Propranolol as an Anxiolytic to Reduce the Use of Sedatives From Critically-ill Adults Receiving Mechanical Ventilation

• Status: Recruiting
• Trial end date: 2021-07-01
• Target enrollment: 0
• Participant gender: All

Summary

The COVID-19 pandemic has led to shortages of intravenous sedatives due to increased ICU patient admissions and greater use of mechanical ventilation. A shortage of sedatives is as concerning as a shortage of mechanical ventilators since critically ill patients require sedation for comfort and to tolerate mechanical ventilation. Anti-adrenergic medications are increasingly recognized for their role in sedation of critically ill patients. Propranolol is a plentiful and inexpensive, non-selective beta-adrenergic blocker with good penetration of the blood-brain barrier, which can reduce agitation and arousal. The study team published a single-centre retrospective study of 64 mechanically-ventilated patients which found the initiation of propranolol was associated with an 86% reduction in propofol dose and a roughly 50% reduction in midazolam dose while maintaining the same level of sedation. Propranolol has the potential to mitigate the threat posed by worldwide sedative shortages and improve critical care management of patients who require mechanical ventilation.

This study seeks to evaluate whether the addition of propranolol to a standard sedation regimen reduces the dose of sedative needed in critically ill patients requiring mechanical ventilation. This study is an open-label randomized controlled trial, single-blinded with 1:1 allocation. Both arms will receive sedation according to usual intensive care unit practice with a sedative agent. The intervention arm will additionally receive enteral propranolol 20-60mg q6h titrated up over 24-48h until intravenous sedative doses have fallen to a minimal level (propofol <0.5mg/kg/h or midazolam <0.5mg/h) or the maximum dose of propranolol is reached. Intravenous sedative doses will be titrated downwards in response to sympatholysis produced by the propranolol, as evidenced by a decreasing heart rate or blood pressure. The control arm will receive sedation without the addition or propranolol.

The primary outcome will be the change in primary sedative dose from baseline to Day 3 of enrollment. Analysis of the primary outcome will be a difference in differences; the change in sedative dose from baseline to Day 3 in the intervention group versus the same change in the control group. The Mann-Whitney U test will be used as a nonparametric test of independent samples for this outcome.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Ottawa Hospital Research Institute
• Collaborators: Hamilton Health Sciences Corporation; McMaster University; Sinai Health System; The Ottawa Hospital; Toronto General Hospital; University Health Network, Toronto
• Treatments: Propranolol

Criteria

Inclusion Criteria:

• Adult patients admitted to an intensive care unit requiring mechanical ventilation and anticipated to require mechanical ventilation >48h

• Patient has a sedation target (e.g. using the Richmond Agitation Sedation Scale or Sedation Agitation Scale) that is anticipated to be stable >48h

• Minimum sedative infusion doses (any one of):

• Propofol >1.5 mg/kg/h >24h

• Midazolam >1.5 mg/h >24h

Exclusion Criteria:

• Sedation for paralysis

• Use of neuromuscular blocking agents (patients may be eligible once these are discontinued)

• Asthma or known reactive airways disease

• 1st, 2nd or 3rd-degree heart block (with no permanent pacemaker) at the time of screening

• Known history of congestive heart failure with ejection fraction <20%

• Hypotension requiring vasopressor support above the following levels

• Norepinephrine dose >0.15mcg/kg/min

• Epinephrine dose >0.15 mcg/kg/min

• Phenylephrine >1.4 mcg/kg/min

• Pregnancy or lactation

• Allergy to propranolol

• Unable to obtain informed consent from patient or substitute decision maker

• Patients on chronic betablockers are eligible for enrolment. Patients allocated to the intervention arm will have their betablocker replaced with propranolol. Once propranolol is discontinued, the treating team may resume their usual betablocker. Control patients may continue their usual betablocker (unless it is propranolol) at the treating team's discretion.