A Review of Pharmacologic Management and Prevention Strategies for Delirium in the Intensive Care Unit

Delirium prevalence is estimated at 10%–30% in general medical population and as high as 80% in the ICU population. Given these statistics, it is not surprising that a large percentage, if not a majority, of delirium consults arise from the critical care setting. Definitive treatment of delirium in any setting centers on the correction of underlying physiologic and iatrogenic insults; however, the pathogenesis of delirium is often multifactorial and definitive precipitants are not always known. As a result, psychiatric consultants are often asked to suggest pharmacologic management strategies for the delirious patient while simultaneously addressing predisposing and precipitating risk factors. The higher incidence of morbidity (including injury to self and staff as well as long-term cognitive impairment) and mortality (3-fold increase in 6-month mortality) in ICU patients with delirium underscores the importance of early identification and treatment.¹ With delirium often comes the added burden of prolonged mechanical ventilation and extended hospitalization. This leads to significantly increased risks for nosocomial infection and an increase in overall healthcare costs.

To underscore the importance of addressing delirium in the ICU, a recent study by Heymann and colleagues showed that in a cohort of 204 ICU patients, treating delirium within the first 24 hours of onset significantly reduced mortality (3-fold higher rate of mortality in the delayed treatment group vs. immediate treatment group).² Studies such as these highlight the necessity for vigilance in identifying and treating delirium in the ICU setting and promote moving away from the archaic notion that delirium is a transient, benign process, with no long-term sequelae.

The purpose of this review is to familiarize the reader with the major prospective clinical trials that have looked at pharmacologic interventions for delirium in the adult ICU population (Table 1). Studies in non-ICU patients were excluded in an attempt to minimize confounding variables that are inherent when generalizing findings between very different study populations. Furthermore, this review serves as an update of the current evidence and rationale behind using various pharmacologic agents for the management of delirium in the ICU.

Antipsychotics

Antipsychotics are currently the mainstay of pharmacotherapy for the management of delirium in most settings. They are thought to exert their influence primarily via dopaminergic blockade as it relates to the dopamine excess/acetylcholine deficiency hypothesis of delirium pathophysiology.³ There is also some evidence that antipsychotics, in particular haloperidol, may also impart a neuroprotective effect by proposed σ-1 receptor antagonism, which helps attenuate oxidative stress that then leads to neuronal damage in delirium.⁴ Furthermore, there are studies showing that antipsychotics may also function as immunomodulators via indirect antagonism of IL-1.⁵ Even in sedative-hypnotic and alcohol withdrawal delirium, where GABA-receptor agonists are first-line agents, antipsychotics have been shown to be useful adjuncts.

To date, there are few large-scale studies of antipsychotics for delirium exclusively in the ICU population. Per Society of Critical Care Medicine guidelines, haloperidol remains the first-line pharmacotherapeutic agent for the management of delirium in the intensive care setting.⁶ Its use in managing delirium in the ICU is supported by a long track record with multiple observational studies and case series that have shown both efficacy and safety even at high doses administered via intravenous (IV) infusion.^7,8 The use of haloperidol for delirium remains off-label, however, and relatively few placebo-controlled trials exist in the ICU population. Furthermore, though IV haloperidol is thought to carry less of a risk for extrapyramidal symptoms (EPS), its use warrants caution, given an increased risk for QTc prolongation and polymorphic ventricular tachyarrhythmias, such as torsades de pointes.^9,10

With the advent of second generation antipsychotics, we now have more options in patients who are sensitive to dopamine antagonism (specifically D₂ receptor antagonism). Studies thus far have not shown atypical antipsychotics to be superior in efficacy to haloperidol for the management of delirium in the ICU setting; however, there are multiple studies attesting to the equal efficacy of atypical antipsychotics and haloperidol.^11―13 With the added benefit of multiple dosage forms and routes of administration, however, haloperidol will likely remain a first-line agent in managing delirium in the ICU.

While studies comparing atypical antipsychotics and haloperidol have mostly been done in non-ICU populations, a recent study by Skrobik and colleagues looked at a cohort of 73 ICU patients who developed delirium.¹⁴ The study sample was subsequently randomized to receive either haloperidol or olanzapine. Comparable to non-ICU studies, findings showed that there were no significant differences in delirium index, benzodiazepine dose administered over time, or clinical improvement between the two study groups. As expected, the olanzapine group had a lower incidence of EPS. Limitations of this study included a lack of blinding, no placebo arm, as well as a relatively small sample size. In addition, both groups utilized additional PRN haloperidol, which may have confounded results.

To date, there are only two major randomized, placebo-controlled trials of antipsychotics for delirium exclusively in the ICU population. The MIND (Modifying the Incidence of Delirium) trial looked at 101 adult mechanically-ventilated medical and surgical ICU patients who were randomly assigned to receive haloperidol, ziprasidone, or placebo every 6 hours for up to 14 days.¹⁵ Delirium was then assessed for up to 21 days. Findings showed that there were no differences between groups in the duration of delirium or days alive without delirium. Interestingly, this study also showed that neither haloperidol nor ziprasidone was significantly better than placebo in treating delirium in this population. In addition, mortality, length of hospitalization, and ventilator-free days were all similar between groups. One must take these results with caution, however. There were major study limitations in the MIND trial including: small sample size, inclusion of non-delirious patients in the study group, exposure to open-label PRN haloperidol for breakthrough agitation in each study arm, and multiple rigid exclusion criteria.^15,16

The second study, by Devlin and colleagues, looked at 36 ICU patients with delirium who were assigned to receive either quetiapine or placebo in addition to PRN haloperidol.¹⁷ Study findings showed that quetiapine was associated with a shorter “time to first resolution” of delirium (1 day vs. 4.5 days in the placebo arm) and reduced duration of delirium (36 hours vs. 120 hours, respectively). In addition, the quetiapine group required less PRN haloperidol than the placebo group. Mortality and length of ICU stay were similar between study groups. Again, major limitations included small sample size and multiple exclusion criteria. In addition, when measuring “time to first resolution” of delirium, the investigators may have inadvertently included patients that were in a lucid interval yet still delirious.

Generalizations cannot be made based on the findings of the study by Devlin and colleagues or on those of the MIND trial. Both studies were underpowered and excluded patients with multiple co-morbidities including: patients with primary neurologic conditions and those exposed to antipsychotics prior to the studies, in addition to patients on QTc-interval prolonging medications and those with various cardiac anomalies. Extrapolation of these findings to most ICU populations would be premature at this point. Furthermore, there remains an abundance of anecdotal data that supports the routine usage of antipsychotics for the management of delirium. Additional large-scale prospective studies are still needed to solidify practice guidelines in the ICU population. Both of the above studies did, however, show that prospective, placebo-controlled trials of antipsychotics for delirium in the ICU population are both possible and safe.

Cholinesterase Inhibitors

Cholinesterase inhibitors have garnered recent attention as possible pharmacotherapeutic options in treating delirium. The reasoning behind their use relates to the central cholinergic deficiency hypothesis of delirium.³ Cholinesterase inhibitors function primarily by inhibiting enzymatic breakdown of acetylcholine. Observational studies and anecdotal reports using physostigmine, a prototypical cholinesterase inhibitor, in the reversal of anticholinergicinduced delirium were promising and prompted further investigation into the potential utility of using newer agents (such as donepezil, galantamine, and rivastigmine). As with other agents, there is a relative lack of data in the ICU population. The results are currently mixed, with successful reports of cholinesterase inhibitors treating delirium in case studies and smaller prospective studies offset by relatively poor outcomes in larger prospective trials.

For the most part, recent studies of cholinesterase inhibitors in ICU patients who have been diagnosed with delirium have focused on rivastigmine. The single largest prospective study to date was a multi-center, randomized, placebo-controlled trial by van Eijk and colleagues in the Netherlands.¹⁸ This study initially planned to look at 440 ICU patients diagnosed with delirium who were randomized to receive an increasing dose of either rivastigmine or placebo as an adjunct to haloperidol for the management of delirium. The study was prematurely stopped, after the inclusion of 104 patients, due to an increase in mortality in the rivastigmine group (n = 12, 22%) compared with placebo (n = 4, 8%). Furthermore, the median duration of delirium was longer in the rivastigmine group (5 days) compared with placebo (3 days). In addition, the patients in the rivastigmine group had a higher severity of delirium, stayed longer in the ICU, and received higher cumulative doses of haloperidol, lorazepam, and propofol. Overall, the van Eijk study did not support the widespread use of cholinesterase inhibitors in treating delirium in the ICU. If anything, this study suggested that these agents should be used with the utmost caution in the critically ill, though further studies are still needed to make any definitive conclusions.

α-2 Agonists

Though most often used in sedation and analgesia protocols in the ICU, α-2 agonists have recently been shown to reduce the incidence of, and treat, delirium in the critically ill. These agents have the added benefit of minimizing respiratory suppression and facilitating the maintenance of a low heart rate, thereby minimizing hemodynamic fluctuations and reducing energy/demand expenditure that may contribute to global cerebral insult.¹⁹ These agents are also thought to be neuroprotective by inhibiting the release and production of neurotoxic glutamate.²⁰

Recent studies investigating the efficacy in treating delirium with α-2 agonists have focused on the novel agent, dexmedetomidine. This is a centrally-acting α-2 agonist that is eight times more selective for α-2 adrenoreceptors than clonidine.²¹ Dexmedetomidine works both pre- and post-synaptically to decrease norepinephrine release and reduce sympathetic activity in the CNS.²¹ While initially approved for use in ICU patients for a duration of less than 24 hours, at least four recent clinical trials have shown that dexmedetomidine can be used safely for up to 30 days.^22–27 Though shown to have a lower incidence of rebound hypertension and tachycardia on abrupt discontinuation compared with clonidine, dexmedetomidine carries an increased risk for hypotension and bradycardia, especially with high-rate infusions.²¹

The proposed benefit of dexmedetomidine over standard agents for sedation/analgesia has centered on its lack of significant anticholinergic effects, promotion of sleep/wake cycle regulation, and reduced need for opioid analgesics (by as much as 40% in some studies) and GABA agonists.^28–33 These properties impart a unique profile to dexmedetomidine, thereby reducing the potential precipitating risk factors that play a role in delirium pathophysiology. Case in point, a recent study by Pandharipande and colleagues underscored the potential risks of benzodiazepine use in a cohort of 198 mechanically-ventilated ICU patients, showing that lorazepam use was an independent risk factor for progression to delirium in this at risk population.³⁴ Findings showed that in addition to a substantial increase in the risk for developing delirium at low doses, the probability of progressing to delirium reached 100% after total daily lorazepam doses of ≥ 20 mg.³⁴ Studies such as these underscore the importance of seeking out alternative agents for sedation and analgesia protocols.

There are numerous case studies examining the efficacy of using dexmedetomidine as both a primary and adjunctive therapy in sedation/analgesia protocols. Many of these studies examine the effectiveness of dexmedetomidine in treating symptoms attributable to delirium (such as agitation) as well as the incidence of delirium. Most prospective studies have evaluated the efficacy of using dexmedetomidine for sedation/analgesia protocols in mechanically-ventilated patients and looked at delirium incidence only as a secondary endpoint. There are few studies using dexmedetomidine as a primary agent in patients who were diagnosed with delirium at the onset on the study and even fewer have actually looked at the reduction in severity or resolution of delirium as primary endpoints.

The pivotal prospective study was performed by Reade and colleagues on 20 ICU patients exhibiting severe agitation presumed to be secondary to delirium at onset, then subsequently randomized to receive either dexmedetomidine or haloperidol infusions.²⁷ Time to extubation was the primary outcome measure and delirium incidence and severity was a secondary measure. A total of 10 patients (five in each study arm) met criteria for delirium by the end of the study; however, the dexmedetomidine group had an increased proportion of time spent with minimal or no delirium symptoms as measured by the Intensive Care Delirium Screening Checklist (ICDSC), with the dexmedetomidine group spending 95.5% of the time with a ICDSC score of <4 and 61% of the time with a score <1 compared with the haloperidol group who spent 31.5% and 0% of the time with the same respective scores. In addition, the dexmedetomidine group had a shorter time to extubation (median length of 19.9 hours vs. 42.5 hours in the haloperidol group), shorter length of ICU hospitalization (4.5 days vs. 8 days in the haloperidol group), as well as an overall shorter time in mechanical restraints and a reduced necessity for supplemental propofol when compared to the haloperidol group. Though promising, this study had multiple limitations including: small sample size, lack of blinding, possible underdosing in the haloperidol arm, and the assumption that agitation was due to delirium when, in fact, agitation is a nonspecific symptom with multiple potential causes.²⁷

Large-scale, randomized, placebo-controlled trials are still needed to establish the efficacy of using dexmedetomidine as a primary agent in treating delirium in the ICU population. Furthermore, the high cost of dexmedetomidine (on average $300–$400 per day) seems to be a limiting factor at first glance; however, a recent cost minimization analysis comparing dexmedetomidine and midazolam for sedation in a cohort of 366 mechanically-ventilated ICU patients showed that usage of dexmedetomidine resulted in a median total ICU cost savings of $9679 compared with midazolam.^25,35 Findings such as these are promising and suggest that usage of dexmedetomide may in fact lower overall healthcare costs; however, further replication of such studies is necessary to make any definitive conclusions on this basis. Nonetheless, dexmedetomidine remains a viable alternative in managing treatment-refractory delirium in the critical care population.

Pharmacologic Prophylaxis

The increasingly apparent morbidity and mortality associated with delirium in the ICU promotes the search for possible pharmacologic prevention strategies. While such prophylactic measures are still experimental, some promising studies have shown a possible role for premedicating certain at-risk patient populations in the interest of reducing delirium incidence and resultant sequelae. Most of these studies have been done in non-ICU populations, are relatively underpowered, and remain mixed at best. Those studies limited to the ICU population are far fewer.

A large proportion of studies looking at pharmacologic prophylaxis measures for delirium have been limited to patients undergoing elective surgical procedures. Of these, only the studies examining prophylaxis in elective cardiac surgery have involved patients in the ICU setting.^31,36–39 While α-2 agonists are discussed below, the studies to date have also looked at antipsychotics, ketamine, and cholinesterase inhibitors. One such study, by Prakanrattana and colleagues, looked at 126 patients undergoing cardiac surgery who were randomized to receive a single dose of either risperidone or placebo post-surgically.³⁶ The risperidone group was found to have a lower incidence of postoperative delirium (11.1% vs. 31.7% in the placebo arm). Similarly, a smaller study by Hudetz and colleagues examined the incidence of postoperative delirium in 58 cardiac surgery patients randomized to receive either ketamine or placebo during anesthetic induction with fentanyl and etomidate.³⁷ Findings showed that patients who received ketamine had a lower incidence of postoperative delirium (3% vs. 31% in the placebo arm). Finally, Gamberini and colleagues looked at 120 patients undergoing cardiac surgery who were randomized to receive either rivastigmine (three doses daily starting the evening before surgery and continued until the sixth postoperative day) or placebo.³⁸ Akin to the findings of most large-scale studies using cholinesterase inhibitors for delirium, there was no significant difference in the incidence of postoperative delirium between the rivastigmine and placebo groups (32% vs. 30%, respectively).

When looking exclusively at the ICU population, studies examining the efficacy of pharmacologic delirium prophylaxis have focused mainly on α-2 agonists. Despite one small-scale placebo-controlled study looking at the incidence of delirium with IV clonidine during ventilator weaning, most large-scale studies have focused on dexmedetomidine.⁴⁰ A pivotal trial was performed by Pandharipande and colleagues and is known as the maximizing efficacy of targeted sedation and reducing neurologic dysfunction (MENDS) trial.²⁴ In this double-blind trial, 106 mechanically-ventilated patients from two tertiary care centers were randomized to receive either dexmedetomidine or lorazepam for sedation. The primary outcome measure was days alive without delirium or coma. The dexmedetomidine group was found to have significantly more days alive without coma or delirium compared with the lorazepam group (7 days vs. 3 days). Furthermore, though not statistically significant, mortality measured after 28 days was found to be lower in the dexmedetomidine group compared with the lorazepam group (17% vs. 27%) as were ventilator-free days (22 days vs. 18 days, respectively). Subsequent subgroup analysis looking at septic vs. non-septic patients in the MENDS trial showed even greater differences, with septic patients in the dexmedetomidine group having significantly more days alive without delirium or coma, 70% less risk of mortality at 28 days, and more ventilator-free days compared with the septic patients in the lorazepam group.⁴¹

Limitations of the MENDS trial included the lack of a placebo arm and exclusion of patients with neurologic diseases (such as stroke or active seizures), severe liver disease, alcohol abuse, active myocardial infarction, second- or third-degree heart block, dementia, benzodiazepine dependence, severe hearing impairment, or being non-English speaking. Furthermore, per study design guidelines implemented by the FDA, dexmedetomidine could not be administered for more than 120 hours.²⁴ This may have potentially introduced confounders given the necessity to switch to standard sedation (lorazepam or midazolam) in patients who were in the dexmedetomidine study arm and necessitated continued sedation beyond 120 hours.²⁴

A similar study by Maldonado and colleagues looked at 118 mechanically ventilated cardiac surgery patients randomized to receive dexmedetomidine, propofol, or midazolam for postoperative sedation.³¹ The incidence of delirium was found to be significantly lower in the dexmedetomidine group (3%) compared with the propofol (50%) and midazolam groups (50%). The study lacked a placebo arm, was limited to patients undergoing valve replacement surgery, and excluded patients with the following conditions: dementia, on psychotropic medications, those with a history of substance abuse, advanced heart block, pregnancy, stroke within the past 6 months, and those age <18 years or >90 years. Furthermore, despite the lower incidence of delirium in the dexmedetomidine group, there were no significant differences in mean ICU or hospital stay.

Similarly, Shehabi and colleagues looked at 306 mechanically ventilated patients who underwent cardiac surgery and were randomized to receive either dexmedetomidine or morphine at equivalent levels of sedation/analgesia with delirium incidence as the primary endpoint.³⁹ Findings showed that there was no statistically significant difference in delirium incidence between groups (8.6% in the dexmedetomidine vs. 15% in the morphine group); however, dexmedetomidine patients spent 3 fewer days in delirium compared with the morphine group and were extubated sooner. Upon subgroup analysis, those patients who required an intra-aortic balloon pump and were in the dexmedetomidine group had a significantly lower incidence of delirium compared with the same subgroup of patients in the morphine arm (15% vs. 36%, respectively). This particular study was limited by its homogeneous population (cardiac surgery patients aged 60 yrs and older), a lack of delirium surveillance beyond 5 days, and the fact that the use of open-label morphine in the dexmedetomidine study group may have confounded results.

Other studies with dexmedetomidine in various sedation/analgesia protocols have looked at delirium incidence and duration only as secondary endpoints and have yielded mixed results. Compared with standard sedation protocols, dexmedetomidine has been shown to be as effective for moderate sedation with the added benefit of a significantly lower incidence of delirium in one study.²⁵ On the other hand, a similar study did not show a significant reduction in the incidence of delirium.²⁶ Results remain mixed and further studies looking at delirium incidence as a primary endpoint are still needed to make any definitive conclusions. Dexmedetomidine remains a viable alternative to standard sedating medications in mechanically-ventilated ICU patients who are already at an increased risk for developing or exacerbating delirium; however, use in delirium prophylaxis alone should still be exercised with caution as efficacy is yet to be solidified.

Conclusions

This article summarizes the spectrum of pharmacologic intervention studies for delirium in the critical care population. It remains of paramount importance for the practicing psychiatrist to be familiar with the breadth of pharmacotherapeutic options for the management and potential prevention of delirium. Studies to date remain mixed at best and warrant further investigation in this population.