Dexmedetomidine - Sugar and Spice for the Mechanically Ventilated Patient?

When the FDA approved dexmedetomidine (DEX) in 1999, intensive care medicine had a novel and highly promising drug at its disposal. Compared to clonidine, dexmedetomidine is an 8 times more selective, central alpha 2 agonist, which binds to all 3 subtypes of the receptor. The properties of this substance were auspicious, among them: sedation, analgesia, neuroprotective effects and a lack of respiratory depression.

- Sedation decreases sympathetic activity, aggression and leads to a non-REM-like state, which of all sedatives comes closest to natural sleep. Cognitive functions are maintained, and patients usually remain arousable. 

- Dexmedetomidine has a particular analgesic effect via modulation in the region of the posterior horn of the spinal cord. This has shown to reduce the use of opiates.

- By reducing cerebral catecholamines, dexmedetomidine exerts a neuroprotective effect.

- Interestingly, sedation with dexmedetomidine is not associated with significant respiratory depression.

These properties pointed to a wide range of applications in the intensive care unit:

- Sedation in patients with non-invasive ventilation
- Weaning of invasively ventilated patients
- Agitated delirium
- Treatment of various withdrawal syndromes
- Fiberoptic awake intubation in theatre conditions

Dexmedetomidine comes with its side effects, though. Most commonly bradycardia and hypotension are observed, making second and third-degree heart block a contraindication. Also, nausea and a dry mouth might be seen.

Interestingly, prolonged use might be associated with some extent of discontinuation syndrome similar to clonidine. This involves hypertension, tachycardia, nervousness etc.
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What Evidence Do We Have So Far?
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Current data indicate that dexmedetomidine, compared to benzodiazepines: 

- Might reduce the duration of sedation in mechanically ventilated patients, JAMA. 2007 Dec 12;298(22):2644-53.

- Might improve performance in patients with sepsis in regards to delirium, coma-free days and maybe even survival, Crit Care. 2010;14(2):R38. PMC2887145.

- Seems to reduce delirium in ICU and the need for mechanical ventilation in critically ill patients, JAMA. 2009 Feb 4;301(5):489-99.

- Seems to allow earlier extubation in mechanically ventilated patients and makes them more alert to communicate pain, and

- Compared to propofol, dexmedetomidine was comparable in terms of duration of mechanical ventilation, length of stay in ICU and hospital and also the incidence of hypotension and bradycardia. JAMA. 2012 Mar 21;307(11):1151-60. 

- Some further evidence indicates that dexmedetomidine might be helpful in the treatment of mechanically ventilated patients with agitated delirium, resulting in more ventilator-free days. JAMA. 2016 Apr 12;315(14):1460-8.

According to all this, the question arises, whether we should use dexmedetomidine early in ventilated, critically ill patients.

The SPICE III Trial

Precisely this question was now addressed by Shehabi et al., published in the NEJM

They performed an

International (8 countries, 74 ICU's), randomised controlled, unblinded trial

In which they evaluated

4000 ICU patients that were expected to need mechanical ventilation for at least 48 hours and required sedation for safety or comfort

They compared

Patients sedated with propofol, midazolam or other agents as prescribed by the treating physician with patients receiving dexmedetomidine as a continuous infusion 
(if DEX alone was insufficient, other agents could be added! In fact, 64% of patients also received propofol, 3% midazolam and 7% received both)

They found

1. No difference in 90-day mortality (primary outcome) and

2. No difference in death after 180 days, institutional dependency at 180 days, mean cognitive decline and assessment of the quality of life. Also no difference in median days free from coma to day 28 and median ventilator-free days at day 28 (all secondary outcomes)

3. Dexmedetomidine was though associated with significantly more events of bradycardia, hypotension​ (no further info on the use of vasopressors) and asystoles (14 vs 2; 7 required mechanical resuscitation measures)
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​- DEX is an attractive sedative in certain situations (alcohol withdrawal, other forms of delirium, weaning process etc.), BUT

- DEX doesn't seem to provide any advantage in the sedation of mechanically ventilated patients in the ICU and

- Might be problematic due to adverse cardiovascular effects, especially in this group of patients


Shehabe et al. N Engl J Med 2019; 380:2506-2517

Did you Know?

Apparently, intranasal dexmedetomidine seems used successfully for sedation in adults and children. J Clin Neurophysiol. 2019 May 16.