<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/NCT04459884</url>
  </required_header>
  <id_info>
    <org_study_id>VENTIBRAIN</org_study_id>
    <nct_id>NCT04459884</nct_id>
  </id_info>
  <brief_title>Multicenter Observational Study on Practice of Ventilation in Brain Injured Patients</brief_title>
  <official_title>Multicenter Observational Study on Practice of Ventilation in Brain Injured Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Milano Bicocca</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Milano Bicocca</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Rationale Several experimental and clinical studies have shown how brain injury can cause&#xD;
      secondary lung injury. Lung injury could be due either to mechanical ventilation- often&#xD;
      necessary in brain injured patients- or to inflammatory response that follows primary acute&#xD;
      brain injury. The concept of 'Protective lung ventilation' has shown to reduce morbidity and&#xD;
      mortality of intensive care unit (ICU) patients with acute respiratory distress syndrome&#xD;
      (ARDS) but seems also to have a beneficial effect on patients with healthy lungs and in the&#xD;
      perioperative settings. However, these recommendations often come into conflict with the&#xD;
      management of patients affected by acute brain injury, in which permissive hypercapnia and&#xD;
      increased intrathoracic pressure as consequence of protective ventilation strategies can be&#xD;
      dangerous.&#xD;
&#xD;
      Study design This is an international multi-center prospective observational study.&#xD;
&#xD;
      Study population This study will include all consecutive brain injured patients (traumatic&#xD;
      brain injury (TBI) or cerebrovascular) intubated and ventilated in ICU and observed for a&#xD;
      7-day period.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness Seen the observational design of the study, there is no patient burden.&#xD;
      Collection of data from ICU and hospital charts and/or (electronic) medical records systems&#xD;
      is of no risk to patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION AND RATIONALE Mechanical ventilation (MV) is a frequently applied and often a&#xD;
      life-saving strategy in neurocritically ill patients. Paradoxically, ventilation itself has&#xD;
      the potential to cause further pulmonary and cerebral damage and can increase mortality and&#xD;
      morbidity [1].&#xD;
&#xD;
      The so-called 'protective lung ventilation' strategies include the use of low tidal volume&#xD;
      (TV), positive end expiratory pressure (PEEP), and eventually recruitment maneuvers (RMs),&#xD;
      and are aimed to prevent lung damage and to reduce morbidity and mortality in patients with&#xD;
      acute respiratory distress syndrome (ARDS) [2]. In particular, low tidal volume seems to have&#xD;
      the greater importance [3-5], and guidelines strongly recommend its use in critically ill&#xD;
      patients with ARDS [6].&#xD;
&#xD;
      Results from one multicenter randomized controlled trial suggest that also ICU patients&#xD;
      without ARDS could benefit from 'protective lung ventilation strategies [7]. A recent&#xD;
      meta-analysis showed a higher incidence of pulmonary complications and even increased&#xD;
      mortality in patients who received 'conventional ventilation' with traditionally sized or&#xD;
      higher tidal volumes compared to patients undergoing protective strategies [8].&#xD;
&#xD;
      Present ventilation guidelines for patients with acute brain injury The fourth edition of the&#xD;
      Guidelines for the Management of Severe Traumatic Brain Injury [10] suggests maintaining&#xD;
      normocapnia in this subset of patients and aiming for peripheral saturation of oxygen higher&#xD;
      than 90% to guarantee an adequate cerebral perfusion and avoid secondary brain damages due to&#xD;
      hypoxia or inappropriate cerebral vasodilatation [10]. However, BTF guidelines do not provide&#xD;
      any advice on ventilator settings or targets. There is still uncertainty regarding the use of&#xD;
      protective ventilation in neurologically ill patients. Brain injured patients have been&#xD;
      traditionally excluded from the major trials regarding mechanical ventilation and the use of&#xD;
      lung protective ventilator strategies because low tidal volumes, high PEEP and RMs can&#xD;
      increase carbon dioxide levels (CO2) and increase intrathoracic pressure, thus having&#xD;
      detrimental effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP).&#xD;
&#xD;
      METHODS&#xD;
&#xD;
      Objectives&#xD;
&#xD;
      This observational study aims to determine the ventilation practice of consecutive intubated&#xD;
      and ventilated neuro-ICU patients in the first week from admission in intensive care units.&#xD;
&#xD;
      Hypotheses&#xD;
&#xD;
        -  In patients with acute brain injury, protective ventilation strategies are not often&#xD;
           applied; in particular, tidal volumes are higher than those used in patients with no&#xD;
           brain injury. The adoption of protective ventilation in this group of patients might&#xD;
           result in a beneficial effect on outcome.&#xD;
&#xD;
        -  Ventilation practice, in particular tidal volume size, varies among patients with acute&#xD;
           brain injury and among different centers and different countries.&#xD;
&#xD;
        -  In patients with acute brain injury outcomes can be dependent on ventilator setting.&#xD;
&#xD;
      Study design&#xD;
&#xD;
      International multicenter prospective observational study of consecutive ventilated neuro-ICU&#xD;
      patients in the first week since admission to ICU.&#xD;
&#xD;
      Study population&#xD;
&#xD;
      We will collect data of consecutive patients with acute brain injury intubated and&#xD;
      ventilated, admitted to the intensive care unit (ICU).&#xD;
&#xD;
      Sample size calculation&#xD;
&#xD;
      The primary endpoint of the study is the exploration of the ventilator settings in clinical&#xD;
      practice in braininjured patients. The hypotheses of the study are exploratory; hence a&#xD;
      sample size calculation has not been conducted. This international prospective observational&#xD;
      study aims to recruit&gt;3000 patients in coma after acute brain damage admitted to &gt;200&#xD;
      Intensive Care Units (ICUs). Recruitment will last 12 weeks at each center, aiming to enroll&#xD;
      about 20 patients/center. To avoid any overrepresentation of some centers we ceil the data&#xD;
      collection to 30 patients/center. This number of enrolled patients and ICUs reflects an&#xD;
      adequate sample size to capture a range of variation in practice between ICUs. We aim to&#xD;
      include also low-middle income countries, in order to have a representation of the&#xD;
      variability worldwide.&#xD;
&#xD;
      Follow-up/Outcomes&#xD;
&#xD;
      Enrolled patients will be followed until ICU-discharge or death (whatever comes first), for&#xD;
      collection of patient demographics (on day of admission), and ventilation characteristics&#xD;
      (from start of ventilation till stop of ventilation). At 6 months, data on length of hospital&#xD;
      stay and outcome (Extended Glasgow Coma Scale) will be collected.&#xD;
&#xD;
      Outcomes will be assessed as:&#xD;
&#xD;
        -  6-months mortality and neurological outcome (as for extended Glasgow Outcome Scale,&#xD;
           eGOS)&#xD;
&#xD;
        -  Hospital length of stay (in days), in hospital mortality.&#xD;
&#xD;
        -  Mortality, duration of mechanical ventilation (in days), ventilator free days (days) at&#xD;
           ICU discharge.&#xD;
&#xD;
      Study procedures&#xD;
&#xD;
      Patients in participating centers are screened on a daily basis. ICU-patients under&#xD;
      mechanical ventilation and with diagnosis of acute brain injury will be included. Demographic&#xD;
      data on screened patients regardless of meeting enrollment criteria will be recorded&#xD;
      (registry).&#xD;
&#xD;
      The inclusion period will be flexible for participating centers and determined at a later&#xD;
      stage together with the study-coordinator.&#xD;
&#xD;
      Times points of data collection&#xD;
&#xD;
        -  Demographic data and baseline data, including severity scores (e.g. APACHE II- scores&#xD;
           and SAPS III) will be collected from clinical files on the day of start of mechanical&#xD;
           ventilation.&#xD;
&#xD;
        -  Ventilation settings, gas exchange variables and vital parameters will be collected once&#xD;
           daily in the morning till the day when ventilation is stopped or till day 7, whichever&#xD;
           comes first.&#xD;
&#xD;
        -  Chest radiography data from available chest X-rays (i.e., no extra chest X-rays are&#xD;
           obtained) in the first week.&#xD;
&#xD;
        -  Lung echography data are collected from clinical files in the first week.&#xD;
&#xD;
        -  Predefined complications are recorded from medical chart (Appendix 1)&#xD;
&#xD;
        -  At ICU discharge: mortality, duration of mechanical ventilation (in days), ventilator&#xD;
           free days (days).&#xD;
&#xD;
        -  At 6-months: mortality and neurological outcome (as for extended Glasgow Outcome Scale,&#xD;
           eGOS), length of stay (in days), in hospital mortality.&#xD;
&#xD;
      Inclusion During a 3 months period, all admitted patients will be screened daily by a local&#xD;
      investigator.&#xD;
&#xD;
      STATISTICAL ANALYSIS&#xD;
&#xD;
      Patient characteristics will be compared and described by appropriate statistics. Student's&#xD;
      t-test or Mann-Whitney U-tests will be used to compare continuous variables and chi-squared&#xD;
      tests will be used for categorical variables. Data will be expressed as means (SD), medians&#xD;
      (interquartile range) and proportions as appropriate. Comparisons between and within groups&#xD;
      will be performed using one-way ANOVA and post-hoc analyses for continuous variables.&#xD;
&#xD;
      Plan of analysis The primary analysis will concern the determination of (variation of) the&#xD;
      ventilator settings in neurologically critically ill patients. Univariate analysis will be&#xD;
      performed to identify potential factors associated with outcomes including, but not limited&#xD;
      to, GOS, mortality, duration of ventilation, or hospital LOS. A multivariate logistic&#xD;
      regression model will be used to identify independent risk factors. A stepwise approach will&#xD;
      be used to enter new terms into the model, with a limit of p &lt; 0.2 to enter the terms. Time&#xD;
      to event variables will be analyzed using Cox regression and visualized by Kaplan-Meier.&#xD;
      Statistical analyses will be conducted using R. A p value of less than 0.05 was considered&#xD;
      statistically significant.&#xD;
&#xD;
      ETHICAL CONSIDERATIONS Ethical standards The PI and Steering Committee will ensure that this&#xD;
      study is conducted in full conformity with the Declaration of Helsinki and Good Clinical&#xD;
      Practices.&#xD;
&#xD;
      Ethics committee Each NC/PI will notify the relevant ethics committee, in compliance with the&#xD;
      local legislation and rules. The national coordinators will facilitate this process. The&#xD;
      approval of the protocol (if required by local authorities) must be obtained before any&#xD;
      participant is enrolled. Any amendment to the protocol will require review and approval by&#xD;
      the SC before the changes are implemented to the study.&#xD;
&#xD;
      Lack of capacity and Delayed Consent Informed consent will be obtained from patients with no&#xD;
      lack of capacity. For patients not be able to provide informed consent at the time of&#xD;
      recruitment, the responsible clinical/research staff will act as Consulter and consent&#xD;
      eligible patients after discussion with the next- of-kin.If the patient has a Power of&#xD;
      Attorney or a Legal tutor or an, he/she will act as Consultee and will be asked to&#xD;
      consent/decline participation to the study on legal behalf of the patient.&#xD;
&#xD;
      If patients have Advance Decision Plan including participation in research studies the Plan&#xD;
      will be respected and recruitment pursued/abandoned accordingly. At follow-up, patients who&#xD;
      have regained capacity will be asked to provide Informed Consent and will be given the&#xD;
      possibility to:&#xD;
&#xD;
        -  Provide Informed Consent for the acute data and follow-up.&#xD;
&#xD;
        -  Deny research participation and request destruction of acute data collected.&#xD;
&#xD;
      Expected impact of the study The investigators expect to obtain data of &gt;3000 patients&#xD;
      admitted to ICU. These data will allow a detailed description of patient's characteristics,&#xD;
      management strategies resource use and correlation with clinical outcomes. In particular, the&#xD;
      study will provide insights in relation to clinical management, monitoring and treatment,&#xD;
      practice variation in neurointensive care units around the world, differences in the&#xD;
      ventilator management of brain injured patients and their potential association with outcome.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 23, 2021</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Actual">February 28, 2023</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>6 Months</target_duration>
  <primary_outcome>
    <measure>Description of different ventilatory strategies applied to acutely brain injured patients admitted to the ICUs</measure>
    <time_frame>12 months</time_frame>
    <description>We will compare the different ventilatory approaches to intubated and mechanically ventilated neurocritically ill patients admitted to worldwide ICUs.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation between ventilatory targets and neurological outcome at ICU discharge and after 6 months from admission</measure>
    <time_frame>12 months</time_frame>
    <description>We explore the correlation of ventilator settings and targets with outcome in the whole population (neurological outcome Glasgow Outcome Scale Extended)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Description of different ventolatory approaches to nuerocritically-ill patients</measure>
    <time_frame>12 months</time_frame>
    <description>The differences in ventilator settings among different countries will be described</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Description of mechanical ventilation-associated complication</measure>
    <time_frame>12 months</time_frame>
    <description>We will describe the incidence of pulmonary complications (including pneumonia, ARDS, neurogenic pulmonary edema) in the whole cohort of patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between ventilatory targets and neurological secondary injury</measure>
    <time_frame>12 months</time_frame>
    <description>We will describe the ventilator settings applied when intracranial pressure is raised (&gt;20 mmHg) and we will describe the need for adjustments related to intracranial hypertension</description>
  </secondary_outcome>
  <enrollment type="Anticipated">3000</enrollment>
  <condition>Mechanical Ventilation</condition>
  <condition>Acute Brain Injury</condition>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>mechanical ventilation</intervention_name>
    <description>mechanical ventilation &gt; 48h</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        We will collect data of consecutive patients with acute brain injury intubated and&#xD;
        ventilated, admitted to the intensive care unit (ICU).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients admitted to the ICU with a diagnosis of&#xD;
&#xD;
               -  traumatic brain injury or&#xD;
&#xD;
               -  cerebrovascular diseases (intracranial hemorrhage, subarachnoid hemorrhage,&#xD;
                  ischemic stroke)&#xD;
&#xD;
          -  Patients requiring intubation and mechanical ventilation in the ICU&#xD;
&#xD;
          -  Expected ventilation for more than 48 hours&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Pregnant patients&#xD;
&#xD;
          -  Patients not intubated or not mechanically ventilated or receiving only non-invasive&#xD;
             ventilation (i.e., the patient never received invasive ventilation during the present&#xD;
             admission)&#xD;
&#xD;
          -  Patients under invasive mechanical ventilation before the 7-day period of inclusion&#xD;
&#xD;
          -  Expected ventilation or death&lt; 48 hours&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chiara Robba, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Milano Bicocca</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chiara Robba, MD</last_name>
    <phone>+390392334335</phone>
    <email>kiarobba@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Giuseppe Citerio, Prof</last_name>
    <phone>+390392334316</phone>
    <email>giuseppe.citerio@unimib.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>ASST-Monza</name>
      <address>
        <city>Monza</city>
        <state>MB</state>
        <zip>20900</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Giuseppe Citerio, MD</last_name>
      <phone>+390392334316</phone>
      <email>giuseppe.citerio@unimib.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <results_reference>
    <citation>Slutsky AS. Lung injury caused by mechanical ventilation. Chest. 1999 Jul;116(1 Suppl):9S-15S. doi: 10.1378/chest.116.suppl_1.9s-a. No abstract available.</citation>
    <PMID>10424561</PMID>
  </results_reference>
  <results_reference>
    <citation>Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009 Oct 20;151(8):566-76. doi: 10.7326/0003-4819-151-8-200910200-00011. Erratum In: Ann Intern Med. 2009 Dec 15;151(12):897.</citation>
    <PMID>19841457</PMID>
  </results_reference>
  <results_reference>
    <citation>Esteban A, Ferguson ND, Meade MO, Frutos-Vivar F, Apezteguia C, Brochard L, Raymondos K, Nin N, Hurtado J, Tomicic V, Gonzalez M, Elizalde J, Nightingale P, Abroug F, Pelosi P, Arabi Y, Moreno R, Jibaja M, D'Empaire G, Sandi F, Matamis D, Montanez AM, Anzueto A; VENTILA Group. Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit Care Med. 2008 Jan 15;177(2):170-7. doi: 10.1164/rccm.200706-893OC. Epub 2007 Oct 25.</citation>
    <PMID>17962636</PMID>
  </results_reference>
  <results_reference>
    <citation>Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012 Aug;122(8):2731-40. doi: 10.1172/JCI60331. Epub 2012 Aug 1.</citation>
    <PMID>22850883</PMID>
  </results_reference>
  <results_reference>
    <citation>Needham DM, Colantuoni E, Mendez-Tellez PA, Dinglas VD, Sevransky JE, Dennison Himmelfarb CR, Desai SV, Shanholtz C, Brower RG, Pronovost PJ. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. BMJ. 2012 Apr 5;344:e2124. doi: 10.1136/bmj.e2124.</citation>
    <PMID>22491953</PMID>
  </results_reference>
  <results_reference>
    <citation>Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.</citation>
    <PMID>23361625</PMID>
  </results_reference>
  <results_reference>
    <citation>Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, Hofstra JJ, de Graaff MJ, Korevaar JC, Schultz MJ. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010;14(1):R1. doi: 10.1186/cc8230. Epub 2010 Jan 7.</citation>
    <PMID>20055989</PMID>
  </results_reference>
  <results_reference>
    <citation>Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci Mde O, Damasceno MC, Schultz MJ. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012 Oct 24;308(16):1651-9. doi: 10.1001/jama.2012.13730.</citation>
    <PMID>23093163</PMID>
  </results_reference>
  <results_reference>
    <citation>Neto AS, Barbas CSV, Simonis FD, Artigas-Raventos A, Canet J, Determann RM, Anstey J, Hedenstierna G, Hemmes SNT, Hermans G, Hiesmayr M, Hollmann MW, Jaber S, Martin-Loeches I, Mills GH, Pearse RM, Putensen C, Schmid W, Severgnini P, Smith R, Treschan TA, Tschernko EM, Melo MFV, Wrigge H, de Abreu MG, Pelosi P, Schultz MJ; PRoVENT; PROVE Network investigators. Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study. Lancet Respir Med. 2016 Nov;4(11):882-893. doi: 10.1016/S2213-2600(16)30305-8. Epub 2016 Oct 4.</citation>
    <PMID>27717861</PMID>
  </results_reference>
  <results_reference>
    <citation>Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.</citation>
    <PMID>27654000</PMID>
  </results_reference>
  <results_reference>
    <citation>Picetti E, Pelosi P, Taccone FS, Citerio G, Mancebo J, Robba C; on the behalf of the ESICM NIC/ARF sections. VENTILatOry strategies in patients with severe traumatic brain injury: the VENTILO Survey of the European Society of Intensive Care Medicine (ESICM). Crit Care. 2020 Apr 17;24(1):158. doi: 10.1186/s13054-020-02875-w.</citation>
    <PMID>32303255</PMID>
  </results_reference>
  <results_reference>
    <citation>Gajic O, Dabbagh O, Park PK, Adesanya A, Chang SY, Hou P, Anderson H 3rd, Hoth JJ, Mikkelsen ME, Gentile NT, Gong MN, Talmor D, Bajwa E, Watkins TR, Festic E, Yilmaz M, Iscimen R, Kaufman DA, Esper AM, Sadikot R, Douglas I, Sevransky J, Malinchoc M; U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS). Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med. 2011 Feb 15;183(4):462-70. doi: 10.1164/rccm.201004-0549OC. Epub 2010 Aug 27.</citation>
    <PMID>20802164</PMID>
  </results_reference>
  <results_reference>
    <citation>ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.</citation>
    <PMID>22797452</PMID>
  </results_reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 1, 2020</study_first_submitted>
  <study_first_submitted_qc>July 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>May 25, 2023</last_update_submitted>
  <last_update_submitted_qc>May 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Data collection will be web-based. Participating centres will collect data via an electronic Case-Report Form (REDCAP cloud); data will be automatically pseudoanonymized with a numeric alpha code; the list of correspondence between the patient's code and its identity will be stored in a safe place and access to this data will be granted only to study PI and study staff delegated by the PI and listed in the delegation log. The data resides at the University of Milano-Bicocca. The study will be conducted in accordance with the Helsinki Declaration and in accordance with the rules of Good Clinical Practice (D.M. Healthcare of 15/07/1997 and s.m.i.) as well as with the applicable regulatory provisions.&#xD;
The patient's personal data will be processed in accordance with the European Personal Data Protection Regulation (GDPR), Di.Lgs. 196/2003 and subsequent changes and additions, and any other Italian law applicable to the protection of personal data.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT04459884
org study id: VENTIBRAIN
nct id: NCT04459884
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Rationale Several experimental and clinical studies have shown how brain injury can cause
      secondary lung injury. Lung injury could be due either to mechanical ventilation- often
      necessary in brain injured patients- or to inflammatory response that follows primary acute
      brain injury. The concept of 'Protective lung ventilation' has shown to reduce morbidity and
      mortality of intensive care unit (ICU) patients with acute respiratory distress syndrome
      (ARDS) but seems also to have a beneficial effect on patients with healthy lungs and in the
      perioperative settings. However, these recommendations often come into conflict with the
      management of patients affected by acute brain injury, in which permissive hypercapnia and
      increased intrathoracic pressure as consequence of protective ventilation strategies can be
      dangerous.

      Study design This is an international multi-center prospective observational study.

      Study population This study will include all consecutive brain injured patients (traumatic
      brain injury (TBI) or cerebrovascular) intubated and ventilated in ICU and observed for a
      7-day period.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness Seen the observational design of the study, there is no patient burden.
      Collection of data from ICU and hospital charts and/or (electronic) medical records systems
      is of no risk to patients.
INTRODUCTION AND RATIONALE Mechanical ventilation (MV) is a frequently applied and often a
      life-saving strategy in neurocritically ill patients. Paradoxically, ventilation itself has
      the potential to cause further pulmonary and cerebral damage and can increase mortality and
      morbidity [1].

      The so-called 'protective lung ventilation' strategies include the use of low tidal volume
      (TV), positive end expiratory pressure (PEEP), and eventually recruitment maneuvers (RMs),
      and are aimed to prevent lung damage and to reduce morbidity and mortality in patients with
      acute respiratory distress syndrome (ARDS) [2]. In particular, low tidal volume seems to have
      the greater importance [3-5], and guidelines strongly recommend its use in critically ill
      patients with ARDS [6].

      Results from one multicenter randomized controlled trial suggest that also ICU patients
      without ARDS could benefit from 'protective lung ventilation strategies [7]. A recent
      meta-analysis showed a higher incidence of pulmonary complications and even increased
      mortality in patients who received 'conventional ventilation' with traditionally sized or
      higher tidal volumes compared to patients undergoing protective strategies [8].

      Present ventilation guidelines for patients with acute brain injury The fourth edition of the
      Guidelines for the Management of Severe Traumatic Brain Injury [10] suggests maintaining
      normocapnia in this subset of patients and aiming for peripheral saturation of oxygen higher
      than 90% to guarantee an adequate cerebral perfusion and avoid secondary brain damages due to
      hypoxia or inappropriate cerebral vasodilatation [10]. However, BTF guidelines do not provide
      any advice on ventilator settings or targets. There is still uncertainty regarding the use of
      protective ventilation in neurologically ill patients. Brain injured patients have been
      traditionally excluded from the major trials regarding mechanical ventilation and the use of
      lung protective ventilator strategies because low tidal volumes, high PEEP and RMs can
      increase carbon dioxide levels (CO2) and increase intrathoracic pressure, thus having
      detrimental effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP).

      METHODS

      Objectives

      This observational study aims to determine the ventilation practice of consecutive intubated
      and ventilated neuro-ICU patients in the first week from admission in intensive care units.

      Hypotheses

        -  In patients with acute brain injury, protective ventilation strategies are not often
           applied; in particular, tidal volumes are higher than those used in patients with no
           brain injury. The adoption of protective ventilation in this group of patients might
           result in a beneficial effect on outcome.

        -  Ventilation practice, in particular tidal volume size, varies among patients with acute
           brain injury and among different centers and different countries.

        -  In patients with acute brain injury outcomes can be dependent on ventilator setting.

      Study design

      International multicenter prospective observational study of consecutive ventilated neuro-ICU
      patients in the first week since admission to ICU.

      Study population

      We will collect data of consecutive patients with acute brain injury intubated and
      ventilated, admitted to the intensive care unit (ICU).

      Sample size calculation

      The primary endpoint of the study is the exploration of the ventilator settings in clinical
      practice in braininjured patients. The hypotheses of the study are exploratory; hence a
      sample size calculation has not been conducted. This international prospective observational
      study aims to recruit>3000 patients in coma after acute brain damage admitted to >200
      Intensive Care Units (ICUs). Recruitment will last 12 weeks at each center, aiming to enroll
      about 20 patients/center. To avoid any overrepresentation of some centers we ceil the data
      collection to 30 patients/center. This number of enrolled patients and ICUs reflects an
      adequate sample size to capture a range of variation in practice between ICUs. We aim to
      include also low-middle income countries, in order to have a representation of the
      variability worldwide.

      Follow-up/Outcomes

      Enrolled patients will be followed until ICU-discharge or death (whatever comes first), for
      collection of patient demographics (on day of admission), and ventilation characteristics
      (from start of ventilation till stop of ventilation). At 6 months, data on length of hospital
      stay and outcome (Extended Glasgow Coma Scale) will be collected.

      Outcomes will be assessed as:

        -  6-months mortality and neurological outcome (as for extended Glasgow Outcome Scale,
           eGOS)

        -  Hospital length of stay (in days), in hospital mortality.

        -  Mortality, duration of mechanical ventilation (in days), ventilator free days (days) at
           ICU discharge.

      Study procedures

      Patients in participating centers are screened on a daily basis. ICU-patients under
      mechanical ventilation and with diagnosis of acute brain injury will be included. Demographic
      data on screened patients regardless of meeting enrollment criteria will be recorded
      (registry).

      The inclusion period will be flexible for participating centers and determined at a later
      stage together with the study-coordinator.

      Times points of data collection

        -  Demographic data and baseline data, including severity scores (e.g. APACHE II- scores
           and SAPS III) will be collected from clinical files on the day of start of mechanical
           ventilation.

        -  Ventilation settings, gas exchange variables and vital parameters will be collected once
           daily in the morning till the day when ventilation is stopped or till day 7, whichever
           comes first.

        -  Chest radiography data from available chest X-rays (i.e., no extra chest X-rays are
           obtained) in the first week.

        -  Lung echography data are collected from clinical files in the first week.

        -  Predefined complications are recorded from medical chart (Appendix 1)

        -  At ICU discharge: mortality, duration of mechanical ventilation (in days), ventilator
           free days (days).

        -  At 6-months: mortality and neurological outcome (as for extended Glasgow Outcome Scale,
           eGOS), length of stay (in days), in hospital mortality.

      Inclusion During a 3 months period, all admitted patients will be screened daily by a local
      investigator.

      STATISTICAL ANALYSIS

      Patient characteristics will be compared and described by appropriate statistics. Student's
      t-test or Mann-Whitney U-tests will be used to compare continuous variables and chi-squared
      tests will be used for categorical variables. Data will be expressed as means (SD), medians
      (interquartile range) and proportions as appropriate. Comparisons between and within groups
      will be performed using one-way ANOVA and post-hoc analyses for continuous variables.

      Plan of analysis The primary analysis will concern the determination of (variation of) the
      ventilator settings in neurologically critically ill patients. Univariate analysis will be
      performed to identify potential factors associated with outcomes including, but not limited
      to, GOS, mortality, duration of ventilation, or hospital LOS. A multivariate logistic
      regression model will be used to identify independent risk factors. A stepwise approach will
      be used to enter new terms into the model, with a limit of p < 0.2 to enter the terms. Time
      to event variables will be analyzed using Cox regression and visualized by Kaplan-Meier.
      Statistical analyses will be conducted using R. A p value of less than 0.05 was considered
      statistically significant.

      ETHICAL CONSIDERATIONS Ethical standards The PI and Steering Committee will ensure that this
      study is conducted in full conformity with the Declaration of Helsinki and Good Clinical
      Practices.

      Ethics committee Each NC/PI will notify the relevant ethics committee, in compliance with the
      local legislation and rules. The national coordinators will facilitate this process. The
      approval of the protocol (if required by local authorities) must be obtained before any
      participant is enrolled. Any amendment to the protocol will require review and approval by
      the SC before the changes are implemented to the study.

      Lack of capacity and Delayed Consent Informed consent will be obtained from patients with no
      lack of capacity. For patients not be able to provide informed consent at the time of
      recruitment, the responsible clinical/research staff will act as Consulter and consent
      eligible patients after discussion with the next- of-kin.If the patient has a Power of
      Attorney or a Legal tutor or an, he/she will act as Consultee and will be asked to
      consent/decline participation to the study on legal behalf of the patient.

      If patients have Advance Decision Plan including participation in research studies the Plan
      will be respected and recruitment pursued/abandoned accordingly. At follow-up, patients who
      have regained capacity will be asked to provide Informed Consent and will be given the
      possibility to:

        -  Provide Informed Consent for the acute data and follow-up.

        -  Deny research participation and request destruction of acute data collected.

      Expected impact of the study The investigators expect to obtain data of >3000 patients
      admitted to ICU. These data will allow a detailed description of patient's characteristics,
      management strategies resource use and correlation with clinical outcomes. In particular, the
      study will provide insights in relation to clinical management, monitoring and treatment,
      practice variation in neurointensive care units around the world, differences in the
      ventilator management of brain injured patients and their potential association with outcome.
observational model: Cohort
time perspective: Prospective
measure: Description of different ventilatory strategies applied to acutely brain injured patients admitted to the ICUs
time frame: 12 months
description: We will compare the different ventilatory approaches to intubated and mechanically ventilated neurocritically ill patients admitted to worldwide ICUs.
measure: Correlation between ventilatory targets and neurological outcome at ICU discharge and after 6 months from admission
time frame: 12 months
description: We explore the correlation of ventilator settings and targets with outcome in the whole population (neurological outcome Glasgow Outcome Scale Extended)
measure: Description of different ventolatory approaches to nuerocritically-ill patients
time frame: 12 months
description: The differences in ventilator settings among different countries will be described
measure: Description of mechanical ventilation-associated complication
time frame: 12 months
description: We will describe the incidence of pulmonary complications (including pneumonia, ARDS, neurogenic pulmonary edema) in the whole cohort of patients
measure: Correlation between ventilatory targets and neurological secondary injury
time frame: 12 months
description: We will describe the ventilator settings applied when intracranial pressure is raised (>20 mmHg) and we will describe the need for adjustments related to intracranial hypertension
intervention type: Procedure
intervention name: mechanical ventilation
description: mechanical ventilation > 48h
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Chiara Robba, MD
role: Principal Investigator
affiliation: University of Milano Bicocca
last name: Chiara Robba, MD
phone: +390392334335
email: kiarobba@gmail.com
last name: Giuseppe Citerio, Prof
phone: +390392334316
email: giuseppe.citerio@unimib.it
facility: 
status: Recruiting
contact: 
country: Italy
citation: Slutsky AS. Lung injury caused by mechanical ventilation. Chest. 1999 Jul;116(1 Suppl):9S-15S. doi: 10.1378/chest.116.suppl_1.9s-a. No abstract available.
PMID: 10424561
citation: Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009 Oct 20;151(8):566-76. doi: 10.7326/0003-4819-151-8-200910200-00011. Erratum In: Ann Intern Med. 2009 Dec 15;151(12):897.
PMID: 19841457
citation: Esteban A, Ferguson ND, Meade MO, Frutos-Vivar F, Apezteguia C, Brochard L, Raymondos K, Nin N, Hurtado J, Tomicic V, Gonzalez M, Elizalde J, Nightingale P, Abroug F, Pelosi P, Arabi Y, Moreno R, Jibaja M, D'Empaire G, Sandi F, Matamis D, Montanez AM, Anzueto A; VENTILA Group. Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit Care Med. 2008 Jan 15;177(2):170-7. doi: 10.1164/rccm.200706-893OC. Epub 2007 Oct 25.
PMID: 17962636
citation: Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012 Aug;122(8):2731-40. doi: 10.1172/JCI60331. Epub 2012 Aug 1.
PMID: 22850883
citation: Needham DM, Colantuoni E, Mendez-Tellez PA, Dinglas VD, Sevransky JE, Dennison Himmelfarb CR, Desai SV, Shanholtz C, Brower RG, Pronovost PJ. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. BMJ. 2012 Apr 5;344:e2124. doi: 10.1136/bmj.e2124.
PMID: 22491953
citation: Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.
PMID: 23361625
citation: Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, Hofstra JJ, de Graaff MJ, Korevaar JC, Schultz MJ. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010;14(1):R1. doi: 10.1186/cc8230. Epub 2010 Jan 7.
PMID: 20055989
citation: Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci Mde O, Damasceno MC, Schultz MJ. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012 Oct 24;308(16):1651-9. doi: 10.1001/jama.2012.13730.
PMID: 23093163
citation: Neto AS, Barbas CSV, Simonis FD, Artigas-Raventos A, Canet J, Determann RM, Anstey J, Hedenstierna G, Hemmes SNT, Hermans G, Hiesmayr M, Hollmann MW, Jaber S, Martin-Loeches I, Mills GH, Pearse RM, Putensen C, Schmid W, Severgnini P, Smith R, Treschan TA, Tschernko EM, Melo MFV, Wrigge H, de Abreu MG, Pelosi P, Schultz MJ; PRoVENT; PROVE Network investigators. Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study. Lancet Respir Med. 2016 Nov;4(11):882-893. doi: 10.1016/S2213-2600(16)30305-8. Epub 2016 Oct 4.
PMID: 27717861
citation: Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.
PMID: 27654000
citation: Picetti E, Pelosi P, Taccone FS, Citerio G, Mancebo J, Robba C; on the behalf of the ESICM NIC/ARF sections. VENTILatOry strategies in patients with severe traumatic brain injury: the VENTILO Survey of the European Society of Intensive Care Medicine (ESICM). Crit Care. 2020 Apr 17;24(1):158. doi: 10.1186/s13054-020-02875-w.
PMID: 32303255
citation: Gajic O, Dabbagh O, Park PK, Adesanya A, Chang SY, Hou P, Anderson H 3rd, Hoth JJ, Mikkelsen ME, Gentile NT, Gong MN, Talmor D, Bajwa E, Watkins TR, Festic E, Yilmaz M, Iscimen R, Kaufman DA, Esper AM, Sadikot R, Douglas I, Sevransky J, Malinchoc M; U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS). Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med. 2011 Feb 15;183(4):462-70. doi: 10.1164/rccm.201004-0549OC. Epub 2010 Aug 27.
PMID: 20802164
citation: ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.
PMID: 22797452
responsible party type: Sponsor
mesh term: Brain Injuries
sharing ipd: No
ipd description: Data collection will be web-based. Participating centres will collect data via an electronic Case-Report Form (REDCAP cloud); data will be automatically pseudoanonymized with a numeric alpha code; the list of correspondence between the patient's code and its identity will be stored in a safe place and access to this data will be granted only to study PI and study staff delegated by the PI and listed in the delegation log. The data resides at the University of Milano-Bicocca. The study will be conducted in accordance with the Helsinki Declaration and in accordance with the rules of Good Clinical Practice (D.M. Healthcare of 15/07/1997 and s.m.i.) as well as with the applicable regulatory provisions.
The patient's personal data will be processed in accordance with the European Personal Data Protection Regulation (GDPR), Di.Lgs. 196/2003 and subsequent changes and additions, and any other Italian law applicable to the protection of personal data.