Why hasn’t dad woken up after his heart surgery?

Sedation helps patients tolerate the uncomfortable bodily invasions of high tech intensive care. But when dad isn’t “waking up”, or just “isn’t himself”, many family members want to know whether sedatives are responsible for the prolonged problems with wakefulness, memory, and cognition seen in a significant number of patients who have received care in the Intensive Care Unit (ICU).

Benzodiazepines like lorazepam (Ativan)(cousin:Valium) are inexpensive, effective and safe sedatives for this purpose, with very little impact on organ systems other than the brain (that’s a good thing).Flowers

Dexmedetomidine is a new sedative drug marketed as the more easily pronounceable Precedex™. It is cousin to clonidine, a blood pressure medicine that’s been around for many years, which also has sedative properties. Precedex has pain-relieving properties and can cause the heart to slow and the blood pressure to drop in some patients.

Because Precedex works in a different way to the standard sedatives (it blocks alpha-adrenergic receptors) there is hope that it represents a better option for some conditions and procedures. Could it have less long term effect than other drugs on the brain?

There are many potential causes of brain dysfunction in critically ill patients. They include organ failure (heart, liver, kidney, lungs), drugs and drug interactions, infection, pain, sleep deprivation, electrolyte disorders, etc. But inevitably, when patients don’t “wake up” the finger gets pointed at sedative drugs which are, in effect, reversible poisons for the brain.

Sedatives are considered necessary in the ICU setting, so we can’t do a placebo-controlled trial but we certainly can compare one sedative with another. The appropriate way to sort this out is to do a randomised, controlled trial.

Just such a study was published in JAMA late last year, in which patients in the ICU sedated with Precedex did better on a variety of measures compared with those sedated with lorazepam. The study was double-blind and randomised, the strongest design for a clinical trial.

The Results

  • Patients sedated with dexmedetomidine had more days alive without delirium or coma (7.0 vs 3.0) and a lower prevalence of coma (63% vs 92%) than those sedated with lorazepam.
  • Patients sedated with dexmedetomidine spent more time close to their sedation goal compared with patients sedated with lorazepam (80% vs 67%).
  • Startlingly, the mortality after one month in the dexmedetomidine group was 17% vs 27% in the lorazepam group but this did not meet the usual standard of statistical significance.
  • More patients in the dexmedetomidine group (42% vs 31%) were able to complete post-ICU neuropsychological testing.

Precedex appeared to be safe. Patients on it were given more pain medication, paradoxically, but there were no other statistically significant safety issues or adverse events.

The Precedex patients hospital costs ($101,00 vs $79,000) were quite a bit higher, and pharmacy costs were approximately $7,000 greater, but again these differences were not statistically significant.

We can expect to see more studies which will try and confirm these impressive findings.

People will also ask whether Precedex might be a better choice than benzodiazepines like midazolam and lorazepam for sedation in the operating room as well as the ICU. In this context a study from Scandinavia could find no link between benzodiazepines and postoperative cognitive dysfunction in the elderly.

What you can do

Don’t expect to see Precedex go into routine use in the ICU just yet, unfortunately. Confirmatory studies will be sought, because of the rather high cost of the drug, and because the FDA has not approved it for longer than 24 hours of use. That does not prohibit its use – it becomes an “off-label” use – but makes it much less likely that hospitals will put it “on the menu” for routine sedation in the ICU.

Reference

Effect of Sedation With Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients. The MENDS Randomized Controlled Trial. Link: JAMA. 2007;298(22):2644-2653

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