Investigators publish the results of the PODCAST trial in The Lancet

Jun 05, 2017

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In the general medical journal, The Lancet, one of the Editor’s Choice articles was titled, “Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.” The PODCAST trial (Prevention of Delirium and Complications Associated with Surgical Treatments) was conducted in the United States, Canada, South Korea and India. In total 672 surgical patients older than sixty were enrolled to this study, and were randomly allocated to one of three groups. In two groups they received low doses of ketamine, and in the third group they received placebo (no ketamine). Contrary to the study’s hypothesis, there was no decrease in delirium, pain or opioid usage after surgery in the ketamine groups. However, with increasing ketamine doses, there was a concomitant increase in hallucinations and nightmares for up to three days after surgery. The study is accompanied by an editorial written by Dr. James Eisenach, which contextualizes the results of the trial and reflects on its implications.

Pain is unique among surgical complications in that almost every patient who undergoes an operative procedure experiences some degree of pain. Indeed, it is frequently the most distressing aspect of surgery for patients and family members. Postoperative pain is often challenging to treat, especially in older adults, and acute pain can lead to chronic pain. Opioid medications, like morphine, are commonly administered to treat surgical pain, but they are associated with impaired breathing and addiction. The use of opioids after surgery is likely contributing to the worsening opioid addiction crisis that is currently unfolding in the United States and other countries. Opioids can also cause delirium, which is another common and serious complication of surgery, especially in those over sixty. Delirium is a state of acute confusion that, similar to pain, is very distressing to patients and their families. Postoperative delirium is associated with increased morbidity and mortality, and has been linked to persistent decrements in function, cognition, and quality of life. As such, postoperative pain and delirium are major public health challenges.

For these reasons clinicians internationally are highly motivated to find safe analgesic alternatives to opioid medications. Ketamine is an anesthetic and analgesic medication that has been in use for over 50 years, and does not depress breathing or heart function. Many small studies have shown that even a very low dose of ketamine, administered during surgery, decreases pain and opioid usage postoperatively. Also recent studies have suggested many other benefits of ketamine, including anti-depressant effects, brain protection and notably decrease in postoperative delirium. Therefore, in recent years many clinicians around the world have incorporated low doses of ketamine into routine practice. The PODCAST investigators felt that it was important to conduct a rigorous trial to determine whether or not ketamine truly yields the positive outcomes for which it is currently being administered.

Dr. Dan Emmert, the site principal investigator at Washington University stated, “the success of this study was attributable to a dedicated team of investigators around the world. I am optimistic that the results of this study will inform practice and point to important new research questions going forward.”  The PODCAST trial has important general lessons for clinicians and researchers. It is critically important to replicate the findings of small studies in large rigorous trials before we implement treatments in routine clinical care. Even when there are compelling mechanisms suggesting that medications will have specific benefits, this does not always mean that these benefits will be realized in the real world when medications are administered in clinically relevant doses. Finally, on a cautionary note, premature implementation of evidence into routine clinical practice has the potential to result in unintended harm to our patients.

PODCAST article:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31467-8/fulltext
Accompanying editorial:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31504-0/fulltext

 

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Tags: Research