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
Results
- 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)
Weaknesses:
- 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
Strengths:
- 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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