Pain, Agitation/Sedation, Delirium, Immobility, Sleep Disruption, and Neuromuscular Blockade

and research is undergoing. Given the multifactorial nature of delirium in the ICU, clinicians should be

leery of solely assigning blame to medications but should remain vigilant when assessing the need and

doses of the aforementioned medications.

Benzodiazepines: The PADIS guidelines state “benzodiazepine use may be a risk factor for

the development of delirium in adult ICU patients.” Of interest, research directed at finding an

independent association between the use of benzodiazepines and the development of delirium in

the ICU including a meta-analysis, a randomized trial, and a systematic review has yielded mixed

Investigators used more appropriate statistical analysis for a fluctuating illness such as delirium

(e.g., Markov monitoring was used to determine the probability of a daily transition to delirium

while assuming this was independent of the patient history beyond the prior day) in addition to

more frequent delirium monitoring to examine the use of benzodiazepines and the transition from

an awake state without delirium to delirium, or from coma to delirium by the next day (Intensive

increased the odds of developing delirium the next day by 4%, and the use of benzodiazepine

infusions was an independent risk factor for the transition to delirium in the study population.

However, there was a large difference in the daily dose of benzodiazepines between the continuous

infusion (daily median dose 99 mg) compared with the intermittent dosing group (daily median

dose 4.1 mg), bringing into question whether the risk factor for the transition to delirium was

indeed the cumulative dose and not the method of administration. As the data evolve, the scrutiny

of benzodiazepine use should persist for ICU clinicians. Routine strategies to preferentially use

a non-benzodiazepine sedative (e.g., propofol or dexmedetomidine) and to avoid benzodiazepine

infusions unless clinically indicated should be used in addition to diligent performance of daily

SATs to discontinue use as soon as possible.

Anticholinergics: These medications are known for their sedating and altering effects on mentation

and should be avoided or used with extreme caution in the ICU setting. One proposed mechanism

for delirium is a decline in acetylcholine concentrations; therefore, any medication that may further

inhibit the activity of acetylcholine could worsen the patient’s mental status. A prospective cohort

study of 1112 critically ill patients was conducted to determine whether anticholinergic exposure

increased the probability of transitioning to delirium. On 6% of ICU days, transition from “awake

and without delirium” to “delirium” occurred. A nonsignificant increase in the probability of

transitioning to delirium the following day resulted from a 1-unit increase in the Anticholinergic

Drug Scale (odds ratio 1.05; 95% CI, 0.99–1.10). The dose of the medication was not evaluated

to determine the effects on the transition to delirium, and it was not evaluated if patients were

Med 2015;43:1846-52).

Systemic corticosteroids: The neuropsychiatric effects of systemic steroids in various clinical

settings have been described for more than 50 years. Common symptoms include mania,

depression, mood lability, anxiety, insomnia, delirium, and psychosis. The incidence of these

symptoms varies greatly depending on the clinical setting, dose of steroid, and patient’s underlying

medical history. Reported risk factors for neuropsychiatric effects secondary to steroids include a

daily prednisone dose equivalent to 40 mg or greater, hypoalbuminemia, underlying psychiatric

disorder, and blood-brain barrier damage (Curr Opin Organ Transplant 2014;19:201-8). Although

steroids are commonly used in the ICU for various indications and at various doses, significant

research directed at the neuropsychiatric effects of steroids in the critically ill population is

lacking. In a secondary analysis of a multicenter observational study of adult medical and surgical

ICU patients with acute lung injury (n=330), Schreiber et al. found a significant and independent

association between the use of systemic corticosteroids and the transition to delirium from a non-