Propranolol as an Anxiolytic to Reduce the Use of Sedatives From Critically-ill Adults Receiving Mechanical Ventilation: An Open-label Randomized Controlled Trial (PROACTIVE)

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.