MedicalResearch.com Interview with:
Yahya Shehabi PhD, FANZCA, FCICM, EMBA, GAICD
Director of Research, Critical Care and Peri-operative Medicine, Monash Health
Professor, School of Clinical Sciences, Faculty of Medicine Nursing and Health Sciences, Monash University
Professor Intensive Care Medicine, Clinical School of Medicine, University New South Wales
Critical Care and Peri-Operative Medicine Lead – Monash Health Translational Precinct
MedicalResearch.com: What is the background for this study?
Response: SPICE III was the final phase of a series of SPICE studies. SPICE I showed 2 important findings, first, deep sedation in the first 48 hours is strongly associated with higher mortality, longer ventilation time and higher risk of delirium.
Second; that Dexmedetomidine is mainly used as an adjunct secondary agent 3-4 days after commencing mechanical ventilation and not as a primary sedative agent. In addition, albeit with several limitations, previous RCTs comparing Dexmedetomidine with conventional sedatives showed reduced iatrogenic coma, shortened ventilation time and reduced delirium with Dexmedetomidine treatment.
So based on the above we hypothesized that using Dexmedetomidine soon after commencing ventilation as a primary sedative agent, through reducing early iatrogenic coma, ventilation time and delirium, would impact 90 day-mortality.
MedicalResearch.com: What are the main findings?
Response: The key finding is that the use of Dexmedetomidine early as the primary sedative agent did not reduce the overall 90-day mortality.
Of the secondary outcomes, there was a small one day increase in the number of ventilator free-days and the number of days alive-coma-delirium free at 28 days in favour of Dexmedetomidine.
In a pre-specified subgroup analysis, age was a significant modifier of treatment effect on mortality. Treatment with Dexmedetomidine resulted in a significant increase in mortality in patients younger than the median age (67.3 yrs) and a significant reduction in mortality in those older than the median age. The secondary outcome and the sub-group analysis remained significant after adjustment for multiplicity. Reported adverse events were more frequent in the Dexmedetomidine treated patients.
Finally, the decline in cognitive function and quality of life at 6 months, in this population, was minimal in contrast to previous observational data. Essentially, survivors of critical illness who have no neurological injury on admission do very well long-term.
MedicalResearch.com: What should readers take away from your report?
Response: This study supports the notion that Dexmedetomidine, provides more arousable sedative state, increases vent free and delirium coma free days and possibly have a survival benefit in older patients. In addition, the potential harm in younger patients can not be ignored. The adverse event profile of Dexmedetomidine seems consistent with previous reports.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Our study brings an end to the age independent sedation paradigm. Future studies must stratify for age at randomization. Although mortality at 90-day is a popular primary outcome, more discussion is needed to address better outcomes for sedation trials. addressing clinicians attitude towards light sedation is a challenge and as such a tighter sedation targets should be prescribed in future trials.
MedicalResearch.com: Is there anything else you would like to add?
Response: This study presents new frontiers in ICU sedation literature.
First; Conducted in 74 ICU in ANZ, Europe, UK, and Asia, it reflects real worldwide ICU sedation practice, outside the US perhaps.
Second; Patients were enrolled very early within 4.6 hours of eligibility, it captured a blind spot in ICU sedation, the first 48-72 hours after commencement of mechanical ventilation. Third, the large sample size allowed adequate power for pre-specified sub-group analysis
for the primary outcome of 90-day mortality. The study was an investigator initiated RCT funded by the Australian Government Research Council, New Zealand Government Research Council with Dexmedetomidine provided by Pfizer and Orion Pharma as in-kind contribution.
None of funding agencies or companies involved had any input in the study conduct. I and my employer received payment and reimbursements for participation in educational sponsored symposia an the fringes of major scientific meetings.
May 19, 2019
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