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

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ClinicalTrials.gov Identifier: NCT04467086
Recruitment Status : Recruiting
First Posted : July 10, 2020
Last Update Posted : May 20, 2021
Sponsor:
Collaborators:
Hamilton Health Sciences Corporation
Toronto General Hospital
University Health Network, Toronto
The Ottawa Hospital
McMaster University
Sinai Health System
Information provided by (Responsible Party):
Ottawa Hospital Research Institute

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.


Condition or disease Intervention/treatment Phase
Mechanical Ventilation Sedation Critical Illness COVID Drug: Propranolol Hydrochloride Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized Controlled Trial with 1:1 allocation (intervention and control group)
Masking: Single (Participant)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Propranolol as an Anxiolytic to Reduce the Use of Sedatives From Critically-ill Adults Receiving Mechanical Ventilation: An Open-label Randomized Controlled Trial (PROACTIVE)
Actual Study Start Date : December 11, 2020
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Control Arm - Usual Care
Participants in the control group will receive usual intravenous sedation according to practices already in place at each participating site (3 quaternary hospitals). 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.
Experimental: Intervention Arm - Propranolol hydrochloride
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

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.

Other Name: Teva-propranolol




Primary Outcome Measures :
  1. Primary sedative dose change [ Time Frame: 24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment) ]
    Change from baseline in total daily dose of primary sedative on Day 3


Secondary Outcome Measures :
  1. Sedation scores [ Time Frame: Daily upon enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first) ]
    Proportion of measured sedation scores within target range (to be defined a priori by treating team): Richmond Agitation-Sedation Scale and/or the Sedation-Agitation Scale

  2. Primary sedative dose [ Time Frame: Day 3 of study (60-84hrs after enrollment) ]
    Proportion of participants whose sedative dose on day 3 are below a minimum level (propofol <0.5mg/kg/h or midazolam <1.9mg/h)

  3. Total sedative daily dose change [ Time Frame: 24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment) ]
    Change from baseline in total daily dose of all sedatives (in mg of midazolam equivalents) on Day 3

  4. Total opioid daily dose change [ Time Frame: 24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment) ]
    Change from baseline in total daily dose of all opioids (in mcg of fentanyl equivalents) on Day 3

  5. Adverse event - bradycardia [ Time Frame: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first) ]
    Incidence of bradycardia (HR <50 or requiring intervention)

  6. Adverse event - hypotension [ Time Frame: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first) ]
    Incidence of hypotension (MAP <60 requiring new vasopressor agents or an increase of >0.1 mcg/kg/min of norepinephrine or epinephrine persisting more than 2h after reducing sedative doses)

  7. Adverse event - bronchospasm [ Time Frame: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first) ]
    Incidence of clinically-important bronchospasm requiring a change in mechanical ventilation settings

  8. Adverse event - ECG conduction delays [ Time Frame: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first) ]
    Incidence of new ECG conduction delays


Other Outcome Measures:
  1. Duration of propranolol use [ Time Frame: Daily from enrollment to study withdrawal/completion (last day of propranolol dose given; discharge from ICU, 28 days, or death - whichever is first) ]
    Total number of days of propranolol use

  2. Propranolol dose [ Time Frame: Day 3 of study (60-84hrs after enrollment) ]
    Mean propranolol dose on day 3

  3. Ventilator-free days [ Time Frame: Day 1 of admission to the intensive care unit until 30 days, discharge from intensive care, or death (whichever is first) ]
    Mean number of ventilator-free days in first 30 days of hospital intensive care unit admission

  4. Delirium-free days [ Time Frame: Day 1 of admission to the intensive care unit until 30 days, discharge from intensive care, or death (whichever is first) ]
    Mean number of delirium-free days in first 30 days of hospital intensive care unit admission, measured using the Intensive Care Delirium Screening Checklist

  5. Hospital Length of Stay [ Time Frame: Day 1 of hospital admission until hospital discharge date or date of death (whichever is first) ]
    Mean length of stay in hospital

  6. Intensive Care Unit Length of Stay [ Time Frame: Day 1 of intensive care unit admission until discharge date from intensive care unit or date of death (whichever is first) ]
    Mean length of stay in the intensive care unit

  7. Hospital Mortality [ Time Frame: Upon study completion (after all 108 participants have completed the study, estimated at 6 months) and after 50 patients have been enrolled (estimated at 3 months) ]
    Mortality rate among participants while in hospital

  8. Direct Costs [ Time Frame: Upon study completion (after all 108 participants have completed the study, estimated at 6 months) ]
    Mean cost of sedative medication used in the intensive care unit among the intervention and control arms



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04467086


Contacts
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Contact: James Downar, MDCM, MHSc 613-562-6262 ext 1502 jdownar@toh.ca
Contact: Julie Lapenskie, MSc 613-562-6262 ext 1498 jlapenskie@bruyere.org

Locations
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Canada, Ontario
Hamilton Health Sciences Centre - Hamilton General Hospital Not yet recruiting
Hamilton, Ontario, Canada, L8L2X2
Contact: Alison Fox-Robichaud, MD    (905) 525-9140 ext 22782    afoxrob@mcmaster.ca   
Principal Investigator: Alison Fox-Robichaud, MD         
The Ottawa Hospital Recruiting
Ottawa, Ontario, Canada, K1H8M8
Contact: James Downar, MDCM    6135626262 ext 1502    jdownar@toh.ca   
Contact: Julie Lapenskie, MSc    6135626262 ext 1498    jlapenskie@bruyere.org   
Principal Investigator: James Downar, MDCM         
Sponsors and Collaborators
Ottawa Hospital Research Institute
Hamilton Health Sciences Corporation
Toronto General Hospital
University Health Network, Toronto
The Ottawa Hospital
McMaster University
Sinai Health System
Investigators
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Principal Investigator: James Downar, MDCM Ottawa Hospital Research Institute
Publications:
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Responsible Party: Ottawa Hospital Research Institute
ClinicalTrials.gov Identifier: NCT04467086    
Other Study ID Numbers: 776228483
First Posted: July 10, 2020    Key Record Dates
Last Update Posted: May 20, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Ottawa Hospital Research Institute:
randomized clinical trial
phase III
propranolol
sedative use; sedative sparing
sedative shortages
critical care
cost savings
Additional relevant MeSH terms:
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Critical Illness
Disease Attributes
Pathologic Processes
Propranolol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents