Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults (inDEX)

Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: An International Pragmatic Randomized Controlled Trial (inDEX Trial)

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 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Invasive Ventilation
• Intervention / Treatment: Drug: Dexmedetomidine; Other: Placebo Control

Detailed Description

Acute respiratory failure (ARF) is a common reason for admission to an intensive care unit (ICU). Non-invasive positive pressure ventilation (NIV) is a life-saving intervention for selected patients with ARF. Compared to endotracheal intubation and invasive mechanical ventilation (IMV), NIV is safer, less invasive, preferred by most patients, and is associated with a reduced ICU length of stay (LOS), less pneumonia and mortality, and lower healthcare costs.

NIV failure can occur, necessitating IMV. Risk factors associated with NIV failure including intolerance, agitation, and delirium. Sedation is a potential solution for NIV intolerance, however the evidence is sparse and the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents.

Dexmedetomidine (Dex) is an α2-adrenergic agonist sedative commonly used in IMV that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and reduces delirium. The investigators hypothesize that Dex, when compared to placebo, reduces NIV failure in hospitalized adults with ARF and agitation or NIV intolerance.

Overall Goal: To determine if Dex, compared to placebo, reduces the risk of NIV failure in patients that admitted to hospital with acute respiratory failure and are intolerant of NIV.

Target Population: 826 patients will be enrolled into the vanguard trial if they meet all the following criteria: 1) ≥18 years old; 2) Receiving any NIV modality for ARF of any etiology; 3) Admitted to ICU, PACU, step-down unit (surgical or medical), or emergency department; 4) Presence of one or more of the following: a) Agitation, b) Patient expresses intolerance or requests removal of NIV secondary to self-reported discomfort, anxiety, or claustrophobia, or c) Other reason that the physician feels the patient is intolerant of NIV or agitated, not captured above.

Methods: The inDEX trial is a pragmatic, international, multi-centred, stratified, randomized, parallel-group, placebo-controlled trial. Patients, investigators, healthcare team, data collectors, outcome assessors, and the statistician will be blinded to trial arms. The trial will maximize external validity by including patients in a range of hospitals across the world. Patients randomized to the experimental arm will receive Dex while those randomized to the control arm will receive placebo.

Assessment: The primary outcome is NIV failure. The investigators define NIV failure as the proportion that require intubation or have died at 28 days.

• Study Type: Interventional
• Enrollment (Estimated): 826
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kimberley Lewis, MD; Phone Number: (289)775-7334; Email: kimberley.lewis@medportal.ca
• Study Contact Backup: Name: Jose Estrada; Email: jestrada@stjosham.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years
2. Patient receiving any NIV modality for acute respiratory failure of any etiology
3. Admitted to ICU, PACU, step-down unit (surgical or medical), or emergency department

4. Presence of one or more of the following after optimized NIV treatment (Appendix 1 Table 1):

   1. Agitation (Defined as a Richmond Agitation and Sedation Scale [RASS] score of ≥+2 or a Riker Sedation-Agitation Scale [SAS] score of ≥5) (Appendix 1 Table 2 and Table 3)
   2. Patient expresses intolerance or requests removal of NIV secondary to self-reported discomfort, anxiety, or claustrophobia
   3. Other reason that the physician feels the patient is intolerant of NIV or agitated, not captured above (all reasons will be recorded)

Exclusion Criteria:

1. Bradycardia defined as: a-Persistent bradycardia defined as a heart rate (HR) ≤60bpm; b-Second or third-degree heart block; or c- Tachybrady syndrome
2. Persistent hypotension, defined as a mean arterial pressure (MAP) ≤65mmHg despite volume resuscitation and vasopressors
3. Acute hepatic failure
4. Imminent need for endotracheal intubation
5. Death is deemed imminent and inevitable
6. Patients already on dexmedetomidine at time of enrolment
7. Known allergy to dexmedetomidine
8. Current pregnancy (should not breastfeed until 24 hours from discontinuation of medication)
9. Treating physician refuses enrolment (reasons for refusal will be captured)
10. Previously enrolled in the inDEX trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine Intervention; Dexmedetomidine (Dex) is an α2-adrenergic agonist sedative commonly used in IMV that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and reduces delirium. Patients randomized to the experimental arm will receive dexmedetomidine. At initiation, a bolus will NOT be administered. In keeping with Health Canada Guidelines, we will start the infusion at a mid-range dose of 0.5mcg/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 (RASS = -2 to +1 or SAS 3-4). Each bag will be composed of a 200mcg/mL dexmedetomidine vial mixed in a 100mL 0.9% sodium chloride mini-bag and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans.	Drug: Dexmedetomidine; Dexmedetomidine (Dex) is an α2-adrenergic agonist sedative commonly used in IMV that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and reduces delirium
Placebo Comparator: Placebo Control; 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 100mL of 0.9% sodium chloride and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans	Other: Placebo Control; 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 100mL of 0.9% sodium chloride and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NIV Failure	The primary outcome is NIV failure, defined by either mortality or intubation	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physiologic outcomes: Incidence of delirium	Delirium assessed using the ICU-CAM or ICDSC every 12 hours during NIV and daily thereafter until ICU discharge	28 days
Physiologic outcomes: Incidence of agitation	Agitation defined as Richmond Agitation Sedation Scale (RASS) ≥2+ during NIV), where RASS scale ranges from -5 (unrousable) to +4 (combative).	28 days
Process outcomes: Drug co-interventions during investigational product (IP) exposure	If the patient has moderate or severe agitation (RASS score +3 or +4), at any time, treating clinicians can initiate, at their own discretion, one or more of the following co-interventions: acetaminophen, opioids, anti-psychotics, or benzodiazepines for pain, agitation or delirium, respectively	14 days
Process outcomes: Number of patient-initiated device removal episodes	Number of patient initiated device removal episodes recorded by nurse	14 days
Process outcomes: Mean Non-Invasive Positive Pressure Ventilation Tolerance score	Scale ranges from +1 (comfortable and relaxed) to +4 ( severe intolerance)	14 days
Adverse events	Bradycardia (HR <60 bpm); severe bradycardia (HR <50 bpm); clinically significant bradycardia (bradycardia requiring inotropes, vasopressors, external pacing, temporary pacemaker, or discontinuation of the trial medication); hypotension (MAP< 60mmHg, or >20mmHg below admission baseline); clinically significant hypotension (hypotension requiring vasopressors, fluid administration, or discontinuation of the trial medication); hypertension (a SBP >180mmHg or a DBP >110mmHg); cardiac arrest; fevers not explained by another cause (defined as a temperature of 38.0°Celsius).	14 days
Major morbidity or mortality outcomes: Intubation	Intubation	14 days
Major morbidity or mortality outcomes: ICU Mortality	ICU mortality	28 days
Hospital outcomes	Hospital Length of Stay (LOS)	90 days
Functional outcomes	Quality of life and clinical frailty (assessed by EQ-5D questionnaire scores and the clinical frailty questionnaire score)	90 days

Collaborators and Investigators

• Sponsor: St. Joseph's Healthcare Hamilton
• Investigators: Principal Investigator: Kimberley Lewis, MD, St. Joseph's Healthcare Hamilton

Study record dates

Study Major Dates

• Study Start (Estimated): October 2, 2024
• Primary Completion (Estimated): January 2, 2025
• Study Completion (Estimated): January 2, 2025

Study Registration Dates

• First Submitted: December 27, 2023
• First Submitted That Met QC Criteria: February 6, 2024
• First Posted (Actual): February 14, 2024

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: 4257

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No