Patients suffering lung failure, possibly from COVID-19 or hypoxic lung failure, willneed life-saving support from a breathing machine. Any patient needing this supportrequires 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 drugsare in short supply worldwide due to the high number of COVID-19 patients needing thesemachines.Another way to provide sleep is by using gases that are breathed in. These are used everyday in operating rooms to perform surgery. These gases, also called "inhaled agents" canalso be used in intensive care units and may have several important benefits for patientsand the hospital. Research shows they may reduce swelling in the lung and increase oxygenlevels, which allows patients to recover faster and reduce the time spent on a breathingmachine. In turn, this allows the breathing machine to be used again for the next sickpatient. These drugs may also increase the number of patients who live through theirillness. Inhaled agents are widely available and their use could dramatically lesson thepressure on limited drug supplies.This research is a study being carried out in a number of hospitals that will compare howwell patients recover from these illnesses depending on which type of sedation drug theyreceive. The plan is to evaluate the number who survive, their time spent on a breathingmachine and time in the hospital. This study may show immediate benefits and may providea cost effective and practical solution to the current challenges caring for patients andthe hospital space, equipment and drugs to the greatest benefit. Furthermore, the studywill be investigating inflammatory profile and neuro-cognitive profiles in ventilatedpatients. Finally, this trial will be a team of experts in sedation drugs who care forpatients with proven or suspected COVID-19 who need lifesaving treatments.
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
Drug: Isoflurane Inhalant Product
Isoflurane will be administered using an inhalation device
Drug: Sevoflurane inhalant product
Sevoflurane will be administered using an inhalation device
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. Mechanically ventilated patients +/- extracorporeal membrane oxygenation
(extracorporeal life) support with:
1. Proven or suspected (under investigation) COVID-19, or
2. 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.
Note: If arterial blood gas measurement is unavailable, the PaO2 can be imputed from the
pulse oximetry measurement
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
University of Alberta Hospital
Edmonton, Alberta, Canada
Grey Nuns Community Hospital
Edmonton, Alberta, Canada
London Health Sciences Centre - University Hospital
London, Ontario, Canada
London Health Sciences Centre - Victoria Hospital
London, Ontario, Canada
The Ottawa Hospital
Ottawa, Ontario, Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
University Health Network - Toronto General Hospital
Toronto, Ontario, Canada
University Health Network - Toronto Western Hopsital
Toronto, Ontario, Canada
Centre Hospitalier de l'Université de Montréal
Montréal, Quebec, Canada
McGill University Health Centre - Royal Victoria Hospital
Montréal, Quebec, Canada
Hôpital Sacré-Coeur de Montréal
Montréal, Quebec, Canada
Institut Universitaire de Cardiologie et de Pneumologie de Quebec (IUCPQ)
Québec, Quebec, Canada
Universite de Sherbrooke
Sherbrooke, Quebec, Canada
Angela Jerath, MD
416.480.6100
angela.jerath@sunnybrook.ca
Iman Hussain
SAVE-ICU@sunnybrook.ca