Careful Ventilation in Acute Respiratory Distress Syndrome (COVID-19 and Non-COVID-19) (CAVIARDS)

Careful Ventilation in Acute Respiratory Distress Syndrome

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.).

Study Overview

• Status: Recruiting
• Conditions: ARDS
• Intervention / Treatment: Other: Standard Ventilation Strategy; Other: Respiratory Mechanics

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.

• Study Type: Interventional
• Enrollment (Anticipated): 740
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laurent Brochard, MD; Phone Number: 5686 416-864-6060; Email: Laurent.brochard@unityhealth.to

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Recruiting
    • Hospital Britanico de Buenos Aires
    • Contact: Gustavo Plotnikov, RRT
  • Buenos Aires, Argentina
    • Not yet recruiting
    • Centro de Educación Médica e Investigaciones Clínicas Dr Norberto Quirno (CEMIC)
    • Contact: Pablo Rodriguez, MD
  • Buenos Aires, Argentina
    • Recruiting
    • Complejo Médico Policía Federal Argentina Churruca Visca
    • Contact: Maria Guaymas, MD
  • Buenos Aires, Argentina
    • Recruiting
    • Sanatorio Anchorena Recoleta
    • Contact: Daniela Vazquez, MD
  • Buenos Aires, Argentina
    • Not yet recruiting
    • Sanatorio Mater Dei
    • Contact: Magalí Gutiérrez, MD
  • San Martín, Argentina
    • Recruiting
    • Sanatorio Anchorena San Martín
    • Contact: Matias Accoce, RRT
• Canada
  • Toronto, Canada
    • Recruiting
    • Toronto General Hospital
    • Contact: Ewan Goligher, MD
  • Toronto, Canada
    • Recruiting
    • St. Michael's Hospital
    • Contact: Laurent Brochard, MD
  • Toronto, Canada
    • Recruiting
    • Toronto Western Hospital
    • Contact: Irene Telias, MD
• Chile
  • Santiago de Chile, Chile
    • Recruiting
    • Pontificia Universidad Catolica de Chile
    • Contact: Felipe Damiani, PhD
• France
  • Angers, France
    • Recruiting
    • Centre hospitalier universitaire d'Angers
    • Contact: Francois Beloncle, MD
  • Argenteuil, France
    • Recruiting
    • CH Victor Dupouy
    • Contact: Gaetan PLANTEFEVE, MD
  • Beauvais, France
    • Recruiting
    • CH de Beauvais
    • Contact: Jack Richecoeur, MD
  • Bordeaux, France
    • Recruiting
    • CHU Bordeaux - Haut Leveque
    • Contact: Hadrien Roze, MD
  • Brest, France
    • Recruiting
    • Hopital de la Cavale Blanche - CHRU Brest
    • Contact: Gwenael Prat, MD
  • Cholet, France
    • Recruiting
    • CH de Cholet
    • Contact: Johann Auchabie, MD
  • Creteil, France
    • Recruiting
    • Hôpital Intercommunal de Créteil
    • Contact: Tommaso Maraffi, MD
  • Grenoble, France
    • Recruiting
    • CHU Grenoble-Alpes
    • Contact: Nicolas Terzi, MD
  • Lille, France
    • Recruiting
    • Hopital Roger Salengro - CHU Lille
    • Contact: Saad Nseir, MD
  • Mulhouse, France
    • Recruiting
    • Groupe hospitalier de la région de Mulhouse et Sud Alsace
    • Contact: Khaldoun Kuteifan, MD
  • Nice, France
    • Recruiting
    • Hopital de l'Archet 1 - CHU de Nice
    • Contact: Jean Dellamonica, MD
  • Paris, France
    • Recruiting
    • Hôpital Européen Georges-Pompidou
    • Contact: Jean-Luc Diehl, MD
  • Poitiers, France
    • Recruiting
    • CHU de Poitiers - La miletrie
    • Contact: Remi Coudroy, MD
  • Vannes, France
    • Recruiting
    • CH Bretagne Atlantique vannes-Auray
    • Contact: Agathe DELBOVE, MD
  • Villenave-d'Ornon, France
    • Recruiting
    • HIA Robert Picqué
    • Contact: David Tran-Van, MD
• Italy
  • Ferrara, Italy
    • Recruiting
    • Arcispedale Sant'Anna
    • Contact: Savino Spadaro, MD
  • Foggia, Italy
    • Recruiting
    • University of Foggia
    • Contact: Michela Rauseo, MD
  • Rome, Italy
    • Recruiting
    • Policlinico Universitario Agostino Gemelli IRCCS
    • Contact: Domenico L Grieco, MD
• Spain
  • Barcelona, Spain
    • Recruiting
    • Vall D'Hebron University Hospital
  • Barcelona, Spain
    • Recruiting
    • L'Hospital de la Santa Creu i Sant Pau
    • Contact: Jordi Mancebo, MD
• United States
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • New York University Grossman School of Medicine
      • Contact: David Kaufman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause 60-day mortality	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.	60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of ventilation	Duration of ventilation in days	May exceed 60 days
Duration of ICU and hospital stay	Duration of ICU and hospital stay in days	May exceed 60 days
Number of patients with organ dysfunction	Organ dysfunction as per the SOFA score	Day 1-7, 14, 21, 28
Number of patients with barotrauma	Barotrauma defined as new onset of pneumothorax	Up to 60 days
Mortality at ICU discharge, 28 days, and hospital discharge	Mortality	Up to date of ICU discharge, 28 days, and hospital discharge

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in biomarker expression	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	Baseline, 24 and 72 hours

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); University of Toronto; Applied Health Research Centre

Publications and helpful links

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2020
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: May 6, 2019
• First Submitted That Met QC Criteria: May 23, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Estimate): December 29, 2022
• Last Update Submitted That Met QC Criteria: December 27, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; ARDS; Ventilation; Lung recruitment; Airway closure; Basket trial
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: 1765 (Other Identifier: OHSU IRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No