Clearing or clouding the mind?

Antipsychotics can resolve agitation in patients with delirium, but that may not provide much overall benefit.

When the Society of Critical Care Medicine asks you to conduct an evidence review on drug treatment for delirium, you expect to find some evidence. But in her research for revised guidelines on analgesia and sedation in management of delirium in the critically ill, Yoanna Skrobik, MD, didn't come up with much.

“I was very surprised to find that in the critical care literature there's actually very little to support administering antipsychotic drugs. In fact, there's no proof that haloperidol, which is the drug we use most often, has any effectiveness,” said Dr. Skrobik, professor of medicine and critical care at the Université de Montréal in Canada.

Photo by Thinkstock
Photo by Thinkstock.

Of course, there's no definitive proof that haloperidol doesn't work, either. In an effort to remedy the lack of evidence, Dr. Skrobik and other scientists have been researching the effects of antipsychotics on inpatient delirium. They haven't found any clear answers, and critical care guidelines on the subject have yet to be released, but in the meantime, the experts do have advice for hospitalists and intensivists.

Do something

Despite the lack of evidence to guide them, physicians have been forced to find ways to treat this common condition. As many as 80% of intensive care patients have been found to suffer from delirium, as well as a significant, albeit smaller, proportion of general medical patients.

Delirium is associated with not only worse long-term outcomes, but also challenges in immediate treatment. “If patients with delirium are also agitated and uncooperative, they become dangers to both themselves and caregivers and are difficult to extubate. Given that calming or environmental strategies are frequently not successful, a medication with sedative properties is usually required,” said John W. Devlin, PharmD, associate professor of pharmacy at Northeastern University in Boston.

Antipsychotics can resolve that agitation, but experts aren't certain how much good that does for the patient overall. “The patient becomes less bothersome to take care of because they're not trying to get out of bed and they're not hallucinating or having delusions. But in fact now they're very sleepy and lethargic and not moving, so the patient really isn't better and I would argue that the delirium isn't better,” said ACP Member Edward Marcantonio, MD, a geriatrician and associate professor of medicine at Harvard University.

The antipsychotics may simply have converted the patient from hyperactive delirium to the hypoactive variety, Dr. Marcantonio added. “Because delirium is not assessed systematically, physicians will often miss the hypoactive cases. Since the patient is no longer disruptive, the care team may think that the delirium is improved. However, studies have demonstrated that the long term outcomes of hypoactive delirium are equal to, or worse than, hyperactive delirium,” he said.

Better detection of both types of delirium could potentially increase the effectiveness of treatment. Dr. Devlin is currently studying the use of antipsychotics for subsyndromal delirium. “Patients with subsyndromal delirium are starting to exhibit signs of delirium, but they don't meet DSM-IV criteria,” he explained. “We are currently completing an ICU pilot study to evaluate the safety and efficacy of low-dose antipsychotic therapy to prevent the conversion of subsyndromal delirium to [full-blown] delirium.”

The appearance of a decrease is about as positive a result as research on antipsychotics for delirium can claim. The MIND trial, one of the largest investigations of the subject (involving 101 patients and published in Critical Care Medicine in February 2010), concluded only that “a randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible.”

“We definitely need more data,” said study author Timothy D. Girard, MD, assistant professor of medicine at Vanderbilt University in Nashville. The trial did not find that the drugs provided any improvement in the time patients survived without coma or delirium.

Only one study has actually found benefit in giving ICU patients antipsychotic drugs. In the same issue of Critical Care Medicine, Drs. Devlin and Skrobik and colleagues published a positive trial of quetiapine for ICU delirium. “It was the only study that ever showed that any antipsychotic drug has any beneficial effect. The number of days that patients had delirium symptoms was shortened,” said Dr. Skrobik.

“I was really excited about that study because I think it's pointing us in the right direction,” said Dr. Girard. But, he and the study authors note, the study had limitations, most notably that it only included 36 patients.

Not just haloperidol

Still, the results make it clear that haloperidol, the traditional drug of choice, doesn't have to be the only antipsychotic option for treatment of delirium. “The antipsychotic drugs aren't all equivalent. They bind to different receptors in the brain,” said Dr. Skrobik. “It's a little bit like antibiotics: Some work against some bacteria and others work against others.”

Quetiapine offered some specific benefits that led researchers to choose it for the study. “It's shorter acting. It is associated with greater sedative effects than other atypical antipsychotics which may be beneficial in a patient who is agitated. It has fewer cardiac side effects than haloperidol and can be easily crushed and administered down a feeding tube,” said Dr. Devlin.

Other atypical antipsychotics might be possibilities, too. Dr. Girard is enrolling patients in a study comparing haloperidol, placebo and ziprasidone. “One of the good things about the atypicals is that they can be given infrequently. If you're giving an oral agent, such as quetiapine or risperidone or ziprasidone, you often give it twice a day. IV pushes of haloperidol, on the other hand, are often given multiple times in the course of a day,” he said.

Having more drug choices may only make treatment decisions even more difficult for clinicians, he acknowledged. “Which one should you use? It's really hard to know. I don't think we have clear answers,” Dr. Girard said.

There's also the question of how much to use. Since haloperidol is the most commonly used option, experts had more definitive opinions on proper dosing. “I may start with giving a patient 1 or 2 or even 5 mg of haloperidol and then I will increase the dose,” said Dr. Girard. “I will go up to giving that drug two or three or four times a day.”

ICU vs. medical ward

However, an appropriate dose of haloperidol in the ICU may be too high for a general medical patient, Dr. Marcantonio cautioned. “There's probably a difference depending on the age of the patient and also the setting of care. For instance, in a younger patient population, where these medications may be better tolerated, you could be more aggressive initially,” he said. “In a ventilated ICU patient, the issues of maintaining adequate ventilation, airway protection, and mobility are different than on a general medical ward.”

The more typical case on the medical floor might be elderly and more mildly delirious, in which case an appropriate initial dose is 0.5 to 1 mg orally or 0.25 to 0.5 mg parentally, Dr. Marcantonio advised in an “In the Clinic” article in the June 7 Annals of Internal Medicine. “In more severe delirium, somewhat higher doses may be used initially (0.5 to 2 mg parenterally), with additional dosing every 60 minutes as required,” the article said. “In this setting, the classic geriatrics dictum ‘Start low, Go slow’ pertains,” Dr. Marcantonio added.

The difference between ICU and general inpatient delirium is another unresolved question, experts said. Trial data in either setting are limited, and it's not clear how generalizable the small set of existing data is. “I think you can extrapolate some of it,” said Dr. Devlin.

However, Dr. Girard offered a caution. “It's probably the case that there are very important differences between delirium in the ICU and delirium outside the ICU,” he said. “This may be in some ways a different process.”

“There's a further need for treatment trials in the patient over age 80, not in the ICU, on a general medical ward with delirium,” said Dr. Marcantonio.

The need for more research was one thing that all the experts could agree on. The response to the quetiapine study disappointed Dr. Skrobik. “We were pretty excited about this. We thought surely somebody would go out and do a larger study and…that didn't happen,” she said.

Drs. Devlin and Girard are working on additional research, but the results won't be available for some time. “We're talking five years before we're able to get data from our latest trial into the hands of the ICU practitioner,” said Dr. Girard.

In the meantime, the experts encourage physicians to treat and prevent delirium by all the evidence-based methods, including addressing pain and reducing or eliminating drugs known to contribute to delirium. An antipsychotic should be a last resort, and a temporary one, according to Dr. Girard.

“ICU clinicians should stop antipsychotics in the ICU or have a very clear plan of how long they're going to continue it, and then hospitalists should stop the drugs before the patient leaves the hospital,” he said.