Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial

Kawazoe Y. JAMA. Published online March 21, 2017

Clinical Question

• In ventilated patients with sepsis, does a sedation strategy with dexmedetomidine compared with no dexmedetomidine improve mortality and number of ventilator-free days?

Design

• Randomised control trial
  • Permuted block randomisation – stratified by centre, presence of emergency surgery, COPD, soft tissue infection
  • Block size of 4 (physicians were not notified of this during study)
• Open-label (Physicians non-blinded)
• Blinding of statistician performing statistical analysis
• Consecutive patients
• Superiority trial
• Intention to treat analysis
• Primary outcomes changed during study period
  • Initially set as mortality and duration of mechanical ventilation
  • Changed in 05/2015 to mortality and 28 day ventilator free days as duration of ventilation highly influenced by mortality
• Pre-determined weaning criteria
• Power calculation
  • Based on results of MENDS trial with a predicted 60% mortality in the intervention group vs. 80% based in control group: 172 patients to achieve 80% power with a 2-sided α level of 0.05 for 28-day survival
  • Aimed to recruit 200 patients to allow for 15% drop-out/withdrawal rate
• Statistical tests
  • Cox-proportional hazards model to estimate hazards ratio and 95% confidence intervals
  • Chi-squared or Fisher exact tests for other clinical outcomes between groups with categorical variables; t-tests or Wilcoxon rank sum tests for continuous variables

Setting

• Eight ICUs in Japan
• Data collected: February 2013 – January 2016

Population

• Inclusion criteria:
  • ≥20 years old
  • Patients with sepsis (defined as SIRS due to infection as per 1992 ACCP guidelines)
  • Mechanically ventilated for >24hrs (NIV or IPPV)
  • Acute pancreatitis included as ‘treatments are similar to those of septic patients’
• Exclusion criteria:
  • Severe chronic liver disease (Child-Pugh Class B or C)
  • Acute myocardial infarction or severe heart failure (NYHA Class IV)
  • History of drug dependency, alcoholism, psychological illness, cognitive dysfunction
  • Pregnant or lactating
• Participant numbers: 203 patients assessed for eligibility, one refusal and one excluded – 201 patients randomised and included in primary analysis
• Comparing baseline characteristic of dexmedetomidine vs. control group:
  • Mean age: 68 vs. 69 years
  • Emergency surgery: 37% vs. 36%
  • Renal replacement therapy: 22% vs. 20%
  • Median APACHE II score: 23 vs. 22
  • Median SOFA score: 8 vs. 9
  • Site of infection
    • Abdomen 39% vs. 35%
    • Thorax 39% vs. 33%
    • Pancreatitis: 3% vs. 9%
    • Skin and soft tissue: 6% vs. 7%
  • No significant difference between groups in co-morbidities (chronic haemodialysis, chronic respiratory disease, chronic heart failure, liver insufficiency)

Intervention

• Patients received dexmedetomidine and analgesia continuously, and other sedatives added as needed
  • Dexmedetomidine titrated 0.1-0.7μg/kg/h
  • Fentanyl 0-5μg/kg/h as needed
  • Minimum propofol/midazolam as needed

Control

• Conventional propofol/midazolam based sedation without Dexmedetomidine
  • Fentanyl 0-5μg/kg/h as needed
  • Propofol titrated 0-3mg/kg/h
  • Midazolam titrated 0-0.15mg/kg/h

Treatments common to both intervention and control groups

• Target sedation depth of RASS score 0 during day and -2 during night
• Analgesia targets: Visual analogue scale goal ≤2, under deep sedation Behavioural Pain Score ≤4
• Sedation maintained during mechanical ventilation or as required
• Sedation protocols in compliance with ‘Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult’
• Treatment protocol for sepsis based on national guidelines

Outcome

• Primary outcomes: comparing dexmedetomidine vs. control groups – no significant differences
  •  28 day mortality: 19% vs. 28%, p=0.14
    • Fragility index: -4 patients
  • Cumulative incidence of death at 28 days
    • 22.8% vs. 30.8%, p=0.20
    • Hazard ratio 0.69 (95% CI, 0.38-1.22; P=0.2)
  • Median number of 28-day ventilator-free days: 20 vs. 18 days, p=0.2
• Secondary outcomes: comparing dexmedetomidine vs. control group
  • No significant differences in:
    • Median ICU length of stay (LOS): 7 vs. 8 days, p=0.43
    • Median Hospital LOS: 25.5 vs. 30 days, p = 0.27
    • Renal replacement therapy: 38% vs. 39%, p=0.93
    • Delirium (CAM-ICE positive): 44% vs. 45%, p=0.94
    • Daily SOFA score
    • Ventilator days: 6 vs. 6, p=0.64
    • Rate of adverse events:
      • Bradycardia: 7% vs. 2%, p=0.1
      • Acute coronary syndrome: 1% vs 1%
  • Rate of well-controlled sedation during ICU stay significantly higher in dexmedetomidine group than control group
    • Range: 17%-58% vs 20%-39%, p=0.01
  • Frequency and dose of propofol and midazolam were lower in the dexmedetomidine group than control group, but frequency and dose of fentanyl were not significantly different
• Subgroup analyses:
  • Patients with APACHE II scores ≥23
    • Significantly lower mortality in dexmedetomidine group
    • Hazard Ratio, 0.39; 95% CI, 0.16-0.91; p=0.03

Authors’ Conclusions

• In patients requiring mechanical ventilation, the use of dexmedetomidine compared with no dexmedetomidine did not result in significant improvements in mortality or ventilator-free days

Strengths

• Robust study design, multicentre trial
• Attempts to reduce effects of bias from unblinding – use of a prearranged spontaneous breathing trial protocol
• Whilst not an international study, the choice of pharmacological agents, scoring systems and weaning protocols was largely generalisable to most developed countries
• Validated techniques for assessing sedation, delirium and pain
• Registered with US National Institute of Health Clinical Trials Registry

Weaknesses

• Open-label study open to bias – efforts taken to reduce bias but assessment of delirium and sedation may be considered a largely subjective measure; with small block sizes clinicians may have been able to predict which group the patient was likely to be allocated to.
• Lower dose of dexmedetomidine used in Japan due to limits placed by Japanese medical insurance
• MENDS trial used to calculate sample size required for this study but important differences exist between DESIRE and MENDS: higher APACHE II scores in MENDS subgroup, lower dosage limit of dexemedetomidine and increased age of patients in DESIRE
  • The study was underpowered to detect an absolute difference in mortality of 9%, which is still clinically significant
• Study had two primary outcomes. Did not perform power calculation for ventilator free days; and primary outcome changed during study period.
• Six patients in control group received dexmedetomidine at physicians discretion
• Measurement of ventilator-free days is arguably not a patient-centered outcome and no long-term patient outcomes recorded
• Although not statistically different there were some baseline differences between groups. The numbers of patients with pancreatitis were 3% vs. 9%. As pancreatitis is not an infection, including it as part of a sepsis trial may not have been appropriate due to differences in mortality and length of ventilation.
•  No mention of how many patients received NIV or IPPV in each group

The Bottom Line

• In ventilated patients with sepsis or pancreatitis, this study fails to demonstrate a significant impact of dexmedetomidine on 28-day survival or ventilator-free days but was likely underpowered for mortality. Further well-powered studies with clear patient-centered outcomes are required before dexmedetomidine should be considered as the gold standard sedative for ventilated patients with sepsis on ICU.

External Links

• [article] Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial
• [further reading] LITFL Dexmedetomidine

Metadata

Summary author: Gary Misselbrook
Summary date: 29th March 2017
Peer-review editor: @davidslessor