Pharmacologic Approaches to Managing Delirium

Delirium is a negative consequence of illness; it is upsetting for patients and families and costly to the healthcare system.  Since medications are easy to give to patients, it is tempting to use a drug to help resolve delirium and its bad outcomes – however, the strongest evidence to prevent and successfully treat delirium points to non-pharmacologic approaches.  These include getting patients  out of bed and moving as soon as possible,  reorienting them regularly,  avoiding deeply sedating them and offering sleep aids like earplugs and eye masks to promote adequate rest..  These strategies should be incorporated into the care delivered by every medical and surgical service. 

While research shows that up to one third of delirious episodes can be prevented with non-pharmacologic management, we still want and need to find better ways to prevent and treat the remainder of delirium episodes that occur. Furthermore, it is thought that an imbalance of neurotransmitters (the chemicals released in the brain) and several types of disease processes (such as inflammation from infections) contribute to the clinical picture of delirium. For these reasons, clinicians and researchers have turned to medications in hopes of finding something that helps.

This post briefly reviews what we know about pharmacologic or medication treatment approaches.  Note that there are no FDA approved medications for the treatment of delirium.

 

Antipsychotic Medications

Studies have examined the use of antipsychotic medications (most often haloperidol) for preventing or shortening the course of delirium. The studies that are available are generally small in size, study different types of patients, and measure outcomes in different ways.  When the findings are examined as a group, we do not see clear evidence that using antipsychotics to treat delirium changes the number of people who die, the duration of delirium, the severity of delirium, time spent in the Intensive Care Unit (ICU) or time to breathing on one’s own in the ICU.  With all antipsychotics having the potential to cause serious side effects, they should not be administered unless the potential benefit outweighs any safety concerns.

Antipsychotics also do not seem to prevent the occurrence of delirium when given before surgery.  However, one small but well-conducted study found that giving a newer antipsychotic drug, called risperidone, to people with very mild symptoms of delirium in the recovery room after surgery, decreased delirium in the recovery period. This study needs to be repeated in a larger group of patients before we can recommend such an approach for everyone.

None of the studies referred to above address whether the use of antipsychotics was helpful in making the patient feel better.  Delirium sometimes causes hallucinations and delusions and often results in anxiety and fear.  Antipsychotics are effective treatments of such symptoms when they accompany major illness. Therefore, it may be justifiable to treat these symptoms during delirium with low doses of medicationsfor brief periods of time, even if we are not convinced that the antipsychotic decreases the length of the delirium episode itself.  More research is needed to study this question.

 

Melatonin and Melatonin Agonist Medications

Melatonin is a naturally occurring hormone in our bodies that regulates the diurnal rhythm. Delirium researchers have been interested in melatonin because delirium frequently disrupts the day-night pattern.  Early studies suggested that melatonin might prevent delirium from occurring, but recently a carefully conducted experiment in The Netherlands did not demonstrate any significant benefit after melatonin was used in elderly patients who had been hospitalized for a hip fracture.

Ramelteon is a melatonin receptor-stimulating agent that is marketed in the US as a sleep medicine.  A recent study reported that delirium in older hospitalized patients in Japan could be prevented with ramelteon.  We need more research to understand if melatonin or associated medications can be useful in preventing or treating delirium.   

 

Acetylcholinesterase Inhibitors

This class of medications was thought to hold some promise in treating delirium, but a well-designed treatment trial was discontinued because of concern that the acetylcholinesterase inhibitor might be causing harm to the participants in the study.  This line of research has been stopped for now.

 

Benzodiazepines

Medications from the benzodiazepine class, such as diazepam and lorazepam, are not found to help patients with delirium and may result in making the delirium worse.  One exception is possibly the treatment of delirium that is caused by alcohol or benzodiazepine withdrawal.  Avoid using benzodiazepines in the agitated patient who has no recent history of alcohol or benzodiazepine dependence and consider the use of dexmedetomidine instead for a patient in the ICU.

 

In Summary

  • There is no evidence for the use of medication to prevent or shorten an episode of delirium.
  • We need more research in larger groups of patients with the same kinds of conditions and outcomes to see if there are very specific situations where particular medications may be useful (for example: antipsychotics like risperidone in subsyndromal delirium immediately after surgery, melatonin agonists such as Ramelteon in older hospitalized adults, antipsychotics in relation to the patient’s experience of delirium). 
  • Benzodiazepines should not be the first line treatment of fearfulness or anxiety in patients with delirium and should be avoided if possible except in particular situations where indicated (such as in alcohol and or benzodiazepine withdrawal).

 

Karin J. Neufeld, MD, MPH
Clinical Director –Bayview Psychiatry
Associate Professor
Department of Psychiatry and Behavioral Sciences
Johns Hopkins University School of Medicine

 

Suggested Reading

American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. (2015). American geriatrics society abstracted clinical practice guideline for postoperative delirium in older adults. Journal of the American Geriatrics Society, 63(1), 142-150. doi:10.1111/jgs.13281 [doi]

Barr, J., Fraser, G. L., Puntillo, K., Ely, E. W., Gelinas, C., Dasta, J. F. American College of Critical Care Medicine. (2013). Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Critical Care Medicine, 41(1), 263-306. doi:10.1097/CCM.0b013e3182783b72 [doi]

Neufeld, K, Huberman, A., Needham, D.  The Detection and Treatment of Delirium. In McKean, Ross, Dressler, Brotman & Ginsberg (Eds.) Principles and Practice of Hospital Medicine. McGraw Hill, March 29, 2012 | ISBN-10: 0071603891 | ISBN-13: 978-0071603898 | 1st Edition

 

Other References

de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, van Velde R, Levi M, de Haan RJ, de Rooij SE, de Rooij SE, on behalf of the Amsterdam Delirium Study Group. Effect of melatonin on incidence of delirium among patients with hip fracture: A multicentre, double-blind randomized controlled trial. CMAJ. 2014 Sep 2. [Epub ahead of print]

Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: A randomized trial. Anesthesiology. 2012; 116: 987-997.

Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, Nakamura H, for the DELIRIA-J Group. Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial. JAMA Psychiatry. 2014 Feb; 71(4):397-403.

Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet. 2014 Mar 8;383(9920):911-22.

Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotics for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis.  JAGS. 2015 in press.

van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, Spronk PE, van Gool WA, van der Mast RC, Kesecioglu J, Slooter AJ. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: A multicentre, double-blind, placebo-controlled randomised trial. Lancet. 2010 Nov 27; 376(9755): 1829-1837.

Comments

Email: 
Khan, Babar Ali <bakhan@iu.edu>

The recent blog post by Dr. Neufeld nicely summarizes the pharmacologic approaches to delirium and hammers home the point that currently there are no efficacious pharmacologic approaches to reduce delirium burden. Delirium is a complex brain disorder with multiple intersecting pathophysiological pathways that do not lend well to a simplistic single drug pharmacologic approach. On the other hand, non-pharmacologic approaches targeting multiple sensory aspects have shown some promise in reducing delirium. It could very well be the multi-component nature of the non-pharmacologic interventions that has been able to reduce the burden of risk factors among patients vulnerable to delirium. Unfortunately, even with data favoring non-pharmacologic multi-component interventions, only 3% of US health care centers have adopted such approaches.

As mentioned above, the complex pathophysiology of delirium involving inflammatory cytokines, dopaminergic, serotoninergic and other neurotransmitters may not be receptive to a simplistic approach of delirium management by single pharmacologic approaches. This can be ascertained based on the evidence cited and synthesized in the post by Dr. Neufeld. There could be some instances where this approach may work if the patients are clinically similar as mentioned in the examples of risperidone use post-surgically and of ramelteon in elderly hospitalized patients, but scenarios like that are rare. There is some evidence that a multi-component model incorporating pharmacologic approaches may be useful. An approach suggested by Campbell et al. is to reduce exposure to benzodiazepines and block the dopaminergic system with neuroleptics in an attempt to reduce delirium duration and severity among hospitalized patients. Similar approaches combining pharmacologic and non-pharmacologic interventions may hold the key to reducing delirium burden and need to be tested.

The field of delirium is expanding and the understanding of its pathophysiology is increasing, but there is still a lot that needs clarification. As the science of delirium evolves, so will the efficacious interventions. Currently, we can safely say that the devil is in the details, and the delirium details are still emerging.

Babar A. Khan MD, MS
Assistant Professor
Indiana University School of Medicine
Indianapolis, IN

References.

1. Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999;340(9):669–676.
2. Campbell N, Boustani M, Ayub A, et al. Pharmacological management of delirium in hospitalized adults: a systematic evidence review. J Gen Intern Med. 2009;24:848–853.
3. Campbell N, Khan B, Farber M, et al. Improving the care of delirium in the ICU: Design of a pragmatic study. Trials. 2011 Jun 6;12:139.

4. Khan BA, Zawahiri M, Campbell NL et al. Delirium in hospitalized patients: Implications of current evidence on clinical practice and future avenues for research -- a systematic evidence review. J Hosp Med. 2012 Sep;7(7):580-9

Email: 
james-amos@uiowa.edu

I’m so glad to see this basic information, although it seems inordinately difficult to do more than simply disseminate it to my colleagues in medicine and surgery. Time and time again I’m consulted to help manage delirium and the expectation is that there is some drug (usually an antipsychotic) that will stop or shorten the course or weaken the intensity of the patient’s delirium.

This can happen when the patient has hypoactive delirium, often found late because the behavioral agitation is missing and the patient doesn’t draw attention to herself. We just recently had a case presentation and short literature review on our consultation service from one of our pharmacy trainees about whether or not there is any compelling evidence that pharmacologic treatment of hypoactive delirium makes any difference in the course of the syndrome. The bottom line is there is none, essentially; at least none that would change my practice, http://thepracticalpsychosomaticist.com/2015/12/22/cpcp-pharmacologic-ma...

Email: 
melodyhume@yahoo.de

Appreciate the recommendation. Let me try it out.