Clonidine sedates as well as dex or propofol in vented patients? (Part 1)
... or might there be more to it than that (A2B Trial)
An earlier version of this post contained an error, saying clonidine mediates peripheral vasodilation via alpha-1 receptors rather than alpha-2 receptors. It has been corrected. -Ed.
Which sedative is “best” for mechanically ventilated patients? It must be either propofol, fentanyl, dexmedetomidine, or … clonidine?
Most clinicians know clonidine only as an antihypertensive. But clonidine shares pharmacologic properties with dexmedetomidine (brand name: Precedex) that make it a potential substitute for dex as a sedative agent in the ICU.
Both drugs are alpha-2 adrenergic receptor agonists that act in the central nervous system to reduce sympathetic tone.
How does that produce sedation?
A quick refresher on alpha-1 and alpha-2 receptors:
Alpha-1 and alpha-2 receptors are found throughout the body; both influence blood pressure, sympathetic nervous system activity, and other functions.
Alpha-1 receptors are mostly found in vascular smooth muscle; when stimulated, they increase tone (and blood pressure).
Alpha-2 receptors are found throughout the body, but are particularly concentrated in the brain, from where they regulate norepinephrine release.
The locus ceruleus in the pons (brainstem) is a key regulator of arousal and alertness via its neuronal projections to the cortex, hypothalamus, and spinal cord. Stimulating alpha-2 receptors in the locus ceruleus’s noradrenergic neurons inhibits their release of norepinephrine to other parts of the brain, producing a sleep-like state.
So why isn’t the alpha-2-stimulating-but-much-cheaper clonidine (which can be delivered intravenously as well as orally) used as a sedative in the ICU?
It is, actually: intensivists in France, Germany, the Netherlands, and many lower-income countries commonly use clonidine as an adjunctive sedative. But it might have some limitations.
Clonidine is much less selective for CNS alpha-2 receptors than dexmedetomidine. This can cause hypotension and other “off-target” effects. (Although clonidine’s antihypertensive effects are primarily mediated through stimulation of alpha-2 receptors in the CNS, its lower selectivity and peripheral alpha-2 agonism can also cause peripheral vasodilation, lowering blood pressure.)
A 2017 systematic review by Wang et al in Critical Care found that in 7 randomized trials (half were in children, n=642), clonidine as an adjunctive agent reduced the need for opioids, but was associated with a ~3x risk in clinically significant hypotension.
But did we mention clonidine is cheap? It can cost as little as 2-5% of the price of dex. It has never been meaningfully tested as a primary sedative in the ICU, so there is no good evidence against its efficacy.
And as authors of a new multicenter trial point out, dexmedetomidine isn’t mother’s milk. In the SPICE III trial, dex came under suspicion of causing excess mortality in younger patients, a question mark emphasized by subsequent post hoc analyses. We reviewed SPICE III here:
In a wonderful non-sequitur, the authors argue that another alpha-2 agonist (clonidine) that is already commonly believed to be riskier than dexmedetomidine should therefore be tested as a primary sedation agent.
The A2B Trial: Clonidine Vs. Dexmedetomidine
From 2019 to 2023, 1,438 critically ill patients requiring mechanical ventilation were enrolled at 41 ICUs in the UK. They were randomized to either receive propofol, dexmedetomidine (0.7 to 1.4 μg/kg/hour), or clonidine (1.0 to 2.0 μg/kg/hour).
This was a pragmatic trial; the assignments were unblinded (i.e., sedation was given “open label”). Treating physicians were strongly encouraged to continue to provide the original sedative, but could add propofol if the primary agent was at maximum dose or the clinician was worried about adverse events. Opioids could also be used. Benzodiazepines or other off-protocol sedatives were discouraged and marked as failures (“rescue”).
There were no statistically significant differences between groups in time to extubation after randomization, 180-day mortality, time to ICU discharge, time to first achieve a target sedation level, or percentage of days achieving the target sedation level. Patients receiving clonidine did not have any greater need for rescue medications.
Patients receiving clonidine did not have higher rates of severe hypotension.
Conclusion
So there you have it: clonidine works equally well as propofol or dexmedetomidine as a primary sedation agent for mechanically ventilated patients in the ICU. It costs a tiny fraction of the brand-name agents. Intensivists around the world will surely now change practice and adopt what will soon come to be called the “clonidine first” sedation strategy.
Or is there more to this story than that?
We’ll find out in Part 2.
Dex is a great, relatively clean sedative that is not perfect by any means. It does drop BP and it does drop HR. Some patients are very sensitive to it and do not tolerate it - mostly the elderly and those with conduction disease. THAT being said, its very useful as an adjunct. I often leave it on for vent weaning and extubation purposes..."The last man standing" of the sedatives
I’m getting old enough to remember why clonidine sucks.
You never know what it’s going to do - drop someone’s pressure, raise it, do nothing, sedate them, activate them…. It has a 5 minute half life in some people, in others it’s 5 hours.
It’s an unpredictable med. We’re gonna push it down the NG? The patches are fine. But we don’t like long acting meds in the icu that much… what dose? Who knows.
Some patients don’t tolerate dex. But I can turn it off. I give clonidine- the patient owns it for however long.
I’m not a huge dex fan, especially for ETOH w/d. But at least I can stop the pump.