Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis

C G Hughes. N Engl J Med 2021; 384:1424-1436. DOI: 10.1056/NEJMoa2024922

Clinical Question

• In mechanically ventilated adults with sepsis, does the use of dexmedetomidine, compared with propofol, for continuous sedation improve the number of days alive without delirium or coma?

Background

• Worldwide we treat around 20 million patients a year with sepsis complicated by severe organ dysfunction, of whom around 20% are mechanically ventilated
• Sedation is frequently administered for patient comfort but is associated with short-term and long-term effects. Expanding areas of interest include the prevention of cognitive and functional impairment, and quality of life after critical illness
• Dexmedetomidine is an alpha2 receptor agonist that causes sedation and may promote biomimetic sleep. Additional putative mechanisms that make it an attractive agent in sepsis include anti-inflammatory and bacterial clearance properties
• The MENDS trial showed that 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
• However, several studies have identified benzodiazepines as an independent risk factor for the development of delirium and time spent receiving mechanical ventilation, so this may not be the most useful comparator. A head to head study demonstrated non-inferiority of dexmedetomidine compared to propofol with regards to maintaining light to moderate sedation and patients receiving dexmedetomidine were more interactive
• When considering the dosing regime in this trial it is worth mentioning the secular trend towards reducing sedation doses administered in ICU as studies have demonstrated the impact this has on the duration of mechanical ventilation and ICU length of stay

Design

• Double-blind (with the exception of bedside nurses), multi-centre, investigator initiated, randomised controlled trial
• Randomisation in a 1:1 ratio to receive either dexmedetomidine or propofol using computer-generated permuted blocks
• Stratification by enrolment site and age (<65 years vs ≥65 years)
• The trial protocol was amended due to slow enrolment such that the enrolment target was reduced from 530 patients to 420 patients receiving the trial drug to provide 85% power to detect a 1.5-day difference in days alive without delirium or coma and 80% power to detect a 12% absolute difference in mortality at 90 days, assuming an expected mortality of 30% in the control group
• Modified intention-to-treat analysis (patients who were randomised and received trial drug)
• Trial registered at ClinicalTrials.gov

Setting

• 438 patients were recruited in 13 medical centres in the United States between May 2013 and December 2018, of whom 422 began receiving dexmedetomidine (214 patients) or propofol (208 patients) as some patients were subsequently found to be ineligible

Population

• Inclusion: Adults who were sequentially admitted to a medical or surgical ICU, had suspected or known infection, and were treated with continuous sedation for invasive mechanical ventilation
• Exclusion: The main exclusion criteria were as follows:
  • Baseline severe cognitive impairment
  • Pregnancy or breast-feeding
  • Second-degree or third-degree heart block, persistent bradycardia requiring intervention
  • Indication for benzodiazepines
  • Anticipated to have immediate discontinuation of mechanical ventilation
  • Moribund state
  • Had received mechanical ventilation for more than 96 hours
• Baseline demographics (dexmedetomidine vs propofol)
  • Median age: 59 vs 60 years
  • Female sex: 43% vs 42%
  • Median Charlson Comorbidities Index score: 2 vs 2
  • Median APACHE II score at ICU admission: 27 vs 27
  • Median days from mechanical ventilation before trial enrolment: 0.98 vs 0.97
  • Vasopressor treatment at enrolment: 56% vs 49%
  • Infection status:
    • Confirmed by culture: 68% vs 63%
    • Suspected but not confirmed by culture: 27% vs 33%
    • Ruled out: 5% vs 4%
  • Dexmedetomidine before enrolment: 15% vs 12%
  • Propofol before enrolment: 61% vs 62%
  • Delirium at enrolment: 35% vs 44%

Intervention

• Dexmedetomidine
  • Infusion (5 mcg/ml) titrated according to a weight-based dosing guideline (0.15-1.5 mcg per kilogram of actual body weight per hour)

Control

• Propofol
  • Infusion (10 mg/ml) titrated according to a weight-based dosing guideline (5-50 mcg per kilogram of actual body weight per minute)

Management common to both groups

• Pharmacists prepared the trial drugs in identical intravenous fluid bags covered with opaque bags and bedside nurses covered tubing with opaque coverings and begun infusing at a dose corresponding to the sedative dosing that the patient was receiving immediately before randomisation
• Protocolised titration of trial drug using a weight-based dosing guideline every 10 minutes to target sedation goals according to the Richmond Agitation–Sedation Scale (RASS) target set by the clinical team, primarily to a light sedation target (RASS 0 to -2)
• Protocolised temporary holding and permanent discontinuation criteria
• Protocolised rescue protocol for pain, rescue sedation, chemical paralysis or hyperactive delirium
• All centres performed, and investigators reinforced, the ABCDE bundle

Outcome

• Trial interventions (dexmedetomidine vs propofol):
  • Median daily dose on days administered (IQR): 0.27 mcg/kg/hr (0.11-0.61) vs 10.2 mcg/kg/min (5.5-18.4)
  • Trial or clinical team aware of the drug used: 13% vs 15%
  • Withdrawal from trial during hospitalisation: 5% vs 4%
  • Median RASS score while receiving drug (IQR): -2.00 (-3.00 to -1.00) vs -1.95 (-3.03 to -0.98)
  • Percent time at target sedation level while receiving drug: 57% vs 60%
  • Percent of days with adherence to ABCDE bundle:
    • Spontaneous awakening trial: 98% vs 98%
    • Spontaneous breathing trial: 93% vs 95%
    • Coordination of awakening and breathing trials: 86% vs 84%
    • Non-drug delirium interventions: 99% vs 99%
    • Early mobilisation: 91% vs 92%
  •  Median daily fentanyl dose on days administered (IQR): 68mcg/hr (28-119) vs 56mcg/hr (20-95)
  • Midazolam ever used: 53% vs 43%
  • Median daily midazolam dose on days administered (IQR): 3.8mg/day (2.0-10.9) vs 4.0mg/day (2.0-10.8)
  • Antipsychotics ever used: 42% vs 42%
  • Open-label propofol every used: 13% vs 8%
  • Open-label dexmedetomidine ever used: 4% vs 3%
• Primary efficacy endpoint: Adjusted number of days alive without delirium or coma over the 14-day intervention period was not significantly different between the dexmedetomidine and propofol groups
  • 10.7 days vs 10.8 days (OR 0.96; 95% CI 0.74 to 1.26)
• Secondary efficacy endpoints: There were no significant differences in the number of ventilator-free days (VFD) at 28 days, death at 90 days or global cognition at 6 months between the dexmedetomidine and propofol groups
  • VFD at 28 days: Adjusted median 23.7 vs 24.0 days (OR 0.98; 95% CI 0.63 to 1.51)
  • Death at 90 days: 38% vs 39% (HR 1.06; 95% CI 0.74 to 1.52
  • Global cognition at 6 months assessed with an age-adjusted Telephone Interview for Cognitive Status total score (TICS-T): 40.9 vs. 41.4 (OR 0.94; 95% CI 0.66 to 1.33)
    • Overall around 25% in each group had age-adjusted TICS-T scores that were 2 standard deviations below population norms, suggesting clinically important cognitive dysfunction
•  Safety endpoints: 
  • There were no significant differences in any organ dysfunction during the 14-day study treatment between the dexmedetomidine and propofol groups
  • 1 patient had suspected propofol-related infusion syndrome – later disproved

Authors’ Conclusions

• “Among critically ill adults with sepsis who were receiving mechanical ventilation and for whom recommended light-sedation approaches were used, dexmedetomidine did not lead to better outcomes than propofol with respect to days alive without acute brain dysfunction, ventilator-free days, death at 90 days, or cognition at 6 months.”

Strengths

• Multi-centre, randomised, controlled trial
• A relevant clinical question given the position of equipoise between the study drugs and a logical extension of the MENDS trial where the sepsis subgroup appeared to benefit from dexmedetomidine  
• Randomisation technique with computer-generated permuted blocks ensured allocation concealment
• Well designed study with the use of protocolised titration and rescue using validated tools such as RASS, as well as temporary holding and permanent discontinuation criteria 
• Excellent adherence to the ABCDE bundle, which was reinforced throughout the study
• Baseline demographics were generally well matched
• All patients were included in the modified intention to treat analysis for the primary outcome with minimal imputation for missing data
• Outcome measures placed emphasis on short-term and long-term cognitive outcomes as well as long-term functional and quality of life outcomes. Long-term data was captured in over 90% of survivors at 6 months
• Another study demonstrating the safety of dexmedetomidine, given earlier concerns about cardiovascular risk in particular

Weaknesses

• Although the authors did a commendable job at blinding it was not feasible to blind the trial drugs to bedside nurses, which could have introduced bias, although not obviously in any one direction
• Unmasking of the trial drug occurred in 14% of patients, which could have introduced bias, although not obviously in any one direction
• There was a higher incidence of delirium at enrolment in the propofol group, which may bias away from the null
• Over 90% of eligible patients were excluded with a notable proportion due to physicians or relatives declining participation, limiting external validity and hinting at a loss of equipoise
• Slow enrolment over a number of years is susceptible to secular trend and also necessitated an adjustment to the sample size, although statistical power was maintained
• The doses of trial drugs administered were relatively low and there was a frequent need for rescue sedatives. The use of an analgesic, fentanyl, as a first line rescue sedative may be considered controversial 
• There was some contamination between groups, particularly off-label use of propofol in the dexmedetomidine group during the study, although the doses used were low

The Bottom Line

• Despite its excellent design, the validity of this study was limited by the low doses of trial drugs administered and use of rescue analgesics and sedatives
• Clinically important cognitive dysfunction occurred in approximately 25% of patients in both groups at 6 months
• Ultimately this trial supports a position of equipoise between dexmedetomidine and propofol for use in mechanically ventilated patients with sepsis requiring continuous sedation

External Links

• Abstract: Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis
• Further reading: The MENDS2 Trial: Dexmedetomidine vs Propofol for Sedation
• Further reading: PulmCrit Wee – MENDS2: Fentanyl or fentanyl for sedation in mechanically ventilated adults with sepsis

Metadata

Summary author: Andrew Achilleos
Summary date: April 22, 2021
Peer-review editor: David Slessor