Acute respiratory distress syndrome (ARDS) is a type of acute inflammatory lung injury in the absence of cardiac causes of pulmonary edema, leading to increased lung weight, increased pulmonary vascular permeability, and loss of aerated lung tissue (1). The leading causes of ARDS include pneumonia, sepsis, trauma, pneumonia, and massive transfusions of blood products transfusions (2 , 3). These conditions are common in the patients admitted to the ICUs, and the concomitant presence of ARDS is associated with a significantly increased mortality (4). Depending on the severity of ARDS, mechanical ventilation as well as adjunctive therapies are lifesaving interventions (2 , 5). Numerous studies have been conducted to reveal the pathophysiology and to find the potential therapeutic approaches for ARDS. Up to date, only a few treatment interventions have been found to be clinically useful in ARDS such as low tidal volume mechanical ventilation, conservative fluid strategy, and use of prone position for severe ARDS (6–10). The effectiveness of other interventions such as the use of elevated positive end-expiratory pressure (PEEP) were still controversial (6 , 7).
Epidemiologic studies exploring the mortality in ARDS patients show conflicting results (8 , 9). Although systematic analysis of ARDS Network (ARDSNet) trials documented a significant improvement in survival from 1996 to 2005 (10), another review of observational studies and randomized controlled trials (RCTs) failed to identify decrease in mortality between 1994 and 2006, probably due to the use of 1994 consensus definition of ARDS (9). ARDSNet trials also had significant impact on mechanical ventilation practice, which in turn resulted in improved management of ARDS (11). Furthermore, these studies did not investigate the possible modifiable factors such as daily fluid balance which could result in the improvement in survival. Conservative fluid management strategy for ARDS has been extensively studied and found to be clinically useful (12) and is increasingly being used in clinical practice. However, it is largely unknown whether this changing practice parallels with the improvement in survival outcome. This study aims to investigate the temporal trends of hospital mortality in ARDS patients and to examine whether the daily fluid balance strategy paralleled with the changes in the mortality outcome. We hypothesized that there is declining risk of death and increased occurrence rate of the patients being discharge to home with unassisted breathing (UAB) over time, which is in parallel with the expanding use of optimal ventilation and fluid strategy.
The study included individual patient data from nine RCTs conducted by the ARDSNet (13–22). Table 1 shows the demographic details of these RCTs. The Late Steroid Rescue Study (LaSRS) trial was excluded from analysis because it enrolled patients with stable or worsening ARDS for 7–28 days and were simply not comparable with all the early ARDS intervention trials. All individual RCTs were approved by the ethics committee of participating centers, and informed consents were obtained. The data were available in the Biologic Specimen and Data Repository Information Coordinating Center (https://biolincc.nhlbi.nih.gov/). The secondary analyses of the data were approved by the ethics committee of the Sir Run-Run Shaw hospital.
Demographic data such as age at randomization and the gender were obtained for all the patients. The severity of illness was assessed using The Acute Physiology and Chronic Health Evaluation (APACHE) III score. Baseline data were data obtained on day 0 immediately before randomization. Intraoperative laboratory values and values related to cardiac arrest or death were not included. Daily fluid balance was calculated as the difference between total fluid intake (including blood product, fluid intake, and so on) and output (including urine and gastric output) and was recorded from day 0 to day 7 after randomization. For patients on continuous veno-venous hemofiltration/dialysis, add the negative balance to “total fluid out”, add a positive balance to “total fluid in”. Ventilation variables including calculated delivered tidal volume (inspired tidal volume [mL] set on the ventilator minus any additional tidal volume added to correct for compression and ventilator tube expansion), PEEP (this is the external or applied PEEP, not the total PEEP, auto-PEEP, or intrinsic PEEP), plateau pressure (e.g., the plateau pressure measurement should be made with a 0.5 s inspiratory pause), FIO2, and respiratory rate were captured on day 0 as the most recent values prior to time of randomization (baseline value). Ventilator variables on other days were captured closest to 8:00 AM. The types of ICU were medical ICU, surgical ICU (SICU), coronary ICU, cardiac SICU, Neuro ICU, and others. Locations before the ICU admission included another special care unit, direct admission to the ICU, emergency department, operating room, recovery room, and stepdown unit.
The primary outcome was mortality at 90 days. “Dead” was defined if a patient died prior to the discharge or died before achieving UAB at home for 48 hours. The secondary outcome was discharge to “home” on UAB. UAB was defined as the presence any of the following: 1) extubated with face mask, nasal prong oxygen, or room air, or 2) T-tube breathing, or 3) tracheostomy mask breathing, or 4) continuous positive airway pressure (CPAP) equals to five without pressure support or intermittent mechanical ventilation assistance, or 5) use of CPAP or bilevel positive airway pressure solely for sleep apnea management. “Home” was defined as the original living place where a patient lived before the hospital admission or equivalent. For example, if a patient lived in an apartment before hospitalization and returned to a different apartment with the same level of independence (or dependence), then that was considered as discharge home. In contrast, patients previously living at home who are discharged to a rehabilitation facility on UAB from the study hospital would NOT qualify as being “home on UAB”. If neither home on UAB nor dead applied, the outcome status for the patient was defined as “Other”.
Clinical characteristics and outcomes were compared between the different trials. Comparisons between different trials were performed using the CBCgrps package in R (23).
Mortality rates were compared for each year. Two multiple logistic regression models were built with mortality as the response variable: model 1 included covariates age, gender, APACHE III, ICU type, and admission source; and model 2 was the model 1 plus ventilation variables (tidal volume, PEEP, plateau pressure, respiratory rate) on day 0 before randomization and daily fluid balance on day 1 (one trial did not report fluid balance on day 0). To visualize the changes of daily fluid balance, PEEP, tidal volume, plateau pressure, respiratory rate and FIO2 over time, their values from day 0 to 7 were plotted against years with locally weighted scatterplot smoothing (LOWESS) method, allowing for nonlinear trends over time (24). Furthermore, statistical testing for changes of daily fluid balance, PEEP, tidal volume, and plateau pressure over the years were made by using linear regression model.
Death was considered as a competing risk for home on UAB because it could preclude its occurrence (25 , 26). Cause-specific Cox proportional hazard model and Fine-Gray model were employed to estimate the impact of time on the cumulative occurrence rate of home on UAB. Covariates such as the age, APACHE III, daily fluid balance on day 1, locations before ICU admission, ICU type, and vasopressor use were included in the models. The cause-specific hazard ratio (CSHR) and subdistribution hazard ratio (SHR) were also reported (27).
All statistical analyses were performed using the RStudio (Version 1.1.383; https://www.rstudio.com/). Two-tailed p values below 0.05 were considered statistically significant.
Our study included eight ARDSNet trials with a total of 5,159 critically ill patients enrolled from the year 1996 to 2013. Clinical characteristics of these trials are shown in Table S1 (Supplemental Digital Content 1, http://links.lww.com/CCM/E165). Patients were oldest in the Statins for Acutely Injured Lungs from Sepsis (SAILS) trial (p < 0.001). The ARDSNet1 database included the patients with the least severity of illness, and the Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury (ALVEOLI) trial included the most critically ill patients (p < 0.001). Albuterol to Treat Acute Lung Injury trials had the most daily fluid balance on day 0, and it was the least in Fluid And Catheter Treatment Trial (FACTT). The ALVEOLI trial did not report daily fluid balance on day 0 (Table S1, Supplemental Digital Content 1, http://links.lww.com/CCM/E165). Because the LaSRS trial enrolled patients with stable or worsening ARDS for 7–28 days and were simply not comparable with all the early ARDS intervention trials, it was excluded from subsequent analysis.
Changes in the Mortality Over Time
Figure 1 depicts the changes in the unadjusted hospital mortality over time. The crude mortality rate decreased from 35.4% (95% CI, 29.9–40.8%) in 1996 to 28.3% (95% CI, 22.0–34.7%) in the year 2013. The lowest mortality rate was 22.7% (95% CI, 18.5–26.8%) in 2009. A linear regression model showed that the study years were significantly associated with the mortality rate (slope: –0.0054; p = 0.005). The absolute mortality rate was reduced by 5.4% per decade. With adjustment for baseline APACHE III score, there was a decline in the risk of hospital deaths by 35.9% over a period of 17 years (odds ratio [OR], 0.697; 95% CI: 0.613–0.792 for each decade increase; p < 0.001). A simple univariate logistic regression model showed that the mortality risk declined over time (OR for each 5-yr increase: 0.87; 95% CI, 0.81–0.92; p < 0.001).
The model 1 showed that year was significantly associated with mortality: as compared to patients enrolled before 2000, patients enrolled in 2005–2010 (OR, 0.61; 95% CI, 0.50–0.74) and those enrolled after 2010 (OR, 0.73; 95% CI, 0.58–0.92) were associated with lower risk of death. Other factors such as APACHE III (OR for each 10-point increase, 1.29; 95% CI, 1.26–1.33) and age (OR for each 10-year increase, 1.41; 95% CI, 1.34–1.47) were also associated with mortality outcome. Model 2 included covariates in model 1 plus PEEP, tidal volume, and plateau pressure on day 0 before randomization and daily fluid balance on day 1. The result showed that the year was no longer associated with mortality. Instead, daily fluid balance (OR, 1.07; 95% CI, 1.04–1.11 for each 1,000 mL increase), plateau pressure (OR, 1.54; 95% CI:, 1.29–1.84 for each 10 cm H2O increase), and PEEP (OR, 0.78; 95% CI, 0.66–0.92 for each 5 cm H2O increase) were associated with the risk of mortality (Table 2). Since the SAILS trial enrolled patients with ARDS from infection, the lower disease severity subsets of patients with ARDS from trauma were excluded. Sensitivity analysis was performed by excluding this trial. Similar results were obtained (Table S2, Supplemental Digital Content 1, http://links.lww.com/CCM/E165). Furthermore, sensitivity analysis by excluding patients with tidal volume greater than 12 mL/kg also showed similar results (Table S3, Supplemental Digital Content 1, http://links.lww.com/CCM/E165).
Changes in Cumulative Incidences of Home on UAB Over Time
During the follow-up period, early trials such as ARDSNet1 and ARDSNet3 (1996–1999) reported an occurrence rate of home on UAB of 0.44, and later trials such as SAILS (2010–2013), Omega Nutrition Supplement Trial (OMEGA) (2008–2009), and Early vs. Delayed Enteral Nutrition (EDEN) (2008–2011) reported an occurrence rate of 0.67, 0.72, and 0.68, respectively (Table 2). The cumulative occurrence rate of home on UAB increased by 53.5% over the study period. After adjustment for baseline APACHE III, there was an increase in the occurrence rate of home on UAB of 64.2% over the period of 17 years. As per the Fine-Gray model, the patients enrolled during 2000–2010 had increased cumulative occurrence rate of home on UAB compared with patients enrolled before 2000 (SHR, 1.591; 95% CI, 1.457–1.737; p < 0.001). Similarly, patients enrolled after 2010 had increased cumulative occurrence rate of home on UAB compared with patients enrolled before 2000 (SHR, 1.727; 95% CI: 1.535 to 1.943; p < 0.001). Age (SHR, 0.986; 95% CI: 0.983–0.988 for each 1-year increase; p < 0.001), APACHE III score (SHR, 0.917; 95% CI, 0.903–0.932 for each 10 points increase; p < 0.001), day 1 daily fluid balance (SHR, 0.918; 95% CI, 0.895–0.942 for each 2 L increase; p < 0.001), and vasopressor use (SHR, 0.898; 95% CI, 0.828–0.973; p < 0.001) were associated with decreased cumulative occurrence rate of home on UAB. CSHR estimated by Cox proportional model showed similar results (Table S4, Supplemental Digital Content 1, http://links.lww.com/CCM/E165).
Temporal Trend of Tidal Volume, Plateau Pressure, PEEP, and Daily Fluid Balance Over Time
Changes of tidal volume, plateau pressure, PEEP, and daily fluid balance over the 17 years were visualized by LOWESS method (Fig. 2). Daily fluid balance on days 1–7 consistently showed declining trend. However, daily fluid balance on day 0 did not show a declining trend. Tidal volume declined rapidly from 1996 to 2002 and became stable thereafter (remarkably for the baseline value). PEEP on day 1 increased from 1996 to 2002 and declined after 2002. Mean plateau pressure declined consistently over the 17 years. Mean respiratory rate increased from 1996 to 2002 and declined after 2002. Although there was no significant change in the daily fluid balance on day 0 across years (coefficient: –2 mL; 95% CI, –19 to 16 mL; p = 0.863), days 1–7 consistently showed declining amount of daily fluid balance over time (Table 3). Tidal volume was decreased over the years consistently from day 0 to 7. PEEP on day 0 was increased, but PEEPs on other study days decreased.
In this analysis of 5,159 critically ill patients with ARDS enrolled in nine RCTs, we found a decline in the mortality rate of 35.9% over the period of 17 years. The cumulative occurrence rate of home on UAB increased by 53.5% over this period. The decline in mortality rate and increased occurrence rate of home on UAB over this period paralleled with the use of a conservative fluid management strategy, lower tidal volume and plateau pressure, and higher PEEP. The effect of year on mortality decline disappeared after adjustment for daily fluid balance, PEEP, tidal volume, and plateau pressure.
Hospital mortality rate for ARDS patients has been reported generally higher in epidemiologic studies compared with RCTs included in our study. Before 1996, the hospital mortality for ARDS was reported to be as high as 59% (28). Later, the Acute Lung Injury Verification of Epidemiology (ALIVE) study involving 78 ICUs in ten European countries outlined a mortality rate of 57.9% for ARDS patients (29). However, some other studies reported lower mortality rates (30 , 31). For example, an Irish study revealed a mortality rate of 37.8% for ARDS (32). More recently, The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study, an International, multicenter, prospective cohort study conducted in 50 countries, provided new insights into the mortality outcomes of ARDS. This landmark study showed that the hospital mortality related to mild, moderate, and severe ARDS was 34.9% (95% CI, 31.4–38.5%), 40.3% (95% CI, 37.4–43.3%), and 46.1% (95% CI, 41.9–50.4%), respectively (3). Surprisingly, mild ARDS had mortality rate equivalent to that reported in the 1996 ARDSNet trial probably due to the fact that the LUNG SAFE trial did not exclude patients for severe comorbidities, but the ARDS Network trials did.
The results of our analysis are consistent with a previous analysis of ARDSNet trials (1996–2005) by Erickson et al (10) where the ARDS related mortality rate declined from 35% to 26% over a period of 10 years, and this trend persisted even after adjustment for baseline characteristics. Erickson et al (10) proposed that the advances in critical care other than low tidal volume may be responsible for the improvement in survival. However, they did not assess the temporal trend in daily fluid balance. Our study adds to the literature that the daily fluid balance was reduced during the study period from 1996 to 2013, and the declining trend retained after 2005, indicating that the conservative daily fluid balance strategy could have contributed to the further improvement in survival benefit after 2005. However, in some studies, conservative daily fluid balance strategy was found only to be able to reduce ventilator-free days, but not the mortality (12 , 22). Probably, the daily fluid balance could only partially explain the declining mortality rate, and other advances in critical care medicine could also have contributed to the improvement in the survival such as decreased peak inspiratory pressure, increased PEEP, and low tidal volume ventilation (15 , 21 , 31). As shown in our study, changes in ventilator settings also explained the declining mortality over time. Sigurdsson et al (31) found that the hospital mortality decreased by 1% per year (p = 0.03) during the year 1988–2010, from 50% in 1988–1992 to 33% in 2006–2010. In our study, the annual mortality reduction was 0.54% (p = 0.005). The difference between the two studies may be explain by the higher baseline mortality rate in the study by Sigurdsson et al (31). In the 1980s, the mortality rate was high, and the slope of annual mortality reduction became steeper with the improvement in the management of ARDS. However, there are conflicting results with regard to the mortality trend. Li et al (8) reported that the ARDS case-fatality was not changed during 2001–2008 in Olmsted County in the United States (p = 0.449). These results persisted even after adjustment for APACHE III score. Their study was a population-based study, and the study patients had lower APACHE III score than in our RCTs (median: 70 vs 89).
Some of the limitations of our study need to be acknowledged. The study was based on ARDSNet trials, in which subjects were screened with strict inclusion/exclusion criteria (33 , 34). Thus, the external validity of the study could have been compromised. However, using the RCT dataset is advantageous because the variables are recorded with the standard protocols. In contrast, missing values and errors are common in studies using electronic healthcare records, which requires advanced data cleansing techniques (35). Changes in daily fluid balance and ventilator settings might not reflect the temporal trends in usual care. For example, in the early ARDS Network trials (Acute Respiratory Management in Acute lung injury/Acute respiratory distress syndrome, ALVEOLI, etc.), fluid balance was controlled by treating clinicians and was representative of usual care. In the middle ARDS Network trial (FACTT), half of the patients were treated with liberal and half with conservative fluid management. And in all subsequent ARDS Network trials (EDEN, OMEGA, SAILS, etc.), all patients were treated with conservative fluid management as a protocolized cointervention (36). Some important interventions for ARDS patients such as curarization, extracorporeal membrane oxygenation, and prone positioning were not included for analysis, which might also influence the mortality outcome. Finally, exclusion criteria in ARDS network trials had changed over time, which has much to do with mortality in these trials. For example, all ARDS network trials excluded patients with advanced chronic liver disease. However, these trials over time increased the Child Pugh threshold for enrollment (higher disease severity were allowed in more recent trials) thus biasing the estimates for mortality in the enrolled cohort. This bias actually strengthens the observed mortality decline over time.
In conclusion, our study showed that the mortality rate declined over a period of 17 years, which might be explained by the reductions in the daily fluid balance, plateau pressure, and tidal volume and the increase in PEEP over this period.
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