MENDS2

In Review

Hughes CG, et al. "Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis". New England Journal of Medicine. 2021. online ahead of print:.
PubMed • Full text • ClinicalTrials.gov

Clinical Question

In adult septic patients requiring mechanical ventilation and managed with light sedation targets, does dexmedetomidine as compared to propofol, lead to better short and long term outcomes like development of delirium, duration of ventilation, and mortality.

Bottom Line

Outcomes did not differ between dexmedetomidine and propofol for patients needing light sedation, but there was a higher rate of self-extubation and requirement of open label propofol for those patients randomized to receive dexmedetomidine

Major Points

The Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Sepsis trial-a follow-up trial to MENDS-randomized 432 septic patients in the USA to receive either dexemedetomidine or propofol for ICU sedation. Enrolling from 2013 to 2018, the patients were titrated to maintain a RASS of 0 to -2, and all received the ABCDE ICU Liberation Bundle as standard of care.

For the primary outcome of days alive without coma or delirium, the trial found no difference for dexmedetomidine vs. propofol, 10.7 days vs. 10.8 day (odds ratio 0.96; 95% CI 0.74 to 1.26) P=0.7. There was no difference for secondary outcomes of ventilator free days, mortality, impairment and quality of life scoring at 90 days. For safety outcomes the two interventions were similary except there was more bradycardia in dexmedetomidine, 30% vs. 19%, and the rate of self-extubation requiring reintubation the same day, 39% vs. 20%.

Overall, this suggests that dexmedetomidine is no better than propofol and may have greater safety concerns. The trial did have some criticisms including a long enrollment period leading to a decease in the target population (and a decrease in power) which may have meant that this trial was underpowered. Opioid analgesia was used as rescue therapy for agitation instead of a sedative and comparatively small doses of both sedatives were used in the trial. Despite the impressive blinding procedure, the clinical team was unblinded in 14% of patients.

Guidelines

SCCM Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult ICU Guidelines (2018)

• use light sedation (RASS 0 to -2)
• use protocolized Daily Sedation Interruption protocols to achieve light sedation
• Choice of sedation:
  • Cardiac Surgery: use propofol over benzodiazepine
  • Non-Cardiac Surgery: use propofol or dexmedetomidine over benzodiazepine

Design

• Multicentre, double-blind, randomized, controlled trial
• N=432
  • dexmedetomidine (n=214)
  • propofol (n=208)
• Setting: 13 medical centres in USA
• Enrollment: May 2013 to December 2018
• Mean follow-up:
• Analysis: modified intention-to-treat
• Primary Outcome: number of calendar days alive without delirium or coma during the 14-day intervention period

Population

Inclusion Criteria

• adults
• sequentially admitted to medical/surgical ICU
• treated with continuous sedation for mechanical ventilation

Exclusion Criteria

• severe cognitive impairment
• pregnant or breast-feeding
• blind, deaf, or unable to understand approved languages
• experiencing second-degree or third-degree heart block
• persistent brady-cardia requiring intervention
• allergy to study drugs
• had indication for benzodiazepine
• anticipated immediate discontinuation of mechanical ventilation
• expected to require neuromuscular blockade > 48 hours
• moribund
• received mechanical ventilation for more than 96 hours before meeting all inclusion criteria.

Baseline Characteristics

Dexmedetomidine group shown

• Demographics: median age 59 years, 43% female, median BMI 30
• Ethnicity: 88% white, 7% black, 6% latinx, 5% other
• Severity of illness: median Charlson Comorbidities Index score 2, median APACHE II score 27, median SOFA score at enrollment 10, 56% shock
• Known/suspected infection source: 43% blood, 54% lung, 9% abdomen, 21% urinary, 11% skin/wound, 6% stool, 11% other
• drug exposure prior to enrollment: 16% dexmedetomidine, 62% propofol, 29% benzodiazepine, 67% opioid, 11% antipsychotic
• delirium at enrollment 35%

Interventions

• Study drug adjusted every 10 minutes to maintain a target RASS score, primarily light sedation (0 to -2), as set by clinical team
  • Dexmedetomidine 0.15 to 1.5 mcg/kg/h
  • Propofol 5 to 50 mcg/kg/h
• continued for 14 days, extubation, or discharge from ICU
• ABCDE (awakening and breathing coordination, choice of sedation, delirium monitoring and management, and early mobility) bundle for all patients

Outcomes

Comparisons are dexmedetomidine vs. propofol.

Primary Outcomes

Adjusted days alive without delirium/coma over the 14-day intervention period

10.7 days vs. 10.8 day (odds ratio 0.96; 95% CI 0.74 to 1.26) P=0.7

Secondary Outcomes

Median ventilator-free days at 28 days

23.7 days vs. 24.0 days (odds ratio 0.98; 95% CI 0.63 to 1.51)

Death at 90 days

38% vs. 39% (hazard ratio 1.06; 95% CI 0.74 to 1.52)

There was no appreciable difference between groups in measures of 6 month impairment, cognitive, functional, or quality-of-life assessments.

Adverse Events

Hypotension

56% vs. 55%

Bradycardia

30% vs. 19%

Severe Lactic acidosis (>5 mmol/L)

14% vs .14%

Self-extubation requiring reintubation on same day

39% vs. 20%

Criticisms

• Enrollment target was lowered in March 2017 due to slow enrollment, power calculation for 85% power to detect a 1.5 day difference
• unmasking of clinical team occurred in 14% of patients
• long duration of enrollment may have lead to some bias in results due to changes in practice
• analgiosedation approach used, fentanyl rescue as first line for agitation may have led to excess dosing of opiates

Funding

• National Institutes of Health (NIH) grants TR000445, HL111111, 1F31AG066460 (Dr Duprey), HL135144 (Dr Girard)
• National Heart Lung and Blood Institute grant HL14678-01 (Dr Pun)
• Pfizer supplied dexmedetomidine