Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND...

Feasibility, efficacy, and safety of antipsychotics for intensive careunit delirium: The MIND randomized, placebo-controlled trial*

Timothy D. Girard, MD, MSCI; Pratik P. Pandharipande, MD, MSCI; Shannon S. Carson, MD;Gregory A. Schmidt, MD; Patrick E. Wright, MD; Angelo E. Canonico, MD; Brenda T. Pun, MSN;Jennifer L. Thompson, MPH; Ayumi K. Shintani, PhD, MPH; Herbert Y. Meltzer, MD; Gordon R. Bernard, MD;Robert S. Dittus, MD, MPH; E. Wesley Ely, MD, MPH; for the MIND Trial Investigators

*See also p. 697.From Department of Medicine, Division of Allergy,

Pulmonary, and Critical Care Medicine (TDG, BTP, GRB,EWE) and Center for Health Services Research (TDG,RSD, EWE), Department of Anesthesiology, Division ofCritical Care (PPP), Department of Biostatistics (JLT,AKS), and Department of Psychiatry (HYM), VanderbiltUniversity School of Medicine, Nashville, TN; Depart-ment of Medicine, Division of Pulmonary and CriticalCare Medicine (SSC), University of North Carolina,Chapel Hill, NC; Department of Internal Medicine, Di-vision of Pulmonary Diseases, Critical Care, and Oc-cupational Medicine (GAS), University of Iowa CarverCollege of Medicine, Iowa City, IA; Moses H. ConeMemorial Hospital (PEW), Greensboro, NC; Departmentof Medicine (AEC), Saint Thomas Hospital, Nashville,TN; Geriatric Research, Education, and Clinical CenterService (TDG, RSD, EWE) and Anesthesia Service(PPP), Department of Veterans Affairs Medical Center,Tennessee Valley Healthcare System, Nashville, TN.

This investigator-initiated study was aided by re-ceipt of study drug from Pfizer, Inc., who had no rolein the design or conduct of the trial; in the collection,analysis, or interpretation of the data; or in the prep-aration, review, approval, or publication strategy of thismanuscript. Dr Girard received support from the Na-

tional Institutes of Health (HL007123), the HartfordGeriatrics Health Outcomes Research Scholars AwardProgram, the Vanderbilt Physician Scientist Develop-ment Program, and the VA Tennessee Valley GeriatricResearch, Education and Clinical Center (GRECC). DrPandharipande received support from the VA ClinicalScience Research and Development Service (VA CareerDevelopment Award), the ASCCA-FAER-Abbott Physi-cian Scientist Award, and the Vanderbilt PhysicianScientist Development Program. Dr Ely received sup-port from the VA Clinical Science Research and De-velopment Service (VA Merit Review Award), the VATennessee Valley GRECC, and the National Institutes ofHealth (AG027472).

Mind Trial Investigators: From Vanderbilt UniversitySchool of Medicine, Nashville, TN: Timothy D. Girard,MD, MSCI, Pratik P. Pandharipande, MD, MSCI, BrendaT. Pun, MSN, Bryan Cotton, MD, Russell R. Miller, MD,MPH, Jennifer L. Thompson, MPH, Ayumi K. Shintani,PhD, MPH, Herbert Y. Meltzer, MD, Paul W. Ragan, MD,Sharlet Anderson, MS, Joyce Okahashi, RN, Gordon R.Bernard, MD, Robert S Dittus, MD, MPH, and E. WesleyEly, MD, MPH. From University of North Carolina,Chapel Hill, NC: Shannon S. Carson, MD, Peter Rock,MD, Lydia H. Chang, MD, and Kayvon Salimi, MD.From University of Iowa Carver College of Medicine,

Iowa City, IA: Gregory A. Schmidt, MD. From Moses H.Cone Memorial Hospital, Greensboro, NC: Patrick E.Wright, MD. From Saint Thomas Hospital, Nashville,TN: Angelo E. Canonico, MD. From Department ofVeterans Affairs Medical Center, TN Valley Health-care System, Nashville, TN: Timothy D. Girard, MD,MSCI, Pratik P. Pandharipande, MD, MSCI, Bryan A.Cotton, MD, Robert S. Dittus, MD, MPH, and E.Wesley Ely, MD, MPH.

Dr. Girard has stock ownership in Pfizer, Inc. Dr.Meltzer has received grant support from Abbott, ACADIA,Dainippon Sumitomo, Eli Lilly, Janssen, Minster, Pfizer,Roche, Solvay. He has also consulted for Astellas, Lund-beck, and Wyeth. Dr. Dittus has received grant sup-port from Pfizer. Dr. Pandharipande has received hono-raria and grant support from Hospira, Inc. Dr. Pun hasreceived honoraria from Hospira, Inc. Dr. Ely has receivedhonoraria and grant support from Pfizer, Lilly, Hospira,and Aspect. The remaining authors have not disclosedany potential conflicts of interest.

For information regarding this article, E-mail:[email protected] and www.icudelirium.org

Copyright © 2010 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3181c58715

Objective: To demonstrate the feasibility of a placebo-con-trolled trial of antipsychotics for delirium in the intensive care unitand to test the hypothesis that antipsychotics would improve daysalive without delirium or coma.

Design: Randomized, double-blind, placebo-controlled trial.Setting: Six tertiary care medical centers in the US.Patients: One hundred one mechanically ventilated medical

and surgical intensive care unit patients.Intervention: Patients were randomly assigned to receive halo-

peridol or ziprasidone or placebo every 6 hrs for up to 14 days. Twiceeach day, frequency of study drug administration was adjustedaccording to delirium status, level of sedation, and side effects.

Measurements and Main Outcomes: The primary end point wasthe number of days patients were alive without delirium or coma.During the 21-day study period, patients in the haloperidol groupspent a similar number days alive without delirium or coma(median [interquartile range], 14.0 [6.0–18.0] days) as did pa-tients in the ziprasidone (15.0 [9.1–18.0] days) and placebogroups (12.5 [1.2–17.2] days; p � 0.66). No differences were

found in secondary clinical outcomes, including ventilator-freedays (p � .25), hospital length of stay (p � .68), and mortality(p � .81). Ten (29%) patients in the haloperidol group reportedsymptoms consistent with akathisia, compared with six (20%)patients in the ziprasidone group and seven (19%) patients in theplacebo group (p � .60), and a global measure of extrapyramidalsymptoms was similar between treatment groups (p � .46).

Conclusions: A randomized, placebo-controlled trial of antip-sychotics for delirium in mechanically ventilated intensive careunit patients is feasible. Treatment with antipsychotics in thislimited pilot trial did not improve the number of days alive withoutdelirium or coma, nor did it increase adverse outcomes. Thus, alarge trial is needed to determine whether use of antipsychoticsfor intensive care unit delirium is appropriate. (Crit Care Med2010; 38:428–437)

Trial Registration: ClinicalTrials.gov, number NCT00096863.KEY WORDS: delirium; intensive care units; antipsychotic agents;

haloperidol; ziprasidone; clinical trial

428 Crit Care Med 2010 Vol. 38, No. 2

Delirium is an acute disorder ofconsciousness and cognitionthat occurs in 60% to 80% ofmechanically ventilated inten-

sive care unit (ICU) patients (1–3). Amongthese patients, this manifestation of acutebrain dysfunction conveys profound risk formorbidity and mortality, as it is associatedwith self-extubation (4), prolonged hospitalstays (5, 6), and increased mortality (1, 6,7). It is estimated, in addition, that ICUdelirium is associated with health carecosts ranging between $6 to $20 billionannually in the US alone (8).

Despite its numerous deleterious ef-fects, no placebo-controlled clinical trialsexist to support the use of pharmacologicagents solely intended to treat deliriumin the ICU. In fact, the majority of delir-ious patients receive no specific treat-ment for this neuropsychiatric syndrome,in large part because it frequently re-mains unrecognized in clinical practice(9, 10). When diagnosed, delirium shouldfirst prompt the identification and man-agement of potential underlying causes.Then, to prevent harmful sequelae, theSociety of Critical Care Medicine has rec-ommended the use of haloperidol for thetreatment of delirium in critically ill pa-tients (11), despite its unproven efficacyand the absence of Food and Drug Ad-ministration approval for this indication.In keeping with this recommendation, hal-operidol is currently the medication mostwidely used to treat ICU delirium (12). Inrecent years, however, newer “atypical” an-tipsychotics (e.g., risperidone, olanzapine,quetiapine, and ziprasidone) have alsogained popularity (13), although until re-cently only olanzapine had been studied inthe ICU (14).

Given the lack of compelling evidencesupporting the use of antipsychotics fordelirium in critically ill patients and thepotential adverse effects associated withthese medications, including torsades depointes and sudden cardiac death (15,16), hypotension (17), neuroleptic malig-nant syndrome (18), and extrapyramidalsymptoms (19), placebo-controlled clini-cal trials are greatly needed to evaluatethe efficacy of antipsychotic medicationsin reducing the burden of delirium in theICU. Thus, to demonstrate the feasibility ofa randomized, placebo-controlled trial ofantipsychotics in mechanically ventilatedICU patients, we conducted the Modifyingthe Incidence of Delirium (MIND) Trial, amulticenter, randomized, double-blind,placebo-controlled trial. We hypothesizedthat both haloperidol and ziprasidone

would be efficacious and safe for the treat-ment of ICU delirium. This work has beenpresented in abstract form (20).

MATERIALS AND METHODS

Patient Population

Study personnel screened all adult (olderthan 18 yrs of age) mechanically ventilatedmedical and surgical ICU patients who hadan abnormal level of consciousness or werereceiving sedative or analgesic medicationsin six tertiary care medical centers: Van-derbilt University Medical Center, SaintThomas Hospital, and the Department ofVeterans Affairs Medical Center in Nashville,TN; University of North Carolina Hospitalsin Chapel Hill, NC; University of Iowa Hos-pitals in Iowa City, IA; and Moses H. ConeMemorial Hospital in Greensboro, NC. Theinstitutional review boards at each partici-pating center approved the study protocol,and we obtained informed consent fromstudy participants or their authorized sur-rogates. In response to our InvestigationalNew Drug Application for this investigator-initiated trial, the Food and Drug Adminis-tration designated the trial exempt.

We excluded patients from enrollment forthe following reasons: pregnancy, continuousmechanical ventilation �60 hrs before screen-ing, no plan for gastric access within 48 hrs,moribund state and/or withdrawal of life sup-port, admission after drug overdose or suicideattempt, ongoing outpatient neuroleptic use,allergy to haloperidol or ziprasidone or historyof neuroleptic malignant syndrome, ongoingseizures, stroke in the past 2 wks, high risk forventricular dysrhythmias (ongoing treatmentwith drugs known to prolong the QT intervalor baseline corrected QT (QTc) �500 msec inthe absence of a bundle branch block, historyof torsades de pointes, clinically significantventricular tachycardia during the currenthospital stay, myocardial infarction in thepast 2 wks, uncompensated stage IV heartfailure, refractory hypokalemia [�3.0 mg/dL] or hypomagnesemia [�1.8 mg/dL]), orpreviously diagnosed neurologic disease(suspected anoxic brain injury, acute trau-matic brain injury, or moderate to severedementia). Dementia was identified usingthe medical record and two validated surro-gate questionnaire: the modified Blessed de-mentia rating scale (21) and the InformantQuestionnaire of Cognitive Dysfunction inthe Elderly (22). We excluded patients with amodified Blessed dementia rating scalescore �4 or an Informant Questionnaire ofCognitive Dysfunction in the Elderly score�4.0, in keeping with previous literatureshowing that these cut-offs identify patientswith moderate to severe dementia (21, 23).

Randomization

After informed consent was obtained, werandomly assigned patients in a 1:1:1 mannerto treatment with haloperidol, ziprasidone, orplacebo, using a computer-generated, permuted-block randomization scheme stratified accord-ing to study center. A coordinating centerbiostatistician designated treatment group as-signments on a list that was provided only tothe investigational pharmacists at each studycenter, who referred to their unique list aftereach patient was enrolled to determine groupassignment. Except for the pharmacist, nei-ther study personnel nor patients were awareof treatment group assignment.

Study Protocol andAssessments

Immediately after enrollment, patients re-ceived one of the three colorless, odorless, andtasteless study drugs: 5 mg haloperidol (as asolution containing 1 mg/mL), 40 mg ziprasi-done (as a solution containing 8 mg/mL), ormatching placebo (as a 5-mL solution). Alter-natively, patients in any treatment group whowere temporarily without gastric access re-ceived blinded study drug per group assign-ment via a 0.5-mL intramuscular injection. Nomore than eight total doses could be givenintramuscularly. The second dose of studydrug was administered 12 hrs after the firstdose as long as the QTc interval remained�500 msec; subsequent doses were adminis-tered every 6 hrs until clinical changesprompted a change in this frequency.

Trained study personnel evaluated patientstwice daily for acute brain dysfunction, diagnos-ing delirium with the Confusion AssessmentMethod for the ICU (24–26) and assessing levelof arousal with the Richmond Agitation–Sedation Scale (RASS) (27, 28). Study drug fre-quency was reduced to every 8 hrs when patientswere negative for the Confusion AssessmentMethod for the ICU (i.e., delirium/coma-free) ontwo consecutive assessments, reduced to every12 hrs when patients were delirium/coma-freeon three consecutive assessments, and discon-tinued when patients were delirium/coma-freeon four consecutive assessments (i.e., �48 con-secutive hours without delirium or coma). Ad-ditionally, study drug frequency was reduced in asimilar manner when patients were overse-dated—diagnosed when observed RASS was �2levels deeper than target RASS (determined bythe managing ICU team)—despite discontinua-tion of sedatives and sedating analgesics. Studydrug was restarted (or dosing frequency wasincreased) when oversedation resolved. Like-wise, if patients who were delirium-free had re-current delirium, the study drug was restarted ifpreviously discontinued or dosing frequency wasincreased to the previously effective frequency.

429Crit Care Med 2010 Vol. 38, No. 2

Regardless of clinical status, all study drugs werediscontinued on study day 14.

Every day that study drug was adminis-tered, research personnel assessed patients forextrapyramidal symptoms using a modifiedSimpson-Angus Scale (29). The original Simp-son-Angus Scale consists of 10 items: gait,arm dropping, shoulder shaking, elbow rigid-ity, wrist rigidity, leg pendulousness, headdropping, glabella tap, tremor, and salivation.Because some of these items cannot be as-sessed reliably in ICU patients, we used a mod-ified scale that included elbow rigidity, wristrigidity, glabella tap, tremor, and salivation, aswell as dystonia. Subjective akathisia was as-sessed on days that patients were not coma-tose or delirious using a 10-cm visual analogscale; we considered any result �0 to indicateakathisia. Patients were also assessed daily forQT interval prolongation and other adverseevents. Study drug was discontinued if extra-pyramidal symptoms (�3 points on three ormore categories of the modified Simpson-Angus Scale) or QTc prolongation �500 msecwas observed and restarted when the adverseeffect resolved. Also, study drug was discon-tinued during any period that the followingdrugs known to prolong the QT interval wereadministered: class Ia or III antiarrhythmics,pimozide, gatifloxacin, moxifloxacin, pentam-idine, cotrimoxazole, tacrolimus, and dolas-etron. Finally, study drug was permanentlydiscontinued if life-threatening drug-relatedadverse events occurred, including neurolep-tic malignant syndrome, torsades de pointes,or other ventricular tachycardia requiringtreatment, or if the patient had dystonia de-velop that was unresponsive to anticholinergictreatment.

Other treatments, including approaches tosedation, were determined by the managingICU team. Each of the participating ICUs uti-lized patient-targeted sedation as part of usualpractice; bedside nurses regularly monitoredlevel of sedation using validated sedationscales and titrated sedative doses up or downto achieve the targeted level of sedation spec-ified in the physicians’ orders, which wereupdated as needed according to changes in theclinical scenario. Daily spontaneous awaken-ing trials (i.e., daily interruption of sedatives)were common but not yet protocolized ormandated in all participating ICUs. Open-labelantipsychotic administration was strongly dis-couraged during the trial but could be used ifthe ICUs’ team considered it necessary forbreakthrough delirium and agitation. None ofthe participating ICUs used formalized non-pharmacologic interventions to prevent ortreat delirium.

All adverse events were reported to an in-dependent Data Safety Monitoring Board. TheData Safety Monitoring Board reviewed twointerim analyses of adverse events after enroll-

ment of 30 and 60 patients; no interim anal-ysis of efficacy end points was conducted.

To evaluate whether the enterally admin-istered study drug was reaching systemic cir-culation, blood was collected from each pa-tient within 48 hrs of study drug initiation. Atthe Nathan Kline Institute (Orangeburg, NY),haloperidol plasma concentration was mea-sured by radioimmunoassay (30), and ziprasi-done plasma concentration was measured byliquid chromatographic assay using fluores-cence detection (31).

End Points and Follow-up

The primary efficacy end point was thenumber of days patients were alive withoutdelirium or coma (i.e., delirium/coma-freedays) during the 21-day study period. Wechose this end point because the sedating ef-fects of antipsychotics could increase comaduration, thereby confounding an analysis ofdelirium duration. We sought to assess theeffect of antipsychotics on the duration of“normal” brain function in the ICU, hypothe-sizing that treatment would increase the num-ber of “normal,” or delirium/coma-free, daysby reducing delirium duration (while comaduration remained unchanged). Secondary ef-ficacy end points included daily delirium risk,duration of delirium, duration of coma, thenumber of days patients were alive and breath-ing without assistance during the 21-day studyperiod (ventilator-free days) (32), time to ICUand hospital discharge, and all-cause 21-daysurvival.

Each study day before ICU discharge ordeath, patients who responded to physical butnot to verbal stimulation (RASS �4) or didnot respond at all to verbal or physical stim-ulation (RASS �5) were classified as coma-tose. Because delirium cannot be diagnosed inthe setting of coma, patients who were notcomatose but were positive for Confusion As-sessment Method for the ICU were classified asdelirious. Those without coma or deliriumwere classified as delirium/coma-free. We as-sumed all patients who were discharged dur-ing the 21-day study period to be delirium/coma-free after discharge.

Accuracy of sedation was determined eachstudy day by comparing observed RASS withtarget RASS (determined by the managing ICUteam). A patient was considered accuratelysedated on days that the observed RASS waswithin 1 point of the target RASS.

Statistical Analysis

Based on pilot data, we anticipated thatpatients in the placebo group would have amean � SD of 10.02 � 8.48 delirium/coma-free days and a median of 12 days (interquar-tile range, 0–18 days). Because this variable isskewed, we transformed delirium/coma-free

days for the power analysis. At a two-sidedsignificance level of 2.5%, after Bonferroniadjustment for pair-wise comparisons of threegroups, a trial with 29 patients in each groupwould have 80% analytical power to detect a25% increase (i.e., improvement) in delirium/coma-free days by the interventions.

We analyzed all data using an intention-to-treat approach. Continuous data are describedusing median and interquartile range and cat-egorical data using frequencies and propor-tions. Except for analyses of repeated mea-sures, we used the Kruskal-Wallis test tocompare continuous variables between thethree treatment groups and the chi-squaretest to compare categorical variables. To com-pare the effects of the two study drugs andplacebo on ICU and hospital length of stay, weused time-to-event analyses; Kaplan-Meieranalyses were used to determine medians andinterquartile ranges, and log-rank tests wereused to assess the effect of the treatments. Toexamine the effect of treatment group on dailydelirium risk, we used a Markov regressionmodel with generalized estimating equationsto analyze the probability of being delirious oneach day after receipt of study drug accordingto treatment group, adjusting for mental sta-tus at the time study drug was administered(33). We analyzed in the model all 24-hr peri-ods of observation (from 7:00 AM to 6:59 AM thenext day) that included study drug adminis-tration (days 1–14) and were followed by adelirium assessment; 24-hr periods ending indeath or coma were excluded. To assess for aninteraction between current mental status andthe effect of study drug on delirium risk, weincluded an interaction term in the Markovregression model. When analyzing repeatedobservations from the same patient, we usedmethods that account for data clustering (34).Specifically, we compared daily RASS targetsbetween the treatment groups using propor-tional odds logistic regression with general-ized estimating equations and daily doses ofsedatives between the treatment groups usinglinear mixed models. No subgroup analyseswere performed. We used R (version 2.7.2Patched; www.r-project.org) for all statisticalanalyses (35).

RESULTS

Enrollment and BaselineCharacteristics

From February 2005 to July 2007,3297 patients who met inclusion criteriawere screened for enrollment. Of these,we enrolled 103 patients. Figure 1 dis-plays the reasons for exclusion and fol-low-up for the study population perCONSORT guidelines (36). All 101 pa-tients from whom any outcomes data


were obtained were included in the anal-yses. Two patients who were enrolled andrandomized to treatment with ziprasi-done were withdrawn from the trial be-cause of ventricular tachycardia beforeever receiving study drug. No outcomesdata for analysis were obtained fromthese two patients.

The three groups were similar at base-line (Table 1). Severity of illness was highat enrollment, and most patients hadsymptoms of acute brain dysfunction;49% of all patients were delirious at en-rollment and 36% were comatose. Onlyseven patients (7%) had received haloper-idol before study enrollment, and no pa-tient had received ziprasidone.

Antipsychotic Therapy

Duration and volume of study drugadministered were similar among thethree treatment groups (Table 2); the ma-jority of patients in each group receivedat least 4 days of study drug. On days thatstudy drug was administered, patients in

the haloperidol group received 15.0 mg/day (10.8–17.0 mg/day) and patients inthe ziprasidone group received 113.3 mg/day (81.0–140.0 mg/day). All but ninedoses of study drug were administered asan enteral solution; three patients (one inthe ziprasidone group and two in theplacebo group) received three intramus-cular doses each.

In addition to study drug, at least onedose of antipsychotic medication was ad-ministered by the ICU team to one-thirdof all patients, almost entirely as open-label haloperidol (Table 2). In the placebogroup, 15 (42%) patients received an an-tipsychotic in addition to study drugcompared with seven (20%) patients inthe haloperidol group and 10 (33%) pa-tients in the ziprasidone group (p � .14).These open-label antipsychotics were typ-ically given as single doses; only seven(19%) patients in the placebo group re-ceived an open-label antipsychotic on �1day compared with two (6%) patients inthe haloperidol group and four (13%) pa-

tients in the ziprasidone group. Amongthese patients, three (8%) in the placebogroup, one (3%) in the haloperidol group,and one (3%) in the ziprasidone groupreceived open-label haloperidol at dosescomparable to those administered perprotocol to patients in the haloperidolgroup (i.e., �15 mg/day). Thus, com-pared to the study drug doses, the totaldoses of open-label haloperidol weresmall; a median dose of 4.5 mg (inter-quartile range, 2.9–23.8 mg) was admin-istered to six patients in the haloperidolgroup over the course of the trial, 10.0mg (interquartile range, 5.0–20.0 mg)was administered to nine patients in theziprasidone group, and 12.5 mg (inter-quartile range, 5.5–50.2 mg) was admin-istered to 14 patients in the placebogroup.

Forty-eight hours after study drug ini-tiation, only patients in the haloperidolgroup had circulating concentrations ofhaloperidol in the range considered ther-apeutic for schizophrenia (Fig. 2); a ther-apeutic range for ICU delirium has notbeen defined. The median haloperidolplasma concentration was 4.5 ng/mL (in-terquartile range, 2.85–5.8 ng/mL) in thehaloperidol group compared with 0ng/mL (interquartile range, 0–0) in theziprasidone group and 0 ng/mL (inter-quartile range, 0–0) in the placebo group(p � .0001). Patients in the ziprasidonegroup had therapeutic circulating con-centrations of ziprasidone 48 hrs afterstudy drug initiation (median, 67 ng/mL;interquartile range, 18.5–138 ng/mL).

Neurologic and Other Outcomes

Neither haloperidol nor ziprasidonesignificantly increased the number ofdays patients were alive without deliriumor coma, compared with placebo, and theduration of both delirium and coma wassimilar among treatment groups (Fig. 3and Table 3). Additionally, daily deliriumrisk was no different for those treatedwith haloperidol (odds ratio for delirium,1.2; 95% confidence interval, 0.6–2.2) orziprasidone (odds ratio, 1.1; 95% CI, 0.5–2.2) compared with placebo (p � .80); nointeraction was noted between currentmental status and the effect of study drugon delirium risk.

Daily sedation goals (i.e., target RASS)were similar in the three groups through-out the study (p � .52); on study day 1,the median target RASS was �2 (lightsedation) in all groups, increasing toRASS �1 (drowsy) by study day 3, and

Figure 1. CONSORT flow diagram showing enrollment, randomization, and follow-up of the studypopulation. *Two patients were excluded after randomization, before study drug was administered,because of ventricular tachycardia (VT). No outcomes data could be collected for these two patientsafter their withdrawal. NMS, neuroleptic malignant syndrome.


RASS 0 (alert and calm) by study day 5 inall groups. To achieve these sedationgoals, patients in the three treatmentgroups received similar doses of sedativemedications (Fig. 4), and accurate seda-tion was achieved on the majority of daysfor patients in all three groups (Table 3).

Other clinical outcomes were simi-larly unaffected by antipsychotic treat-ment, including duration of ICU and hos-pital stay, time spent alive and breathing

without assistance, and mortality duringthe study period.

Safety

No serious adverse event occurredduring the trial; none of the patients hadsigns or symptoms of neuroleptic malig-nant syndrome, and no ventricular ar-rhythmias occurred in patients after ini-tiation of the study drug.

Ten (29%) patients in the haloperidolgroup reported symptoms consistentwith akathisia, compared with six (20%)patients in the ziprasidone group andseven (19%) patients in the placebogroup (p � .60). Among patients whoreported akathisia, severity of symptoms(as determined by the maximum scorereported by each patient on a visual ana-log scale) was not significantly differentaccording to treatment group (median,[interquartile range], 7.5 [2.6–8.0] forthe haloperidol group vs. 4.0 [2.0–8.5] inthe ziprasidone group vs. 5.0 [3.5–9.4] inthe placebo group; p � .65). In contrastto akathisia, other extrapyramidal symp-toms were experienced by fewer patientsaccording to the modified Simpson-Angus Scale; four (11%) patients in thehaloperidol group vs. two (7%) patientsin the ziprasidone group vs. six (17%)patients in the placebo group were ob-served to have these extrapyramidalsymptoms (p � .46). Only one patient,who was in the placebo group, had extra-pyramidal symptoms that promptedtreatment with benztropine.

Ten patients had prolongation of theQTc �500 msec while receiving studydrug, usually within 48 hrs of study druginitiation. Two of these patients were in thehaloperidol group, five were in the ziprasi-done group, and three were in the placebogroup (p � .31). None of the patients had aventricular arrhythmia.

DISCUSSION

In the MIND Trial, the first reportedrandomized, placebo-controlled trial toevaluate the efficacy of antipsychotics fordelirium in the ICU (20), we found noevidence to suggest that either haloperi-dol or ziprasidone effectively treats delir-ium in mechanically ventilated ICU pa-tients. Patients treated with thesemedications spent no more time freefrom delirium and coma during the trialthan did patients treated with placebo.Similarly, the adverse effects classicallyassociated with antipsychotics were notsignificantly more likely to affect patientsin the treatment groups compared withthose receiving placebo. In light of thecurrent widespread use of haloperidol aswell as atypical antipsychotics for themanagement of ICU delirium, these re-sults strongly suggest that a much larger,multicenter, placebo-controlled trial isneeded to definitively determine whethercontinued use of antipsychotics in theICU is warranted.

Table 1. Baseline characteristics

CharacteristicaHaloperidol,

n � 35Ziprasidone,

n � 30Placebo,n � 36

Age, yr 51 (35–59) 54 (47–66) 56 (43–68)Female, n (%) 15 (43) 9 (30) 14 (39)APACHE II score 26 (21–31) 26 (23–32) 26 (21–32)SOFA score 11 (10–13) 10 (9–12) 11 (9–13)Charlson comorbidity index 0 (0–1) 1 (0–2) 1 (0–2)ICU type, n (%)

Medical 20 (57) 20 (67) 23 (64)Surgical 8 (23) 6 (20) 8 (22)Trauma 7 (20) 4 (13) 5 (14)

ICU admission diagnosis, n (%)Sepsis/acute respiratory distress syndrome 10 (29) 10 (33) 9 (25)Chronic obstructive pulmonary disease/asthma 3 (9) 2 (7) 4 (11)Other pulmonaryb 6 (17) 7 (23) 3 (8)Myocardial infarction/congestive heart failure 2 (6) 0 (0) 1 (3)Other medicalc 6 (17) 4 (13) 9 (25)Traumatic injury 7 (20) 4 (13) 5 (14)Surgeryd 1 (3) 3 (10) 5 (14)

Brain dysfunction on first study day, n (%)Coma 12 (35) 9 (32) 14 (40)Delirium 16 (47) 15 (54) 17 (49)

Antipsychotics before enrollment, n (%)Haloperidol 1 (3) 2 (7) 4 (11)Ziprasidone 0 (0) 0 (0) 0 (0)

APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ FailureAssessment; ICU, intensive care unit.

aMedian (interquartile range) unless otherwise noted; bother pulmonary included respiratoryfailure attributable to pulmonary hypertension, pulmonary fibrosis, pulmonary embolism, hemoptysis,and cystic fibrosis; cother medical included altered mental status, gastrointestinal hemorrhage, hepaticfailure, malignancy, and renal failure; dsurgery included colonic, gastric, head/neck, hepatobiliary,pancreatic, and vascular surgery.

Table 2. Study drug delivery and other antipsychotics

DrugaHaloperidol,


n � 30Placebo,n � 36 p

Study drugDays on drug 7 (4–10) 4 (3–10) 5 (3–7) .23Volume, mL 110 (45–158) 56 (28–141) 82 (35–120) .41Total dose, mg 110 (45–158) 450 (220–1130) NA NAAverage daily dose, mg 15 (11–17) 113 (81–140) NA NA

Additional haloperidolb

Patients treated, n (%) 6 (17) 9 (30) 14 (39) .13Total dose, mg 4.5 (2.9–23.8) 10.0 (5.0–20.0) 12.5 (5.5–50.2) .30Average daily dose, mg 4.5 (2.9–12.5) 5.7 (5.0–10.0) 5.0 (10.0–11.9) .65

Additional atypical antipsychoticsb

Patients treated, n (%) 1 (3) 2 (7) 4 (11) .39

NA, not applicable.aMedian (interquartile range) unless otherwise noted; badministered by the intensive care unit

team in addition to study drug for breakthrough delirium and agitation.


Whereas some claim that it is not feasi-ble to randomize this difficult population ofcritically ill patients to treatment with an-tipsychotics or placebo because of frequentuse of these medications in the ICU, theMIND Trial demonstrates that a double-blind, placebo-controlled trial of antipsy-chotics for ICU delirium is feasible. Notonly did the institutional review boards ofmultiple medical centers approve the trialas ethically sound but also ICU cliniciansand surrogate decision-makers similarlyagreed that patients’ participation in theMIND Trial was appropriate, and the pa-tients themselves nearly uniformly con-sented once capable. Withdrawal from thetrial was minimal, as was discontinuationof study drug because of adverse effects. Inaddition, patients were assessed easilythroughout the trial for delirium using avalidated, reliable instrument, and objec-tive tools were available to facilitate moni-toring for adverse effects, including extra-pyramidal symptoms.

Although the pathogenesis of deliriumin critically ill patients remains relativelyunproven, hypotheses generated by re-search outside of the ICU propose thatdelirium results from a decrease in ace-tylcholine and increase in dopamine inthe brain (37), both of which may occurin response to factors promoting cerebraloxidative stress during critical illness.Antipsychotics, which exert their affectsby altering concentrations of a variety ofneurotransmitters in the central nervoussystem, therefore have been recom-mended as potentially effective pharma-cologic therapies for delirium. Haloperi-dol, for instance, works primarily viapotent antagonism of the dopamine D-2receptor (38), whereas ziprasidone (like-wise a dopamine D-2 antagonist) also hasimportant action as an antagonist of se-rotonin 5-HT2A receptors, thereby reduc-ing the extrapyramidal side effects causedby dopamine blockade (39). In addition tothese neurotransmitter-mediated effects,animal and in vitro models suggest thattypical and atypical antipsychotics alsohave immunomodulatory and neuropro-tective effects that may serve to reducethe central nervous system derangementsresulting from critical illness (40, 41).

Two clinical trials have found that anti-psychotics, compared with placebo, hastenthe resolution of delirium in hospitalizedpatients without critical illness. Hu et al(42) found that haloperidol and olanzapineeach led to earlier improvements in Delir-ium Rating Scales scores among 175 el-derly patients, compared with placebo.

Treatment Group

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Haloperidol Ziprasidone Placebo

0

2

4

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14

Figure 2. Haloperidol plasma concentrations on study day 2 according to study group. For patients inthe haloperidol group, the median haloperidol plasma concentration was 4.5 ng/mL (interquartilerange, 2.85–5.8 ng/mL). Alternatively, all but two patients in the ziprasidone group and three in theplacebo group had undetectable haloperidol plasma concentrations.

Figure 3. Line graph of percentage of patients alive without delirium or coma during the 21-day studyperiod according to treatment group. Acute brain dysfunction, in the form of delirium or coma, wascommon at enrollment in all treatment groups and resolved gradually throughout the course of thetrial. Treatment with antipsychotics did not significantly affect the number of days patients were alivewithout delirium or coma; the median delirium/coma-free days was 14.0 days (interquartile range,6.0–18.0 days) in the haloperidol group vs. 15.0 days (interquartile range, 9.1–18.0 days) in theziprasidone group vs. 12.5 days (interquartile range, 1.2–17.2 days) in the placebo group (p � .66).


Similarly, Kalisvaart et al (43) found thathaloperidol reduced the severity and dura-tion of delirium among elderly patients un-dergoing hip surgery, compared with pla-cebo. In the only clinical trial published todate that evaluated antipsychotics for delir-ium in the ICU, Skrobik et al (14) observedthat Delirium Index scores decreased overtime for patients treated with haloperidoland those treated with olanzapine, but noplacebo group was studied.

Despite the findings of these trials anda sound scientific rationale, our resultsdo not support the hypothesis that anti-psychotics definitively treat delirium dur-ing intense critical illness. Several possi-ble explanations for these results exist.First, this pilot investigation, which wasdesigned primarily to demonstrate thefeasibility of a double-blind, placebo-controlled trial of antipsychotics for ICUdelirium, was likely significantly under-powered to demonstrate the potential ef-ficacy of these medications for many out-comes, such as length of stay andsurvival. Second, antipsychotics may ef-fectively treat some “positive” symptomsof hyperactive delirium, e.g., psychomo-tor agitation and hallucinations, withoutreducing “negative” symptoms of hypoac-tive delirium, including inattention, dis-ordered cognition, and a depressed levelof consciousness. Third, changes in drugabsorption attributable to critical illnessmay have diminished circulating concen-trations of the study drugs. Our measure-

ments suggested therapeutic concentra-tions were achieved, but because oflimited resources only one measurement(48 hrs after enrollment) was made perpatient. Finally, delirium in the ICU maybe less responsive to focused pharmaco-logic therapies than delirium in hospital-ized patients without critical illness.Whereas the latter population frequentlyhas delirium develop when one or twoprecipitating risk factors are encoun-tered, critically ill patients are exposed onaverage to 11 different risk factors thatmay contribute to the development andpersistence of delirium in the ICU (4, 5).Antipsychotics may be effective in treat-ing delirium attributable to some riskfactors (e.g., hypoxia caused by cardio-genic pulmonary edema) but not delir-ium attributable to other risk factors(such as inflammation-driven coagulopa-thy caused by sepsis). Treatment with an-tipsychotics without concomitant resolu-tion of the majority of precipitating riskfactors also may be ineffective. Definitivetreatment of ICU delirium undoubtedlyrequires the identification and treatmentof underlying somatic causes, efforts thatwere undertaken by the ICU teams caringfor patients in all three of the treatmentgroups in this trial.

Antipsychotic medications, however,may be beneficial when somatic causes ofdelirium are treated and modifiable delir-ium risk factors are optimized. Nonphar-macologic interventions targeting risk fac-tors for delirium, for example, have been

evaluated in non-ICU cohorts (44), al-though no data exist about the efficacy ofthese approaches in the ICU. Of the phar-macologic strategies intended to reduce theburden of delirium in the ICU, sedationwith the �2-adrenergic receptor agonistdexmedetomidine has been shown to re-duce the duration of delirium as well ascoma in the ICU as compared with moretraditional sedation using benzodiazepines(45, 46).

Important strengths of the MIND Trialinclude randomization, inclusion of aplacebo group, use of validated and reli-able instruments for the diagnosis of de-lirium and coma, and blinding of ICU andresearch personnel as well as patients totreatment allocation (although blindingrequired delivery of study drug enterallyrather than intravenously—as haloperi-dol is most often delivered in the ICU—because the Food and Drug Administra-tion did not permit intravenous adminis-tration of ziprasidone). A placebo group isessential in delirium trials, because thesymptoms of this form of brain dysfunc-tion resolve over time for the majority ofpatients without any specific treatment.

Limitations of the trial include thesmall sample size, lack of enforcement bystudy personnel of a standardized seda-tion protocol, and the exposure of somepatients in the ziprasidone and placebogroups to open-label haloperidol. Thesample size was small by design, becauseour primary objective was to demonstratefeasibility. Ten percent of patients en-rolled did not have delirium; to enrollpatients as early as possible so that studydrug would be administered on all daysthat patients were delirious, we did notrequire a diagnosis of delirium at enroll-ment but instead enrolled patients athigh risk. Thus, inclusion of a smallnumber of non-delirious patients likelyreduced our statistical power when com-paring outcomes. Our results may notapply to some ICU patients who mightnormally be treated with antipsychotics,including patients transferred from an-other hospital after 5 days of mechanicalventilation, those without gastric access,those with severe dementia, and patientsafter suicide attempt. Although cliniciansin all participating ICUs utilize validatedsedation scales and protocols as well asdaily interruption of sedation, it is possi-ble that not all patients were treated withthe same approach to sedation. However,daily sedation goals (as measured byRASS targets determined by the ICUteams) were similar for patients in the

Table 3. Clinical outcomes

OutcomeaHaloperidol,


n � 30Placebo,n � 36 p

Delirium/coma-free daysb 14.0 (6.0–18.0) 15.0 (9.1–18.0) 12.5 (1.2–17.2) .66Delirium days 4 (2–7) 4 (2–8) 4 (2–6) .93Resolution of delirium on study

drug, n (%)c24 (69) 23 (77) 21 (58) .28

Coma days 2 (0–4) 2 (0–4) 2 (0–5) .90% of days accurately sedatedd 70 (56–83) 64 (50–94) 71 (53–92) .91Ventilator-free days 7.8 (0–15.0) 12.0 (0–18.6) 12.5 (0–23.3) .25Length of stay, days

ICU 11.7 (4.6–15.7) 9.6 (3.8–14.5) 7.3 (4.7–12.3) .70Hospital 13.8 (9.4–NA) 13.5 (9.3–NA) 15.4 (8.9–NA) .68

21-day mortality, n (%) 4 (11) 4 (13) 6 (17) .81Average extrapyramidal symptoms

scoree0 (0–0.2) 0 (0–0) 0 (0–0) .56

aMedian (interquartile range) unless otherwise noted; bthe number of days patients were alivewithout delirium or coma during the 21-day study period; cpatients without resolution of delirium onstudy drug included those who died or were discharged with delirium, those who had delirium �21days, and those with resolution of delirium after study drug was discontinued for other reasons, e.g.,at study day 14; dpercentage of days while receiving study drug that patients were either at the levelof sedation targeted by the intensive care unit (ICU) team or within 1 Richmond Agitation-SedationScale point of the stated goal; emeasured using a modified Simpson-Angus Scale (29), composed of sixitems scored from 0 (normal) to 4 (extreme).


three treatment groups, as were dailydoses of benzodiazepines, opiates, andpropofol. Although strongly discouragedby study personnel, ICU teams occasion-ally treated patients with intravenous hal-operidol despite receipt of study drug,primarily because of agitation. As shown,doses of open-label haloperidol were typ-ically administered to such patients on a

single study day; only a very small num-ber of patients were treated on �1 studyday with doses comparable to the doses ofhaloperidol administered per study pro-tocol to patients in the haloperidol group,but these instances may have biased theresults against showing a difference be-tween treatment groups. Future trialsshould work to restrict open-label anti-

psychotic administration and track agita-tion as a distinct outcome.

CONCLUSIONS

The MIND Trial demonstrates that arandomized, placebo-controlled trial ofantipsychotics for delirium in mechani-cally ventilated ICU patients is feasible. In

2 4 6 8 10 12 14

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Benzodiazepines

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HaloperidolZiprasidonePlacebo

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ian

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mg

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Number Receiving BenzodiazepinesHALZIPPBO

21 17 15 14 12 9 14 7 5 5 6 3 3 414 18 13 16 11 9 11 8 7 6 7 4 2 221 21 20 20 14 12 12 11 7 10 8 10 7 5

p = 0.10

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Opiates

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ian

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mcg

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Number Receiving OpiatesHALZIPPBO

29 30 27 26 20 20 16 11 10 10 8 5 4 521 24 19 18 16 10 9 11 10 8 8 5 6 526 29 26 21 19 17 15 10 8 10 7 10 9 8

p = 0.87

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Propofol

Study Day


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Number Receiving PropofolHALZIPPBO

11 9 6 7 5 6 3 2 1 1 0 1 0 16 7 4 4 3 2 1 1 1 1 0 0 1 19 9 6 4 5 4 4 3 2 2 1 3 2 3

p = 0.16

Figure 4. Sedative exposure according to treatment group and study day. During the trial, patients in the three treatment groups received similar dosesper day of benzodiazepines (p � .10), opiates (p � .87), and propofol (p � .16). These graphs display the median dose of these sedatives received by patientsin each treatment group according to study day. Benzodiazepine doses are displayed in lorazepam equivalents; opiate doses are displayed in fentanylequivalents. For each class of sedative, the number of patients in each group who received any sedative is also shown according to study day. HAL,haloperidol; ZIP, ziprasidone; PBO, placebo.


this double-blind, placebo-controlled,multicenter clinical trial, neither halo-peridol nor ziprasidone significantly re-duced the duration of delirium comparedwith placebo. Patients in the three treat-ment groups spent a similar number ofdays alive without delirium or coma. Thispilot investigation, however, was not de-signed to definitively determine whetherantipsychotics are effective for ICU delir-ium. In light of the current widespreaduse of antipsychotics for the treatment ofdelirium in the ICU, a much larger mul-ticenter placebo-controlled trial is neededto decisively and carefully determinewhether continued use of antipsychoticsin the ICU is appropriate.

ACKNOWLEDGMENTS

The authors thank the MIND Trialstudy personnel at Vanderbilt UniversityMedical Center, University of North Caro-lina Hospitals, University of Iowa Hospi-tals, Moses H. Cone Memorial Hospital,Saint Thomas Hospital, and the Depart-ment of Veterans Affairs Medical Centerin Nashville, TN; members of the Dataand Safety Monitoring Board (Arthur P.Wheeler, MD, Jonathan Schildcrout,PhD, and Tina V. Hartert, MD, MPH); andthe ICU staff at Vanderbilt UniversityMedical Center, University of North Caro-lina Hospitals, University of Iowa Hospi-tals, Moses H. Cone Memorial Hospital,Saint Thomas Hospital, and the Depart-ment of Veterans Affairs Medical Centerin Nashville, TN, for their invaluable par-ticipation in the trial.

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