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

Sponsor

Unity Health Toronto (Other)

Overall Status

Recruiting

CT.gov ID

NCT03963622

Collaborator

Canadian Institutes of Health Research (CIHR) (Other), University of Toronto (Other), Applied Health Research Centre (Other)

740

Enrollment

Locations

Arms

47.3

Anticipated Duration (Months)

23.9

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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	N/A

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 Design

Study Type:

Interventional

Anticipated 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.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

Actual Study Start Date :

Nov 23, 2020

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Nov 1, 2024

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

All-cause 60-day mortality [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

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

Other Outcome Measures

The change in biomarker expression [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York University Grossman School of Medicine	New York	New York	United States	10016
2	Centro de Educación Médica e Investigaciones Clínicas Dr Norberto Quirno (CEMIC)	Buenos Aires		Argentina
3	Complejo Médico Policía Federal Argentina Churruca Visca	Buenos Aires		Argentina
4	Hospital Británico de Buenos Aires	Buenos Aires		Argentina
5	Sanatorio Anchorena Recoleta	Buenos Aires		Argentina
6	Sanatorio Mater Dei	Buenos Aires		Argentina
7	Sanatorio Anchorena San Martín	San Martín		Argentina
8	St. Michael's Hospital	Toronto		Canada
9	Toronto General Hospital	Toronto		Canada
10	Toronto Western Hospital	Toronto		Canada
11	Pontificia Universidad Católica de Chile	Santiago de Chile		Chile
12	Centre hospitalier universitaire d'Angers	Angers		France
13	CH Victor Dupouy	Argenteuil		France
14	CH de Beauvais	Beauvais		France
15	CHU Bordeaux - Haut Leveque	Bordeaux		France
16	Hopital de la Cavale Blanche - CHRU Brest	Brest		France
17	CH de Cholet	Cholet		France
18	Hopital Intercommunal de Creteil	Creteil		France
19	CHU Grenoble-Alpes	Grenoble		France
20	Hopital Roger Salengro - CHU Lille	Lille		France
21	Groupe Hospitalier de la Region de Mulhouse et Sud Alsace	Mulhouse		France
22	Hopital de l'Archet 1 - CHU de Nice	Nice		France
23	Hopital Europeen Georges-Pompidou	Paris		France
24	CHU de Poitiers - La Miletrie	Poitiers		France
25	CH Bretagne Atlantique Vannes-Auray	Vannes		France
26	HIA Robert Picque	Villenave-d'Ornon		France
27	Arcispedale Sant'Anna	Ferrara		Italy
28	University of Foggia	Foggia		Italy
29	Policlinico Universitario Agostino Gemelli IRCCS	Rome		Italy
30	L'Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
31	Vall d'Hebron University Hospital	Barcelona		Spain