key: cord-0746317-r36m0jp7
authors: Qadir, Nida; Bartz, Raquel R.; Cooter, Mary L.; Hough, Catherine L.; Lanspa, Michael J.; Banner-Goodspeed, Valerie M.; Chen, Jen-Ting; Giovanni, Shewit; Gomaa, Dina; Sjoding, Michael W.; Hajizadeh, Negin; Komisarow, Jordan; Duggal, Abhijit; Khanna, Ashish K.; Kashyap, Rahul; Khan, Akram; Chang, Steven Y.; Tonna, Joseph E.; Anderson, Harry L.; Liebler, Janice M.; Mosier, Jarrod M.; Morris, Peter E.; Genthon, Alissa; Louh, Irene K.; Tidswell, Mark; Stephens, R Scott; Esper, Annette M.; Dries, David J.; Martinez, Anthony A.; Schreyer, Kraftin E.; Bender, William; Tiwari, Anupama; Guru, Pramod K.; Hanna, Sinan; Gong, Michelle N.; Park, Pauline K.
title: Variation in Early Management Practices in Moderate-to-Severe Acute Respiratory Distress Syndrome in the United States
date: 2021-06-04
journal: Chest
DOI: 10.1016/j.chest.2021.05.047
sha: 002bb39a90755448b3f90306378695512c8e6b76
doc_id: 746317
cord_uid: r36m0jp7

Background While specific interventions have previously demonstrated benefit in patients with the Acute Respiratory Distress Syndrome (ARDS), use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate-to-severe ARDS in the United States (US)? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and PaO2/FiO2 < 150 on positive end expiratory pressure (PEEP) > 5 cm H2O, who were admitted to 29 US centers between October 1, 2016 and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality were also assessed. Results A total of 2,466 patients were enrolled. Median baseline PaO2/FiO2 was 105 (IQR 78.0, 129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (tidal volume < 6.5 ml/kg predicted body weight, plateau pressure and/or peak inspiratory pressure < 30mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), types of modalities used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early lung protective ventilation (LPV) was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03021824

Harry L Anderson III, MD 15 Janice M Liebler MD 16 Jarrod M Mosier MD 17 Peter E Morris MD 18 Alissa Genthon MD 19 Irene K Louh MD 20 Mark Tidswell MD 21 Acute respiratory distress syndrome (ARDS) is a potentially fatal condition characterized by acute hypoxemia and bilateral radiographic infiltrates, with a reported mortality of 36 -47%. [1] [2] [3] [4] [5] Specific interventions in ARDS, including lung protective ventilation (LPV) 6 and prone positioning, 7 have previously been demonstrated to improve survival in clinical trials, but remain underutilized. 1, [8] [9] [10] [11] At the same time, treatment modalities with unclear benefit and potential, including neuromuscular blockade, 12 extracorporeal membrane oxygenation (ECMO), 13 steroids, 14 and pulmonary vasodilators, 15 ,16 continue to be used in the management of ARDS. Regional variation in adoption of different practices for treating ARDS patients has previously been described. 17, 18 More recently, reports of widely variable treatments for COVID-19-related ARDS have emerged. 19 Due to the complexity of ARDS epidemiologic reporting, it is unclear if ARDS mortality has changed over time, 5, [20] [21] [22] [23] [24] [25] and the impact of potential heterogeneity in ARDS management on patient outcomes remains unknown.

To understand the patient-and center-level treatment factors associated with mortality in moderate-severe ARDS in the United States, we conducted a multicenter observational study across US institutions. Center variability in management practices was examined, as well as the association of this variability with patient outcomes. We hypothesized that center management practices would be associated with risk-adjusted 28-day in-hospital mortality.

SAGE (Severe ARDS: Generating Evidence) is a multicenter observational cohort study (NCT 03021824) conducted in 125 intensive care units (ICUs) at 29 academic and community hospital centers across the United States from October 1, 2016 through April 30, 2017. IRB approval was obtained at each center and requirement for informed consent was waived. Study principal investigators were responsible for ensuring data integrity and validity, and reviewing that patients met study criteria.

All consecutive patients > 18 years old who were on invasive mechanical ventilation at participating ICUs were followed for five days for the development of ARDS by Berlin criteria and a J o u r n a l P r e -p r o o f P a O 2 /F I O 2 < 150. 2 Data was subsequently collected for 3 days from the time of inclusion, and patients were followed for 28 days, or until hospital discharge, whichever occurred first. There were no exclusion criteria. Study day one was defined as the first day that patients met enrollment criteria. Inclusion criteria could be met at either the study hospital if the patient was a direct admission, or at a referring hospital, if the patient was transferred to the study hospital. The initial 6-month study period was extended an additional month to capture ongoing presentation of seasonal respiratory illness at the clinical sites.

The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality were also assessed.

Baseline demographic variables, ARDS risk factors, arterial blood gas (ABG) analysis, mechanical ventilator settings, and Sequential Organ Failure Assessment (SOFA) scores were collected.

Ventilator data and respiratory parameters were also collected for the first 3 days of invasive mechanical ventilation, and on days when any adjunctive therapy was initiated. Determination of Day 1 adherence to lung protective ventilation required both documented tidal volume ventilation of < 6.5 ml/kg predicted body weight (PBW) and plateau pressure (Pplat) < 30 cm H2O. In cases where Pplat was not recorded, the combination of tidal volume < 6.5 ml/kg PBW peak inspiratory pressure (PIP) < 30 cm H2O was considered lung protective ventilation. For instances in which an adjunctive therapy was initiated at a transferring hospital, the first known date of adjunctive therapy was collected. Outcomes data that were collected included hospital mortality, liberation from mechanical ventilation, discharge from the ICU, discharge from the hospital at 28 days, and SOFA score at day 7. Patients who were discharged from the hospital alive prior to study day 28 were assumed to be alive at that time point. Site investigators were required to respond to any queries raised by the electronic CRF prior to finalizing individual entries. Additionally, all entries were screened for outliers, potentially erroneous data, or missing outcomes. Data that could not be verified or corrected by site investigators were not included in the final data set

We summarized the baseline, day one ventilator settings, and 28-day outcomes for the study cohort overall using counts and proportions for categorical variables and mean (standard deviation) or median (interquartile range [IQR]) for continuous variables. We then explored the utilization patterns of various adjunctive therapies by summarizing therapies used in isolation and combination as well as timing of treatment initiation.

We explored the univariable relationships between early LPV adherence and the primary outcome of 28-day in-hospital mortality via Kaplan-Meier curves and log-rank tests. We utilized a multivariable generalized mixed effect model for 28-day in-hospital mortality, with fixed terms for baseline variables and random effect for center to investigate which baseline factors are associated with our primary outcome. Model adjustment terms were fixed a priori and included the following: inclusion PaO 2 /FiO 2 , day one SOFA score, age, sex, day one V T >6.5 mL/kg, risk factor for ARDS, and comorbidities.

In order to further explore the variability in mortality rate across centers while accounting for patient-level factors, we derived and compared standardized mortality ratios (SMR). The SMR for a given center was calculated as the ratio between the observed mortality rate and the expected mortality rate. As no appropriate standard population exists for this type of patient population, we used the center-wise average of predicted mortality probabilities from a multivariable logistic regression model, adjusting for the baseline patient-level characteristics listed above, as the best approximation. The 95% confidence interval for SMR was calculated using the Byar approximation.

We described center variability visually and descriptively by summarizing ventilator settings, adjunctive therapy use, and SMR by center. We then explored the relationship between SMR and center median day one V T , rate of adherence to LPV, PEEP, and rate of adjunctive therapy use visually and via Pearson correlation. Statistical analysis was performed using SAS v 9.4 (SAS INC., Cary, NC). All Pvalues were 2-sided and P-values <0.05 were considered statistically significant.

Results:

Of 27,656 patients screened, 2,466 (8.9%) were identified as having moderate-to-severe ARDS [ Figure 1 ]. Baseline characteristics are summarized in Table 1 

For the overall cohort, mean day one tidal volume (V T ) was 7 mL/kg predicted body weight (PBW) (SD 1.5), with 56.3% of patients receiving a V T >6.5 mL/kg PBW, and 21.7% receiving > 8 mL/kg PBW [table 2 ]. Substantial variation among centers was noted in mean tidal volume (6.2 -7.9 mL/kg PBW) as well as initial rate of adherence to LPV (0-65%). [ Figure 2A ]. Mean day one PEEP was 9.2 cm H 2 O (SD 3.9). The overall rate of measurement of the plateau pressure on Day 1 was 49.6%, with 85% of recorded values <30 mm H 2 O. When plateau pressure was not recorded, peak inspiratory pressure < 30 was used to permit classifying lung protective ventilation adherence in over 90% of the remaining cohort. Overall adherence to LPV in this group was 31.4%, with over half of the non adherence to LPV due to use of tidal volumes greater than 6.5 ml/kg PBW. Characteristics of patients who received LPV on day 1 and those who did not were similar, with the exception of day 1 V T (7.6 vs 5.9, Cohen's d - 

Adjunctive therapies were used in 57.5% of patients. Among those receiving adjunctive therapy, systemic steroids were the most commonly used (41.5%), followed by neuromuscular blockade (27.4%), pulmonary vasodilators (11.7%), prone positioning (5.8%), and ECMO (4.5%) [ Table 3 ]. Adjunctive therapies were most often used in combination and the majority were initiated before or within one day of ARDS development. Although the indication for steroid use was not recorded, 71.8% of patients who J o u r n a l P r e -p r o o f received steroids were also noted to have shock requiring vasopressors, and 30.9% had immunosuppression listed as a comorbidity. There was substantial center-to-center variation in specific type and rate of adjunctive therapy use (27.1-96.4%) [ Figure 2B ]. Twenty-nine different combinations of therapy were administered during the study period, with different frequencies at each center.

Overall 28-day in-hospital mortality was 40 In the multivariable generalized mixed effect model, baseline factors found to be associated with 28-day in-hospital mortality were baseline PaO 2 /FiO 2 , day one SOFA, age, and the following comorbidities: cirrhosis, hepatic failure, metastatic carcinoma, and leukemia [ Figure 3 ].

Mortality varied widely across centers, ranging from 16.7%-73.3% [ Figure 4A ]. Evaluation of standardized mortality ratios (SMRs) across centers showed that significant variation persisted (0.33- 

The SAGE study is the largest US observational cohort study of patients with moderate-to-severe ARDS reported to date. The primary findings of this study include the following: 1) there is extensive center-to-center variability in the early use of LPV and adjunctive therapies in moderate-severe ARDS, with improved, but imperfect, adherence to early lung protective strategies; 2) center mortality rates for patients with moderate-to-severe ARDS are highly variable, 3) center-level adherence to early lung protective ventilation was associated with lower standardized mortality rates and 4) the influence of variations in other specific treatment-level factors on variations in mortality remains unclear. The recent COVID-19 pandemic has underscored the variation in care among institutions, with widely disparate reports of outcomes and responses to therapy. 19 However, these variations in ARDS management are neither unique to COVID-19 nor new, as our study demonstrates. Ultimately, variation in center-specific risk-adjusted performance suggests that real opportunity exists for improving ARDS outcomes.

Of ARDS management practices, lung protective ventilation may be the best established as a supportive measure that improves survival, 6, 26 and has more recently been proposed as a center-level performance measure in the care of patients with ARDS. 27 While mean day one V T (7 mL/kg PBW) in our cohort was lower than that seen in recent multicenter observational studies (7.2-7.6 mL/kg PBW), 1,28 the rate of initial LPV non-adherence remained high. Despite the diagnosis of moderate-severe ARDS, more than half of patients received V T > 6.5 mL/kg PBW on day 1, and nearly a quarter received V T > 8 mL/kg PBW. As in prior studies, plateau pressures were inconsistently measured. 1, 29 The finding that higher adherence to early use of LPV on a center level was associated with lower SMR suggests that adherence to LPV may be a surrogate for overall quality of care processes. CHEST_SAGE_revision2_clean_v12.docx considerable variability in its management, the use of day 1 LPV adherence as a metric could also be a pragmatic starting point for quality assessment and improvement. It may however be insufficient, as day 1 LPV may not reflect the subsequent course of ventilator settings during the patient's hospitalization. A recent study examining detailed electronic health record data of mechanically ventilated patients found that, in spite of a low mean tidal volume in the cohort (6.8 mL/kg PBW), 40% of patients were exposed to V T > 8 mL/kg PBW, and prolonged exposure to high tidal volume was associated with increased mortality. 33 With regard to adjunctive therapy, the overall pattern of use was similar in the US to that of a recent international cohort, with frequent use of systemic steroids (41.5% vs 19.4%) and neuromuscular blockade (27.4% vs 25.6%), and low rates of prone positioning (5.8% vs 7.9%), 1 the adjunctive therapy that has most clearly demonstrated benefit in moderate-severe ARDS. 7 While underutilization of evidence-based therapies in ARDS has previously been noted, 18 the number of identified combinations and variation in rates of use within centers implies that clinicians are individualizing treatment rather than strictly following institutional ARDS management protocols. Clinician-level factors such as expertise with particular modalities, 34 have been found to influence the use of different adjunctive therapies, suggesting that rates of their use may be highly modifiable. However, the impact of systems-level barriers, such as staffing ratios and availability of various modalities, remain less well known and warrant further investigation. 35 While variation in center-specific risk-adjusted performance suggests that there is potential for improvement in ARDS care, many questions remain about how to continue to optimize management in this vulnerable patient population. While center-level adherence to early LPV was found to be strongly correlated with SMR, no such correlation was found for any individual adjunctive therapy. Although the extreme heterogeneity in recorded site practice patterns in our cohort may have made the impact of any individual adjunctive therapy difficult to assess, another possibility is that additional processes may need to be examined in order to guide institutional performance improvement. The impact of other aspects of ventilator management, such as the use of PEEP, may also warrant further evaluation. Indeed, the mean PEEP in our cohort was only 9 cm H2O despite higher PEEP being associated with decreased mortality in moderate-severe ARDS. 36 Adherence to supportive measures previously found to be beneficial may be J o u r n a l P r e -p r o o f There are a number of limitations to this study. This study represents a single 7-month, pre- were also truncated at 28 days, and were thus unknown for the patients with longer hospitalizations (14.3%) . Similarly, the assumption that patients discharged from the hospital before day 28 were alive is a further limitation. Additionally, the impact of systems-based factors such as hospital type, ICU type, staffing models, and ARDS case volume were not assessed. Other limitations include the lack of assessment of additional supportive measures that may benefit ARDS patients, such as sedation practices and fluid management.

The management and mortality of patients with moderate-to-severe ARDS remain highly variable at US hospitals. Early adherence to lung protective ventilation at a center-level was associated with improved center performance. Differences in center-specific, risk-adjusted performance suggest that decreasing nontherapeutic variation in care and identifying appropriate targets for treatment optimization represent opportunities to reduce ARDS mortality. Further collaboration is needed in order to understand the impact of specific treatment-level factors on ARDS mortality, the changes through the COVID pandemic and inform rational decision-making in clinical care.

The study was designed by NQ, PKP, RRB, and MNG. Data was acquired from individual sites by the Study Question: What is the impact of treatment variability on mortality in patients with moderate-tosevere ARDS in the United States?

Results: Substantial center-to-center variability exists in ventilator practices, adjunctive therapy use, and mortality; differences in center adherence to early lung protective ventilation are associated with mortality.

Interpretation: Substantial center-to-center variability exists in ventilator practices, adjunctive therapy use, and mortality; differences in center adherence to early lung protective ventilation are associated with mortality.

J o u r n a l P r e -p r o o f Tables Abbreviations: ARDS, acute respiratory distress syndrome; PaO2/FiO2, partial pressure of oxygen to fraction of inspired oxygen; SOFA, Sequential Organ Failure Assessment; PEEP, positive end-expiratory pressure; PBW, predicted body weight; ICU, intensive care unit; UAB, unassisted breathing 

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