Title Slide

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Study: NEJM 2021

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Conflicts – none

First, a little bit of background

Worldwide we treat around 20 million patients a year with sepsis complicated by severe organ dysfunction, of whom
around 20% are mechanically ventilated.

SCCM guidelines: moderate to light sedation in ICU Vent patients

Propofol > benzos Precedex > Benzos

Compared with a benzodiazepine, propofol use was associated with a shorter time to light sedation in seven RCTs (56–
62) and a shorter time to extubation in nine RCTs (56,57,61, 67). Only one RCT assessed delirium and found no
difference (61). No data were available for other critical outcomes. Although propofol was associated with a higher risk
of self-extubation, the CI for this outcome was wide and it remains unclear if harm resulted (i.e., need for reintubation).

Dexmedetomidine, when compared with a benzodiazepine infusion (one study used intermittent boluses), was
associated with a shorter duration of mechanical ventilation in five RCTs (53,67–70) and ICU of stay in three RCTs
(53,68,71). Delirium prevalence was evaluated in four RCTs (53,68,69,71); the Midazolam versus Dexmedetomidine
(MIDEX) (69) trial data could not be pooled as delirium was assessed only once, 48 hours after sedation discontinuation.
Dexmedetomidine was associated with a significant reduction in delirium in the three remaining pooled RCTs that
evaluated delirium bid throughout the ICU stay (53, 68, 71). The Safety and Efficacy of Dexmedetomidine Compared
With Midazolam (53) and Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS)
(68) studies both demonstrated a greater incidence of bradycardia in the dexmedetomidine group; neither study found
that intervention was required for the bradycardia.

We evaluated three RCTs comparing dexmedetomidine and propofol; none of the three demonstrated any difference in
time to extubation (67, 69, 72). No data were available for other critical outcomes. A single RCT, the Propofol versus
Dexmedetomidine (PRODEX) study, showed that delirium incidence was decreased with dexmedetomidine at the single
time point of 48 hours after sedation cessation (69). Patients could communicate more effectively if sedated with
dexmedetomidine when compared with propofol (69). No differences were reported in bradycardia or hypotension
between patients sedated with propofol versus dexmedetomidine (69).

Propofol

Mech: Propofol works by increasing GABA-mediated inhibatory tone in the CNS. Propofol decreases the rate of
dissociation of the GABA from the receptor, thereby increasing the duration of the GABA-activated opening of
the chloride channel with resulting hyperpolarization of cell membranes
Precedex

In 2008 FDA expanded to include non-intubated patients for procedures like colonoscopy

α2:α1 selectivity ratio of 1620:1 = 8x more selective than clonidine

Decreases activity of noradrenergic neurons in the brain stem, thereby increasing the downstream activity of
inhibitory acid (GABA) neurons

Sleep like state, Stage 2 REM demonstrated on EEG

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Discontinuation syndrome

Clinical Question

The original MENDS

The MENDS trial showed that In mechanically ventilated ICU patients the use of dexmedetomidine resulted in more
days alive without delirium or coma compared with lorazepam.

An a priori-designed analysis of the MENDS trial investigating the subgroup of patients with sepsis found that these
effects were more pronounced and that dexmedetomidine was associated with a reduction in 28 day mortality

Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute
Respiratory Failure

The Study

Study Population

Confirmed by culture: 68% vs 63%

Vasopressor treatment at enrolment: 56% vs 49%

Dexmedetomidine before enrolment: 15% vs 12%

Propofol before enrolment: 61% vs 62%

Delirium at enrolment: 35% vs 44%

Interventions
Protocol

Outcomes

Primary: Median Days alive without delirium or coma during 14d intervention period

Secondary:

Ventilator-free days at 28d

Death at 90d

Age-adjusted total score on Telephone Interview for Cognitive Status questionnaire (TICS-T) at 6 months

TICS-T scores range from 0 to 100 with 50 +/-1- and lower scores indicating worse cognition

So what?

*Limitations*

 Unblinding in 14% of patients with similar frequency in the two groups and 10% crossover rate which could
affect outcomes
 Low recruitment, which required adjustment of sample size
 Despite evaluating 4840 patients, the majority met exclusion criteria and 537 declined to participate and 471
were not included due to medical team declining participation

Other
 Doses of dexmedetomidine and propofol that were used were TINY (median dose 0.27ug/kg/hr and
10ug/kg/min)
- CLICK - Use of other agents
- 38% of patients in the low dose precedex group were either RASS -4 (Deep Sedation) or -5 (unarousable)
and additional 14% were moderate sedation RASS -3. So, a total of 52% of these patients were moderate
sedation to comatose in low dose dexmedetomidine group.
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- 36% of patients in the low dose propofol group were either RASS -4 (Deep Sedation) or -5 (unarousable)
and additional 16% were RASS -3 (moderate sedation). So, a total of 54% of these patients were moderate
sedation to comatose in low dose dexmedetomidine group.
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I don’t think this study adequately compared these two agents. WOUld not change my practice