xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06001645</url>
    </required_header>
    <id_info>
      <org_study_id>PNRR-MAD-2022-12376</org_study_id>
      <nct_id>NCT06001645</nct_id>
    </id_info>
    <brief_title>Laboratory Biomarkers and Pulmonary Interstitial Emphysema in ARDS (PIE-ARDS)</brief_title>
    <acronym>PIE-ARDS</acronym>
    <official_title>Pulmonary Interstitial Emphysema (Macklin Effect), Quantitative Imaging Analysis and CytoKine Profiling to Predict Lung Frailty IN ARDS</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Università Vita-Salute San Raffaele</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Università Vita-Salute San Raffaele</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Barotrauma (pneumothorax, pneumomediastinum) is a well-described complication of Acute&#xD;
        Respiratory Distress Syndrome (ARDS), especially in patients with coronavirus disease 2019&#xD;
        (COVID-19) (16.1% in COVID-19, and about 6% in non-COVID-19 ARDS). Macklin effect was&#xD;
        recently discovered by our group as an accurate radiological predictor of barotrauma in&#xD;
        COVID-19 ARDS; the Investigators also found that density histograms automatically extracted&#xD;
        from chest CT images provide a reliable insight into lung composition&#xD;
  &#xD;
        . Since lung frailty is a major issue also in non-COVID-19 ARDS, the Investigators want to&#xD;
        confirm the predictive role of Macklin effect also in this setting. In addition, the&#xD;
        Investigators aim to explore inflammatory profiling to decipher different biological aspects&#xD;
        of the same clinical issue. Finally, the Investigators want to develop a specific management&#xD;
        algorithm for patients diagnosed, according to our findings, with a specific ARDS sub&#xD;
        phenotype characterized by increased lung frailty&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Barotrauma occurs frequently in acute respiratory distress syndrome (ARDS), and has a&#xD;
        difficult, non-standardized management. Unfortunately, mortality rates remain high (&gt; 60% in&#xD;
        COVID-19 ARDS, around 46% in non-COVID-19 ARDS). Interestingly, data from COVID-19 patients&#xD;
        suggested that barotrauma may occur also in spontaneously breathing patients with ARDS.&#xD;
        Accordingly, frailty of lung parenchyma represents a major issue in ARDS. Protective&#xD;
        mechanical ventilation (i.e. ventilation with low tidal volume and low airway pressures)&#xD;
        remains a cornerstone of supportive management of ARDS. Unfortunately, mechanical ventilation&#xD;
        may worsen pulmonary damage (ventilator-induced lung injury) and, in high-risk patients, may&#xD;
        induce barotrauma even when ventilator settings are maintained within the &quot;safe&quot; limit of&#xD;
        protective ARDS. Early identification of high-risk features could therefore allow clinicians&#xD;
        to individualize management of high-risk patients, by tailoring respiratory support and&#xD;
        potentially select candidates for advanced support (i.e. extracorporeal membrane oxygenation)&#xD;
        before development of overt barotrauma.&#xD;
  &#xD;
        Macklin effect is a well-described radiological sign originally intended to differentiate&#xD;
        between &quot;peripheral&quot; (distal airway rupture, &quot;respiratory&quot; barotrauma) and &quot;central&quot; (lesion&#xD;
        to large airways/esophaegal injury) causes of air leakage in the mediastinum. However, the&#xD;
        Investigators recently identified Macklin effect as a strong radiological predictor of&#xD;
        barotrauma development in mechanically ventilated COVID-19 ARDS patients (sensitivity: 89.2%;&#xD;
        specificity: 95.6%). In our cohort, radiologically-detected Macklin effect was identified&#xD;
        8-12 days before development of pneumomediastinum/pneumothorax. These preliminary results&#xD;
        have been confirmed in a subsequent multicenter study (sample size 697 patients; sensitivity:&#xD;
        100%; specificity: 99.8%).&#xD;
  &#xD;
        Furthermore, preliminary data suggest that early application of awake veno/venous&#xD;
        extracorporeal membrane oxygenation (ECMO) before invasive mechanical ventilation in COVID-19&#xD;
        patients with severe ARDS and at high-risk for barotrauma (defined as presence of Macklin&#xD;
        effect on chest CT imaging) might result in no barotrauma events with a low intubation rate.&#xD;
  &#xD;
        Concurrently, a hyper inflammatory sub phenotype has been associated with overall worse&#xD;
        outcome both in terms of mortality and ventilator-free days in ARDS. Moreover, the occurrence&#xD;
        of lung injury during mechanical ventilation has been proven to be significantly related to&#xD;
        the recruitment of mast cells via CXCL10/CXCR3 signaling .&#xD;
  &#xD;
        In this view, confirmation of Macklin effect predictive role and identification of further,&#xD;
        novel laboratory biomarkers could provide instruments for early risk stratification in ARDS&#xD;
        patients.&#xD;
  &#xD;
        Taken together, i) quantitative imaging analysis and ii) systemic inflammatory profiling&#xD;
        could decipher different biological aspects of the same clinical issue, possibly laying&#xD;
        foundation for the definition of a multimodality signature of lung frailty in ARDS patients..&#xD;
  &#xD;
        Accordingly, the driving hypotheses of this retrospective/prospective study is that&#xD;
        identification of a novel ARDS sub phenotype characterized, irrespective of the underlying&#xD;
        etiology, by increased lung frailty could substantially improve the poor prognosis routinely&#xD;
        associated with this condition, possibly being a landmark for personalized management&#xD;
        strategies.&#xD;
  &#xD;
        To further validate the role of Macklin effect, the Investigators will:&#xD;
  &#xD;
          -  evaluate the accuracy of Macklin effect in a retrospective cohort of 350 ARDS patients&#xD;
             (COVID-19 and non-COVID-19)&#xD;
  &#xD;
          -  identify, throughout densitometry, machine learning and artificial intelligence-based&#xD;
             approaches, novel imaging biomarkers characteristics of higher lung frailty in the same&#xD;
             cohort.&#xD;
  &#xD;
        In the main prospective study, the Investigators will:&#xD;
  &#xD;
          -  analyse the following biomarkers in the serum and bronchoalveolar lavage fluid of 100&#xD;
             ARDS patients prospectively enrolled: Interleukin-8 (IL-8), Interleukin (IL)-6, IL-1Ra,&#xD;
             IL-18, interferon (IFN ), Angiopoietin-2 (Ang-2), Tumour Necrosis Factor receptor-1&#xD;
             (TNFr1), Plasminogen Activator Inhibitor-1(PAI-1), Receptor for Advanced Glycation&#xD;
             Endproducts (RAGE), Intercellular adhesion molecule-1 (ICAM-1), Surfactant Protein D&#xD;
             (SPD), protein C, Von Willebrand Factor (VWF), CXCL10/CXCR3, and metalloproteases (MMP9,&#xD;
             MMP10).&#xD;
  &#xD;
          -  Develop a specific management algorithm for ARDS patients at high risk for barotrauma by&#xD;
             collecting clinical and outcome data from 10 ARDS patients receiving unconventional&#xD;
             management (e.g. awake ECMO, ultraprotective ventilation, etc)&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 2023</start_date>
    <completion_date type="Anticipated">July 2027</completion_date>
    <primary_completion_date type="Anticipated">April 2027</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Case-Control</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Rate of clinically relevant barotrauma</measure>
      <time_frame>30 days or until hospital discharge. Specifically, from date of basal CT scan until the date of first radiologically documented barotrauma</time_frame>
      <description>Barotrauma is diagnosed only in the case of clear radiological evidence (free air at chest X-ray and/or chest CT scan).&#xD;
  Rate of barotrauma will be compared between patients with an hyperinflammatory pattern as compared with control.</description>
    </primary_outcome>
    <number_of_groups>1</number_of_groups>
    <enrollment type="Anticipated">110</enrollment>
    <condition>Acute Respiratory Distress Syndrome</condition>
    <condition>Barotrauma</condition>
    <arm_group>
      <arm_group_label>Acute Respiratory Distress Syndrome</arm_group_label>
      <description>Patients with ARDS requiring or not requiring invasive ventilation</description>
    </arm_group>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Blood and bronchoalveolar fluid collection and analysis</intervention_name>
      <description>Blood and bronchoalveolar lavage fluid will be collected within 12 hours after intubation. Blood samples will be centrifuged, and the serum immediately stored at less than 70° C. The following biomarkers will be analysed in the serum and bronchoalveolar lavage fluid: 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). Blood samples obtained from the patients will be placed in specimen tubes containing heparin, centrifuged at 1500 G for 10 minutes, and then the plasma will be aspirated and stored at -70° C. Bronchoalveolar lavage fluid will be centrifuged at 1500 G for 10 minutes to remove cellular contents and stored at -70° C.</description>
      <arm_group_label>Acute Respiratory Distress Syndrome</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Chest CT scan</intervention_name>
      <description>Computed Tomography Scan per normal clinical practice</description>
      <arm_group_label>Acute Respiratory Distress Syndrome</arm_group_label>
    </intervention>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Blood and bronchoalveolar lavage fluid will be collected within 12 hours after intubation;&#xD;
        blood samples will be centrifuged, and the serum immediately stored at less than 70° C. The&#xD;
        following biomarkers will be analysed in the serum and bronchoalveolar lavage fluid:&#xD;
        Interleukin-8 (IL-8), Interleukin (IL)-6, IL-1Ra, IL-18, interferon (IFN ), Angiopoietin-2&#xD;
        (Ang-2), Tumour Necrosis Factor receptor-1 (TNFr1), Plasminogen Activator Inhibitor-1(PAI-1),&#xD;
        Receptor for Advanced Glycation Endproducts (RAGE), Intercellular adhesion molecule-1&#xD;
        (ICAM-1), Surfactant Protein D (SPD), protein C, Von Willebrand Factor (VWF), CXCL10/CXCR3,&#xD;
        and metalloproteases (MMP9, MMP10). Blood and BAL samples obtained from the patients will be&#xD;
        placed in specimen tubes (containing heparin for plasma), centrifuged at 1500 G for 10&#xD;
        minutes, and then stored at -70° C&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          Patients with ARDS diagnosis will be enrolled. With the exception of blood and BAL samples&#xD;
          collection, all patients enrolled in the prospective cohort will follow their normal course&#xD;
          of diagnosis/treatment without any further requirements for the scope of this study other&#xD;
          than those provided in the normal management of patients with this condition. Furthermore,&#xD;
          any decision regarding drug or procedure will be made by the physician based on her/his&#xD;
          clinical judgment, independently from the decision to include the patient in this study. No&#xD;
          follow-up medical and/or imaging examinations/laboratory analysis after hospital discharge&#xD;
          are needed by the present study design.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Clinical and radiological signs of ARDS, according to Berlin criteria, requiring ICU&#xD;
               admission;&#xD;
  &#xD;
            -  Obtain duly signed informed consent&#xD;
  &#xD;
            -  Availability of at least one chest CT scan during hospital stay&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          • Poor quality imaging (because of motion/respiratory artefacts).&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>A.O.U. di Cagliari</name>
        <address>
          <city>Cagliari</city>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Gabriele Finco, MD</last_name>
      </contact>
    </location>
    <location>
      <facility>
        <name>IRCCS San Raffaele Scientific Institute</name>
        <address>
          <city>Milan</city>
          <zip>20132</zip>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Diego Palumbo, MD</last_name>
        <email>palumbo.diego@hsr.it</email>
      </contact>
      <contact_backup>
        <last_name>Alessandro Belletti, MD</last_name>
        <email>belletti.alessandro@hsr.it</email>
      </contact_backup>
      <investigator>
        <last_name>Michele De Bonis, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>A.O.U. Pisana</name>
        <address>
          <city>Pisa</city>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Fabio Guarracino, MD</last_name>
      </contact>
    </location>
    <location>
      <facility>
        <name>Ospedale San Carlo</name>
        <address>
          <city>Potenza</city>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Gianluca Paternoster, MD</last_name>
      </contact>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <reference>
      <citation>Murayama S, Gibo S. Spontaneous pneumomediastinum and Macklin effect: Overview and appearance on computed tomography. World J Radiol. 2014 Nov 28;6(11):850-4. doi: 10.4329/wjr.v6.i11.850.</citation>
      <PMID>25431639</PMID>
    </reference>
    <reference>
      <citation>Palumbo D, Zangrillo A, Belletti A, Guazzarotti G, Calvi MR, Guzzo F, Pennella R, Monti G, Gritti C, Marmiere M, Rocchi M, Colombo S, Valsecchi D, Scandroglio AM, Dagna L, Rovere-Querini P, Tresoldi M, Landoni G, De Cobelli F; COVID-BioB Study Group. A radiological predictor for pneumomediastinum/pneumothorax in COVID-19 ARDS patients. J Crit Care. 2021 Dec;66:14-19. doi: 10.1016/j.jcrc.2021.07.022. Epub 2021 Aug 12.</citation>
      <PMID>34392131</PMID>
    </reference>
    <reference>
      <citation>Belletti A, Pallanch O, Bonizzoni MA, Guidi L, De Cobelli F, Landoni G, Zangrillo A, De Bonis M, Palumbo D. Clinical use of Macklin-like radiological sign (Macklin effect): A systematic review. Respir Med. 2023 Apr-May;210:107178. doi: 10.1016/j.rmed.2023.107178. Epub 2023 Feb 28.</citation>
      <PMID>36863617</PMID>
    </reference>
    <reference>
      <citation>Paternoster G, Bertini P, Belletti A, Landoni G, Gallotta S, Palumbo D, Isirdi A, Guarracino F. Venovenous Extracorporeal Membrane Oxygenation in Awake Non-Intubated Patients With COVID-19 ARDS at High Risk for Barotrauma. J Cardiothorac Vasc Anesth. 2022 Aug;36(8 Pt B):2975-2982. doi: 10.1053/j.jvca.2022.03.011. Epub 2022 Mar 17.</citation>
      <PMID>35537972</PMID>
    </reference>
    <reference>
      <citation>Maccarrone V, Liou C, D'souza B, Salvatore MM, Leb J, Belletti A, Palumbo D, Landoni G, Capaccione KM. The Macklin effect closely correlates with pneumomediastinum in acutely ill intubated patients with COVID-19 infection. Clin Imaging. 2023 May;97:50-54. doi: 10.1016/j.clinimag.2023.03.003. Epub 2023 Mar 4.</citation>
      <PMID>36889115</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 31, 2023</study_first_submitted>
    <study_first_submitted_qc>August 17, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 21, 2023</study_first_posted>
    <last_update_submitted>August 17, 2023</last_update_submitted>
    <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Università Vita-Salute San Raffaele</investigator_affiliation>
      <investigator_full_name>Giovanni Landoni</investigator_full_name>
      <investigator_title>Full Professor</investigator_title>
    </responsible_party>
    <keyword>Acute Respiratory Distress Syndrome</keyword>
    <keyword>Mechanical Ventilation</keyword>
    <keyword>Intensive Care</keyword>
    <keyword>Respiratory Failure</keyword>
    <keyword>Pneumothorax</keyword>
    <keyword>Macklin effect</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Respiratory Distress Syndrome</mesh_term>
      <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
      <mesh_term>Acute Lung Injury</mesh_term>
      <mesh_term>Mediastinal Emphysema</mesh_term>
      <mesh_term>Emphysema</mesh_term>
      <mesh_term>Barotrauma</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06001645
  org study id: PNRR-MAD-2022-12376
  nct id: NCT06001645
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Barotrauma (pneumothorax, pneumomediastinum) is a well-described complication of Acute
        Respiratory Distress Syndrome (ARDS), especially in patients with coronavirus disease 2019
        (COVID-19) (16.1% in COVID-19, and about 6% in non-COVID-19 ARDS). Macklin effect was
        recently discovered by our group as an accurate radiological predictor of barotrauma in
        COVID-19 ARDS; the Investigators also found that density histograms automatically extracted
        from chest CT images provide a reliable insight into lung composition
  
        . Since lung frailty is a major issue also in non-COVID-19 ARDS, the Investigators want to
        confirm the predictive role of Macklin effect also in this setting. In addition, the
        Investigators aim to explore inflammatory profiling to decipher different biological aspects
        of the same clinical issue. Finally, the Investigators want to develop a specific management
        algorithm for patients diagnosed, according to our findings, with a specific ARDS sub
        phenotype characterized by increased lung frailty
  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)
  observational model: Case-Control
  time perspective: Prospective
  measure: Rate of clinically relevant barotrauma
  time frame: 30 days or until hospital discharge. Specifically, from date of basal CT scan until the date of first radiologically documented barotrauma
  description: Barotrauma is diagnosed only in the case of clear radiological evidence (free air at chest X-ray and/or chest CT scan).
  Rate of barotrauma will be compared between patients with an hyperinflammatory pattern as compared with control.
  arm group label: Acute Respiratory Distress Syndrome
  description: Patients with ARDS requiring or not requiring invasive ventilation
  intervention type: Diagnostic Test
  intervention name: Blood and bronchoalveolar fluid collection and analysis
  description: Blood and bronchoalveolar lavage fluid will be collected within 12 hours after intubation. Blood samples will be centrifuged, and the serum immediately stored at less than 70° C. The following biomarkers will be analysed in the serum and bronchoalveolar lavage fluid: 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). Blood samples obtained from the patients will be placed in specimen tubes containing heparin, centrifuged at 1500 G for 10 minutes, and then the plasma will be aspirated and stored at -70° C. Bronchoalveolar lavage fluid will be centrifuged at 1500 G for 10 minutes to remove cellular contents and stored at -70° C.
  arm group label: Acute Respiratory Distress Syndrome
  intervention type: Diagnostic Test
  intervention name: Chest CT scan
  description: Computed Tomography Scan per normal clinical practice
  arm group label: Acute Respiratory Distress Syndrome
  Blood and bronchoalveolar lavage fluid will be collected within 12 hours after intubation;
        blood samples will be centrifuged, and the serum immediately stored at less than 70° C. The
        following biomarkers will be analysed in the serum and bronchoalveolar lavage fluid:
        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). Blood and BAL samples obtained from the patients will be
        placed in specimen tubes (containing heparin for plasma), centrifuged at 1500 G for 10
        minutes, and then stored at -70° C
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  facility: 
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  country: Italy
  citation: Murayama S, Gibo S. Spontaneous pneumomediastinum and Macklin effect: Overview and appearance on computed tomography. World J Radiol. 2014 Nov 28;6(11):850-4. doi: 10.4329/wjr.v6.i11.850.
  PMID: 25431639
  citation: Palumbo D, Zangrillo A, Belletti A, Guazzarotti G, Calvi MR, Guzzo F, Pennella R, Monti G, Gritti C, Marmiere M, Rocchi M, Colombo S, Valsecchi D, Scandroglio AM, Dagna L, Rovere-Querini P, Tresoldi M, Landoni G, De Cobelli F; COVID-BioB Study Group. A radiological predictor for pneumomediastinum/pneumothorax in COVID-19 ARDS patients. J Crit Care. 2021 Dec;66:14-19. doi: 10.1016/j.jcrc.2021.07.022. Epub 2021 Aug 12.
  PMID: 34392131
  citation: Belletti A, Pallanch O, Bonizzoni MA, Guidi L, De Cobelli F, Landoni G, Zangrillo A, De Bonis M, Palumbo D. Clinical use of Macklin-like radiological sign (Macklin effect): A systematic review. Respir Med. 2023 Apr-May;210:107178. doi: 10.1016/j.rmed.2023.107178. Epub 2023 Feb 28.
  PMID: 36863617
  citation: Paternoster G, Bertini P, Belletti A, Landoni G, Gallotta S, Palumbo D, Isirdi A, Guarracino F. Venovenous Extracorporeal Membrane Oxygenation in Awake Non-Intubated Patients With COVID-19 ARDS at High Risk for Barotrauma. J Cardiothorac Vasc Anesth. 2022 Aug;36(8 Pt B):2975-2982. doi: 10.1053/j.jvca.2022.03.011. Epub 2022 Mar 17.
  PMID: 35537972
  citation: Maccarrone V, Liou C, D'souza B, Salvatore MM, Leb J, Belletti A, Palumbo D, Landoni G, Capaccione KM. The Macklin effect closely correlates with pneumomediastinum in acutely ill intubated patients with COVID-19 infection. Clin Imaging. 2023 May;97:50-54. doi: 10.1016/j.clinimag.2023.03.003. Epub 2023 Mar 4.
  PMID: 36889115
  responsible party type: Principal Investigator
  investigator affiliation: Università Vita-Salute San Raffaele
  investigator full name: Giovanni Landoni
  investigator title: Full Professor
  mesh term: Respiratory Distress Syndrome
  mesh term: Respiratory Distress Syndrome, Newborn
  mesh term: Acute Lung Injury
  mesh term: Mediastinal Emphysema
  mesh term: Emphysema
  mesh term: Barotrauma
  sharing ipd: No