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

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.

Conditions

• Mechanical Ventilation
• Sedation
• Critical Illness
• COVID

Interventions

DRUG

Propranolol Hydrochloride

Propranolol enterally at a starting dose of 20mg every 6h for 2-4 doses, and then re-assessed for upwards titration every 24 hours (+/- 6 hours) at 10mg dose increases depending on clinical response. Maximum dose of 60mg every 6h. Titration decision to be made by clinical team at daily rounds. Daily titration will be guided by hemodynamic markers indicative of the expected sympatholysis from propranolol. Upward titration of propranolol should coincide with a downward titration in sedatives until a minimum level of sedative infusion is reached (propofol \<0.5mg/kg/h or midazolam \<1.0mg/h). Nurses will be instructed at each assessment to determine if sedative targets can be achieved with lower doses of sedatives. Daily upward titration of propranolol will be recommended if none of these conditions are met: (1)HR\<70 beats/min, (2) Mean Arterial Pressure \<70 mmHg or (3) norepinephrine or equivalent vasopressor dose increase to \>0.15 mcg/kg/min.

Sponsors & Collaborators

• Hamilton Health Sciences Corporation

  collaborator OTHER

• The Ottawa Hospital

  collaborator OTHER

• McMaster University

  collaborator OTHER

• Sinai Health System

  collaborator OTHER

• Ottawa Hospital Research Institute

  lead OTHER

Principal Investigators

• James Downar, MDCM · Ottawa Hospital Research Institute

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

PARALLEL

Eligibility

Min Age

19 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-01-08

Primary Completion

2022-11-30

Completion

2022-11-30

Countries

• Canada

Study Locations