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Treating delirium with antipsychotic medications and using haloperidol (Haldol) to prevent it showed little or no benefit over placebo, a pair of systematic reviews published in Annals of Internal Medicine concluded.

Across 16 randomized controlled trials and 10 observational studies, did not differ from placebo for outcomes including sedation status, delirium duration, hospital length of stay, or mortality, reported Dale Needham, MD, PhD, of Johns Hopkins University, and co-authors.

And in a separate review of 14 , haloperidol did not decrease in delirium incidence or duration, hospital length of stay, or mortality relative to placebo or other comparators, according to Karin Neufeld, MD, MPH, also of Johns Hopkins, and colleagues.

Some studies had low and moderate strength of evidence but overall, the findings were line with the 2018 and the 2014 American Geriatrics Society , Neufeld noted.

"Antipsychotic agents have many potential risks, including their inappropriate continuation long after the delirium has resolved," she told 口袋女优. "Clinicians should consider this evidence before starting antipsychotics as a general treatment for delirium or using haloperidol to prevent delirium."

Both reviews looked at potential harms of antipsychotics, Neufeld added. "Using haloperidol or second-generation antipsychotics to prevent or treat delirium made little or no difference in neurologic side effects, but potentially harmful cardiac side effects did occur more frequently overall in groups of patients receiving antipsychotics," she pointed out.

The reviews' findings echo outcomes seen in recent trials like MIND-USA, which showed that the longstanding practice of treating delirium with antipsychotics wasn't effective in critically ill patients.

"Thirty years ago, during my internal medicine residency, I was taught that it was 'normal' for hospitalized patients, particularly older adults, to get confused. This confusion had little significance and no impact on outcomes but could be a nuisance. If so, 10 mg of haloperidol ('vitamin H') would take care of the problem," wrote Edward Marcantonio, MD, of Beth Israel Deaconess Medical Center in Boston, in an accompanying the reviews.

But in the past 30 years, "we now know acute confusion is delirium and that it is never 'normal.' We have standardized methods to identify delirium, though over one half of cases still go unrecognized. We also know that delirium is common, affecting one third of hospitalized elders and three quarters of all adults in the intensive care unit (ICU) and in palliative care," he added. "Far from being of little consequence, delirium is a powerful predictor of short- and long-term adverse outcomes, including in-hospital complications such as falls, functional decline, cognitive decline, and death."

Meanwhile, physicians still turn to the same treatment, although second-generation antipsychotics represent a potential advance due to an "arguably" better side-effect profile, Marcantonio noted. "Nonetheless, over the past 30 years, no new effective treatments have emerged, and antipsychotics are still the most often used drug class for delirium (off-label)."

In the systematic reviews, researchers looked at studies published through July 11, 2019. They developed a with a panel of experts from the Agency for Healthcare Research and Quality (AHRQ) and the American Geriatrics Society, and when possible, pooled data to perform meta-analyses. Their analysis included second-generation antipsychotics like olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), ziprasidone (Geodon), lurasidone (Latuda), amisulpride (Solian), and aripiprazole (Abilify).

The treatment review looked at 16 randomized controlled trials (nine with low risk of bias) and 10 observational studies (nine with moderate or serious risk of bias). That analysis showed:

• No difference in sedation status (low and moderate strength of evidence), delirium duration, hospital length of stay (moderate strength of evidence), or mortality between haloperidol and second-generation antipsychotics versus placebo for delirium treatment.
• No difference in delirium severity (moderate strength of evidence) and cognitive functioning (low strength of evidence) for haloperidol versus second-generation antipsychotics, and insufficient or no evidence for antipsychotics compared with placebo.
• No difference in mortality comparing second-generation antipsychotics against each other, and insufficient or no evidence for a number of other outcomes.

The prevention review included 14 randomized controlled trials; risk of bias was low for nine studies, high for two studies, and unclear for three. Across the trials:

• Haloperidol for prevention showed no differences in delirium incidence or duration, hospital length of stay (high strength of evidence), and mortality compared with placebo.
• There was little or no evidence about the effect of haloperidol on cognitive function, delirium severity, inappropriate continuation, and sedation.
• There was limited evidence that second-generation antipsychotics lowered delirium incidence postoperatively.

In both reviews, the researchers also saw little evidence of neurologic harms with short-term use of antipsychotics, but in some studies, potentially harmful cardiac effects (prolongation of corrected QT interval) occurred more frequently in the antipsychotic group.

"With regard to use of antipsychotics for broad treatment of delirium, I believe the findings presented are sufficient to stop this clinical practice," Marcantonio wrote. "Future research should focus on defining patient subgroups and settings (if any) in which the benefits of antipsychotics outweigh harms, such as short-term use for behavioral control of a patient who is a danger to themselves or others, and for whom behavioral strategies are insufficient."

But a much bigger research priority -- how to manage delirium to improve short-term and long-term outcomes -- has eluded medicine for 30 years, he added. "This includes the many patients with 'quiet delirium' currently not recognized, who have equally poor outcomes as the agitated patients," he noted.

High-risk patients should be for delirium and if they screen positive, clinicians should evaluate their history, medications, lab work, and imaging to identify and treat underlying causes, Neufeld said.

"Non-pharmacologic strategies are the most effective approaches for preventing and decreasing delirium duration and should be employed as a standard of care," she emphasized. "This includes reducing exposure to 'deliriogenic' medications such as benzodiazepines in GABA-ergic naive patients, or antihistamines and other anticholinergic agents in patients over the age of 65; early mobility, physical rehabilitation and cognitive stimulation; sleep/wake cycle hygiene; frequent re-orientation and use of eye glasses and hearing aids; and adequate hydration."

The systematic reviews had several limitations, including heterogeneity in drug dose and frequency, outcomes, and measurement instruments, which limited the ability to synthesize results. Patient populations were diverse; some studies looked at critically ill patients, others at patients in postoperative or hospice care. There also was insufficient or no evidence about multiple outcomes. Efforts to establish and assessment tools in delirium prevention and treatment trials are ongoing, the researchers noted.