Clonidine sedates as well as dex or propofol in vented patients? (Part 2)
Pragmatic A2B trial may elevate the low-cost agent's profile
Thanks to the astute readers who noticed our error in part 1: clonidine mediates peripheral vasodilation via stimulation of alpha-2 receptors, not alpha-1. The post has been corrected. -Ed.
Like dexmedetomidine, intravenous clonidine can produce sedation by binding to alpha-2 receptors in the locus ceruleus in the pons, which inhibits norepinephrine release to numerous brain regions responsible for maintaining wakefulness.
Clonidine is commonly used in Europe and lower-income countries as an adjunctive sedative, but in the U.S., such off-label use is vanishingly rare.
In the pragmatic, UK-based randomized A2B trial (Walsh et al JAMA 2025), patients sedated with clonidine infusions appeared to have virtually identical outcomes (in terms of sedation, duration of ventilation, and mortality) as those assigned to dexmedetomidine or propofol.
Compared to dexmedetomidine, clonidine has lower specificity for alpha-2 receptors in the brain, and can produce hypotension by both central and peripheral effects (hence its wider use as an antihypertensive).
However, in the A2B trial, clonidine-treated patients were not reported to experience excess clinically significant hypotension.
Taken at face value, the trial seemed to elevate clonidine’s role from adjunctive to first-line sedative for mechanically ventilated patients.
But if you took trials at face value, you wouldn’t be reading this.
Alpha-2 Agonists Are Usually Insufficient Sedatives in Vented Patients
Neither dexmedetomidine nor clonidine alone provides adequate sedation for most mechanically ventilated patients.
This was observed in the SPICE III trial (Shehabi et al NEJM 2019), in which ~70% of patients randomized to dexmedetomidine required supplemental propofol to achieve sedation.
In A2B, primary sedation with dex or clonidine was not initially attempted.
The ~1,400 vented patients enrolled were already receiving propofol and an opioid for sedation after intubation, and were then randomized to receive clonidine, dexmedetomidine, or to continue on propofol (control). Opioids were also allowed and continued.
For those assigned to the intervention arms, the protocol’s algorithms guided staff to transition patients as feasible off propofol to either dex or clonidine according to their randomized assignment.
Clonidine or Dex Mitigated Propofol Use, Dramatically
A sizeable minority of patients were successfully sedated with clonidine or dex alone. The data are not granular enough to say much about these patients, but many of them were ventilated and sedated on an alpha-2 agonist alone for a full 7 days (i.e,. they were not postoperative patients extubated the next day).
Those receiving clonidine or dex who did receive propofol required far lower doses—about a 70% reduction in total dose from the propofol-assigned patients.
After the first day of randomization (the transition day):
Fewer than half the clonidine-assigned patients required ≥9 mg/kg/day of propofol, and only 25% required ≥30 mg/kg on any given day.
This translates to the propofol drip being off most of the day, or in single digits on most patients, but with a quarter requiring 20 mcg/kg/min propofol or more.
The dexmedetomidine-assigned patients required even less propofol.
By contrast, propofol-assigned patients usually required 20-40 mg/kg/day or more, or about 15-30 mcg/kg/min continuously.
This was roughly comparable to the propofol use in the dex arm in SPICE III, in which 70% of dex-assigned patients received a median 9 mg/kg/day of propofol.
Opioids were also used in all treatment arms, without obvious statistical differences; however, at least four different opioids were allowed, and total opioid equivalents were not reported.
Representative Population? Yes
Patients enrolled in A2B were critically ill:
They had a median cardiovascular SOFA score of 4 (of a possible 4, indicating shock on vasopressors) and respiratory SOFAs of 3 (e.g., vented for hypoxemia), with total median SOFA 8 (moderate to severe critical illness).
Roughly two-thirds were medical, and one-third were surgical patients.
About half required mechanical ventilation for more than six days.
Did Clonidine Cause Hypotension?
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