Early Sedation with Dexmedetomidine in Critically Ill Patients – part of ANZICS Clinical Trial Group and SPICE III Study (Sedation Practice in Intensive Care Evaluation)

Shehabi Y, Howe BD, Bellomo R et al.

New England Journal of Medicine . 19 May 2019 DOI: 10.1056/NEJMoa1904710


Context of the Study

Does early sedation with dexmedetomidine, as primary or sole agent, improve outcomes in critically unwell patients in ITU versus standard currently used sedatives?

A large multi-centred open-label randomised control trial across 74 ITU departments in 8 countries.

Inclusion Criteria:

  • >18yrs
  • Not in ITU for >12hrs prior to enrolment
  • Ventilated via ETT
  • Not to be extubated within 24hrs
  • Not with primary brain injury

Exclusion Criteria:

  • Death imminent or palliative care
  • Spinal cord or brain lesion
  • Underlying disease makes 90-day survival unlikely
  • Ongoing NMB
  • Hypotension or Bradycardia despite resuscitation
  • Pregnancy, under 18yrs, lactating
  • Admitted for drug overdose or burns

29502 patients met inclusion criteria –  25502 were excluded (4000 randomised)

Dexmedetomidine Group:

  • Dose 1- 1.5mcg/kg/hr titrated to RASS
  • If optimal sedation not achieved 2nd agent (propofol) started
  • BDZ only used for procedures, palliation or refractory agitation or if NMB used.
  • Antipsychotics allowed for agitation
  • No remifentanil or clonidine allowed
  • All non-pharmacological Rx of sleep/comfort/agitation encouraged

Normal Sedation Group:

  • Any sedating agents except clonidine and remifentanil
  • Rescue dexmedetomidine allowed
  • Antipsychotics allowed for agitation
  • All non-pharmacological Rx of sleep/comfort/agitation encouraged


Primary Outcome:

Death from any cause at 90 days

Secondary Outcomes:

  • Death at 180 days
  • Institutional dependency at 180 days
  • Number of coma free days
  • Number of ventilator free days
  • Delirium level


  • No significant difference in 90-day or 180-day mortality
  • No significant difference in rates of delirium
  • High % of DEX group received additional sedation early in course
  • Average 1 extra ventilator free day in dexmedetomidine group
  • Significantly more adverse events in dexmedetomidine group including asystole
  • Some indication of reduced mortality in older dexmedetomidine patients (>63.7yrs) and increased mortality in younger (<63.7yrs) – significance not established

Adverse Outcomes:

  • Significantly more frequent in the dexmedetomidine group (9.6% vs 1.8%) – mainly CVS related (bradycardia, hypotension, asystole)


  • Large proportion of DEX group received additional sedative agents
  • Unblinded trial
  • Multi centre adds power but includes multiple different ‘usual’ practice methods
  • Previous trials have mandated daily sedation holds – this one did not – to assess delirium levels
  • No mandated drug protocol (felt to reflect true practice better)
  • No investigation of vasopressor use/ Fluids given/RRT


  • Large, well powered trial
  • Attempted to encompass realistic clinical practice by including patients with multimodal sedation and fluid protocol
  • Previous RCTs of DEX v other have had delayed use of DEX and poorly recorded sedation levels
  • Adverse events recorded and evaluated

Conclusions/Impact to Practice:

  • Currently little evidence for dexmedetomidine as sole agent or as significantly better for sedating ITU patients from this study
  • May consider its use in the elderly ITU population and avoidance of use in the young – however definitive research needed
  • Be aware of increased hypotension/bradycardias/ asystole rates with dexmedetomidine

Summary by Dr L Rosenbaum. Journal Club Meeting 23 May 2019.

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