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

Official title

Careful Ventilation in Acute Respiratory Distress Syndrome

Overview

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.).

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.

Interventions

• 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 15cmH2
• 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.

Primary outcome measures

• All-cause 60-day mortality [Time frame: 60 days]

Secondary outcome measures (5)

• Duration of ventilation [Time frame: May exceed 60 days]
• Duration of ICU and hospital stay [Time frame: May exceed 60 days]
• Number of patients with organ dysfunction [Time frame: Day 1-7, 14, 21, 28]
• Number of patients with barotrauma [Time frame: Up to 60 days]
• Mortality at ICU discharge, 28 days, and hospital discharge [Time frame: Up to date of ICU discharge, 28 days, and hospital discharge]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 y
• Moderate or severe ARDS (PaO2/FiO2 ≤ 200 mmHg) within 48 h of meeting Berlin ARDS criteria (Patients who were eligible at the time of screening and whose PaO2/FiO2 became > 200 mm Hg under prone positioning when starting the protocol remained eligible)

Exclusion criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

France · 16 centers

• CHU Amiens-Picardie — Amiens
• Centre hospitalier universitaire d'Angers — Angers
• CH Victor Dupouy — Argenteuil
• CH de Beauvais — Beauvais
• CHU Bordeaux - Haut Leveque — Bordeaux
• Hopital de la Cavale Blanche - CHRU Brest — Brest
• CH de Cholet — Cholet
• Hopital Intercommunal de Creteil — Créteil
• … and 8 more centers

Argentina · 6 centers

• Centro de Educación Médica e Investigaciones Clínicas Dr Norberto Quirno (CEMIC) — Buenos Aires
• Complejo Médico Policía Federal Argentina Churruca Visca — Buenos Aires
• Hospital Británico de Buenos Aires — Buenos Aires
• Sanatorio Anchorena Recoleta — Buenos Aires
• Sanatorio Mater Dei — Buenos Aires
• Sanatorio Anchorena San Martín — San Martin

Canada · 3 centers

• St. Michael's Hospital — Toronto
• Toronto General Hospital — Toronto
• Toronto Western Hospital — Toronto

Italy · 3 centers

• Arcispedale Sant'Anna — Ferrara
• University of Foggia — Foggia
• Policlinico Universitario Agostino Gemelli IRCCS — Rome

Spain · 2 centers

• L'Hospital de la Santa Creu i Sant Pau — Barcelona
• Vall d'Hebron University Hospital — Barcelona

United States · 1 center

• New York University Grossman School of Medicine — New York

Chile · 1 center

• Pontificia Universidad Católica de Chile — Santiago

Netherlands · 1 center

• OLVG — Amsterdam

Publications

• Coudroy R, Telias I, Jonkman A, Thille AW, Diehl JL, Peron N, Ko M, Bourion AA, Tiribelli N, Fredes S, Gutierrez M, Manchado Bruno A, Vasquez DN, Pratto RA, Plotnikow GA, Bianchini F, Accoce M, Dorado J, Spadaro S, La Rosa R, Prat G, Bailly P, Delbove A, Pacheco-Reyes A, Roca O, Kuteifan K, Rouze A, Grieco DL, Izura-Gomez M, Mancebo J, Sigaud F, Terzi N, Saccheri C, Dellamonica J, Richecoeur J, Se PMID 41730551
• Villalba DS, Matesa A, Boni S, Gutierrez FJ, Moracci R, Plotnikow GA. Impact of High-Flow Nasal Cannula Oxygen Therapy on the Pressure of the Airway System in Humans. Respir Care. 2025 Jan;70(1):10-16. doi: 10.1089/respcare.12082. PMID 39964860

Identifiers

NCT: NCT03963622 · 1765

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗