Early Sedation With Dexmedetomidine vs. Placebo in Older Ventilated Critically Ill Patients (SPICEIV)

Sedation Practice in Intensive Care Evaluation (SPICE IV) Early Sedation With Dexmedetomidine vs. Placebo in Older Ventilated Critically Ill Patients: A Prospective, Multi-Centre, Double-Blind, Randomized, Controlled Trial

Sedation remains a ubiquitous and crucial component of intensive care treatments in critically ill mechanically ventilated patients. Sedation relieves anxiety, reduces distress, and promotes tolerance of endotracheal intubation and associated life-sustaining interventions such as mechanical ventilation, cardiovascular assistance, and renal support. Thus, choosing the optimal sedative agent is vital to patient comfort, safety, and survival. Despite more than 20 years of intensive care sedation research, there is still no consensus on what constitutes best sedation practice. The Society of Critical Care Medicine, the premier critical care organisation in North America, published the 2018 Clinical Practice Guidelines on the management of Pain, Agitation/Sedation, Delirium, Immobility and Sleep (PADIS) disruption (chaired by our primary applicant W.A.) and issued weak recommendations to provide analgesia before sedation, to target light sedation whenever clinically feasible, and to use either dexmedetomidine or propofol over midazolam for the sedation of mechanically ventilated critically ill patients. Similarly, the American Thoracic Society produced a set of Clinical Practice Guidelines to promote liberation and weaning from mechanical ventilation in critically ill patients, with weak recommendations for the use of non-benzodiazepines as primary sedatives and to target light sedation when clinically possible. A weak recommendation was issued in an Intensive Care Medicine Rapid Practice Guideline published in 2022 to use dexmedetomidine over propofol for sedation of critically ill adults, if the desired outcome is a reduction in delirium. These guidelines, however, do not consider age-dependent pharmacokinetics and pharmacodynamics, illness severity, timing of sedative administration, operative vs medical reason for admission, or the changing dynamics of sedation practice at different phases of critical illness. The lack of high-level evidence to inform sedation practice in the critically ill has led to approaches that are mainly opinion-based and lack the support of evidence from large multicentre, international randomised clinical trials.

Study Overview

• Status: Not yet recruiting
• Conditions: Respiratory Insufficiency
• Intervention / Treatment: Drug: Dexmedetomidine; Other: Placebo

Detailed Description

1. BACKGROUND

   Current guidelines highlight evidence gaps to be addressed in future sedation trials, particularly the need for adequately powered trials to evaluate impact of sedative choice in older adults, as they have a highest overall mortality and the most common demographic to require an ICU admission of all age groups.

   Dexmedetomidine, an α2-adrenergic agonist sedative, may be the solution. The SPICE III trial, a prelude to the SPICE IV study, evaluated early sedation with dexmedetomidine versus usual care sedation in 4000 critically ill patients. The SPICE III trial identified a heterogeneity of treatment effect (HTE) on the primary outcome of 90-day mortality, suggesting lower mortality in older patients. To further evaluate the observed HTE, SPICE IV was designed as a randomized double-blind placebo-controlled trial with a study population restricted to patients at or older than 65 years of age.

2. HYPOTHESIS

   Early sedation with DEX as the primary sedative agent reduces 90-day all-cause mortality in invasively mechanically ventilated patients who are ≥ 65 years of age.

3. OBJECTIVES

   The primary aim is to determine whether, in invasively mechanically ventilated patients who are ≥ 65 years of age, early sedation with DEX as the primary sedative agent reduces 90-day all-cause mortality.

   The secondary aims are to assess the effect of DEX on ventilator free days, coma and delirium free days, major adverse kidney events (MAKE-28) at day 28, duration of ventilation, and hospital stay in survivors.

4. METHODS

This is a prospective, double-blind, placebo controlled, randomised trial of early sedation with dexmedetomidine in invasively mechanically ventilated patients who are ≥ 65 years of age and who are expected to remain ventilated more than one calendar day after randomization. Randomization will occur via a secured website. A total of 300 patients will be recruited across Canadian centres and assigned in a 1:1 ratio to either: early dexmedetomidine (Intervention arm) or placebo (Control arm).Patients in the active intervention arm will receive a dexmedetomidine infusion starting at a recommended dose of 1 µg/kg/h without a loading dose. Patients in the control arm will receive normal saline at equivalent doses. Analgesia will be optimized in both groups as clinically indicated. The sedation target is defined by the Richmond Agitation-Sedation Scale (RASS) score of -1 to +1 at all times, unless otherwise clinically indicated.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jose Estrada; Phone Number: 32873 905-522-1155; Email: jestrada@stjosham.on.ca
• Study Contact Backup: Name: Irene Armanious; Email: iarmanio@stjosham.on.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
      • Contact: Sumesh Shah, CCRP; Phone Number: 1164 416-586-4800; Email: sumesh.shah@sinaihealth.ca
      • Principal Investigator: Samgeeta Mehta, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥ 65 years
2. Intubated and receiving invasive mechanical ventilation in an intensive care unit
3. The treating clinicians believe that the patient will remain intubated and ventilated until the day after tomorrow (i.e. unlikely to be extubated the following day)
4. The patient requires immediate ongoing sedative medication for comfort, safety and to facilitate the delivery of life support measures.

Exclusion Criteria:

1. Has been intubated (excluding time spent intubated within an operating theatre or transport) for greater than 12 hours, with an additional 6-hour grace period, a total of 18 hours, in an intensive care unit
2. Proven or suspected acute primary brain lesion such as traumatic brain injury, haemorrhage, stroke, or hypoxic brain injury
3. Proven or suspected spinal cord injury or other pathology that may result in permanent or prolonged weakness
4. Admission as a consequence of a suspected or proven drug overdose or burns
5. Administration of or need for ongoing neuromuscular blockade
6. A mean arterial blood (MAP) pressure that is less than 50 mmHg, despite adequate resuscitation and vasopressor support at time of randomization
7. Heart rate less than 55 beats per minute or a high grade atrio-ventricular block in the absence of a functioning pacemaker
8. Known sensitivity to dexmedetomidine

9. Acute fulminant hepatic failure with EITHER

   1. hepatic encephalopathy OR
   2. bilirubin (>300 µmol/l) and INR (>3.5), or both, without prior hepatic dysfunction.
10. Receiving full time residential nursing care
11. Death is deemed both imminent and inevitable and either the attending physician, patient or substitute decision maker is not committed to active treatment
12. Underlying disease that makes survival to 90 days unlikely
13. Previously enrolled in the SPICE IV study

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; Patients randomized to the experimental arm will receive dexmedetomidine. The study medication will be reconstituted by mixing 4 vials (8 ml) into a 100 ml bag of normal saline or 5% dextrose, this is the preferred dilution, or 2 vials (4ml) into 50 ml syringe to an equivalent concentration of 8 mcg/ml of dexmedetomidine. The constituted infusion is stable at room temperature for up to 24 hours. The recommended starting infusion rate is equivalent to 1 µg/kg/h of dexmedetomidine, without loading or bolus. This will be titrated to an equivalent dexmedetomidine dose of 0 to 1.0 µg/kg/h according to study algorithm to maintain target sedation of Richmond Agitation-Sedation Scale (RASS) score of -1 to +1.	Drug: Dexmedetomidine; 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.
Placebo Comparator: Control Intervention; Those in the control group will receive a placebo that is identical in colour and packaging and at equal volume to the intervention group. The placebo is a matching vial containing 2 mL sterile normal saline.	Other: Placebo; Normal saline placebo will be given as continuous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	90-day all-cause mortality	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days alive and free of coma and delirium		28 days
Number of days alive and ventilator free		28 days
Major Adverse Kidney Events	Mortality + Acute Kidney Injury > stage II, defined by Kidney Disease Improving Global Outcome (KDIGO) definition	28 days
Duration of mechanical ventilation in survivors		28 days
Hospital Length of Stay in survivors		28 days

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Estimated): September 7, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: February 1, 2024
• First Submitted That Met QC Criteria: February 1, 2024
• First Posted (Actual): February 9, 2024

Study Record Updates

• Last Update Posted (Estimated): September 10, 2025
• Last Update Submitted That Met QC Criteria: September 3, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Sedation; Mechanical Ventilation; Randomized Control Trial; Acute Respiratory Failure
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Substandard Drugs; Pharmaceutical Preparations; Azoles; Imidazoles; Dexmedetomidine; Counterfeit Drugs
• Other Study ID Numbers: 4569

Drug and device information, study documents

• 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