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

NCT04467086 | Completed Phase 3 DMC

• 1 other identifier: 776228483
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

Brief 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

Keywords

randomized clinical trial; phase III; propranolol; sedative use; sedative sparing; sedative shortages; critical care; cost savings

Outcome Measures

Primary Outcomes (1)

• Primary sedative dose change

  Change from baseline in total daily dose of primary sedative on Day 3

  24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment)

Secondary Outcomes (8)

• Sedation scores

  Daily upon enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

• Primary sedative dose

  Day 3 of study (60-84hrs after enrollment)

• Total sedative daily dose change

  24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment)

• Total opioid daily dose change

  24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment)

• Adverse event - bradycardia

  Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

Other Outcomes (8)

• Duration of propranolol use

  Daily from enrollment to study withdrawal/completion (last day of propranolol dose given; discharge from ICU, 28 days, or death - whichever is first)

• Propranolol dose

  Day 3 of study (60-84hrs after enrollment)

• Ventilator-free days

  Day 1 of admission to the intensive care unit until 30 days, discharge from intensive care, or death (whichever is first)

Study Arms (2)

Control Arm - Usual Care

NO INTERVENTION

Participants in the control group will receive usual intravenous sedation according to practices already in place at each participating site. The choice of agent, route of delivery, method of monitoring, and target levels of sedation will be determined by the treating team; however, we will recommend best practice clinical guidelines be followed. Current guidelines recommend "analgesia first" sedation titrated to relief of pain and dyspnea and sedative infusions if need for anxiety or agitation titrated to a prescribed level of sedation using a validated sedation scale. Patients may receive adjunct sedative/analgesic medications (e.g., enteral benzodiazepines) but propranolol use in the control group will be considered a protocol violation.

Intervention Arm - Propranolol hydrochloride

EXPERIMENTAL

Participants in the control arm will received sedation as described for the control arm, but with the addition of propranolol hydrochloride (titrated up as described under "Intervention Description") and a corresponding reduction in sedatives as appropriate and described under "Intervention Description".

Drug: Propranolol Hydrochloride

Interventions

Propranolol Hydrochloride DRUG

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.

Also known as: Teva-propranolol

Intervention Arm - Propranolol hydrochloride

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \>/=3.0 mg/h \>24h

You may not qualify if:

• Sedation for paralysis
• Use of neuromuscular blocking agents (patients may be eligible once these are discontinued)
• Asthma or known reactive airways disease
• st, 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%
• HR\<60 bpm at baseline
• Hypotension requiring vasopressor support above the following levels
• Norepinephrine dose \>0.15mcg/kg/min or equivalent (\>0.15mcg/kg/min epinephrine; \>22.5 mcg/kg/min dopamine; \>0.06 U/min vasopressin)
• Phenylephrine \>2.0 mcg/kg/min
• Receiving 3 or more vasopressors, regardless of dose
• Pregnancy or lactation
• Allergy to propranolol
• Patients for whom an enteral route of drug administration is not available
• Patients who are on digoxin, diltiazem, or verapamil
• 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.

Sponsors & Collaborators

• Ottawa Hospital Research Institute: lead
• Hamilton Health Sciences Corporation: collaborator
• The Ottawa Hospital: collaborator
• McMaster University: collaborator
• Sinai Health System: collaborator

Study Sites (2)

Hamilton Health Sciences Centre - Hamilton General Hospital

Hamilton, Ontario, L8L2X2, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, K1H8M8, Canada

Location

Related Publications (5)

• Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001 May;27(5):859-64. doi: 10.1007/s001340100909.

  PMID: 11430542 BACKGROUND

• Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002 Nov 15;166(10):1338-44. doi: 10.1164/rccm.2107138.

  PMID: 12421743 BACKGROUND

• Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999 Jul;27(7):1325-9. doi: 10.1097/00003246-199907000-00022.

  PMID: 10446827 BACKGROUND

• Downar J, Lapenskie J, Kanji S, Watpool I, Haines J, Saeed U, Porteous R, Polskaia N, Burry L, Himed S, Anderson K, Fox-Robichaud A. Propranolol As an Anxiolytic to Reduce the Use of Sedatives for Critically Ill Adults Receiving Mechanical Ventilation (PROACTIVE): An Open-Label Randomized Controlled Trial. Crit Care Med. 2025 Feb 1;53(2):e257-e268. doi: 10.1097/CCM.0000000000006534. Epub 2025 Feb 21.

  PMID: 39982178 DERIVED

• Bertolini F, Robertson L, Bisson JI, Meader N, Churchill R, Ostuzzi G, Stein DJ, Williams T, Barbui C. Early pharmacological interventions for prevention of post-traumatic stress disorder (PTSD) in individuals experiencing acute traumatic stress symptoms. Cochrane Database Syst Rev. 2024 May 20;5(5):CD013613. doi: 10.1002/14651858.CD013613.pub2.

  PMID: 38767196 DERIVED

MeSH Terms

Conditions

Critical Illness

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Study Officials

• James Downar, MDCM

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will be masked to intervention versus control group allocation. Care providers (including investigators) cannot be masked due to the need to titrate propranolol and sedative doses according to patient condition in the intervention arm. Similarly, outcomes assessors will be recording the daily and total doses of propranolol received by each participant, and thus cannot be blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized Controlled Trial with 1:1 allocation (intervention and control group)

Study Record Dates

• First Submitted: June 30, 2020
• First Posted: July 10, 2020
• Study Start: January 8, 2021
• Primary Completion: November 30, 2022
• Study Completion: November 30, 2022
• Last Updated: December 5, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2)