MENDS

Incomplete

Pandharipande PP, et al. "Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial". JAMA. 2007. 298(22):2644-2653.
PubMed • Full text

Clinical Question

Among adult mechanically ventilated ICU patients, does dexmedetomidine for sedation reduce duration of delirium and coma as compared to lorazepam?

Bottom Line

As compared to lorazepam, dexmedetomidine resulted in less delirium & coma but this may not have been an equal comparison.

Major Points

To provide care to the critically ill requiring mechanical ventilation, sedation is required.

Guidelines

As of April 2022, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, randomized, controlled trial
• N=106
  • Dexmedetomidine (n=54)
  • Lorazepam (n=52)
• Setting: 2 tertiary medical centers in USA
• Enrollment: August 2004 to April 2006
• Follow-up: 1 year
• Analysis: Intention-to-treat
• Primary Outcome: Days alive without delirium/coma; percentage of days spent within 1 RASS point of sedation goal

Population

Inclusion Criteria

• Adult (age ≥18 years)
• Intubated and requiring mechanical ventilation for >24 hours

Exclusion Criteria

• Neurological disease: Previous stroke, Cerebral Palsy, severe dementia, etc
• Active Seizure
• Childs-Pugh Class B or C liver dysfunction
• Moribund state with planned withdraw of life support
• Family or Physician refusal
• Alcohol abuse
• benzodiazepine dependency
• Active MI
• Second or Third degree heart block
• Pregnancy or Lactating
• Severe hearing disabilities
• inability to understand English

Baseline Characteristics

Dexmedetomidine Group displayed

• Demographics: Median age 60, 42% female
• Disease severity: median APACHE II 29, median SOFA 10
• ICU type: 29% surgical, 71% medical
• Characteristics at enrollments: median total lorazepam exposure 0.25mg, median duration of mechanical ventilation 22h, RASS -3
• ICU Admission diagnosis: 37% sepsis / ARDS, 23% other pulmonary, 8% malignancy, 6% ENT, 4% acuite lung injury, 4% COPD, 4% cardiogenic shock, 2% hemorrhagic shock, 2% renal failure, 10% other

Interventions

• Dexmedetomidine, 0.15-1.5 mcg/kg/h, titrated by the bedside nurse to achieve target sedation goal (RASS), until extubation or 120 hours (maximum time set by the FDA)
• Lorazepam 1-10 mg/h, titrated by the bedside nurse to achieve target sedation goal (RASS), until extubation or 120 hours (maximum time set by the FDA)

Outcomes

Comparisons are demedetomidine vs. lorazepam.

Primary Outcomes

Delirium & coma free days (up to study day 12)

7 vs. 3 (p=.01)

Percentage of days spent within 1 RASS point of sedation goal (up to study day 12)

80% vs. 67% (p=.04)

Secondary Outcomes

Prevalence of delirium or coma

87% vs. 98% (p=.03)

Prevalence of delirium

79% vs. 82% (p=.65)

Prevalence of coma

63% vs. 92% (p<.001)

Mechanical ventilator-free days

22 vs. 18 (p=.22)

Intensive care unit length of stay

7.5 days vs. 9 days (p=.92)

28-day mortality

18% vs. 27% (p=.18)

Completion of post-ICU neurological testing from enrollment date

7 days vs. 9 days (p=NS)

Median fentanyl exposure, mcg/day

575 vs. 150 (p=.006)

Use of antipsychotics

46% vs. 35% (p=.26)

Use of propofol

7% vs. 4% (p=.36)

Subgroup Analysis

Delirium free days (up to study day 12)

9 vs. 7 (p=.09)

Coma free days (up to study day 12)

10 vs. 8 (p<.001)

Adverse Events

Sinus bradycardia

17% vs. 4% (p=.03)

All other safety outcomes were similar between groups

Criticisms

• comparison to lorazepam as a continuous infusion instead of bolus dosing may have presented an unbalanced comparison
• The longer duration of action of lorazepam may have led to over-sedation as compared to dexmedetomidine, and affected clearance of coma
• pain managed by nursing assessment, not by objective measure
• more fentanyl used in the dexmedetomidine group may have been due to its sedating properties to help maintain RASS

Funding

• Unrestricted research grant for laboratory and investigational studies from Hospira Inc