Non-invasive Ventilation and Dex in Critically Ill Adults

Study Overview
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Brief Summary
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Non-Invasive ventilation (NIV) is a life saving intervention for patients with acute respiratory failure (ARF). Some patients are not able to tolerate the NIV intervention and ultimately fail, requiring the use of invasive mechanical ventilation (IMV) and intubation. Sedation may improve a patient's NIV tolerance. However, this practice has not been adopted by intensivists as the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents of sedative use in NIV. The Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: a Vanguard Pragmatic Randomized Controlled Trial (inDEX) is looking to evaluate the effectiveness of dexmedetomidine compared to placebo in reducing non-invasive ventilation failures in patients admitted to the hospital with acute respiratory failure. The results from this pilot trial, will subsequently inform a large, pragmatic, powered trial to definitively address the question.

Detailed Description
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BACKGROUND: Non-invasive ventilation (NIV) is a life-saving intervention for patients with acute respiratory failure (ARF). Patients may find NIV intolerable and ultimately fail NIV requiring intubation and invasive mechanical ventilation (IMV). Sedation may improve a patient's NIV tolerance. However, this practice has not been adopted by intensivists as the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents of sedative use in NIV. Current guidelines lack recommendations on which sedative, if any at all, should be used during NIV due to the paucity of reliable data. Dexmedetomidine (dex) is a relatively new sedative. It promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and when compared to γ-aminobutyric acid receptor agonists like benzodiazepines, reduces delirium. Dex has been recommended to use over benzodiazepines for sedation during IMV in critically ill adults, particularly if delirium is precluding weaning. HYPOTHESIS: We hypothesize that dexmedetomidine, when compared to placebo, reduces NIV failure in hospitalized adults with acute respiratory failure and agitation or NIV intolerance. OBJECTIVES: To evaluate the feasibility of assessing if dexmedetomidine compared to placebo results in a reduction of non-invasive ventilation failure in patients admitted to the hospital with acute respiratory failure. This will subsequently inform a large, pragmatic, powered trial to definitively address the question. METHODS 4.1 Study design: The inDEX trial is a pragmatic, international, multi-centered, stratified, randomized, parallel-group, double-blind, placebo-controlled vanguard trial. Patients, investigators, healthcare team, data collectors, outcome assessors, and the statistician will be blinded to trial arms. 4.2 Allocation and randomization: Local Research Coordinators (RC) will randomize eligible patients in a fixed 1:1 allocation using undisclosed variable block sizes of four, six, or eight. The randomization will be achieved using a random number sequence prepared by an independent statistician. The independent statistician will have access to the random number sequence and it will be provided to the research pharmacist. Upon request by the local research coordinator, the research pharmacist will provide the care team with either placebo or dexmedetomidine, according to the randomization schedule. 4.3 Blinding: Both dexmedetomidine and normal saline placebo will be given as continuous infusion. To minimize performance and ascertainment biases, and maintain blinding of patients, investigators, clinical staff, and RCs; a Research Pharmacist, who is not involved in assessment of patient outcomes or patient care, will prepare infusion bags. Titration of the infusion rate for both arms will follow an identical volume-based titration algorithm. Despite optimal blinding efforts, it is possible that the care team may be able to determine who is receiving dexmedetomidine based on improvement in NIV tolerance and/or the decrease in heart rate and blood pressure. However, the cointerventions may also improve tolerance, and can certainly cause a reduction in heart rate and blood pressure.

Official Title
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Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: a Vanguard Pragmatic Randomized Controlled Trial (inDEX Trial)

Conditions
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Respiratory Insufficiency

Intervention / Treatment
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* Drug: Dexmedetomidine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Patient receiving any NIV modality for acute respiratory failure of any etiology Admitted to ICU, PACU, step-down unit (surgical or medical), or emergency department Presence of one or more of the following after optimized NIV treatment Agitation (Defined as a Richmond Agitation and Sedation Scale [RASS] score of ≥+2 or a Riker Sedation-Agitation Scale [SAS] score of ≥5) Patient expresses intolerance or requests removal of NIV secondary to self-reported discomfort, anxiety, or claustrophobia Other reason that the physician feels the patient is intolerant of NIV or agitated, not captured above (all reasons will be recorded) Exclusion Criteria: Absence of a functioning pacemaker with one of the following: a-Persistent bradycardia defined as a heart rate (HR) ≤50bpm; b-Second or third-degree heart block; or c- Tachybrady syndrome Persistent hypotension, defined as a mean arterial pressure (MAP) ≤60mmHg despite volume resuscitation and vasopressors Acute hepatic failure Known allergy to dexmedetomidine Pregnancy Acute withdrawal from drugs or alcohol Patients with post-extubation respiratory failure Imminent need for endotracheal intubation Death is deemed imminent and inevitable Patient's goals of care do not include intubation and IMV Patients already on dexmedetomidine at time of enrollment Previously enrolled in the inDEX trial Treating physician refuses enrollment (reasons for refusal will be captured)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The inDEX trial is a pragmatic, international, multi-centered, stratified, randomized, parallel-group, double-blind, placebo-controlled vanguard trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine Intervention<br>Patients randomized to the experimental arm will receive dexmedetomidine. At initiation, a bolus will NOT be administered. In keeping with Health Canada. Guidelines, the infusion will start at a mid-range dose of 0.6mcg/kg/h with titration either up or down by 0.1mcg/kg/h every 20-30 minutes to a maximum rate of 1.2mcg/kg/h to maintain light sedation (Richmond Agitation-Sedation Scale [RASS] = -2 to +1 or Riker Sedation-Agitation Scale [SAS] 3-4). | Drug: Dexmedetomidine<br>* Dexmedetomidine is an α2-adrenergic agonist sedative commonly used in invasive mechanical ventilation that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and when compared to γ-aminobutyric acid receptor agonists like benzodiazepines, reduces delirium.<br>* Other names: Precedex;|
| Placebo Comparator: Control Intervention<br>Those in the control group will receive a placebo that is identical in colour and packaging and at equal volume to the intervention group. Each bag of placebo contains 50mL of 0.9% sodium chloride and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans. | Other: Placebo<br>* Normal saline placebo will be given as continuous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment Rate | The rate in which patients are enrolled, by calculating the mean number of recruited patients compared to the number of patients screened. | At the completion of the trial (approximately 1 year). | 
| Protocol Adherence; Proportion of patients assigned to the experimental arm that received the intervention and those assigned to the control arm that did not receive the intervention. | Adherence will be calculated as the proportion of patients assigned to the experimental arm that received the intervention and those assigned to the control arm that did not receive the intervention. | At the completion of the trial (approximately 1 year). | 
| Consent Rate | The consent rate will be calculated as the overall proportion of substitute decision makers or patients who consented to be enrolled out of those approached. | At the completion of the trial (approximately 1 year). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute care unit outcomes; Non-invasive ventilation (NIV) failure | Number of participants with NIV failure defined as the patients undergoing invasive mechanical ventilation within 28-post randomization. | 28 days post-randomization. | 
| Acute care unit outcomes; Acute Care Unite Length of Stay | Acute Care Unite Length of Stay is defined as the number of days the patient is admitted to an Acute Care Unit while admitted to the hospital. | 60 days post-randomization. | 
| Acute care unit outcomes; Duration of invasive mechanical ventilation | Duration of invasive mechanical ventilation during hospital stay is defined as the number of days the patient received invasive mechanical ventilation at 60 days post-randomization. | 60 days post-randomization. | 
| Acute care unit outcomes; Ventilation free Days | Ventilation free days is defined as the number of days the patient did not receive and ventilation during hospital stay truncated at 28 days (either invasive mechanical ventilation or NIV). | 28 days post-randomization. | 
| Process Outcomes; Number of patient-initiated device removal episodes. | Number of patient-initiated device removal episodes will be defined as the number of times a patient attempts to remove their device while receiving NIV. | 4 days post-randomization. | 
| Process Outcomes; Richmond-Agitation Sedation Scale (RASS) measurements | The proportion of RASS measurements in target range while on the trial drugs while receiving NIV. | 4 days post-randomization. | 
| Process Outcomes; The mean NIV tolerance score. | The mean NIV tolerance score will be defined as the proportion of tolerance scores that indicate that the patient is comfortable and relaxed while receiving NIV. | 4 days post-randomization. | 
| Process Outcomes; Days spent with delirium | Days spent with delirium will be defined as the number of days that the patient experienced delirium during and after receiving NIV while admitted to the hospital. | 28 days post-randomization. | 
| Process Outcomes; Cointerventions | The use and dose of any cointerventions (i.e. benzodiazepines, opioids, and antipsychotics) during NIV treatment. | 4 days post-randomization. | 
| Hospital Outcomes; Hospital length of stay | Hospital Length of stay is defined at the total number of days the patient spent in the hospital. | 60 days post-randomization. | 
| Hospital Outcomes; Mortality | Mortality is defined at the number of deaths that occur between randomization and 60-Day post-randomization. | 60 days post-randomization. | 
| Adverse Events: Bradycardia | Adverse events will be defined as; bradycardia (heart rate <60 bpm). | 60 Days post-randomization | 
| Adverse Events: Severe bradycardia | Adverse events will be defined as; severe bradycardia (heart rate <50 bpm). | 60 Days post-randomization | 
| Adverse Events: Clinically significant bradycardia | Adverse events will be defined as; clinically significant bradycardia (bradycardia requiring inotropes, vasopressors, external pacing, temporary pacemaker, or discontinuation of the trial medication). | 60 Days post-randomization | 
| Adverse Events: hypotension | Adverse events will be defined as; hypotension (mean arterial pressure < 60mmHg, or >20mmHg below admission baseline). | 60 Days post-randomization | 
| Adverse Events: clinically significant hypotension | Adverse events will be defined as; clinically significant hypotension (hypotension requiring vasopressors, fluid administration, or discontinuation of the trial medication). | 60 Days post-randomization | 
| Adverse Events: hypertension | Adverse events will be defined as; hypertension (a systolic blood pressure >180mmHg or a diastolic blood pressure >110mmHg). | 60 Days post-randomization | 
| Adverse Events: Cardiac Arrest | Adverse events will be defined as; cardiac arrest. | 60 Days post-randomization | 
| Functional Outcomes; quality of life | Functional Outcomes will be defined as; quality of life outcomes will be collected using the EQ-5D-5L questionnaire at pre-hospital, baseline, 28-Days and 60-Days post-randomization. | 60 Days post-randomization | 
| Functional Outcomes; clinical frailty | Functional Outcomes will be defined as the clinical frailty score will be collected at pre-hospital, baseline, 28-Days and 60-Days post-randomization. | 60 Days post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Invasive Ventilation, Sedation, Randomized Control Trial, Acute Respiratory Failure