SedAting With Volatile Anesthetics Critically Ill COVID-19 Patients in ICU: Effects On Ventilatory Parameters And Survival (SAVE-ICU)

April 25, 2023 updated by: Sunnybrook Health Sciences Centre

SedAting With Volatile Anesthetics Critically Ill COVID-19 Patients in ICU: Effects On Ventilatory Parameters And Survival. Multicentre Open-label, Pragmatic, Randomized Controlled Trial and a Parallel Prospective (Non-randomized) Cohort Study

Patients suffering lung failure, possibly from COVID-19 or hypoxic lung failure, will need life-saving support from a breathing machine. Any patient needing this support requires drugs to keep them sleepy, or "sedated" to be comfortable on this machine. Sedation is made possible by using drugs given through a vein. Unfortunately, these drugs are in short supply worldwide due to the high number of COVID-19 patients needing these machines.

Another way to provide sleep is by using gases that are breathed in. These are used every day in operating rooms to perform surgery. These gases, also called "inhaled agents" can also be used in intensive care units and may have several important benefits for patients and the hospital. Research shows they may reduce swelling in the lung and increase oxygen levels, which allows patients to recover faster and reduce the time spent on a breathing machine. In turn, this allows the breathing machine to be used again for the next sick patient. These drugs may also increase the number of patients who live through their illness. Inhaled agents are widely available and their use could dramatically lesson the pressure on limited drug supplies.

This research is a study being carried out in a number of hospitals that will compare how well patients recover from these illnesses depending on which type of sedation drug they receive. The plan is to evaluate the number who survive, their time spent on a breathing machine and time in the hospital. This study may show immediate benefits and may provide a cost effective and practical solution to the current challenges caring for patients and the hospital space, equipment and drugs to the greatest benefit. Furthermore, the study will be investigating inflammatory profile and neuro-cognitive profiles in ventilated patients. Finally, this trial will be a team of experts in sedation drugs who care for patients with proven or suspected COVID-19 who need lifesaving treatments.

Study Overview

Detailed Description

Multicentre open-label, pragmatic, randomized controlled trial and a parallel prospective (non-randomized) cohort study conducted in ICUs and ICU enabled environments caring in critically ill COVID-19 and non-COVID hypoxic respiratory failure patients.

Participants will be mechanically ventilated and will be variably randomized, within 72 hours of start of sedation treatment, in a 1:1 ratio to either an intravenous or inhaled volatile-based sedation arm depending on availability of sedative drugs for both arms. Stratification will be done by:

  1. Age ≥ 65 years
  2. participating centre
  3. PaO2/FiO2 ratio of 150

Patients who cannot be randomized (due to technical or resource issues in some areas of the hospital) will be entered into the parallel prospective (non-randomized) cohort study and will receive intravenous or inhaled sedation as able in their designated unit.

Sedation will be administered according to standard sedation practice and in keeping with current guidelines.

Participants will be followed:

  • daily in ICU until 30 days after enrollment, ICU discharge or death, whichever occurs first;
  • at 30 days after last dose of drug administration by telephone or through the hospital healthcare database;
  • at 60 days, 90 days, and 365 days after enrollment by telephone and/or through data linkages with a provincial or hospital or state healthcare database;
  • Participants will have the option to participate in the neuro-cognitive and / or biomarker assessments

Study Type

Interventional

Enrollment (Anticipated)

758

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Alberta
      • Edmonton, Alberta, Canada, T6G 2B7
        • Recruiting
        • University of Alberta Hospital
        • Contact:
        • Principal Investigator:
          • Michael Jacka, MD
    • Ontario
      • London, Ontario, Canada, N6A 5A5
        • Recruiting
        • London Health Sciences Centre - University Hospital
        • Principal Investigator:
          • Marat Slessarev, MD
      • London, Ontario, Canada
        • Recruiting
        • London Health Sciences Centre - Victoria Hospital
        • Contact:
        • Principal Investigator:
          • Marat Slessarav, MD
      • Ottawa, Ontario, Canada
        • Recruiting
        • The Ottawa Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Johnathan Hooper, MD
      • Toronto, Ontario, Canada, M4N3M5
        • Recruiting
        • Sunnybrook Health Sciences Centre
        • Contact:
        • Principal Investigator:
          • Angela Jerath, MD
      • Toronto, Ontario, Canada, M5G 2C4
        • Recruiting
        • University Health Network - Toronto General Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Ewan Goligher, MD
      • Toronto, Ontario, Canada, M5T 2S8
        • Recruiting
        • University Health Network - Toronto Western Hopsital
        • Contact:
        • Principal Investigator:
          • Ian Randall, MD
        • Contact:
    • Quebec
      • Montréal, Quebec, Canada, H2X 3E4
        • Recruiting
        • Centre Hospitalier de l'Universite de Montreal
        • Principal Investigator:
          • François-Martin Carrier, MD
        • Contact:
      • Montréal, Quebec, Canada, H4A 3J1
        • Recruiting
        • McGill University Health Centre - Royal Victoria Hospital
        • Contact:
        • Principal Investigator:
          • Roupen Hatzakorzian, MD
      • Montréal, Quebec, Canada, H4J1C5
        • Recruiting
        • Hopital Sacre-Coeur de Montreal
        • Contact:
        • Principal Investigator:
          • Alexandros Cavayas, MD
      • Québec, Quebec, Canada, G1V 4G5
        • Active, not recruiting
        • Institut Universitaire de Cardiologie et de Pneumologie de Quebec (IUCPQ)
      • Sherbrooke, Quebec, Canada, J1K 2R1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. ≥ 18 years of age
  2. Mechanically ventilated and expected to remain mechanically ventilated at the end of the next day
  3. Receiving IV sedation by infusion or bolus for ≤72 hours to facilitate mechanical ventilation Transferred patients with escalating ventilation needs are eligible for recruitment within ≤72 hours of sedation commenced within the participating trial site that they were transferred to.

Note: Intravenous sedation required to support mechanical ventilation includes use of one or more of the following agents: benzodiazepines, propofol, ketamine, barbiturates, alpha-2 agonist, opioids. Patients receiving intravenous opioids only i.e., fentanyl ≥ 50mcg/hour, hydromorphone ≥ 0.4mg/hour (or bolus q1h) for analgesia and sedation or agitation to assist mechanical ventilation are eligible for inclusion.

4. a) Proven or suspected (under investigation) COVID-19, or b) COVID-19 negative patients who have a PaO2FiO2 ratio ≤300 measured with arterial blood gas at least once during the 12 hours prior to enrollment.

Exclusion Criteria:

  1. Contraindications to sedatives, such as propofol infusion syndrome or malignant hyperthermia;
  2. Known allergy to any of the ingredients or components of the investigational products; sevoflurane or isoflurane;
  3. Suspect or evidence of high intracranial pressure;
  4. Severe brain injury that is likely to lead to sustained very low conscious levels or vegetative state
  5. Severe neuromuscular disorder for example amyotrophic lateral sclerosis, Gullian Barre Syndrome that are the primary cause of needing ICU admission and mechanical ventilation
  6. One-lung ventilation or pneumonectomy;
  7. Ideal estimated tidal volume too low for delivery of inhaled agents. Target (6ml/kg) < 200ml;
  8. Use of inhaled prostacyclin which is contraindicated in the presence of a miniature vaporizer (i.e., Anesthesia Conserving Device). This agent has a high viscosity that leads to poor vaporization of the volatile agent. Note: Other inhaled pulmonary vasodilators such as nitric oxide can be safely administered in the presence of miniature vaporizers. Use of prostacyclin is permissible with an anesthesia machine and MADM;
  9. Known pregnancy
  10. Moribund patient not expected to survive >12 hours

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Inhaled - volatile anesthetic
The ICU patient will be randomized to either Isoflurane or Sevoflurane, whichever is available at the hospital. Dosage will be modified as per health care team guidance for the best treatment of the participant.
Isoflurane will be administered using an inhalation device
Sevoflurane will be administered using an inhalation device
No Intervention: Standard Care
The ICU patient will be randomized to standard of care, which is any IV sedation supplied by the hospital. Dosage will be modified as per health care team guidance for the best treatment of the participant.
No Intervention: Non-randomized
In this arm, ICU patients who cannot be randomized will receive inhaled or IV sedation as per available in their unit. This is done to try to obtain the maximum amount of information available from the patients present to our ICUs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hospital Mortality
Time Frame: 2 years
Does the use of inhaled volatile anesthetic-based sedation regimen improve participant hospital mortality as compared to standard intravenous sedation regimen with a 10% difference between groups for 752 participants.
2 years
Ventilator-Free Days
Time Frame: 30 days
Does the use of inhaled volatile anesthetic-based sedation regimen improve participant ventilation outcomes after 30 days post enrollment, as compared to standard intravenous sedation regimen for 200 participants
30 days
ICU-Free Days
Time Frame: 30 days
Does the use of inhaled volatile anesthetic-based sedation regimen improve participant time spent in ICU, 30 days post enrollment, as compared to standard intravenous sedation regimen for 128 participants
30 days
Participant Quality of Life at 3 and 12 months after discharge
Time Frame: 365 days
Does the use of inhaled volatile anesthetic-based sedation regimen improve participant quality of life outcomes at 3 and 12 months post discharge as compared to standard intravenous sedation regimen for 144 participants. The EQ-5D questionnaire will be completed at both time points
365 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Median Daily Oxygenation
Time Frame: 3 days
To evaluate participant median daily oxygenation (PaO2/FiO2) at 3 days post enrollment
3 days
Delirium and Coma Free Days
Time Frame: 14 days
To evaluate the days alive and free from delirium and coma while in ICU for 14 days after enrollment
14 days
Adjunctive ARDS therapies
Time Frame: 30 days
To evaluate participant need for adjunctive ARDS therapies (prone, nitric oxide, paralysis, ECMO) during ICU stay
30 days
Hospital-Free Days
Time Frame: 60 days
To evaluate the number of hospital-free days for participants, 60 days after enrollment
60 days
Disability
Time Frame: 365 days
To evaluate participant disability at 3 and 12 months post discharge. The World Health Organization Disabiltity Assessment Score (WHODAS 2.0) will be completed at both timepoints. The scores assigned to each of the items - "none" (0), "mild" (1) "moderate" (2), "severe" (3) and "extreme" (4) - are summed. This method is referred to as simple scoring because the scores from each of the items are simply added up without recoding or collapsing of response categories; thus, there is no weighting of individual items.
365 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 15, 2020

Primary Completion (Anticipated)

June 15, 2024

Study Completion (Anticipated)

June 15, 2025

Study Registration Dates

First Submitted

June 2, 2020

First Submitted That Met QC Criteria

June 2, 2020

First Posted (Actual)

June 4, 2020

Study Record Updates

Last Update Posted (Actual)

April 27, 2023

Last Update Submitted That Met QC Criteria

April 25, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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