Barotrauma occurs frequently in acute respiratory distress syndrome (ARDS), and has a
difficult, non-standardized management. Unfortunately, mortality rates remain high (> 60%
in COVID-19 ARDS, around 46% in non-COVID-19 ARDS). Interestingly, data from COVID-19
patients suggested that barotrauma may occur also in spontaneously breathing patients
with ARDS. Accordingly, frailty of lung parenchyma represents a major issue in ARDS.
Protective mechanical ventilation (i.e. ventilation with low tidal volume and low airway
pressures) remains a cornerstone of supportive management of ARDS. Unfortunately,
mechanical ventilation may worsen pulmonary damage (ventilator-induced lung injury) and,
in high-risk patients, may induce barotrauma even when ventilator settings are maintained
within the "safe" limit of protective ARDS. Early identification of high-risk features
could therefore allow clinicians to individualize management of high-risk patients, by
tailoring respiratory support and potentially select candidates for advanced support
(i.e. extracorporeal membrane oxygenation) before development of overt barotrauma.
Macklin effect is a well-described radiological sign originally intended to differentiate
between "peripheral" (distal airway rupture, "respiratory" barotrauma) and "central"
(lesion to large airways/esophaegal injury) causes of air leakage in the mediastinum.
However, the Investigators recently identified Macklin effect as a strong radiological
predictor of barotrauma development in mechanically ventilated COVID-19 ARDS patients
(sensitivity: 89.2%; specificity: 95.6%). In our cohort, radiologically-detected Macklin
effect was identified 8-12 days before development of pneumomediastinum/pneumothorax.
These preliminary results have been confirmed in a subsequent multicenter study (sample
size 697 patients; sensitivity: 100%; specificity: 99.8%).
Furthermore, preliminary data suggest that early application of awake veno/venous
extracorporeal membrane oxygenation (ECMO) before invasive mechanical ventilation in
COVID-19 patients with severe ARDS and at high-risk for barotrauma (defined as presence
of Macklin effect on chest CT imaging) might result in no barotrauma events with a low
intubation rate.
Concurrently, a hyper inflammatory sub phenotype has been associated with overall worse
outcome both in terms of mortality and ventilator-free days in ARDS. Moreover, the
occurrence of lung injury during mechanical ventilation has been proven to be
significantly related to the recruitment of mast cells via CXCL10/CXCR3 signaling .
In this view, confirmation of Macklin effect predictive role and identification of
further, novel laboratory biomarkers could provide instruments for early risk
stratification in ARDS patients.
Taken together, i) quantitative imaging analysis and ii) systemic inflammatory profiling
could decipher different biological aspects of the same clinical issue, possibly laying
foundation for the definition of a multimodality signature of lung frailty in ARDS
patients..
Accordingly, the driving hypotheses of this retrospective/prospective study is that
identification of a novel ARDS sub phenotype characterized, irrespective of the
underlying etiology, by increased lung frailty could substantially improve the poor
prognosis routinely associated with this condition, possibly being a landmark for
personalized management strategies.
To further validate the role of Macklin effect, the Investigators will:
evaluate the accuracy of Macklin effect in a retrospective cohort of 350 ARDS
patients (COVID-19 and non-COVID-19)
identify, throughout densitometry, machine learning and artificial
intelligence-based approaches, novel imaging biomarkers characteristics of higher
lung frailty in the same cohort.
In the main prospective study, the Investigators will:
analyse the following biomarkers in the serum and bronchoalveolar lavage fluid of
100 ARDS patients prospectively enrolled: Interleukin-8 (IL-8), Interleukin (IL)-6,
IL-1Ra, IL-18, interferon (IFN ), Angiopoietin-2 (Ang-2), Tumour Necrosis Factor
receptor-1 (TNFr1), Plasminogen Activator Inhibitor-1(PAI-1), Receptor for Advanced
Glycation Endproducts (RAGE), Intercellular adhesion molecule-1 (ICAM-1), Surfactant
Protein D (SPD), protein C, Von Willebrand Factor (VWF), CXCL10/CXCR3, and
metalloproteases (MMP9, MMP10).
Develop a specific management algorithm for ARDS patients at high risk for
barotrauma by collecting clinical and outcome data from 10 ARDS patients receiving
unconventional management (e.g. awake ECMO, ultraprotective ventilation, etc)