Adaptive Ventilation Strategies + Corticosteroids for Critical Respiratory Insufficiency

(PRACTICAL Trial)

Overseen by John Muscedere, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Ewan Goligher

Must not be taking: Corticosteroids

Disqualifiers: Age over 65, Pregnancy, COVID-19, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing new ways to help patients with severe breathing problems. It includes using special machines to remove carbon dioxide from the blood, trying new ventilator methods, and giving steroids early. These treatments aim to improve breathing and reduce lung damage.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are currently using corticosteroids, you may not be eligible for certain parts of the trial.

What data supports the effectiveness of the treatment Adaptive Ventilation Strategies + Corticosteroids for Critical Respiratory Insufficiency?

Research suggests that ultra-lung-protective ventilation, especially when combined with extracorporeal support, may help reduce lung injury in severe respiratory conditions like acute respiratory distress syndrome (ARDS). However, the benefits are mainly seen in very severe cases, and there are risks involved, such as blood-related complications. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Lung-protective ventilation strategies, including ultra-protective ventilation with extracorporeal support, are generally considered safe and have been standard practice for managing severe lung conditions like acute respiratory distress syndrome (ARDS). However, they can be associated with blood-related complications, especially when using devices not designed for low blood-flow rates. ^{1 2 4 6 7}

How does the treatment 'Adaptive Ventilation Strategies + Corticosteroids for Critical Respiratory Insufficiency' differ from other treatments for this condition?

This treatment is unique because it combines ultra-protective ventilation, which uses lower airway pressures to minimize lung injury, with extracorporeal support to remove carbon dioxide from the blood, potentially benefiting patients with severe respiratory distress. Conventional treatments may not include this combination of strategies, which aims to protect the lungs while managing respiratory acidosis. ^{1 3 5 7 8}

Research Team

Ewan Goligher, MD, PhD

Principal Investigator

University Health Network, Toronto

Eddy Fan, MD, PhD

Principal Investigator

University Health Network, Toronto

Niall Ferguson, MD, MSc

Principal Investigator

University Health Network, Toronto

Lorenzo Del Sorbo, MD

Principal Investigator

University Health Network, Toronto

Bram Rochwerg, MD, MSc

Principal Investigator

McMaster University

Bijan Teja, MD

Principal Investigator

Unity Health Toronto

John Muscedere, MD

Principal Investigator

Queens University

Eligibility Criteria

Adults over 18 with acute hypoxemic respiratory failure (AHRF) needing high-flow nasal cannula, non-invasive or invasive ventilation can join. They must have had corticosteroids for AHRF for at least 10 days and not be suffering from conditions like heart failure or pulmonary embolism. Exclusions include allergy to dexamethasone, severe brain injury, certain contraindications to anticoagulation, previous neuromuscular disorders, suspected COVID-19 infection among others.

Inclusion Criteria

I have been treated with corticosteroids for acute respiratory failure for 10 days.

You have new lung problems in one or both lungs.

I am currently on high-flow oxygen or ventilation support.

Exclusion Criteria

I have had severe low oxygen levels for more than 6 hours.

I am over 65 years old.

My weight is more than 1kg for every cm of my height.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive various interventions for acute hypoxemic respiratory failure, including mechanical ventilation strategies and pharmacological agents

28 days

Daily monitoring for intervention duration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including ventilator-free days and survival status

4 weeks

Weekly assessments

Open-label extension (optional)

Participants may continue to receive study interventions as part of ongoing evaluation

Long-term

Treatment Details

Interventions

• Conventional lung-protective ventilation (Other)
• Ultra-protective ventilation facilitated by extracorporeal support (Other)

Trial Overview The trial is testing various interventions: usual care without extended corticosteroids; different mechanical ventilation strategies such as ultra-protective ventilation facilitated by ECMO and driving pressure-limited ventilation; early versus extended doses of corticosteroids in patients with persistent AHRF.

Participant Groups

Group I: Ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal (ULTIMATE) domain Experimental Treatment 2 Interventions

Patients with acute hypoxemic respiratory failure in the high elastance state will be randomized to ultra-protective ventilation facilitated by extracorporeal carbon dioxide removal or to conventional lung-protective ventilation.

Group II: The Nebulized Furosemide for the Treatment of Pulmonary Inflammation (FAST-3) domain Experimental Treatment 2 Interventions

Patients with Respiratory Failure Secondary to Pulmonary Infection.

Group III: The Invasive Mechanical Ventilation Strategies in Venovenous-Extracorporeal Life Support (IMV-ECLS) Experimental Treatment 3 Interventions

Patients with acute hypoxemic respiratory failure receiving extracorporeal life support will be randomized to one of three positive end-expiratory pressure (PEEP) strategies.

Group IV: The Fludrocortisone in Acute Hypoxemic Respiratory Failure with Airspace Disease (FLUDRO-1) domain Experimental Treatment 2 Interventions

Patients with acute hypoxemic respiratory failure with airspace disease will be randomized to usual care with or without fludrocortisone.

Group V: The Corticosteroid Early and Extended (CORT-E2) Randomized Controlled Trial domain Experimental Treatment 4 Interventions

Patients with acute hypoxemic respiratory failure (AHRF) requiring invasive or non-invasive respiratory support will be randomized in the Early Cohort to receive corticosteroid or usual care without corticosteroids. Patients treated with corticosteroids who still require invasive or non-invasive respiratory support after 10 days will be randomized in the Extended Cohort to extending corticosteroid use or stopping corticosteroids after 10 days.

Group VI: Invasive Mechanical Ventilation (IMV) Strategies domain Experimental Treatment 3 Interventions

Patients on invasive mechanical ventilation in the low elastance, high elastance, and ECLS states will be randomized to one of two or three mechanical ventilation interventions (including conventional lung-protective ventilation as a control group). Most sites will randomize patients to two arms (one of which is the control group, LPV). A subset of sites will randomize patients to all three arms.

Who Is Running the Clinical Trial?

Ewan Goligher

Lead Sponsor

Trials

1

Recruited

6,300+

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Dr. Brad Wouters

University Health Network, Toronto

Chief Medical Officer since 2020

MD from University of Toronto

Dr. Kevin Smith

University Health Network, Toronto

Chief Executive Officer since 2018

Professor at McMaster University and University of Toronto

Findings from Research

Ultra-lung-protective ventilation strategies may offer benefits for patients with acute respiratory distress syndrome (ARDS) by using lower airway pressures and tidal volumes, but their application is often limited by respiratory acidosis.

Extracorporeal membrane oxygenation (ECMO) can help facilitate ultra-lung-protective ventilation, but recent studies indicate that this approach may only be beneficial for patients with very severe ARDS, highlighting the need for careful consideration of risks versus benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and Benefits of Ultra-Lung-Protective Invasive Mechanical Ventilation Strategies with a Focus on Extracorporeal Support. Abrams, D., Agerstrand, C., Beitler, JR., et al.[2022]

Ultraprotective mechanical ventilation (UP-MV) with lower tidal volumes (VT ≈3 ml/kg) reduced lung damage in pigs with severe acute respiratory distress syndrome compared to conventional mechanical ventilation (VT ≈6 ml/kg), but did not improve inflammation levels.

Adding spontaneous breathing (SB) to UP-MV increased lung inflammation, indicating that while UP-MV can protect lung tissue, the method of ventilation and support can influence inflammatory responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ultraprotective ventilation, extracorporeal carbon dioxide removal, and spontaneous breathing on lung morphofunction and inflammation in experimental severe acute respiratory distress syndrome. Güldner, A., Kiss, T., Bluth, T., et al.[2022]

Extracorporeal membrane oxygenation (ECMO) can significantly improve outcomes in severe ARDS cases, but its effectiveness is best when initiated early, as seen in this case where late initiation may have contributed to complications.

The combination of high-frequency oscillatory ventilation (HFOV) and pumpless arteriovenous extracorporeal lung assist (PECLA) can be beneficial for patients with CO2 retention issues, allowing for conventional ventilation to resume after ECMO therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High frequency oscillation, extracorporeal membrane oxygenation and pumpless arteriovenous lung assist in the management of severe ARDS. Banach, M., Soukup, J., Bucher, M., et al.[2020]

In a study involving 39 patients with severe ARDS on vv-ECMO, ultra-lung-protective ventilation did not lead to a reduction in inflammatory biomarkers compared to standard lung-protective ventilation, despite using significantly lower mechanical power.

There was a concerning trend towards higher 60-day mortality in the ultra-lung-protective group (45%) compared to the control group (17%), suggesting that this ventilation strategy may not be beneficial and requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultra-lung-protective ventilation and biotrauma in severe ARDS patients on veno-venous extracorporeal membrane oxygenation: a randomized controlled study. Guervilly, C., Fournier, T., Chommeloux, J., et al.[2022]

In a study of 11 severely burned patients with respiratory dysfunction, a lung-protective ventilation strategy significantly improved oxygenation, as indicated by an increase in the PaO2/FiO2 ratio from 193.54 to 327.14 after treatment.

Despite the improvement in respiratory function, the overall mortality rate was high, with 5 out of 11 patients dying, primarily due to renal failure and multiple organ dysfunction, highlighting the severity of their conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of the efficacy of lung-protective ventilation strategy in burn patients with respiratory dysfunction]. Cao, L., Liu, G., Deng, S.[2006]

Lung-protective mechanical ventilation is a safe and potentially beneficial strategy for patients without acute respiratory distress syndrome (ARDS), based on observational data and systematic reviews.

This ventilation approach includes specific principles such as using lower tidal volumes (4 to 8 ml/kg), maintaining plateau pressures below 30 cmH2O, and ensuring adequate oxygen levels, making it suitable for both perioperative and critical care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial ventilator settings for critically ill patients. Kilickaya, O., Gajic, O.[2021]

Conventional mechanical ventilation can worsen lung damage in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), leading to increased hypoxemia.

Implementing a protective ventilatory strategy, which uses limited volume and pressure during ventilation, can help prevent further lung injury and improve patient outcomes, particularly through the use of positive end-expiratory pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Protective ventilation strategy in the acute respiratory distress syndrome]. Bumbasirević, V., Bukumirović, V., Popović, N., et al.[2020]

In a study involving 19 pigs with induced acute respiratory distress syndrome, flow-controlled ventilation significantly improved oxygen levels (PaO2) and lung aeration compared to traditional volume-controlled ventilation, indicating its potential as a more effective lung-protective strategy.

Flow-controlled ventilation not only enhanced gas exchange but also reduced lung injury by decreasing alveolar wall thickness and cell infiltration, suggesting it could be a promising approach for managing patients with acute respiratory distress syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flow-Controlled Ventilation Attenuates Lung Injury in a Porcine Model of Acute Respiratory Distress Syndrome: A Preclinical Randomized Controlled Study. Schmidt, J., Wenzel, C., Spassov, S., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Risks and Benefits of Ultra-Lung-Protective Invasive Mechanical Ventilation Strategies with a Focus on Extracorporeal Support. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Effects of ultraprotective ventilation, extracorporeal carbon dioxide removal, and spontaneous breathing on lung morphofunction and inflammation in experimental severe acute respiratory distress syndrome. [2022]

3. Poland pubmed.ncbi.nlm.nih.gov

High frequency oscillation, extracorporeal membrane oxygenation and pumpless arteriovenous lung assist in the management of severe ARDS. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Ultra-lung-protective ventilation and biotrauma in severe ARDS patients on veno-venous extracorporeal membrane oxygenation: a randomized controlled study. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Analysis of the efficacy of lung-protective ventilation strategy in burn patients with respiratory dysfunction]. [2006]

6. England pubmed.ncbi.nlm.nih.gov

Initial ventilator settings for critically ill patients. [2021]

7. Serbia pubmed.ncbi.nlm.nih.gov

[Protective ventilation strategy in the acute respiratory distress syndrome]. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Flow-Controlled Ventilation Attenuates Lung Injury in a Porcine Model of Acute Respiratory Distress Syndrome: A Preclinical Randomized Controlled Study. [2023]