Dexmedetomidine in Critically Ill patients

Y. Shehabi, B.D. Howe, R. Bellomo et el recently published results of SPICE III trial (Sedation Practice in Intensive Care Evaluation), dexmedetomidine as the sole or primary sedative comparing to receive usual care (propofol, midazolam, or other sedatives).

BACKGROUND

Dexmedetomidine was initially approved by the United States Food and Drug Administration (FDA) in 1999 for the short-term sedation of intubated and mechanically ventilated patients. Dexmedetomidine has 8 times greater affinity for the alpha-2 receptor than does the prototypical alpha-2 agonist clonidine. It has a selectivity of 1600:1 for the alpha2 receptor as compared to alpha1. Within the central nervous system, alpha-2 receptors are primarily concentrated within the pons and the medulla of the brainstem and are largely responsible for the transmission of sympathetic activity to the peripheral nervous system.  Dexmedetomidine is a lipophilic molecule that is highly bound to plasma proteins, with a large volume of distribution, and is rapidly redistributed to peripheral tissues. It has a distribution half-life of about 6 minutes and shows linear pharmacokinetics over a 24-hour period in patients with normal hepatic and renal function. The context-sensitive half-time of dexmedetomidine can range anywhere from 4 minutes after a 10-minute bolus to more than 250 minutes after an 8-hour continuous infusion.

Dexmedetomidine mainly causes bradycardia and hypotension- which is dose dependent and multifactorial, mediated through both central and peripheral mechanisms but are not the result of direct myocardial depression.  Dexmedetomidine should be avoided in patients with clinically significant heart blocks or concomitant bradyarrhythmias.

Dexmedetomidine is different from other sedatives such as propofol or midazolam as it does not suppress respiratory drive in usual doses and does not act via GABA receptors. Its utility as sedative in mechanically ventilated patients was proven in comparison to lorazepam in 2007 trial (MENDS randomized controlled trial). In mechanically ventilated ICU patients managed with individualized targeted sedation, use of a dexmedetomidine infusion resulted in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion.

In SEDCOM trial, it was compared with midazolam. Dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. A systematic review of existing trials of 1235 patients showed that dexmedetomidine based sedation regimen in critically ill adults may reduce ICU length of stay and duration of mechanical ventilation.

TRIAL

Critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU were randomized to dexmedetomidine or usual other sedatives(propofol and midazolam and others) after adequately getting pain control.  The primary outcome was the rate of death from any cause at 90 days.

Secondary outcomes included 180-day mortality; transfer to a full-time nursing home or rehabilitation center; cognitive function,  the patient-reported health-related quality of life, Additional secondary outcomes were the number of days free from coma or delirium and the number of ventilator-free days at day 28 after randomization.

WHERE

74 ICUs in eight countries (Australia, Ireland, Italy, Malaysia, New Zealand, Saudi Arabia, Switzerland, and the United Kingdom). A total of 4000 patients were enrolled.

SEDATION GOALS

RASS score of −2 (lightly sedated) to +1 (restless).

RESULTS

Primary outcome of event of death from any cause at 90 days was similar in both groups(29.1% in each). 180 days mortality was also similar.

Dexmedetomidine was insufficient alone or as the primary agent to achieve clinically desired target sedation levels and was associated with more reported

adverse events than usual care.

ADVERSE EVENTS

Bradycardia and hypotension, along with prolonged sinus arrest (asystole) (in 14 of 1954 patients [0.7%] and in 2 of 1964 patients [0.1%] was noted in dexmedetomidine group.

LIMITATIONS OF THE TRIAL

  1. Administration of other medications for sedation was unblinded.
  2. 40% of both  groups were deeply sedated.
  3. No daily sedation vacation.
  4. No strategy for management of sedation such as ABCDE bundle
  5. Other aspects of ICU care (e.g., vasopressor use, administration of fluids, or renal-replacement therapy) was not assessed, no effort made to look for impact of these on the sedation.

  6. Nearly 75% of the patients in the dexmedetomidine group also received propofol, benzodiazepines, or both, albeit at lower doses than the patients assigned to receive usual care.

BOTTOMLINE

This new trial of 4000 patients shows no difference in mortality at 90 days when dexmedetomidine is used as a sole agent for sedation in mechanically ventilated patients. However, with above mentioned several limitations, dexmedetomidine will continue to remain an agent of choice for selected patients(specially who are hypertensive and tachycardic). Adverse events, mainly hypotension and bradycardia are reversible. Its short half life makes it even more attractive.