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Careful Ventilation in Acute Respiratory Distress Syndrome (CAVIARDS)

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ClinicalTrials.gov Identifier: NCT03963622
Recruitment Status : Not yet recruiting
First Posted : May 24, 2019
Last Update Posted : November 2, 2020
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
University of Toronto
Applied Health Research Centre
Information provided by (Responsible Party):
St. Michael's Hospital, Toronto

Brief Summary:

This is a multicenter randomized controlled clinical trial with an adaptive design assessing the efficacy of setting the ventilator based on measurements of respiratory mechanics (recruitability and effort) to reduce Day 60 mortality in patients with acute respiratory distress syndrome (ARDS).

The CAVIARDS study is also a basket trial; a basket trial design examines a single intervention in multiple disease populations. CAVIARDS consists of an identical 2-arm mechanical ventilation protocol implemented in two different study populations (COVID-19 and non-COVID-19 patients). As per a typical basket trial design, the operational structure of both the COVID-19 substudy (CAVIARDS-19) and non-COVID-19 substudy (CAVIARDS-all) is shared (recruitment, procedures, data collection, analysis, management, etc.).


Condition or disease Intervention/treatment Phase
ARDS Other: Respiratory Mechanics Other: Standard Ventilation Strategy Not Applicable

Detailed Description:

Acute respiratory distress syndrome (ARDS) is a major public health problem affecting approximately 10% of patients in the intensive care unit (ICU) and 23% of all patients on a breathing machine (mechanical ventilator). The short-term mortality of patients with ARDS is approximately 40% and better ventilation of these patients has the greatest potential to improve outcomes.

The lungs in patients with ARDS are severely inflamed which reduces lung volume and their ability to stretch, making ventilation difficult and dangerous. However, mechanical ventilation is the mainstay of supportive therapy. Although it is life-saving, it can also can generate secondary injury and inflammation, called ventilator-induced lung injury (VILI). The investigators know that inadequate mechanical ventilation worsens outcomes but are uncertain of the optimal way to manage ventilators at the bedside.

Furthermore, ARDS is challenging because there is no treatment for the alveolar-capillary leak characterizing this syndrome; aside from treating the underlying cause, the only supportive therapy is mechanical ventilation. This is specially the case for COVID-19 induced ARDS. Despite best practices, over-distension of the lung or inappropriate positive end expiratory pressure (PEEP) is common. Finally, once spontaneous breathing has resumed and is assisted by the ventilator, an additional phenomenon occurs, called patient self-inflicted lung injury. The drive for breathing in many patients is stimulated by lung inflammation, and strong breathing efforts can generate high distending pressures, causing lung (and systemic) inflammation and organ damage. Whether the management of COVID-19 induced ARDS should differ from all other ARDS has been debated at length but has no clear response

Recent advances in our understanding of bedside physiology (airway closure, recruitability, lung distension, respiratory drive) can now be applied for an individual titration of mechanical ventilation.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 740 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is also a basket design, which examines a single intervention in multiple disease populations. This basket trial consists of an identical 2-arm mechanical ventilation protocol implemented in two different study populations (patients with COVID-19-induced ARDS, and patients with all ARDS not induced by COVID-19). The protocol and procedures are identical between the two study populations in this basket trial.
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Careful Ventilation in Acute Respiratory Distress Syndrome
Estimated Study Start Date : November 2020
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : November 2022


Arm Intervention/treatment
Active Comparator: Control
Standard ventilation strategy.
Other: Standard Ventilation Strategy
Patients randomized to the control arm will receive standard care. The PEEP is adjusted for oxygenation based on a PEEP-FiO2 table, either the low PEEP-FiO2 or the high PEEP-FiO2 table. Volume targeted ventilation with initial VT 6 mL·kg-1 and Plateau pressure at 30 cmH2O or below, targeting PaO2 60-80 or SpO2 90-95%, adjusted as per the protocol. Pressure-support ventilation is at physician's discretion, but recommended when FiO2 <60%, and is titrated VT 6-8 mL·kg-1.

Experimental: Respiratory Mechanics
The goal of this arm is to individualize tidal volume (VT) and PEEP according to respiratory mechanics.
Other: Respiratory Mechanics

Different maneuvers based on respiratory mechanics will be assessed at the bedside and will be used to individualize ventilator parameters. Recruitability will be assessed with a one breath decremental PEEP maneuver, and search for airway closure with a low-flow pressure volume or pressure-time curve. If the patient has airway closure, the minimal PEEP will be set at the airway opening pressure to avoid closure. If the patient is considered recruitable, the goal is to set PEEP at or above 15cmH20 to maximize alveolar recruitment, until the plateau pressure reaches the safety limit. Volume control ventilation at 6ml·kg-1 will be used.

Once spontaneous breathing has started, the occlusion pressure (P0.1) will be maintained within targets.





Primary Outcome Measures :
  1. All-cause 60-day mortality [ Time Frame: 60 days ]
    The lack of an appropriate surrogate endpoint, and the high baseline mortality rate mandate a multicentre RCT to determine the mortality effects of setting the ventilator based on recruitability and effort compared with conventional ventilation.


Secondary Outcome Measures :
  1. Duration of ventilation [ Time Frame: May exceed 60 days ]
    Duration of ventilation in days

  2. Duration of ICU and hospital stay [ Time Frame: May exceed 60 days ]
    Duration of ICU and hospital stay in days

  3. Number of patients with organ dysfunction [ Time Frame: Day 1-7, 14, 21, 28 ]
    Organ dysfunction as per the SOFA score

  4. Number of patients with barotrauma [ Time Frame: Up to 60 days ]
    Barotrauma defined as new onset of pneumothorax

  5. Mortality at ICU discharge, 28 days, and hospital discharge [ Time Frame: Up to date of ICU discharge, 28 days, and hospital discharge ]
    Mortality


Other Outcome Measures:
  1. The change in biomarker expression [ Time Frame: Baseline, 24 and 72 hours ]
    Biomarkers include interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor receptor 1 (TNFr1), soluble receptor of the advanced glycation end products (sRAGE), and surfactant protein D (SPD). All measured in pg/ml



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 y
  2. Moderate or severe ARDS (PaO2/FiO2 ≤ 200 mmHg) within 48 h of meeting Berlin ARDS criteria

Exclusion Criteria:

  1. Received continuous mechanical ventilation > 7 days
  2. Known or clinically suspected elevated intracranial pressure (>18mmHg) necessitating strict control of PaCO2
  3. Known pregnancy
  4. Broncho-pleural fistula
  5. Severe liver disease (Child-Pugh Score ≥ 10)
  6. BMI >40kg/m2
  7. Anticipating withdrawal of life support and/or shift to palliation as the goal of care
  8. Patient is receiving ECMO at time of randomization

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03963622


Contacts
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Contact: Laurent Brochard, MD 416-864-6060 ext 5686 laurent.brochard@unityhealth.to

Sponsors and Collaborators
St. Michael's Hospital, Toronto
Canadian Institutes of Health Research (CIHR)
University of Toronto
Applied Health Research Centre
Investigators
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Principal Investigator: Laurent Brochard, MD St. Michael's Hospital, Toronto
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Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT03963622    
Other Study ID Numbers: 1765
First Posted: May 24, 2019    Key Record Dates
Last Update Posted: November 2, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Michael's Hospital, Toronto:
Ventilation
ARDS
Airway closure
Lung recruitment
COVID-19
Basket trial
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury