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

• 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.

• 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.

• 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.

• 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.

Inclusion criteria

• Age ≥ 65 years
• Intubated and receiving invasive mechanical ventilation in an intensive care unit
• 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)
• The patient requires immediate ongoing sedative medication for comfort, safety and to facilitate the delivery of life support measures.

Exclusion criteria

• 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
• Proven or suspected acute primary brain lesion such as traumatic brain injury, haemorrhage, stroke, or hypoxic brain injury
• Proven or suspected spinal cord injury or other pathology that may result in permanent or prolonged weakness
• Admission as a consequence of a suspected or proven drug overdose or burns
• Administration of or need for ongoing neuromuscular blockade
• A mean arterial blood (MAP) pressure that is less than 50 mmHg, despite adequate resuscitation and vasopressor support at time of randomization
• Heart rate less than 55 beats per minute or a high grade atrio-ventricular block in the absence of a functioning pacemaker
• Known sensitivity to dexmedetomidine
• Acute fulminant hepatic failure with EITHER

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