LUNG SAFE – The Study That Keeps on Giving

What is LUNG SAFE?

The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study (JAMA 2016) is currently the largest epidemiology study of acute respiratory distress syndrome (ARDS). It was conducted during 4 consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries across 5 continents. Out of 29,144 patients admitted to the ICU total of 2377 patients developed ARDS within 48 hours of their acute respiratory failure. Data collection included mostly ventilation data such as the use of invasive or noninvasive ventilation, ventilator settings (i.e. tidal volume and PEEP), measured values (i.e. plateau, total PEEP), arterial blood gas values, and chest x-ray information.

Bellani et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. February 23, 2016, Vol 315, No. 8.

The study that keeps on giving

Since its completion, the LUNG SAFE database has been utilized to answer a wide range of clinical questions regarding global practice. With the help of one of the authors, Dr. Tài Pham, we have provide a list, with brief synopsis of the currently published research, as well as upcoming future/planned analyses.

Currently Published

Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study

The main objective of this study was to determine the factors associated with mortality in patients with ARDS in order to highlight those that could potentially be impacted by ICU treatment. The 2377 intubated patients presenting ARDS in the first days of their respiratory failure were included in this analysis. Potentially modifiable factors associated with hospital mortality were higher peak inspiratory pressure, lower PEEP, higher respiratory rate. In the subgroup of patients having the data available, higher plateau pressure and driving pressure were independently associated with hospital mortality. Along with these variables, non-modifiable characteristics such as patient demographics (higher age, immunocompromised status, chronic liver failure) or severity at admission (lower pH, lower PaO2/FIO2 and higher SOFA score) were also associated with mortality. Interestingly, being treated in an ICU with a higher number of beds was associated with better hospital survial.

Laffey et al. LUNG SAFE Investigators and the ESICM Trials Group. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016 Dec;42(12):1865-1876. Epub 2016 Oct 18.

Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study

As opposed to the previous definition, the most recent definition of ARDS includes patients treated with noninvasive ventilation (NIV). The main goals of this study were to describe the subpopulation of patients with ARDS treated with NIV, to compare patients treated with NIV to intubated patients presenting with similar severity, and to determine the factors associated with NIV failure. We found that 15% of patients with ARDS were initially treated with NIV, whatever the severity of their gas exchange, but the risk of intubation increased with the severity of the initial PaO2/FiO2 and Higher SOFA score. Lower PaO2/FIO2 and increased PaCO2 over the 2 first days were independently associated with NIV failure and intubation. Using a matching procedure adjusting for severity, patients initially treated with NIV had the same outcomes than patients directly intubated globally. However, in the subgroup of patients with a PaO2/FiO2<150 mmHg, NIV was associated with a higher mortality than using early intubation.

Bellani et al, LUNG SAFE Investigators and the ESICM Trials Group. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study. AJRCCM; Vol. 195, No. 1 | Jan 01, 2017 DOI: http://dx.doi.org/10.1164/rccm.201606-1306OC

Geo-economic variations in epidemiology, patterns of care, and outcomes in patients with acute respiratory distress syndrome: insights from the LUNG SAFE prospective cohort study

There is scarce information on the geo-economic variations of characteristics, management and outcome in patients with ARDS internationally. The main goal of this analysis was to decribe the regional differences and the 2813 patients with ARDS within 48 hours of their acute respiratory failure (treated with invasive or noninvasive mechanical ventilation) were separated according to the GNI per capita and the area of the country they lived in: Europe high income; rest of the world high income and middle income. There were significant variations in baseline characteristics and initial severity across areas. The respiratory severity was lower in non-European high income countries and these patients had shorter duration of mechanical ventilation and length of stay in the ICU. The use of rescue therapues such as paralysis or prone position was more frequent in Europe high income countries. Mortality was higher in middle income countries.

Laffey et al. Geo-economic variations in epidemiology, patterns of care, and outcomes in patients with acute respiratory distress syndrome: insights from the LUNG SAFE prospective cohort study.  LUNG SAFE Investigators and the ESICM Trials Group. Lancet Respir Med. 2017 Aug;5(8):627-638. doi: 10.1016/S2213-2600(17)30213-8. Epub 2017 Jun 15. PMID: 28624388

Two pre-defined sub-studies have now also been published:

The Randomised Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome

Interpretation of the chest x-ray for the diagnosis of ARDS is challenging. In order to assess the benefit of an online training module on chest x-ray interpretation accuracy, the LUNG SAFE investigators were invited to be randomized in one of the following group: training module followed by a test module (intervention) or test module followed by training module (control). The set of 11 chest x-ray used for the Berlin ARDS definition previously classified by expert consensus was used as the test module. The main finding is that there was no effect of the training module on chest x-ray interpretation accuracy (58% [intervention] vs 56% [control], p<0.15).

Goddard et al. The Randomised Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome. Crit Care Med. 2018 Feb 12. doi: 10.1097/CCM.0000000000003000. [Epub ahead of print]. PMID: 29438110

Etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicentre study

The Berlin definition of ARDS requires the presence of a “common” risk factor such as pneumonia or septic shock and in the absence of such a risk factor, to objectively exclude acute cardiogenic failure explaining the hypoxemia. There is a subgroup of patients with no risk factors identified and the main objective was to describe their characteristics, management, outcomes, and to compare them with patients having risk factors. Among the 2813 patients with ARDS, 8% had no risk factors identified. They were older, with more comorbidities but less severe at admission. Almost 20% had a work-up that finally identified a cause for ARDS. Adjusting on severity, patients with and without risk factors had the same mortality

de Prost et al. Etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicentre study. Ann Intensive Care. 2017 Dec;7(1):69. doi: 10.1186/s13613-017-0281-6. Epub 2017 Jun 19. PMID: 28631088

Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study

Some patients fulfilling ARDS have significant change in severity in the first 24h (improvement or worsening). The main objective was to compare outcomes in patients who have early resolution of ARDS to patients that still have ARDS after 24h. The 2377 intubated patients with ARDS within the 2 days of respiratory failure were included in this study. One quarter of them did not fulfill all criteria of ARDS 24h following onset. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both resolved and confirmed ARDS, age, non-respiratory SOFA score, lower PEEP and PaO2/FiO2 ratio, higher peak pressure and respiratory rate were each associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated with mortality.

Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database

Immunosuppression is a frequent comorbidity in patients with ARDS and these patients usually have worse outcomes. The aim of this study was to describe characteristics, management and outcome of the immunocompromised patients, and to compare them to the immunocompetent patients with ARDS. Of the 2813 patients with ARDS within the 2 days of their respiratory failure, 20% were immunocompromised and had a significantly higher mortality than immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Noninvasive ventilation use and decision of limiting life-sustaining treatments were more frequent in immunocompromised than in immunocompetent patients.

Planned Work

The list of currently approved OPEN LUNG SAFE Projects is as follows:

1. Assessing the effect of diabetes in ARDS or AHRF (submitted)
2. Use of tracheostomy among mechanically ventilated patients with severe ARDS (submitted)
3. Impact of spontaneous breathing in early ARDS (submitted)
4. Risk factors for progression from MILD to more severe ARDS (submitted)
5. Hyperoxia, oxygenation levels and targets in Patients with Acute Hypoxic Respiratory Failure
6. Hypercapnia and management of arterial CO2 tension in patients with ARDS
7. Role of ECMO in LUNG SAFE database
8. The influence of obesity in patients with ARDS or AHRF
9. Impact of gender in patients with ARDS in LUNG SAFE
10. Impact of acute renal failure in patients with ARDS in LUNG SAFE
11. Impact of comorbidities in patients with ARDS in LUNG SAFE
12. Prone position in ARDS in LUNG SAFE
13. Novel indices of mechanical ventilation in patients with ARDS.
14. Factors influencing severity of hypoxemia and associated mortality in Severe Acute Hypoxemic Respiratory Failure
15. Barriers to low tidal volume ventilation.
16. End of life care decisions for the patient with severe respiratory failure in ICU
17. The characteristics of prolonged ventilation in patients with acute respiratory failure
18. How patients with ARDS are weaned from PEEP
19. Structure of ICU and risk standardised mortality ratio in acute hypoxemic respiratory failure
20. Changes over time in response to therapeutic manoeuvres

Summary

Thanks to the efforts of all the LUNG SAFE investigators, the database has provided unique insights into various aspects of managing patients in hypoxemic failure, particularly with ARDS. The lists of studies being conducted with this data is incredible and will be ongoing. For more information about the LUNG SAFE ESICM group you can visit their website.