In last week's JAMA, Wes Ely's group at Vanderbilt report the results of a trial comparing dexmedetomidine to lorazepam for the sedation of critically ill patients:
This group, along with others, has taken the lead as innovators in research related to sedation and delirium in the ICU (in addition to other topics), and this is a very important article in this area. In short, the authors found that, when compared to lorazepam, dexmed led to better targeted sedation and less time in coma, with a trend toward improved mortality.
One of the most impressive things about this study is stated as a post-script:
“This investigator-initiated study was aided by receipt of study drug and an unrestricted research grant for laboratory and investigational studies from Hospira Inc….Hospira Inc had no role in the design or conduct of the study; in the collection, analysis, and interpretation of the data; in the preparation, review, or approval of this manuscript; or in the publication strategy of the results of this study. These data are not being used to generate FDA label changes for this medication, but rather to advance the science of sedation, analgesia, and brain dysfunction in critically ill patients….”
Investigator-initiated....investigator-controlled design and publication, investigators as stewards of the data.....music to my ears.
But is dexmed going to be the new standard in critical care sedation? For that question, it would appear that it is too early for answers. I have the following observations:
• This study used higher doses of dexmed for longer durations than what the product labeling advises. Should practitioners use the doses studied or the approved doses? My very small experience with this drug so far at the labelled doses is that it is difficult to use in that it does not achieve adequate sedation in the most agitated patients - those receiveing the highest doses of benzos and narcotics, in whom lightenting of sedationl is assigned the highest priority.
• The most impressive primary endpoint achieved by the drug was days alive without delirium or coma, but most of it was driven by coma-free days. Perhaps this is not surprising given two aspects of the study's design
1. Patients did not have daily interruptions of sedative infusions, a difficult-to-employ, but evidence-based practice to reduce oversedation and coma
2. lorazepam was titrated upwards without boluses between dose increases. Given the long half-life of this drug, we would expect overshoot by the time steady state pharmacokinetics were achieved.
So is it surprising that patients in the dexmed group had fewer coma-free days?
• We are not told about the tracheostomy practices in this study. Getting a trach earlier may lead to both sedation reduction and improved mortality (See http://ccmjournal.org/pt/re/ccm/abstract.00003246-200408000-00009.htm;jsessionid=HlfG93Qfvb113sCpnD10053YzKqMB3zFfDTdbGvgCQPdlMZ3S8kV!1219373867!181195629!8091!-1?index=1&database=ppvovft&results=1&count=10&searchid=1&nav=search).
• We are not told the proportion of patients in each group who had withdrawal of support. Anecdotally, I have found that families have greater willingness to withdraw support for patients who are comatose, regardless of other underlying physiological variables or organ failures. Can the trend towards improved mortality with dexmed be attributed to differrences in willingness of families to WD support?
• In spite of substantial data that delirium is associated with mortality (http://jama.ama-assn.org/cgi/content/abstract/291/14/1753?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=delirium&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT ), and these data showing that there is a TREND towards fewer delirium-free days with dexmed, the hypothesis that dexmed improves mortality via improvement in delirium is one that can only be tested by a study with mortality as a primary endpoint.
The data from the current study are compelling, and Ely and investigators are to be commended for the important research they are doing (this article is only the tip of that iceberg of research). However, it remains to be seen if one sedative compared to others can lead to improvements in mortality or more rapid recovery from critical illness, or whether limitation of sedation in general with whatever agent is used is primarily responsible for improved outcomes.
This is discussion forum for physicians, researchers, and other healthcare professionals interested in the epistemology of medical knowledge, the limitations of the evidence, how clinical trials evidence is generated, disseminated, and incorporated into clinical practice, how the evidence should optimally be incorporated into practice, and what the value of the evidence is to science, individual patients, and society.
Sunday, December 16, 2007
Dexmedetomidine: a New Standard in Critical Care Sedation?
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I think the guys from down the road at Toledo must read your blog.ReplyDelete
Mike, wow, thanks for pointing me ot the letters to the editor on MENDS in JAMA!ReplyDelete
If the boys from Toledo are reading my blog, I couldn't be happier. In fact, part of the impetus behind the blog was the the need for a forum to express my many concerns about many studies that did not require writing a letter to the editor. Not only did I feel that I was writing too many letters to the editor, but also there was the problem making use of those that did not get accepted for publication. The blog satisfies both of those needs.
And I'm glad that the boys in Toledo agree with me about steady state pharmacokinetics of lorazepam infusions, the ignorance of which is one of my biggest pet peeves in critical care sedation practices.
Thanks, Mike for leaving your comment!
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