Clearing up the confusion: The results of two pilot studies of antipsychotics for ICU delirium

Methods Objective: To demonstrate the feasibility of a placebocontrolled trial of antipsychotics for delirium in the inten sive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Design: Randomized, double-blind, placebo-controlled trial. Setting: Six tertiary care medical centers in the US. Subjects: One hundred one mechanically ventilated medical and surgical intensive care unit patients. Intervention: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side eff ects. Outcomes: Th e primary end point was the number of days patients were alive without delirium or coma. Secondary effi cacy end points included daily delirium risk, duration of delirium, duration of coma, the number of days patients were alive and breathing without assistance during the 21-day study period (ventilator-free days), time to ICU and hospital discharge, and all-cause 21-day survival.


Background
Given the lack of compelling evidence supporting the use of antipsychotics for delirium in critically ill patients and the potential adverse eff ects associated with these medica tions, placebo-controlled clinical trials are greatly needed.

Methods
Objective: To demonstrate the feasibility of a placebocontrolled trial of antipsychotics for delirium in the inten sive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Design: Randomized, double-blind, placebo-controlled trial. Setting: Six tertiary care medical centers in the US. Subjects: One hundred one mechanically ventilated medical and surgical intensive care unit patients. Intervention: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side eff ects. Outcomes: Th e primary end point was the number of days patients were alive without delirium or coma. Secondary effi cacy end points included daily delirium risk, duration of delirium, duration of coma, the number of days patients were alive and breathing without assistance during the 21-day study period (ventilator-free days), time to ICU and hospital discharge, and all-cause 21-day survival.

Results
During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No diff erences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46).

Conclusions
A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Th us, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.

Background
To date, there are no published double-blind, randomized, placebo-controlled trials to establish the effi cacy or safety of any antipsychotic medication in the management of delirium in the ICU.

Methods
Objective: To compare the effi cacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol. Design: Prospective, randomized, double-blind, placebocontrolled study. Setting: Th ree academic medical centers in the US and Canada. Subjects: Th irty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score >=4), tolerating enteral nutrition, and without a complicating neurologic condition. Intervention: Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy >=10 days, or intensive care unit discharge. Outcomes: Th e primary end point was time to fi rst reso lution of delirium. Secondary outcomes included dura tion of mechanical ventilation, ICU and hospital length of stay, hospital mortality, and discharge disposition. Measures of safety included total number of adverse and serious adverse events related to study drug, incidence of extrapyramidal symptoms, and episodes of QTc interval prolongation.

Conclusions
Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the eff ect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.

Commentary
Delirium is an acute disturbance in consciousness and cognition that fl uctuates in severity. Rather than a passing phase, delirium is now recognized as acute brain dysfunction and is associated with increased length of stay, cost, and mortality. Delirium is very common in the intensive care unit (ICU), occurring in 20-80% of patients, with the highest proportions seen in mechanically ventilated patients. Th ere is no US Food and Drug Administration approved treatment for delirium, though national guidelines recommended haloperidol as the drug of choice [3]. More recently, atypical antipsychotics have also been used. Observational data and one small randomized controlled trial in patients with hip fracture suggest improved outcomes with antipsychotics [4,5], yet until recently there were no placebo-controlled clinical trials in ICU patients to determine whether these drugs improve clinical outcomes or merely treat symptoms.
Th e two pilot studies reviewed in this critique provide the fi rst randomized, placebo-controlled evidence for the pharmacologic treatment of ICU delirium [1,2]. In the fi rst study, Girard and colleagues compared haloperidol, ziprasidone, and placebo in the treatment of delirium in 101 adult mechanically ventilated medical and surgical ICU patients [1]. Twice daily the frequency of study drug administration was adjusted according to delirium status and side eff ects. Th e authors found that neither haloperidol nor ziprasidone signifi cantly reduced the duration of delirium compared with placebo. No diff erences were found in secondary clinical outcomes, including ventilator-free days, hospital length of stay and mortality. Th e adverse events were similar between the three groups with no events being serious. Ten patients had prolongation of the QTc >500 msec (haloperidol 5.7% vs. ziprasidone 16.7% vs. placebo 8.3%, p=0.31), usually within 48 hours of study drug initiation.
In the second study, Devlin and colleagues compared quetiapine and placebo in the treatment of delirium in 36 adult medical and surgical ICU patients [2]. In this study, quetiapine was increased every 24 hours if more than one dose of haloperidol was given in the previous 24 hours. Th e authors found that scheduled, dose-escalated quetiapine added to as-needed haloperidol resulted in faster delirium resolution, less agitation, and a trend toward a greater rate of transfer to home or rehabilitation without any diff erences in mortality. Th ere were no serious study drug-related adverse events. QTc prolongation >500 msec was more common in placebo subjects (28% vs. 22%), though this diff erence was not signifi cant (p=1.0).
Th ese two studies are groundbreaking in the area of ICU delirium. Both were well-conducted and used validated and reliable delirium screening tools. In neither study were serious adverse events more common in active treatment groups, suggesting that antipsychotics were safe, at least within these patient populations and within the context of close monitoring for adverse events. Unfortunately, both studies were too small to reliably detect diff erences in important clinical outcomes, such as mortality or length of stay. Th is limitation was further amplifi ed by the use of open-label, as-needed anti psychotics if the clinical team considered it necessary, thereby minimizing potential diff erences between groups.
When encountering delirium in the ICU, it is important to start with modifi able risk factors, such avoiding polypharmacy, promoting sleep hygiene, correcting electrolyte abnormalities, and reorienting frequently, before reaching for drugs. Practically speaking, non-pharmacologic interventions are frequently insuffi cient. In addition to antipsychotics, emerging research suggests that alternative sedative agents, such as dexmedetomidine [6,7], may be less prone to causing delirium. Furthermore, daily sedation interruption and early physical therapy may also be benefi cial [8].

Recommendation
Taken together, the result of these pilot studies highlight the need for much larger, multicenter, placebo-controlled trials to determine whether continued use of antipsychotics in the ICU is warranted. Th ough screening for delirium using a validated instrument and treating with haloperidol remain recommended by national guidelines, clinicians should routinely monitor for adverse events, especially QTc prolongation.