the static lung compliance curve has been proposed to titrate PEEP. Both the lower inflection point on the aforementioned curve and the stress index calculated from the pressure-time curve have been employed with varying results (39, 40). However, in ARDS the lung does not function as a single compartment model but rather as a multiple one. Therefore, setting PEEP considering the lower and upper inflection points may not be the most reliable strategy. The stress index has been advocated as a favorable parameter to select PEEP level, avoiding potential hyperinflation (Figure 1) (41). To measure it, the ventilator should be set under conditions of constant flow and volume-limited ventilation. The stress index defines the slope of the airway opening pressure during a period of constant flow. Values lower than 1 suggest a continuous decrease in elastance during lung inflation. This is consistent with potential recruitability and, therefore, PEEP can be increased. Values higher than 1 suggest an increase in lung elastance, consistent with lung hyperinflation. In these situations, PEEP should be decreased to avoid overstretching. Even though the stress index represents an interesting physiologic concept, more investigations are needed to validate it as an optimal technique for PEEP titration.

Figure 1.

Graphic representation of the stress index concept. The stress index is the coefficient b of a power equation (airway pressure = a inspiratory time b + c), fitted on the airway opening pressure (Pao) segment (bold lines) corresponding to the period of constant-flow inflation (dotted lines), during constant-flow, volume-cycled mechanical ventilation. For stress index values <1, the Pao curve presents a downward concavity, suggesting a continuous decrease in elastance during constant-flow inflation. For stress index values >1, the curve presents an upward concavity suggesting a continuous increase in elastance. Finally, for a stress index value equal to 1, the curve is straight, suggesting the absence of tidal variations in elastance. Reprinted from Grasso et al, 2007 (41) with permission of the American Thoracic Society. Copyright © American Thoracic Society. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Two other trials have evaluated the optimal level of PEEP in the treatment of ARDS. The Lung Open Ventilation Study (LOVS) was a multicenter randomized controlled trial that included 983 patients (42). The control group was ventilated with low tidal volume, plateau pressures not exceeding 30 cm H₂O, and low levels of PEEP. The intervention group used low tidal volumes, plateau pressures not exceeding 40 cm H₂O, and higher levels of PEEP. In addition, the intervention group performed recruiting maneuvers (40-sec breath holds at pressures of 40 cm H₂0). This last strategy resulted in reduced refractory hypoxemia and lower utilization of rescue techniques for hypoxemia, such as inhaled nitric oxide (iNO), prone ventilation, extracorporeal membrane oxygenation (ECMO), or high-frequency oscillatory ventilation (HFOV). The EXPRESS trial was also a multicenter randomized controlled trial, which included 767 patients from 37 French intensive care units (ICUs) (43). Patients were randomized to a minimal distension group (PEEP 5–9 cm H₂O) or a maximal recruitment group (PEEP increased to reach plateau pressure of 28–30 cm H₂O). The high PEEP recruitment strategy had no mortality benefit, but resulted in better oxygenation, higher compliance values, and more ventilator-free days (7 vs. 3 days; P = 0.04) and organ failure–free days (6 vs. 2 days; P = 0.04) in the subgroup of patients with refractory hypoxemia. A recent meta-analysis, which included data from ALVEOLI, LOVS, and EXPRESS trials, revealed that higher levels of PEEP were associated with improved survival among patients with moderate to severe ARDS (44).

Hemodynamic monitoring and fluid management. Avoidance of intrathoracic fluid accumulation is thought to be beneficial in patients with ARDS. Based on this premise, the Comparison of Two Fluid-Management Strategies in ARDS trial (FACTT) evaluated the hemodynamic management of patients with ARDS guided by a pulmonary artery catheter or a central line catheter, plus an explicit hemodynamic management protocol (45, 46). The FACTT study included 1000 patients, who were randomized to 1 of 4 hemodynamic protocols for a period of 7 days. The conservative hemodynamic strategy aimed for a central venous pressure <4 mm Hg or a pulmonary artery occlusion pressure <8 mm Hg. The liberal hemodynamic strategy aimed for a central venous pressure of 10 to 14 mm Hg or pulmonary artery occlusion pressure of 14 to 18 mm Hg. The mean (± standard error [SE]) cumulative fluid balance during the first 7 days was –136 ± 491 mL in the conservative strategy group and 6992 ± 502 mL in the liberal strategy group (P < 0.001). Also, the conservative strategy improved the oxygenation index and increased the number of ventilator-free days (14.6 ± 0.5 vs. 12.1 ± 0.5; P < 0.001) during the first 28 days. Interestingly, despite restrictions in the use of fluids in the conservative group, there was no increase in the incidence of shock or need for dialysis during the first 60 days (10% vs. 14%; P = 0.06) (46). These results support a conservative fluid strategy in the management of patients with ARDS.

Refractory hypoxemia

In certain situations, in which patients with ARDS do not improve their oxygenation with conventional therapies, other treatment options deemed as “salvage therapies” or “rescue therapies” have been advocated.

High-frequency oscillatory ventilation. HFOV delivers very low tidal volumes (equal to or less than anatomic dead space) at frequencies of 3 to 15 Hz. It also maintains a high airway pressure to permit recruitment. Ventilation is inversely related to the respiratory frequency and is directly related to the pressure amplitude of oscillation. Ideally, this strategy permits a more homogenous distribution of ventilation by maintaining mean airway pressure (47, 48), but avoiding hyperinflation (49, 50) and ventilator-induced lung injury by minimizing swings in tidal volumes (51).

Several randomized controlled trials have failed to show a mortality benefit with HFOV. Two large multicenter randomized controlled trials were recently published. The OSCILLATE trial was a multicenter randomized controlled trial conducted at 39 ICUs in five countries (52). The study included 548 patients with moderate to severe ARDS who were randomly assigned to HFOV targeting lung recruitment or a conventional low tidal volume–high PEEP ventilation strategy. The HFOV group had increased in-hospital mortality (47% vs. 35%; P = 0.005). Also, those in the HFOV group required more sedation, paralytics, and vasopressor agents. The OSCAR trial included nearly 800 patients in 17 United Kingdom ICUs. This study also failed to demonstrate a survival benefit at 30 days (41.7% mortality in the HFOV group and 41.1% mortality in the control group; P = 0.85) (53).

Airway pressure release ventilation. Airway pressure release ventilation (APRV) is a pressure-targeted, time-cycled mode of mechanical ventilation that permits spontaneous breathing across the full breathing cycle. It involves a long inspiratory time followed by a very short expiratory time, creating inverse ratio ventilation. By increasing the inflation period, the mean airway pressure is increased without an increase in the peak pressure. The superimposed spontaneous breathing has the advantage of providing more even ventilation distribution as well as augmentation of cardiac filling (54). In a randomized controlled trial, 30 mechanically ventilated trauma patients were randomly assigned to either APRV or pressure-limited ventilation (55). APRV was found to be associated with shorter duration of mechanical ventilation, a shorter ICU length of stay, and use of less sedatives and paralytics. Numerous studies have shown that APRV can decrease the peak airway pressure, improve alveolar recruitment, and improve oxygenation (56–60). Nevertheless, there is no evidence of an improved mortality outcome by using this mode, as compared to other modes of mechanical ventilation.

Extracorporeal membrane oxygenation. ECMO is used in ARDS patients with very severe hypoxemia, uncompensated hypercapnia (pH < 7.15), or excessively high end-inspiratory plateau pressures (>35–45 cm H₂O) despite the use of standard-of-care treatments for the management of ARDS (61–64). Despite earlier negative trials (65), the Conventional Ventilator Support vs. ECMO for Severe Adult Respiratory Failure (CESAR) study suggests there may be some benefit with extracorporeal lung support in patients with severe ARDS (66). In this randomized controlled study, 180 patients were randomized to receive veno-venous ECMO (after being transferred to a specialized center) or conventional mechanical ventilation (in regional centers). The former group had a higher 6-month survival than the latter (63% vs. 47%; P = 0.03). Nevertheless, it is important to note that the intervention group underwent mechanical ventilation using a lung protective strategy, whereas it was used in only 70% of patients in the control group. Also, despite mortality benefits in the intervention group, only 75% of these patients actually received ECMO upon arrival to the specialized center. Therefore, the CESAR study demonstrated a mortality benefit in a specialized center vs. a regional center, but not necessarily a clear benefit of ECMO.

Vasodilator therapy. The rationale for using selective inhaled pulmonary vasodilators is to cause selective vasodilation in normal lung segments and recruit blood flow to these areas, where it can be oxygenated (67). Due to their local action and short half-lives, selective pulmonary vasodilators do not usually have systemic side effects, such as hypotension. Two metaanalyses compared iNO to either placebo or conventional management and found a modest and transient improvement in oxygenation, without improvement in survival, duration of mechanical ventilation, or ventilator-free days (68). It was also noted that patients without sepsis or septic shock responded more frequently to iNO than patients with septic shock (69). Inhaled epoprostenol has also been used in patients with ARDS, and it has similar physiologic effects as iNO. As with iNO, no study has demonstrated a clear survival benefit.

Recruitment maneuvers. Recruitment maneuvers can be defined as a strategy to increase transpulmonary pressure transiently with the goal of reexpansion of previously collapsed but recruitable lung alveolar units. This strategy can be performed by using conventional ventilators or oscillators. Gattitoni et al showed that the amount of lung mass that can be recruited averages 9% of the total lung mass, with pressures between 5 and 45 cm H₂O (70). Recruitment maneuvers can increase the aerated lung mass and prevent atelectrauma caused by repeated opening and closing of terminal respiratory units (71). Two commonly used recruitment maneuvers are the sigh and sustained inflation. “Sigh” involves increasing tidal volume or PEEP for one or several breaths per minute to a prespecified plateau pressure. The other form of recruitment maneuver is the sustained inflation method, which consists of pressurizing the airways at a specific level and maintaining it for a given duration. A common combination is the application of 40 cm H₂O of airway pressure for 40 seconds. Despite the physiological advantages associated with recruitment maneuvers, three randomized controlled trials and one metaanalysis were not able to demonstrate a beneficial effect of recruitment maneuvers on oxygenation. Current evidence does not recommend their routine use, but recruitment maneuvers remain an option as a rescue therapy in severe hypoxemic patients (72–74).

Prone positioning. Conceptually, prone position may lead to a more uniform distribution of lung stress and strain, leading to improved ventilation-perfusion matching and regional improvement in lung and chest wall mechanics. However, prior reports indicated that prone positioning was associated with a variety of complications, such as hardware displacement and pressure ulcers. Prior clinical trials showed that prone positioning improved oxygenation in patients with ARDS, without benefits in terms of survival (75–77). In those studies, investigators used either repeated sessions of prone ventilation lasting 6 to 8 hours per day (14, 78) or prolonged prone ventilation lasting 17 to 20 hours (79–81) with similar results. While previous randomized controlled trials had not shown a survival benefit in patients with ARDS (80, 82), some observation studies and metaanalysis revealed a positive signal in a subset of patients with severe ARDS (83, 84). A recent multicenter prospective controlled trial (the PROSEVA study) randomized 466 patients with severe ARDS (PaO₂:FiO₂ <150, FiO₂ ≥ 0.6, PEEP ≥ 5 cm H₂O) to undergo early (within 33 hours of intubation) prone-positioning sessions of at least 16 hours, or to be left in the supine position (79). Prone positioning decreased 28-day mortality (16% vs. 33%; P < 0.001), decreased 90-day mortality (24% vs. 41%; P < 0.001), increased ventilator–free days (14 vs. 10 days at day 28), and decreased time to extubation. The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. Absolute and relative contraindications for prone positioning include spinal instability, elevated intracranial pressure, hemodynamic and cardiac abnormalities, massive hemoptysis, thoracic and abdominal surgeries, anterior chest tubes with leaks, and deep venous thrombosis treated for <2 days.

Adjunctive therapy

Neuromuscular blocking agents. Lung-protective mechanical ventilation has become the cornerstone management strategy for ARDS (85). However, patients with ARDS are still exposed to the risk of atelectrauma and barotrauma due to suboptimal ventilator strategies. Neuromuscular blocking agents have been proposed as adjuvant therapy in ARDS, as they may decrease patient-ventilator asynchrony and, potentially, avoid the risk of barotrauma and biotrauma (86).

A recent multicenter double-blinded randomized controlled trial (ACURASYS) was conducted with 340 patients with severe ARDS. The study compared cisatracurium with placebo (13). All patients were sedated, titrating the Ramsay sedation score to 6 (no response on glabellar tap). Muscle paralysis monitoring, using train-of-four testing, was not allowed in order to maintain study blinding. Cisatracurium was associated with decreased adjusted 90-day mortality (31.6% vs. 40.7%; P = 0.08). Furthermore, mortality at 28 days was 23.7% in the cisatracurium group and 33.3% in the placebo group (P = 0.05). In this study, there was no difference in the rate of myopathy between the two groups.

Steroids. Inflammation is a key component in ARDS. Multiple studies have investigated the role of steroids in the prevention of ARDS and in the treatment of its different phases. Four trials have assessed the use of methylprednisolone for prevention of ARDS in a high-risk group of patients (sepsis/septic shock) (87–90). Specifically, Weigelt et al looked at high-risk surgical ICU patients (90). In this study, methylprednisolone at a dose of 30 mg/kg every 6 hours for 2 days increased the incidence of ARDS (64% vs. 33%), as well as the rate of infections (77% vs. 43%). Similarly, Bone et al demonstrated an increased 14-day mortality in the steroid group compared with a control group (52% vs. 22%) (88).

Multiple controlled studies have evaluated the role of glucocorticoid therapy in early and late ARDS. Bernard et al performed the first multicenter double-blinded prospective randomized controlled trial to assess the role of a short course of steroids given for 24 hours to patients with early ARDS (91). The study showed that there was a small decrease in 45-day mortality (60% vs. 63%) and an increased chance of ARDS reversal (39% vs. 36%) among patients receiving methylprednisolone compared with placebo. A large multicenter randomized controlled trial was conducted by the National Heart, Lung, and Blood Institute ARDSnet group to determine the efficacy and safety of a moderate dose of steroids for a period of 21 days in patients with persistent ARDS (>7 days). The study showed no survival benefit at 60 or 180 days (92). Similar results were reported by Annane et al in the same year (93). Meduri et al performed a multicenter double-blinded randomized controlled trial with 91 patients with ARDS who received steroids within 72 hours of entry into the study (94). The authors used a prolonged course of methylprednisolone (a loading dose of 1 mg/kg, followed by an infusion of 1 mg/kg/day from day 1 to day 14, 0.5 mg/kg/day from day 15 to day 21, 0.25 mg/kg/day from day 22 to day 25, and 0.125 mg/kg/day from day 26 to day 28). This study showed a significant decrease in mortality (20.6% vs. 42.9%; P = 0.03), reduction in the duration of mechanical ventilation (P = 0.002), and reduction in ICU stay (P = 0.007).

The contradictory results of the ARDSnet and Meduri trials are likely due to the rapid taper of steroids in the ARDSnet study and the use of steroids during different phases of the disease. Clinical trials evaluating the effect of a prolonged course of steroids in ARDS have consistently shown a significant improvement in oxygenation (PaO₂/FiO₂ ratio) (92, 95–97) and a reduction in systemic inflammation (95–97), organ dysfunction score (92, 95–97), duration of mechanical ventilation (95–97), and ICU length of stay (95–97). Data from five recently conducted large trials were analyzed and showed that patients who received corticosteroids early (<14 days after onset of ARDS) had reduced mortality (38% vs. 52.5%; P = 0.02) (98). Both the ARDSnet group and Meduri showed an increase in the number of ventilator-free days and decreased length of ICU stay. Review of available data shows that the beneficial effect of corticosteroids is seen only when used in the early phase of ARDS and not in the late phase. Therefore, a recent consensus statement recommended early initiation of prolonged glucocorticoid therapy for patients with moderate to severe ARDS (PaO₂/FiO₂ < 200 mm Hg on PEEP 10 cm H₂0), and before day 14 (99).

CONCLUSION

ARDS continues to be associated with a high mortality. Despite multiple randomized controlled trials, only lung protective ventilation strategies, neuromuscular blocking agents, and prone ventilation have been shown to decrease mortality. Many trials are underway looking at nebulized heparin, aspirin, stem cell therapy, growth factors, interferon-β, and vascular endothelial growth factor. The new Berlin definition of ARDS may assist future trials of novel therapies by improving diagnostic reliability and allowing more precise stratification of patients according to severity.