Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients

SFY – Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients

What was it?

A multicenter, open-label, randomized clinical trial comparing dexmedetomidine-based and clonidine-based sedation versus propofol-based sedation (usual care) in critically ill patients on mechanical ventilation. The trial tested whether α2-adrenergic receptor agonist-based sedation reduces time to successful extubation.

The Devil in the Details!

• 1,404 patients (457 dexmedetomidine, 476 clonidine, 471 propofol) across 41 UK ICUs.
• Patients: ≥18 years, within 48 hours of starting mechanical ventilation, expected to need ≥48 hours of ventilation.
• Interventions: Dexmedetomidine (0.7–1.4 μg/kg/h) or clonidine (1.0–2.0 μg/kg/h) vs. propofol (usual care, no specific dosing).
• Primary outcome: Time to successful extubation (extubation with 48 hours of spontaneous breathing).
• Secondary outcomes: 180-day mortality, ICU length of stay, sedation quality (RASS score ≥−2, agitation, pain), delirium, safety (bradycardia, arrhythmia, cardiac arrest).
• Long-term outcomes: Quality of life, anxiety/depression, posttraumatic stress, cognition at 90/180 days.

The Results!

• No difference in time to successful extubation:
  • Dexmedetomidine vs. propofol: sub distribution HR 1.09 (95% CI 0.96–1.25, p=0.20).
  • Clonidine vs. propofol: subdistribution HR 1.05 (95% CI 0.95–1.17, p=0.34).
• Median extubation times: 136 hours (dexmedetomidine), 146 hours (clonidine), 162 hours (propofol).
• No differences in 180-day mortality or ICU length of stay.
• Higher agitation rates: Dexmedetomidine (RR 1.54, 95% CI 1.21–1.97) and clonidine (RR 1.55, 95% CI 1.22–1.97) vs. propofol.
• Severe bradycardia more frequent: Dexmedetomidine (33%, RR 1.62, 95% CI 1.36–1.93) and clonidine (33%, RR 1.58, 95% CI 1.33–1.88) vs. propofol (20%).
• Cardiac arrhythmia higher with dexmedetomidine (RR 1.27, 95% CI 1.15–1.40), not clonidine.
• No differences in delirium, pain behaviors, or long-term outcomes (quality of life, anxiety, PTSD, cognition).
• Propofol used adjunctively in 77% (dexmedetomidine) and 76% (clonidine) of intervention group days.

They concluded

Neither dexmedetomidine- nor clonidine-based sedation reduced time to successful extubation compared to propofol in critically ill patients requiring ≥48 hours of mechanical ventilation.

Gripe Point Summary!

Further gripes here

• Open-label design: Unblinded intervention and outcome assessment risks bias.
• Propofol crossover: 76–77% of intervention group days included propofol, potentially diluting effects.
• Safety concerns: High bradycardia rates (33% in intervention groups) limited dose escalation.
• Increased agitation: Higher rates in intervention groups may reflect clinician inexperience.
• Limited generalizability: Excluded brain injury, cardiac surgery, or less severe cases.
• Pragmatic but loose protocols: Variable sedation, weaning, and analgesia practices may confound results.
• Sample size reduction: Dropped from 1,737 to 1,437 due to COVID-19, impacting non-inferiority power.
• No delirium benefit: High delirium risk, but no reduction observed.
• Subgroup limitations: Weak age interaction for dexmedetomidine; secondary analyses need cautious interpretation.

Our Summary

In critically ill patients on mechanical ventilation, neither dexmedetomidine nor clonidine outperformed propofol for extubation time or delirium reduction. Higher agitation and bradycardia rates, plus frequent propofol use in intervention groups, raise concerns about α2-agonist benefits. The pragmatic design reflects real-world ICU settings, but safety issues and unblinded assessments temper conclusions. Larger, blinded trials with stricter protocols are needed to define α2-agonist roles in ICU sedation.

Who’s worked on this before?

• Shehabi et al. SPICE III trial – Dexmedetomidine vs. usual care in ICU sedation.
• Liu et al. Critical Care, 2024 – Low-dose clonidine for sleep in postoperative HDU patients.
• Wu et al. Anesthesiology, 2016 – Dexmedetomidine for sleep in elderly ICU patients.
• Heavner et al. Pharmacotherapy, 2020 – Pharmacologic sleep promotion in ICU.
• Maldonado et al. Psychosomatics, 2009 – Dexmedetomidine and postoperative delirium.
• Jakob et al. JAMA, 2012 – Dexmedetomidine vs. midazolam/propofol in ICU sedation.

Further gripes

• Unblinded outcome measurement: Extubation assessed by unblinded teams, risking bias.
• Propofol confounding: Adjunctive propofol (25–30% of propofol group doses) in intervention groups may obscure α2-agonist effects.
• Bradycardia over-reporting: Daily monitoring may inflate rates compared to prior trials’ nonsystematic reporting.
• Clinical variability: Pragmatic design allowed discretion in sedation/weaning, introducing heterogeneity.
• COVID-19 disruptions: Enrolment pause and staffing issues may have reduced intervention fidelity.
• No opioid sparing: Similar opioid use across groups despite α2-agonist analgesic properties.
• High illness severity: Mean APACHE II score 20.3 and 66% sepsis prevalence limit applicability to milder cases.
• Short long-term follow-up: 90/180-day assessments may miss later differences in quality of life or cognition.
• Rescue medication ambiguity: Similar rates (31–38%), but specific agents (e.g., benzodiazepines) not detailed.
• Age interaction uncertainty: Weak dexmedetomidine-age interaction for extubation not consistent across outcomes.

CCN’s Reflection

This well-executed multicentre trial punctures the optimism around α2-agonists for ICU sedation, showing no edge over propofol for extubation time or delirium. Its real-world design is a strength, but unblinded assessments, propofol crossover, and safety signals (bradycardia, agitation) cloud the picture. Clinicians banking on clonidine’s cost or dexmedetomidine’s “lighter” sedation may need to rethink. Tighter, blinded trials minimizing adjunctive sedatives are crucial to settle whether α2-agonists have a place in the ICU. For now, propofol holds the throne…flaws and all.

Review by JW.