Acute respiratory distress syndrome (ARDS) is characterized by severe hypoxemia and non-cardiogenic pulmonary edema. In 1967, Ashbaugh et al.  reported a case series of 12 critically ill patients with tachypnea and hypoxemia accompanied by decreased lung compliance and pulmonary infiltrates on chest X-rays from different etiologies. This was the first established ARDS. Thenceforth, there was no common definition of ARDS , resulting in various published prevalences in intensive care units (ICUs). Until 2012, Berlin definition of ARDS was created by a consensus panel of experts (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) to simplify the diagnosis and prognosticate outcomes . ARDS was defined as a clinical entity, which consisted of an acute onset (less than 1 week), bilateral opacities on computed tomography or chest radiograph, a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2 ratio) ≤300 mmHg with a minimum of 5 cm H2O positive end-expiratory pressure (PEEP), and no cardiac failure or fluid overload.
ARDS is associated with high mortality. For over 20 years, many therapeutic strategies have been provided to improve patients’ outcomes. In 2000, the ARDS network established an important study “Ventilation with lower tidal volumes as compared with traditional tidal volumes for ALI and ARDS.” The study demonstrated that the use of low tidal volume (TV; 6 mL/kg predicted weight) significantly reduced mortality from 40% to 30% and increased ventilator-free days, compared with traditional TV (12 mL/kg predicted weight) . In 2010, the ACURASYS study investigators reported that the use of neuromuscular blockade (cisatracurium) in patients with early ARDS with PaO2/FiO2 ratio <150 for 48 h significantly reduced both 28-day and 90-day mortalities and increased ventilator-free days without increased incidence of ICU-acquired weakness . In addition, PROSEVA study showed that prone position with lung-protective strategy reduced 28-day and 90-day mortalities and this strategy should be considered in patients with early ARDS and severe hypoxemia who have the PaO2/FiO2 ratio of <150 despite FiO2 of ≥0.6 and PEEP of ≥5 cm H2O .
On the contrary, some strategies did not improve survival and might be harmful to ARDS patients. There were 2 landmark studies of high-frequency oscillation ventilation (HFOV), including OSCAR and OSCILATE trials [7, 8]. The former study showed that HFOV did not reduce mortality and increased the need of sedatives and muscle relaxants. The latter study showed that HFOV increased hospital mortality (47% in the HFOV group vs 35% in the low TV with the high PEEP group) and the need of sedatives, muscle relaxants, and vasopressors. Furthermore, a recent study showed that lung recruitment with PEEP set by respiratory system compliance significantly increased 28-day and 6-month mortalities with higher incidences of barotrauma and hypotension in moderate to severe ARDS patients .
Besides the ventilator management, several trials demonstrated benefits of conservative fluid management in patients with ARDS [10, 11, 12, 13]. The Fluid and Catheter Treatment Trial (FACTT) demonstrated that a conservative fluid management strategy improved oxygenation, shortened duration of mechanical ventilation (MV), and ICU stay without a risk of nonpulmonary organ failure in ARDS patients . However, it did not show a mortality benefit and potentially increased a risk of long-term cognitive impairment .
Epidemiological studies of the practice and outcomes of ARDS were mostly conducted in high-income countries, and the data in low- to middle-income countries were still limited. Moreover, some studies such as LUNG SAFE study were not focused on ARDS patients . We hypothesized that routine clinical practice and outcomes of ARDS in our hospital might be different from the previous reported data from developed countries due to limited ICU resource and shortage of health care personnel. This study aimed to evaluate the clinical outcomes of ARDS patients, associated factors predicting outcomes, and current physicians’ practice in our medical ICUs.
Materials and methods
We conducted a retrospective cross-sectional study of clinical outcomes of ARDS patients and physicians’ practice in the medical ICUs at tertiary referral university teaching hospital. We included all ARDS patients admitted in the medical ICUs from September 2010 to September 2014. The patients were identified using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code: J80 (ARDS) and Diagnosis and Procedure Codes (ICD-9-CM) codes: 997x, 96.7. The data were collected from inpatient medical records. Only patients with fulfilled ARDS criteria (Berlin definition) were reviewed and analyzed. This study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine, Chulalongkorn University, for authorization for medical record review (approval certificate no. 457/59). The clinical trial registration number is TCTR20180212002.
ARDS patients admitted in medical ICUs at tertiary referral university teaching hospital with 14 beds in ICU between September 2010 and September 2014, using the raw data that made up the various components of the Berlin ARDS definition .
Acute Physiology and Chronic Health Evaluation (APACHE II) was determined at the onset of ARDS. Other recorded variables included age, sex, etiology, blood gas analysis, ventilator management, and clinical outcomes of ARDS. The primary outcome was 28-day mortality. The secondary outcomes were 7-day mortality, and other clinical outcomes were hospital length of stay (LOS) and duration of MV, and ventilator management.
SPSS (versions 22) was used to analyze the data, using odds ratio (OR), P-value, and 95% confidence intervals (CIs). Univariate and multivariate analyses (using variables with P < 0.2 in univariate analysis) for 7- and 28-day mortalities were performed using a binary logistic regression model.
Between 2010 and 2014, 266 of 4,090 (6.5%) patients admitted in our medical ICUs met the Berlin criteria for ARDS diagnosis. Approximately 11.7%, 44.4%, and 44.0% of the patients fulfilled mild, moderate, and severe ARDS criteria, respectively. The severity of ARDS correlated with APACHE II score (r2 = 0.235, P < 0.001). Demographic data of the patients are summarized in Table 1.
Characteristics of enrolled patients
|Overall||Mild ARDS||Moderate ARDS||Severe ARDS|
|N (%)||266 (100.0%)||31 (11.7%)||118 (44.4%)||117 (44.0%)|
|Age (years), mean ± SD||54.81 ± 18.66||48.84 ± 21.40||53.67 ± 18.64||57.54 ± 17.56|
|Gender, n (%)|
|Male||153 (57.5%)||16 (51.6%)||66 (55.9%)||71 (60.7%)|
|Female||113 (42.5%)||15 (48.4%)||52 (44.1%)||46 (39.3%)|
|BMI (kg/m2), mean ± SD||22.21 ± 4.44||21.91 ± 3.59||21.96 ± 3.97||22.56 ± 5.11|
|Etiology of ARDS (%)|
|Pneumonia||217 (81.6%)||26 (83.9%)||100 (84.7%)||91 (77.8%)|
|Sepsis||25 (9.4%)||4 (12.9%)||6 (5.1%)||15 (12.8%)|
|HLH||3 (1.1%)||0 (0%)||2 (1.7%)||1 (0.9%)|
|Pneumonitis||10 (3.8%)||1 (3.2%)||4 (3.4%)||5 (4.3%)|
|Multiple factors||6 (2.3%)||0 (0%)||5 (4.2%)||1 (0.9%)|
|Unspecified cause||2 (0.8%)||0 (0%)||1 (0.8%)||1 (0.9%)|
|Diffuse alveolar hemorrhage||3 (1.1%)||0 (0%)||0 (0%)||3 (1.1%)|
|APACHE II median (25%, 75% quartile)||26 (22, 31)||23.16 (19, 27)||25.09 (21, 29)||27.69 (23, 32)|
|PaO2/FiO2, day 1, mean ± SD||122.40 ± 58.64||237.88 ± 53.81||138.96 ± 28.08||75.29 ± 18.04|
|Initial mode (%)|
|PCV||233 (87.6%)||22 (71%)||105 (89%)||106 (90.6%)|
|VCV||5 (1.9%)||1 (3.2%)||2 (1.7%)||2 (1.7%)|
|PSV||14 (5.3%)||4 (12.9%)||5 (4.2%)||5 (4.3%)|
|SIMV||2 (0.8%)||1 (3.2%)||1 (0.8%)||0 (0%)|
|NIV||7 (2.6%)||2 (6.5%)||1 (0.8%)||4 (3.4%)|
|Bird mark 7||4 (1.5%)||0 (0%)||4 (3.4%)||0 (0%)|
|Nasal high flow||1 (0.4%)||1 (3.2%)||0 (0%)||0 (0%)|
|Adjunctive interventions (%)|
|APRV||15 (5.6%)||1 (3.2%)||4 (3.4%)||10 (8.5%)|
|HFOV||4 (1.5%)||0 (0%)||3 (2.5%)||1 (0.9%)|
|Prone||10 (3.8%)||0 (0%)||5 (4.2%)||5 (4.3%)|
|Recruitment maneuver||128 (48.1%)||10 (32.3%)||58 (49.1%)||60 (51.3%)|
|PIP in PCV, day 1,||31 ± 6||27 ± 5||31 ± 6||32 ± 6|
|mean ± SD (cm H2O)|
|TV/kg IBW day 1,||8.56 ± 2.48||8.71 ± 2.22||8.45 ± 2.56||8.64 ± 2.47|
|mean ± SD (mL/kg IBW)|
|PEEP, day 1,||10 ± 4||7 ± 3||10 ± 4||12 ± 5|
|mean ± SD (cm HO) 2|
|Neuromuscular blockade use (%)||94 (35.3%)||7 (22.6%)||46 (39%)||41 (35%)|
|Sedative drugs (%)||229 (86.1%)||25 (80.6%)||102 (86.4%)||102 (87.2%)|
|Morphine||30 (11.3%)||1 (3.2%)||11 (9.3%)||18 (15.4%)|
|Fentanyl||194 (72.9%)||22 (71.0%)||86 (72.9%)||86 (73.5%)|
|Midazolam||197 (74.0%)||20 (64.5%)||87 (73.7%)||90 (76.9%)|
|Propofol||45 (16.9%)||7 (22.3%)||19 (16.1%)||19 (16.2%)|
|I/O balance, day 1,||2,484.94 ± 2,406.92||2,221.45 ± 2,202.28||2,161.26 ± 2,145.60||2,881.19 ± 2,694.55|
|mean ± SD (mL/day)|
|Total I/O balance in 3 days,||5,029.31 ± 4,550||3,760 ± 3,370||4,370 ± 4,306||6,037 ± 4,892|
|mean ± SD (mL/day)|
|Total I/O balance in 7 days,||6,634.97 ± 6,718.06||4,615.92 ± 6,327.18||5,771.69 ± 6,947.38||8,052.71 ± 6,337.84|
|mean ± SD (mL/day)|
|Enteral calories (kcal/day), AVG in||673.75 ± 546.29||651.57 ± 590.71||724.63 ± 533.06||628.30 ± 547.78|
|7 days, mean ± SD|
|Ventilator day (days), mean ± SD||16.46 ± 20.11||24.77 ± 30.88||16.61 ± 17.38||14.11 ± 20.11|
|Hospital LOS (days), mean ± SD||27.1 ± 26.47||34.26 ± 33.60||29.63 ± 25.01||22.65 ± 25.26|
|7-day mortality, n (%)||83 (31.1)||4 (12.9)||30 (25.4)||49 (41.9)|
|28-day mortality, n (%)||184 (69.2)||16 (51.6)||82 (69.5)||86 (73.5)|
The majority of the ARDS patients had pneumonia and were assisted with pressure-controlled ventilation with the mean peak inspiratory pressure (PIP) and PEEP on the first day of MV of 31 ± 6 and 10 ± 4 cm H2O, respectively. The plateau pressure (Pplat) was recorded in only 4.1% of the patients. The mean TV on the first day was 8.56 ± 2.48 mL/kg ideal body weight (IBW), and the average TV during the first 3 days of MV was 8.81 ± 2.39 mL/kg IBW. Approximately 55.4% of the patients had TV on the first day of MV of >8 mL/kg IBW and 60.9% of the patients had average TV during the first 3 days of MV of >8 mL/kg IBW.
Neuromuscular blockades and sedative drugs were prescribed to 35.3% and 86.09% of the patients, respectively. Adjunctive interventions including prone position, recruitment maneuver, and rescued modes such as airway pressure release ventilation (APRV) and HFOV were applied to patients with moderate and severe ARDS (Table 1). Noticeably, recruitment maneuver was performed in a half of the patients, especially in the patients with moderate to severe ARDS. However, the incidence of pneumothorax was not different between the patients who received recruitment maneuver (79.7%) and who did not receive recruitment maneuver (82%).
Overall, the crude 7-day mortality was 31.1%, associated with age, ARDS severity, APACHE II score, PaO2/FiO2 ratio on day 1, mean PaO2/FiO2 ratio during the first 3 days, fluid balance on day 1 and cumulative fluid balance during the first 3 and 7 days, and average daily calories during the first week (Table 2). The crude 28-day mortality was 68.9%, associated with age, ARDS severity, APACHE II score, PaO2/FiO2 ratio on day 1, mean PaO2/FiO2 ratio during the first 3 days, TV/kg IBW on day 1, PIP on day 1, neuromuscular blockade use, fluid balance on day 1 and cumulative fluid balance during the first 3 and 7 days, and average daily calories during the first week (Table 2). After adjusting for confounding factors, the mean PaO2/FiO2 ratio during the first 3 days, cumulative fluid balance on day 3, and average daily calories during the first week were independent predictors for 7-day mortality, whereas APACHE II score, fluid balance on day 1, cumulative fluid balance during the first 7 days, and average daily calories during the first week were independent predictors for 28-day mortality (Table 3). Furthermore, the patients who received average daily calories during the first week of <60% of estimated daily energy requirement had a greater risk of death (OR = 3.28, 95% CI 1.79–6.01, P < 0.001). Moreover, interestingly, the risk of death within 28 days increased with increasing 7-day cumulative fluid balance as shown in Figure 1.
Univariate analysis for 7- and 28-day mortalities
|Univariate analysis||7-day mortality||28-day mortality|
|Crude HR||95% CI||P||Crude HR||95% CI||P|
|PaO2/FiO2 ratio, day 1||0.992||0.987–0.997||<0.01*||0.997||0.993–1.001||0.18|
|Mean PaO2/FiO2 ratio||0.99||0.980–0.992||<0.01*||0.994||0.990–0.998||<0.01*|
|TV/kg IBW, day 1||0.996||0.883–1.124||0.95||0.914||0.810–1.031||0.14|
|Mean TV/kg IBW||0.924||0.801–1.067||0.28||0.917||0.802–1.048||0.20|
|PEEP, day 1||1.006||0.948–1.067||0.85||0.966||0.911–1.024||0.25|
|PIP, day 1||1.061||1.004–1.121||0.04||1.040||0.983–1.101||0.17|
|I/O balance, day 1 (L/day)||1.325||1.175–1.495||<0.01*||1.200||1.063–1.354||<0.01*|
|Total I/O balance in 3 days (L/day)||1.229||1.142–1.324||<0.01*||1.137||1.066–1.212||<0.01*|
|Total I/O balance in 7 days (L/day)||1.112||1.071–1.176||<0.01*||1.128||1.077–1.181||<0.01*|
|7-day AVG enteral calories (kcal/day)||0.998||0.997–0.999||<0.01*||0.999||0.998–0.999||<0.01*|
Multivariate analysis for 7- and 28-day mortalities
|Multivariate analysis||7-day mortality†||28-day mortality‡|
|Adjusted HR||95% CI||P||Adjusted HR||95% CI||P|
|PaO2/FiO2 ratio, day 1||1.003||0.995–1.011||0.50||1.003||0.994–1.013||0.46|
|Mean PaO2/FiO2 ratio||0.988||0.981–0.994||<0.01*||0.997||0.989–1.006||0.55|
|TV/kg IBW, day 1||1.001||0.997–1.004||0.68|
|PIP, day 1||1.037||0.966–1.114||0.32|
|I/O balance, day 1||0.984||0.818–1.182||0.86||0.816||0.666–0.998||0.048*|
|Total I/O balance in 3 days (L/day)||1.192||1.102–1.289||<0.01*||0.969||0.802–1.169||0.74|
|Total I/O balance in 7 days (L/day)||1.061||0.979–1.150||0.15||1.103||1.026–1.186||<0.01*|
|7-day AVG enteral calories (kcal/day)||0.998||0.997–0.999||<0.01*||0.999||0.998–1||<0.01*|
This study demonstrated that the 28-day mortality of the ARDS patients admitted in our medical ICUs was high, compared with the mortalities in other studies [15, 16, 17, 18, 19] (Table 4). We postulated that the higher mortality rate resulted from limited ICU beds, delayed ICU admission, delayed sedative and neuromuscular blockade administration, and shortage of medical staff. Our mortality rate tended to be increasing with the greater ARDS severity; however, it was not significant. It might be explained that there were multiple factors affecting the mortality rate such as ventilator-induced lung injury, ventilator-associated pneumonia, and positive cumulative fluid balance. Noticeably, 42.3% of our patients received TV greater than 8 mL/kg IBW on the first day, compared with 30% of the patients in the PRoVENT study . Moreover, there were limited data of the Pplat in our study (4%), compared with 17.2% in ALIEN , 40% in LUNG SAFE , 41% in PRoVENT , and 90.7% in APRONET . These findings might indicate that the physicians less concerned about ventilator-induced lung injury. Furthermore, the prevalence of prone position in our severe ARDS patients was only 4%, compared with 16% in LUNG SAFE  and 32.9% in APRONET . Prone position was infrequently used in our study because of different study periods. The PROSEVA  reported the mortality benefit of prone position in 2013, but we retrospectively reviewed the data between 2010 and 2014. In addition, the prevalence of the use of neuromuscular blocking agent was 35.3% in our study, higher than LUNG SAFE (21.7%)  due to the higher proportion of severe ARDS patients in our study. Despite the greater use of neuromuscular blockade, the mortality rate was higher, which might be from inadequate doses of this medication and no ventilator asynchrony monitoring. Recruitment maneuver was performed to 48.12% of the patients, which was quite high, compared with 20.9% in the LUNG SAFE . Despite the fact that the recruitment maneuver potentially increased the risk of barotrauma and death [21, 22], our study did not show the association between the procedure and the complications. Finally, similar to other studies, there were low prevalence of HFOV, APRV, and extracorporeal membrane oxygenation (ECMO) use, which less affected the ARDS outcomes [7, 8, 23, 24, 25, 26, 27, 28, 29].
Comparison of 28-day mortality of ARDS patients and factors possibly associated with mortality between our study and other studies including ALIEN, LUNG SAFE, PRoVENT, and APRONET
|Our study||ALIEN||LUNG SAFE||PRoVENT||APRONET|
|All severity of ARDS||69.2%||42.7%||34.8%||29%||NA|
|TV (mL/kg IBW) on day 1||8.56 ± 2.48||7.2 ± 1.1||7.6||7.6||6.7|
|Percentage of patients with TV >8 mL/kg IBW on day 1||42.3%||NA||NA||30%||NA|
|Percentage of Pplat measurement||4%||17.2%||40%||41%||90.7%|
|Percentage of patients with prone position (in severe ARDS)||4%||NA||16%||NA||32.9%|
|Percentage of patients receiving neuromuscular blockage||35.3%||NA||21.7%||NA||NA|
|Percentage of patients with recruitment maneuver||48.1%||NA||20.9%||NA||NA|
|Percentage of patients with ECMO||0%||NA||3.2%||NA||1.9%|
|Percentage of patients with HFOV||1.5%||NA||1.2%||NA||NA|
|Percentage of patients with APRV||5.63%||NA||NA||NA||NA|
According to the ventilator complications, barotrauma was not different between ARDS survivors and non-survivors. Nevertheless, ventilator-associated pneumonia was higher in the non-survivors group (18.4% vs 13.4%).
Besides, most of the patients had positive cumulative fluid balance, which contributed to the significantly greater mortality in our study (Figure 1). Compared with FACTT , our ARDS patients had cumulative fluid balance over 7 days close to the fluid balance of the patients in the liberal fluid management group (6,634.97 ± 6,718.06 mL in our study vs 6,992 ± 502 in liberal FACTT), who had worse clinical outcomes, including less ventilator-free days and deteriorated oxygenation index and lung injury score. Nevertheless, FACTT did not demonstrate the mortality risk from liberal fluid management. The different findings might be explained by the fact that there were limited data of hemodynamic status, which possibly confounded to the significantly higher mortality rate in our study.
Furthermore, our study showed that the patients receiving daily calories less than 60% of the estimated daily caloric need during the first week had higher mortality. This result was different from the findings in the EDEN study , which demonstrated that initial trophic enteral feeding for up to 6 days in patients with acute lung injury resulted in similar ventilator-free days, 60-day mortality, and infectious complications, compared with full enteral feeding. It might be explained that our patients with lower caloric intake possibly had more severe conditions such as hemodynamic instability or severe lung injury treated with prone position, which had an impact on mortality outcome.
Our study had limitations. Due to the retrospective design, the information was obtained from the recorded documents. Thus, there were some missing data such as height, body weight, Pplat, and driving pressure. In addition, there might be uncontrolled factors confounding to the mortality rate such as inadequate antibiotics and source control, inappropriate resuscitation of shock, or the different severity of comorbidities.
The 28-day mortality of ARDS was high. In addition, the average TV and fluid balance were greater than the protective limits. These findings indicated the potential improvement of ARDS outcomes in our hospital. The educational program focusing on ARDS management, follow-up, and feedback activities should be provided to our medical personnel.
A part of this study was presented at the 21st Congress of the Asian Pacific Society of Respirology and published in the poster presentation abstract in Respirology. 2016; 21(Suppl. 3):3–213.
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Lim J, Litton E, Robinson H, Das Gupta M. Characteristics and outcomes of patients treated with airway pressure release ventilation for acute respiratory distress syndrome: A retrospective observational study. J Crit Care. 2016; 34:154–9.)| false 10.1016/j.jcrc.2016.03.002 27020770
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Peek GJ, Elbourne D, Mugford M, Tiruvoipati R, Wilson A, Allen E, et al. Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR). Health Technol Assess. 2010; 14:1–46.)| false 20642916
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Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009; 374:1351–63.)| false 10.1016/S0140-6736(09)61069-2
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National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, et al. Initial trophic vs full enteral feeding in patients with acute lung injury the EDEN randomized trial. JAMA. 2012; 307:795–803.)| false 22307571 10.1001/jama.2012.137