SEDCOM

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Riker RR, et al. "Dexmedetomidine vs. Midazolam for Sedation of Critically Ill Patients". Journal of American Medical Association. 2009. 301(5):489-499.
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Clinical Question

In mechanically ventilated ICU patients, what is the efficacy and safety of prolonged sedation with dexmedetomidine compared to midazolam?

Bottom Line

Among mechanically ventilated ICU patients, there was no difference between dexmedetomidine and midazolam in achieving the time within the targeted sedation level, but dexmedetomidine resulted in less time on the ventilator, less delirium, and less tachycardia and hypertension, at the cost of more bradycardia.

Major Points

The Safety and Efficacy of Dexmedetomidine Compared with Midazolam (SEDCOM) trial was a multicenter trial that randomly assigned 375 mechanically ventilated ICU patients to receive dexmedetomidine or midazolam until extubation or for a maximum of 30 days. Contrary to previous studies which suggested that dexmedetomidine attained the sedation target more frequently than benzodiazepines, there was no difference in the trial's primary endpoint, time at the targeted sedation level. The dexmedetomidine group had 30% less delirium and spent 1.9 fewer days on the ventilator. Bradycardia was more common among dexmedetomidine-treated patients while hypertension and tachycardia were more common among midazolam-treated patients.

These results are consistent with the MENDS trial (2007) which randomly assigned 106 mechanically ventilated ICU patients to receive dexmedetomidine or lorazepam for sedation and demonstrated more days without delirium or coma in the dexmedetomidine-treated patients. These trials lend support to the changing practice of using fewer benzodiazepines and more dexmedetomidine for routine sedation in the ICU.

Design

  • Multicenter, double-blind, parallel-group, phase-4, randomized, controlled trial
  • N=375
    • Dexmedetomidine (n=244)
    • Midazolam (n=122)
  • Setting: 68 centers in 5 countries
  • Enrollment: March 2005 to August 2007
  • Analysis: both on-treatment and intention-to-treat

Population

Inclusion Criteria

  • Age ≥18 years
  • Intubated and mechanically ventilated for <96 hours prior with anticipated ventilation/sedation duration of ≥3 more days

Exclusion Criteria

  • Admitted for trauma or burns
  • Dialysis
  • Pregnancy or lactation
  • Neuromuscular blockade other than for intubation
  • Epidural or spinal analgesia, general anesthesia 24 hours prior to or planned after start of study drug infusion
  • Serious CNS pathology (acute stroke, uncontrolled seizures, severe dementia)
  • Acute hepatitis or severe liver disease (Child-Pugh class C)
  • ACS
  • LVEF <30%
  • HR <50 bpm
  • Second- or third-degree heart block
  • SBP <90mmHg despite continuous infusions of 2 vasopressors

Baseline Characteristics

Comparisons are dexmedetomidine vs. midazolam.

  • Age: 62 years
  • Male: 50%
  • Weight: 88 kg
  • APACHE II score: 18.8
  • MICU patients: 86%
  • SICU patients: 13.6%
  • Severe sepsis: 75.4%
  • Shock: 33.6%
  • Pneumonia: 63.4%
  • Liver dysfunction: Childs-Pugh A (48.8%), B (49.8%)
  • Median creatinine: 1.03 mg/dL
  • Pre-study drug sedative:
    • Benzodiazepines: 80.6%
    • Propofol: 49.4%
    • Dexmedetomidine: 0.8%
  • Time from ICU admission to start of study drug: 40.2 h
  • Delirium at enrollment: 60%

Interventions

  • Randomized in 2:1 fashion within 96 hours after intubation to receive:
    • Dexmedetomidine 0.2-1.4 µg/kg/h IV; optional 1 µg/kg loading dose, then maintenance infusion starting at 0.8 µg/kg/h
    • Midazolam 0.02-0.1 mg/kg/h IV; optional 0.05 mg/kg loading dose, then maintenance infusion starting at 0.06 mg/kg/h
  • Sedation assessed according to Richmond Agitation-Sedation Scale (RASS); dosing titrated to achieve light sedation (scores between -2 and +1); f still not adequately sedated, open-label midazolam bolus doses of 0.01-0.05 mg/kg at 10- to 15-minute intervals could be administered (maximum dose of 4 mg over 8 h)
  • Delirium assessed according to Confusion Assessment Method for ICU (CAM-ICU)
  • Fentanyl 0.5-1.0 µg/kg bolus q15 mins prn pain
  • Haldol 1-5 mg IV q 10-20 mins prn agitation or delirium
  • No other sedatives or analgesics allowed
  • Infusions stopped at extubation, after maximum of 30 days, or if deemed in the best interest of the patient

Outcomes

Comparisons are dexmedetomidine vs. midazolam. Analysis is on-treatment analysis unless otherwise stated.

Primary Outcomes

Percentage of time within target RASS range (score -2 to +1)
77.3% vs. 75.1% (P=0.18)
75.4% vs. 73.3% (intention-to-treat)

Secondary Outcomes

Delirium
54% vs. 76.6% (P<0.001)
24.9% reduction (intention-to-treat)
Mean delirium-free days
2.5 vs. 1.7 days (P=0.002)
Median time to extubation
3.7 vs. 5.6 days (P=0.01)
3.8 vs. 5.7 days (intention-to-treat)
ICU length of stay
5.9 vs. 7.6 days (P=0.24)
5.9 vs. 7.7 days (intention-to-treat)
Patients completing all daily arousal assessments
92% vs. 84.3% (P=0.02)
Patients requiring study drug interruption to maintain RASS score -2 to +1
91% vs. 91.8% (P=0.85)
Median duration of study drug treatment
3.5 vs. 4.1 days (P=0.01)
Open-label midazolam use
63% vs. 49% (P=0.02)
Mean dose 0.09 vs. 0.11 mg/kg (P=0.65)
Fentanyl use
73.8% vs. 79.5% (P=0.25)
Mean dose 6.4 vs. 9.6 µg/kg (P=0.27)
30-day all-cause mortality
22.5% vs. 25.4% (P=0.60)

Subgroup Analysis

Long-term use subgroup (N=297), defined as patients receiving study drug >24 hours.

Percentage of time within target RASS range (score -2 to +1)
80.8% vs. 81% (P=0.54)
Delirium
24% reduction (P<0.001)
Median time to extubation
3.9 vs. 5.8 days (P=0.03)
ICU length of stay
6.4 vs. 8.0 days (P=0.46)

High enrollment subgroup (N=298), defined as sites enrolling ≥5 patients.

Percentage of time within target RASS range (score -2 to +1)
76.5% vs. 74% (P=0.17)
Delirium
24.2% reduction (P<0.001)
Median time to extubation
3.8 vs. 4.9 days (P=0.03)
ICU length of stay
5.8 vs. 7.7 days (P=0.12)

Adverse Events

Adverse events
40.6% vs. 28.7% (P=0.03)
Bradycardia (HR < 40 or 30% decrease from baseline)
42.2% vs. 18.9% (P<0.001)
Bradycardia requiring intervention (titration, interruption of infusion or use of atropine)
4.9% vs. 0.8% (P=0.07)
Tachycardia (HR >120 or 30% increase from baseline)
25.4% vs. 44.3% (P<0.001)
Tachycardia requiring intervention
9.8% vs. 9.8 % (P=NS)
Hypotension (SBP <80 or DBP <50)
56.1 vs. 55.7% (P=NS)
Hypotension requiring intervention
28.3% vs. 27% (P=0.90)
Hypertension (SBP >180 or DBP >100)
43.4% vs. 44.3% (P=0.91)
Hypertension requiring intervention
18.9% vs. 29.5% (P=0.02)
Hyperglycemia (serum glucose >150)
56.6% vs. 42.6% (P=0.02)
Infections
10.2% vs. 19.7% (P=0.02)

Criticisms

Internal

  • High starting dose of midazolam (approximately 5 mg/h)
  • Lack of daily interruption of sedative infusions ("sedation vacations" which are now considered standard-of-care)
  • High dexmedetomidine dose (up to twice the currently FDA-approved dose, 0.7 mcg/kg/h)

External

  • Many centers in this study enrolled few (<5) patients, raising concern for variability and unbalanced center effect.
  • Common alternatives to midazolam such as lorazepam or propofol were not tested.

Funding

  • Supported by Hospira Inc, the manufacturer of dexmedetomidine.
  • Multiple financial disclosures.