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

Background and Rationale:

Critically ill patients often require sedation for comfort and to tolerate mechanical
ventilation. There are internationally accepted guidelines for sedation of critically ill
patients, and dexmedetomidine and propofol are recommended as sedative agents over
alternatives, such as benzodiazepines. There is now a worrying shortage of propofol in
Canada, the European Union, and parts of the US. The supply of dexmedetomidine, an expensive
alternative to propofol, is now considered to be at risk. It is unsuitable as monotherapy for
deep sedation, and most hospitals in Canada limit use to 48h, due to high costs. This
therefore makes it inadequate for COVID-19 treatment. Other sedative agents for mechanical
ventilation include benzodiazepines (e.g. midazolam), but these are associated with higher
mortality from sepsis, higher incidence of delirium, and longer length of stay in the ICU.
That notwithstanding, midazolam is also currently in short supply. Shortages of sedative
medications will be as impactful on critical care practice as shortages of mechanical
ventilators; propofol, midazolam, and dexmedetomidine were all listed on March 31, 2020 as
"Tier 3 Shortages" by Health Canada - having "the greatest potential impact on Canada's drug
supply and health care system….based on low availability of alternative supplies, ingredients
or therapies."

In critically-ill patients, the sympathetic nervous system can become hyperactive, producing
neurotransmitters such as norepinephrine (NE) to increase blood pressure and heart rate. In
the brain, a pontine nucleus called the locus ceruleus (LC) provides the majority of brain
NE. LC adrenergic input to the medial septal area and medial preoptic area of the forebrain
mediates arousal.

Sympatholytics have previously been prescribed to manage agitation in critical illness.
Dexmedetomidine is one such example, an intravenous alpha-2 agonist, which readily penetrates
the central nervous system. It has an anti-noradrenergic effect in the locus ceruleus,
consequently increasing inhibitory GABA neuron activity in the forebrain. Clonidine, is an
oral and intravenous agent that is highly lipid soluble, with good penetration of the Central
Nervous System, has been well studied in the ICU environment. However a recent meta-analysis
showed clonidine use did not reduce length of stay or length of ventilation for critically
ill patients, and only led to a small reduction in the use of opioids. Propranolol is a
non-selective beta-adrenergic antagonist, approved for treating hypertension, angina,
arrhythmias, migraines and pheochromocytoma in Canada. It has also been used off label to
treat anxiety disorders such as Post-Traumatic Stress Disorder. It is a lipophilic molecule,
crosses the blood brain barrier, and can block the locus ceruleus' ability to activate the
forebrain, similar to alpha 2 agonists. In rat models, propranolol delays arousal from a
state of anaesthesia.

An extensive search of PubMed and Web of Science did not reveal published trials of
propranolol as a sedative agent in critical illness or mechanical ventilation. However,
propranolol was shown to significantly reduce agitation in a randomized controlled trial in
patients with traumatic brain injury. Observational studies in traumatic brain injury have
shown that propranolol use is associated with a shorter length of hospital and ICU stay, and
possibly a lower mortality risk, without reports of significant side effects. A meta-analysis
of 10 randomized controlled trials in severely burned patients found propranolol reduced
hospital length of stay. Other studies have shown that propranolol may have beneficial
effects on catabolism in critical illness, and improve cardiac function and survival in
animal models of cardiac resuscitation. This study team published a single centre
retrospective study of 64 mechanically-ventilated patients which found that the initiation of
propranolol was associated with an 86% reduction in propofol dose, and an approximately 50%
reduction in midazolam dose, while maintaining the desired sedation target.

If propranolol reduces sedative doses required by mechanically ventilated patients (either
with or without COVID illness) to the degree seen in this team's retrospective study, this
would effectively reduce usage of sedatives two- to seven-fold. The cost of the average daily
dose of propranolol used in the retrospective study (~120mg) would be $0.27 (pharmacy cost at
The Ottawa Hospital), and propranolol is in abundant supply in Canada and around the world.

Based on this data, propranolol may enable critical care providers to sedate mechanically
ventilated patients using their usual approaches except with substantially lower doses of
sedatives. This would not only extend the use of currently limited supply of sedatives, it
would significantly reduce medication costs in critical care units in Canada and worldwide.

Trial Objective:

Does the addition of propranolol to a standard sedation regimen reduce the dose of sedative
needed in critically ill patients requiring mechanical ventilation?

Study Design:

Open-label, Randomized Controlled Trial (RCT), 1:1 allocation

Patient Population:

Participants are adult patients admitted to an intensive care unit who are anticipated to
require mechanical ventilation >48h, who are requiring intravenous sedatives to achieve a
sedation goal that is anticipated to be stable for >48h.

Intervention:

Patients randomized to the intervention arm will receive propranolol enterally at a starting
dose of 20mg every 6 hours for two to four doses, and then re-assessed for upwards titration
every 24 hours (+/- 6 hours) at 10mg dose increases depending on clinical response. The
maximum dose to be used in the intervention group is 60mg every 6 hours. The decision to
titrate propanolol will be made daily at rounds; this is why participants will receive 2-4
doses at 20mg (to accommodate for time from enrollment to rounds the next day) and titration
will occur every 24 hours +/- 6 hours (to accommodate rounds timing). Titration timing is
based on clinical rounds so that the decision to titrate can be made by the clinical team in
a way that aligns with their clinical workflows and reflects actual clinical practice in the
ICU.

Daily dose 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 <0.5mg/h). For each participant, the intervention will be
administered from enrollment until approximately 48h after the patient is liberated from the
mechanical ventilator, and the study will continue until death, ICU discharge, or 30 days
after enrollment, whichever is first. Enrollment can begin as early as 24h after the start of
a sedative infusion in the ICU.

Primary Outcome and Sample Size:

The primary outcome will be a comparison of the change in primary sedative dose from baseline
to Day #3 of the study in the intervention group compared with the same change in the control
group- the difference in differences. Given the global need for a substantial reduction in
sedative consumption for mechanically ventilated patients, we will assume that a 70%
reduction in sedative dose would be clinically meaningful, which corresponds to the
difference between the sedative infusion doses required for study eligibility (ie. propofol
>1.5 mg/kg/h) and the minimum doses below which propranolol would no longer be increased (ie.
propofol <0.5 mg/kg/h). Since we do not have (or know of) any data with which to estimate the
standard deviation of the change in sedative use, we base our sample size calculation on the
Cohen's d statistic (also known as the standardized effect size). The standardized effect
size is computed as the magnitude of the difference between groups divided by the pooled
standard deviation of the response measure (in our case, the change in sedative dose from
baseline to day 3). By widespread consensus, standardized effect sizes of 0.2, 0.5, and 0.8
are respectively considered to be small, moderate, and large effect sizes. Given we would
need to see at least a moderately large change in sedative use (decrease of 70%) to effect a
substantial improvement in the overall sedative supply, we choose to power our trial to
detect a standardized effect of 0.5. In order to have 80% power to detect such a minimal
clinically important difference, we require a total of 32 participants in each study arm. in
a 1:1 randomized controlled trial. Allowing a 10% dropout rate (a previous study of sedation
strategies at these sites reported a dropout rate of 3%30), we will aim to enroll 72 patients
(36 control; 36 intervention).

Statistical Analysis:

The primary outcome will be analyzed as a difference in differences- the change in sedative
dose from baseline to Day #3 (defined as the 24h period starting 60h after enrollment) in the
intervention group vs 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, as well as the
secondary outcomes that relate to sedative dosing on Day #3 compared to baseline. For
secondary outcomes, groups will be compared using unpaired statistical tests- Chi-square for
proportions, and unpaired t-tests or Mann-Whitney tests as appropriate for parametric and
non-parametric data. The effect of age, sex and gender, and pre-ICU beta-blocker prescription
will be analyzed as planned subgroup analyses.

Ethical Considerations:

A No Objection Letter from Health Canada and Research Ethics Board approval have been
obtained to conduct this clinical trial. An established data safety monitoring committee
(DSMC) will evaluate adverse events. Two interim safety analyses will be conducted by the
DSMC and the study will be terminated if the DSMC determines the risk of adverse events,
based on the rate of adverse events reported in this clinical trial to the committee,
outweighs the potential benefits. Informed consent will be obtained from each participant or
their legal substitute decision maker.