Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients with Agitated Delirium. A Randomized Clinical Trial

Reade. JAMA 2016; published on line first March 15th 2016

Clinical Question

•  Is Dexmedetomidine effective in reducing the incidence of agitated delirium and days on a ventilator?

Design

• Double-blind, parallel-group, randomised control trial
• Multicenter
• Stratification by site and age (<55 years and >55 years)
• No interim analysis
• Sample size of 96 patients, based on a pilot study, was estimated to provide 80% power to detect a 20 hour difference using a 2-tailed hypothesis at an alpha level of 0.5

Setting

• 15 ICU’s in Australia and New Zealand
• May 2011 – December 2013

Population

• Inclusion: Adult ICU patients who needed to remain mechanically ventilated because their degree of agitation was considered so severe as to make lessening their sedation and extubation unsafe
  • This was based on 4 objective measures and patients were eligible for the study if they met any of these in the 4 hours prior to randomisation:
    • need for mechanical restraint, antipsychotic or sedative medication
    • delirium as defined by Confusion Assessment Method (CAM-ICU)
    • Motor Activity Scale (MAAS) score of 5 or greater
• Exclusion: pregnant or breast feeding; dementia requiring professional nursing care; had a head injury as the cause of their altered mental status; already receiving dexmedetomidine or clonidine; known contraindication to haloperidol or alpha-agonists
• 21500 patients were screened and 71 patients were randomised
  • median age 57 years; 24% women; similar low APACHE II scores; more emergency and cardiovascular patients in the dexmedetomidine group

Intervention

• Dexmedetomidine
  • commenced at a rate of 0.5mcg/kg/hr and then titrated to rates between 0 and 1.5mcg/kg/hr to achieve physician-prescribed sedation goals
  • clinical-directed option for bolus of 1.0mcg/kg over 20 minutes
  • aim was to achieve a Richmond Agitation-Sedation Scale score of 0 or to achieve a physician-prescribed goal

Control

• Placebo
  • saline in an identically labelled syringe as the intervention group. Titration and bolus dose option the same as the intervention group

In both groups

• Patients also received opioids and sedatives
  • Patients in the placebo group received significantly more antipsychotics meds (65.6% vs 36.8%, 95% CI -51.3,-6.3%, p=0.02), more opioid, and a significantly higher dose of propofol for the 7-days after randomisation.
  • The use of midazolam was similar in both groups and there was no statistical difference in the dosage during the 7-days after randomisation
• After 48 hours of study drug infusion, the treating physician could prescribe open-label dexmedetomidine and the study drug infusion would be stopped. More than 7 days of infusion of study drug was considered treatment failure; at that point, the study drug was stopped and open label dexmedetomidine could be commenced

Outcome

• Primary outcome: Statistically significant increase in median ventilator free hours at 7 days in the dexmedetomidine group
  • 144.8 vs. 127.5 hours, P=0.01

• Secondary outcome: 21 secondary outcomes
  • none significantly worse with dexmedetomidine
  • 3 favoured dexmedetomidine
    • reduced median hours until bedside nurse thought the patient was ready for extubation:  19.1 vs 40.5 hours
    • reduced median time to extubation: 21.9 vs 44.3 hours
    • accelerated median time to resolution of delirium: 23.3 vs 40.0 hours
  • patients in the placebo group received significantly more antipsychotics meds (65.6% vs 36.8%, 95% CI -51.3,-6.3%, p=0.02), more opioid, and a significantly higher dose of propofol for the 7-days after randomisation
  • dexmedetomidine was associated with a non-significant decrease in ICU LOS (2.9 vs 4.1 days, -1.0 days, p=0.09)
• No difference in adverse events

 

Authors’ Conclusions

• Among patients with agitated delirium receiving mechanical ventilation in the Intensive Care Unit, the addition of dexmedetomidine to standard care compared with standard care alone resulted in more ventilator-free hours at 7 days.

Strengths

• RCT
• Multicentre
• Patient-centred primary end point
• Physicians and nurses treating study patients were blinded to group allocation
• Study drugs were prepared by pharmacists or nurses not involved with treating study patients

Weaknesses

• Underpowered. The sponsoring pharmaceutical company declined the option to extend funding beyond the planned completion date. 74 of the planned 96 patients had been randomised at this point
• Details of the choice of sedatives and opioids are supplied for the 24 hours prior to randomisation. However there are no details about the dosage received or what was administered prior to this time.
• A recognition that there was a lack of physician equipoise in this study is considered a strength by the authors. The study accommodated this by permitting open-label dexmedetomidine at 48 hours after randomisation. In fact, a lack of equipoise is arguably an inherent weakness in this study
• Patients in the dexmedetomidine group were ventilated for longer prior to enrolment in the study. Median times were 63 hours vs 43.5 hours
• The MAAS score was used as a component for diagnosing delirium, but further MASS data was then not collected, as part of the criteria for determining resolution of delirium

The Bottom Line

• This underpowered study showed potential benefits of using dexmedetomidine, in addition to standard care, for ventilated patients with agitated delirium, who are otherwise ready for extubation. In particular, there was a modest reduction in time for liberation from the ventilator, more rapid resolution of delirium and sedation and opioid sparing effects. Until there is better evidence and a cost analysis, I will continue to use clonidine as a cheaper alternative to dexmedetomidine

External Links

• [article] Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients with Agitated Delirium. A Randomized Clinical Trial
• [further reading]The Bottom Line summary: MIDEX-PRODEX: Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation: Two Randomized Controlled Trials
• [videocast] Valerie Page explaining CAM-ICU score

Metadata

Summary author: Steve Mathieu
Summary date: date when ready for review
Peer-review editor: Adrian Wong

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