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DOI: 10.1177/08850666114031102012 27: 354 originally published online 25 March 2011J Intensive Care Med

Neil A. Gilchrist, Ifeoma Asoh and Bruce GreenbergAtypical Antipsychotics for the Treatment of ICU Delirium

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Atypical Antipsychoticsfor the Treatment of ICU Delirium

Neil A. Gilchrist, PharmD, BCPS1,2

, Ifeoma Asoh, PharmD1

, andBruce Greenberg, MD, MBA 3

AbstractDelirium is commonly described in critically ill patients as 1 factor contributing to increased length of intensive care unit andhospital stay, secondary complications, and increased mortality. Initial screening tools for delirium in hospitalized patients aregenerally easy to use; however, many centers have struggled with implementing these tools in a consistent and systematicmanner. Haloperidol has traditionally been prescribed as the primary agent of choice for the treatment of delirium in criticallyill patients. Clinicians have been challenged to consider alternative agents due to adverse effects such as extrapyramidalsymptoms, QTc prolongation, and possible torsades de pointes with haloperidol use. The atypical antipsychotics are attractivealternatives to haloperidol with improved safety profiles but are flawed by limited data to support dosing and efficacy in thispatient population. Future studies that provide large, prospective, double-blinded, placebo-controlled data to support the imple-mentation of these agents as standard therapy over haloperidol are needed.

Keywordsdelirium, atypical antipsychotics, olanzapine, quetiapine, risperidone

IntroductionConfusion in acutely ill patients has been described since thetime of Hippocrates. 1 More recently, delirium in the intensivecare unit (ICU) has been identified as a major and underappre-ciated problem. Delirium is an acute confussional state, whosemain features are a fluctuating level of consciousness withreduced awareness of the environment, inattention or disorga-nized thinking, and abnormal memory. 2 As diagnosed by theConfusion Assessment Method for the ICU (CAM-ICU),delirium occurs in about 50 % (22 % -87 % ) of the patientsadmitted to ICU 3-6 ; however, it is unrecognized in the majorityof these patients. 7 Delirium is associated with increased ICUand hospital length of stay, mortality, placement inskilled nursing facilities, and with higher health care expendi-tures. 4,8-11 Cognitive dysfunction associated with ICU care can

persist for months or years even in the absence of preexistingdementia, and ICU delirium may be associated with adementia-like illness. 11 Preexisting dementia is a common risk factor for ICU delirium and delirium occurring in this settingmay worsen the prognosis of the dementia. 12

The majority of patients with ICU delirium have a hypoac-tive inattentive delirium rather than the hyperactive type clas-sically seen in hospitalized elderly patients at night. 13 Thediagnosis therefore relies on a high index of suspicion and theuse of a validated diagnostic tool. The most commonly used tool is the CAM-ICU though other instruments exist and have

also been validated. 14 The CAM-ICU is a simple bedsideassessment tool that assists nurses and physicians to diagnosedelirium using a stepwise approach. The user of this tool

assesses for the presence of abnormal or fluctuating mental sta-tus such as variable scores on an ICU sedation scale, inattentionmanifested by inability to attend to a simple letter or picturerecall test, and either disorganized thinking or altered level of consciousness evidenced by incorrect answers to simple ques-tions or inability to follow simple commands. 3 Use of theCAM-ICU has increased the identification of ICU delirium,though inclusion of this test has not to our knowledge beenassociated with improved patient outcomes.

There is only limited data available to guide prevention and treatment of ICU delirium. Detection and management in patients requiring sedation and analgesia for mechanical

1 Department of Pharmacy, UMass Memorial Medical Center, Worcester, MA,USA2 Massachusetts College of Pharmacy and Health Sciences, Worcester, MA,USA3 Department of Pulmonary, Allergy, and Critical Care Medicine, UMassMemorial Medical Center, Worcester, MA, USA

Corresponding Author:Neil A. Gilchrist, Department of Pharmacy, UMass Memorial Medical Center,55 Lake Avenue, Worcester, MA 01655, USAEmail: [email protected]

Journal of Intensive Care Medicine27(6) 354-361 The Author(s) 2012Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/0885066611403110http://jicm.sagepub.com

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ventilation is especially difficult and benzodiazepine use iscommon in this patient population. While many risk factors have been identified, few of these are readily modifiable. 13 A complexmulticomponent intervention has been shown to decrease the fre-

quency and duration of delirium in hospitalized older patients,15

but this has not been repeated in the patientsadmittedto ICU.This protocol includedcare guided by multiplegeriatricspecialists and involved reorienting communication, cognitive stimulation3 times daily, sleep enhancement, early mobilization, regular encouragement, and visual and auditory assist devices. Thestudies of alternatives to benzodiazepines, which are a major modifiable risk factor for delirium, have shown cautiously pro-mising results. A 2-center study of 106 mechanically ventilated patients found that the use of dexmedetomidine decreased theincidence of coma and deliriumcombined in the study patients. 16

A larger, multinational study involving 68 hospitals and 375 patientsfound a 23 % absolutereduction in theprevalence of delir-ium. 6 However,widespread use of this agent hasbeen limited dueto cardiovascular side effects, cost, and Food and Drug Adminis-tration (FDA) approval for only 24 hours of use.

Once delirium is established, there is a dearth of evidence toguide treatment. The Society of Critical Care Medicine guide-line recommends haloperidol for the treatment of delirium as agrade C recommendation, which results from limited published data linking positive outcomes to haloperidol therapy. 17 Typi-cal antipsychotics such as haloperidol have significant sideeffects, including anticholinergic effects, QTc prolongation,and extrapyramidal symptoms. These side effects, particularlythe risk of QTc prolongation, often preclude use in the patients

admitted to ICU. Newer antipsychotics agents tend to havefewer adverse effects and thus offer a promising option for thetreatment of ICU delirium. The purpose of this article is toreview the atypical antipsychotic agents, their pharmacology,and the available data addressing their use in the treatment of ICU delirium.

PharmacologyHaloperidol, a first-generation antipsychotic, was originallysynthesized at Janssen Laboratories in Belgium in 1958 by PaulA. Janssen. This compound showed significant pharmacologic

potential by exhibiting antipsychotic activity 50 times more potent than chlorpromazine, the first antipsychotic agent intro-duced in 1950. 18 Over 5 decades later, haloperidol continues tohave a significant role in the treatment of psychiatric diseases.

Practice guidelines for the treatment of delirium recommend haloperidol as first-line therapy for acute cases. 19 With theintroduction of the atypical antipsychotics (Table 1), prescribersnow have available agents of similar efficacy to haloperidol withreduced risk of adverse side effects, including extrapyramidalsymptoms and prolongation of the QTc interval.

The term atypical antipsychotic is not clearly defined buthas been used to describe the agents that treat both positive and negative symptoms of schizophrenia. In addition, they produceonly a transient elevation in prolactin levels, antagonize theserotonin receptors 5-HT 2a and 5-HT 2C , block mesolimbicdopamine (DA) receptors over the nigrostriatal neurons, and are efficacious in treatment-resistant schizophrenia. 20 The atypical antipsychotic agents include clozapine, olanzapine, que-tiapine, risperidone, aripiprazole, ziprasidone, and morerecently paliperidone. These agents display varying degreesof dopaminergic-blocking properties at the D 2 receptor.

21

Clozapine, the first atypical antipsychotic, demonstrated superior efficacy in the management of treatment-resistantschizophrenia 22 ; however, cases of fatal agranulocytosis are alimiting factor in utilizing this medication in the treatment of ICU delirium. 23 As a result, clozapine is not well-studied in themanagement of ICU delirium. Similarly, paliperidone, the lat-est atypical antipsychotic is yet to be evaluated in this setting.Therefore, the discussion of atypical antipsychotics in this arti-

cle will be limited to olanzapine, risperidone, quetiapine, aripiprazole, and ziprasidone.

Although atypical antipsychotics share similar mechanismsof action, their pharmacologic activities at neuroreceptors varywidely. The primary sites of activity targeted by these agentsinclude the DA receptors, specifically dopamine (D 2) receptorsin the mesolimbic system, and serotonin (5-HT) receptors, atthe serotonin (5-HT 2) receptors throughout the brain.

24 Atypi-cal antipsychotics generally have a higher ratio of 5-HT 2 :D 2 blockade than typical antipsychotics. The degree of affinityof atypical antipsychotics for 5HT 2 receptors over D 2 receptorscorrelates to their lower propensity to induce EPS.

Table 1. Pharmacokinetics of Atypical Antipsychotics 24,28,29,67

Parameter Olanzapine Quetiapine Risperidone Ziprasidone Aripiprazole

Receptors DA, 5-HT, a 1 , H1 , M1 DA, 5-HT, a 1 , H1 , M1 DA, 5-HT, a 1, a 2, H2 DA, 5-HT, a 1 DA, 5-HT, a 1 , H1 ,Bioavailability (%) 60 73 70-85 60 87Half-life (hours) 33 6 3-24 6.6 47-68

Usual starting dose(elderly patients mayrequire lower dose)

5 mg daily 25 mg bid 0.5 mg bid 40 mg q6hra

5 mg dailya

Renal adjustment No No Yes, slower titrationmay be necessary

No No

Dosage form Oral (tablet and SL), IM Oral Oral, IM Oral, IM Oral, IMa Single trial to support dosing.

Gilchrist et al 355



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Among the atypical antipsychotics, ziprasidone displays thehighest 5HT 2A :D2 ratio and binding affinity to 5HT 1D and 5HT 1A receptors, displaying antagonist and agonist activity,respectively, and acts as a norepinephrine reuptake inhibitor. 25

These attributes confer decreased risk of inducing EPS and antidepressant and anxiolytic properties; however, the clinicalutility of ziprasidone may be limited secondary to the concernsof QTc prolongation and potential development of torsades de pointes. 26,27 Risperidone is unique in the fact that it displayssubstantial binding to both D 2 and 5-HT 2 receptors with similar binding affinities, while the incidence of EPS effects is mini-mal. This adverse drug effect may be offset based on signifi-cant 5-HT 2 receptor affinity. Olanzapine, a structural analogof clozapine, displays broad receptor-binding with greater selectivity of D 2 receptors located in the mesolimbic regionsthan other regions (e.g. nigrostriatal). 28 A more comprehensivelist of drug-specific receptors is provided in Table 1.

PharmacokineticsThe pharmacokinetic profiles of atypical antipsychotics have been thoroughly described in previous reports. 28,29 They arewell absorbed in the gastrointestinal tract following oral admin-istration; however, olanzapine undergoes extensive first passmetabolism resulting in approximately 40 % of the dose metabolized before reaching systemic circulation. These agents may be administered without regard to food with the exception of quetiapine, 30 which may have increased serum levels withhigh-fat meals. Pharmacokinetic studies of these agents indi-cate that oral bioavailabilities range from 60 % to 87 % .29 Peak serum concentrations ( C max ) are attained within 1 to 5 hours.These agents are highly plasma protein bound, mainly to albu-

min and a -1 glycoprotein. Clinically significant drug displace-ment interactions of atypical antipsychotics with other highly plasma protein-bound drugs are lacking.

Biotransformation of atypical antipsychotics occurs almostexclusively via the hepatic cytochrome P450 (CYP) system.Risperidone undergoes hydroxylation by CYP 2D6 to its activemetabolite, 9-hydroxyrisperidone (paliperidone). 31 Genetic polymorphisms of CYP 2D6 create variable responses torisperidone resulting in fairly long elimination half-lives inindividuals considered poor metabolizers. 32 The major metabolic pathway of olanzapine involves CYP 1A2 and flavinmonooxegenase (FMO), resulting in inactive glucuronidated

and desmethylated compounds. Quetiapine is metabolized byCYP 3A4 into several metabolites, 2 of which are active but areconsidered clinically insignificant. 30 The metabolism of zipra-sidone is largely independent of the CYP 450 system, withaldehyde oxidase responsible for 66 % of its metabolites. 25

Elimination of atypical antipsychotics occurs via renal and fecal routes. Terminal elimination half-lives ( t 1/2 ) are variableand may be prolonged with some metabolites. 33 Adjustmentof doses for renal insufficiency is generally not necessary, aslisted in Table 1.

Clinical TrialsProspective Trials in Critically Ill PatientsThere are a limited number of prospective clinical trials evalu-ating the utilization of atypical antipsychotics in the treatmentof delirium of critically ill patients. This section summarizesthe clinical trials evaluating atypical antipsychotics in the treat-ment of delirium in both critically ill and acutely ill patients.The utility of reviewing data for atypical agents in non-ICU patients allows clinicians to extrapolate safety and efficacydata to be used in the patients admitted to ICU.

The most recent trial by Girard et al 34 was a randomized,multicenter, double-blind, placebo-controlled trial involving101 mechanically ventilated medical and surgical patientsadmitted to ICU. Patients were randomized to receive either haloperidol, ziprasidone, or placebo every 6 hours for up to14 days. The primary endpoint was the number of days patientswere alive without delirium or coma. Patients included in thisstudy had an abnormal level of consciousness or were receivingsedative or analgesic medications. Baseline characteristicswere similar in all 3 groups including median age (51, 54, and

56), median Acute Physiology and Chronic Health Enquiry(APACHE) II scores (26, 26, 26), and median Sequential OrganFailure Assessment (SOFA) scores (11, 10, 11).

Results from this trial showed no difference in the mediannumber of delirium/coma-free days between any of the 3 treat-ment arms (haloperidol 14.0 days, ziprasidone 15.0 days, pla-cebo 12.5 days, P .66). Additional results reflected similar findings with no significant difference in median deliriumdays, ventilator-free days, and length of ICU and hospital stay.To randomize the study drug in a blinded fashion, doses of haloperidol and ziprasidone were administered as oral solu-tions. Safety data reported from this trial demonstrated no

Table 2. Side Effects of Atypical Antipsychotics68-71

Sedation EPS NMS QTc Prolongation Weight Gain

Olanzapine Moderate Low Low Low HighQuetiapine Moderate Very low Very low Low ModerateRisperidone Low Low to moderate Low to moderate a Low Mild to moderate

Ziprasidone Low Low Unknown Moderate LowAripiprazole Very low Low Very low Low Very low

Abbreviations: EPS, extrapyramidal symptoms; NMS, neuroleptic malignant syndrome.a Seen at doses >6 mg/day.

356 Journal of Intensive Care Medicine 27(6)



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serious adverse events; however, a minimal number of patientsdeveloped symptoms consistent with akathisia (haloperidol 10 patients, ziprasidone 6 patients, and placebo 7 patients, P .60). In all, 10 patients had prolongation of the QT C inter-val to >500 ms (haloperidol 2 patients, ziprasidone 5 patients,and placebo 3 patients, P .31).

Possible limitations of this study included a small samplesize (n 101), nonstandardized approach to sedation at eachstudy center, and exposure of patients in the ziprasidoneand placebo arm to open-label haloperidol therapy. Theauthors of this study did demonstrate the feasibility of con-ducting a randomized, placebo-controlled trial in critically ill patients with antipsychotics or placebo. A larger, multicenter, placebo-controlled trial will be needed to accurately determinewhether these commonly used agents impact the number of delirium/coma-free days resulting in increased ventilator-freedays and reduced length of ICU and hospital days.

A prospective, randomized, double-blind, placebo-controlled study compared the efficacy and safety of scheduled

quetiapine to placebo for the treatment of delirium in criticallyill patients requiring as-needed haloperidol. 35 A total of 36 patients were included in this study and based on their cri-teria of delirium diagnosed (Intensive Care Delirium ScreeningChecklist 4) by the primary care team, had an order for as-needed haloperidol, and were tolerating enteral nutrition,defined as 20 mL/h for at least 12 hours. Delirium wasassessed and documented at baseline and during every nursingshift. Patients randomized to the quetiapine arm received aninitial dose of 50 mg every 12 hours. The dose was titrated up daily by increments of 50 mg every 12 hours to a maximumof 200 mg every 12 hours if a patient received at least 1 dose of haloperidol in the previous 24 hours.

The quetiapine group demonstrated a shorter time to the firstresolution of delirium (1.0 day vs 4.5 days; P .001), areduced duration of delirium (36 vs 120 hours; P .006), and less agitation (Sedation-Agitation Scale score 5) (6 vs.36 hours; P .02). Quetiapine-treated patients were also morelikely to be discharged home or to rehabilitation versus beingtransferred to a chronic care facility or dying (89 % vs 56 % ; P .06). Reported mortality and ICU length of stay were sim-ilar between groups. Quetiapine was well tolerated with thisrapid escalating regimen. The most common adverse effectobserved in quetiapine-treated patients was somnolence and 1 episode of hypotension. There was no statistical difference

between quetiapine and placebo for incidence of QTc prolon-gation and no reports of extrapyramidal symptoms.

A prospective, single-center, randomized trial compared thetreatment of delirium in a critical care setting with olanzapine vshaloperidol in 73 medical and surgical patients admitted to ICU. 36

All patients admitted were screened for delirium utilizing theICU Delirium Screening Checklist (ICU-DSC). Patients with anICU-DSC score of 4 or with clinical symptoms of deliriumreceived confirmatory diagnosis of delirium using DSM-IVcriteria. Initial dosing of olanzapine began at 5 mg daily or haloperidol 2.5 to 5 mg every 8 hours given either orally or viaenteral tube.

Results demonstrated a similar decrease in overall deliriumindices for both the olanzapine and the haloperidol groups.Additionally, treatment with olanzapine or haloperidol resulted in a decrease of the mean daily dose of benzodiazepinesfrom day1 to day5. Safety data in this trial reported no extrapyr-amidal manifestations with olanzapine therapy while 6 patients

in the haloperidol group experienced such symptoms.Limitations of this study include the use of intravenous haloperidol; however, both groups received similar quantities onday 1 of therapy and rarely required rescue haloperidol in thefollowing 4 days of inclusion. The method of distribution of patients relied upon odd/even day randomization which in theend resulted with an n of 48 in the haloperidol arm and 28 in theolanzapine arm. Additionally, the trial did not blind the treating physicians and nurses to the assigned drug.

A 4th prospective, randomized, double-blind trial compared risperidone and haloperidol in the treatment of delirium in24 patients from either a medical ward, oncology ward, or ICU. 37 The diagnosis of delirium was conducted using the

Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revised [ DSM- III-R]; SCID). The initial starting dose of haloperidol or risper-idone was 0.75 or 0.5 mg by mouth twice daily, respectively,and titrated depending on the symptoms of delirium during the7-day study period.

The results included no significant difference in meanDelirium Rating Scale scores between the haloperidol and therisperidone groups (21.83 vs 23.50, P .35) or mean MemorialDelirium Assessment Scale scores between groups at day 7. Theaverage time to respond to therapy was 4.22 days in the haloper-idol group and 4.17 days in the risperidone group ( P .95). Inaddition, the number of patients who responded on the 3rd daywere higher in the haloperidol group (58.4 % ) compared to therisperidone group (33.3 % , P value not reported).

Limitations of this study include a small sample size, possibleunder dosing of antipsychotics due to a deficiency in data to support any particular dosing regimen, and lack of formal evaluationand reporting process for adverse drug effects. The study popula-tion was mixed and the authors did not report how many patientsdeveloped delirium while in the ICU. The doses reported are alsomuch lower than the usual doses prescribed in critically ill patients,which may lead to a higher risk of complications if acutedelirium and agitation are not controlled effectively.

Clinical Trials in Acutely Ill PatientsThe role of atypical antipsychotics in the treatment of deliriumin noncritically ill patients has been reviewed extensively byPeritogiannis et al. 38 The first report of utilizing atypical agentsincluded risperidone for the treatment of delirium in a group of 11 patients. 39 Although this study did not have a comparator group or a standardized scoring system of delirium, this led thesame authors to a later trial comparing olanzapine tohaloperidol for delirium. 40 The results of this trial demon-strated significant improvement with both treatment groups;the olanzapine group reported no side effects, while 5 patients

Gilchrist et al 357



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in the haloperidol group had either extrapyramidal symptomsor excessive sedation. The conclusion that olanzapine, as wellas other atypical agents, may be similar in efficacy to haloper-idol with minimal to no adverse effects intrigued many clini-cians to look further.

Since the first trial with risperidone, there have been

well over a dozen trials evaluating the efficacy of atypicalagents for delirium. The majority of these studies are limited due to their small sample size, open label or retrospectivedesign, and single-center participation. 40-44 Despite theselimitations, these studies provide useful information in dosingstrategies (Table 1) that did not result in significant adverseeffects when used alone, compared to haloperidol, or whencombined with open-label haloperidol therapy in noncriticallyill patients.

Adverse EffectsThe most commonly reported adverse effects in clinical trials

using antipsychotics for ICU delirium include QTC prolonga-tion, EPS, and sedation. These adverse effects have beenreported with both atypical agents and haloperidol therapy. Thelower incidence of EPS observed with atypical agents is mostlikely associated with the effect on 5-HT receptors, as previ-ously discussed in this article. There is limited information thatthe risk of EPS may differ between routes of administration of haloperidol. An abstract evaluating this risk retrospectively in238 participants receiving haloperidol found IV therapy had alower incidence compared to PO treatment (7.2 % vs 22.6 % ;no P value reported). 45 Comparison of IV vs PO therapy and risk of adverse effects has not been thoroughly reported withatypical antipsychotics to date.

Aside from the pharmacologic targets of these drugs,adverse effects are seen secondary to activity at D 2 receptorsin the striatum and tuberohypophysial DA tracts, adrenergicreceptors, muscarinic receptors, and histaminergic receptors. 21

Atypical antipsychotics are associated with a decreased capacity to induce neurological disorders compared to conven-tional agents but result in a higher incidence of metabolicside effects. The side effects which may be observed in theshort-term administration may include QTc prolongation,movement disorders, sedation, hyperglycemia, seizures, and neuroleptic malignant syndrome (NMS). Adverse effectsseen with prolonged therapy may include weight gain, the

development of diabetes mellitus, and elevated prolactinlevels (Table 2).

Electrocardiogram (ECG) abnormalities, representative of QTc prolongation, have been associated with antipsychotictherapy. Reports of QTc prolongation leading to torsades de pointes with resulting cardiac death has led to some antipsy-chotics to fall out of favor. 46,47 Among the atypical agents,ziprasidone has been shown to have the most potential to pro-long the QTc interval at doses used in the clinical trials. 25 A prospective, open-label trial investigated the cardiovascular effects of ziprasidone and other antipsychotics in 164 patients. 48 Treatment regimens included ziprasidone 160 mg/

day, quetiapine 750 mg/day, olanzapine 20 mg/day, risperidone6 to 16 mg/day, haloperidol 15 mg/day, and thioridazine 300mg/day. QTc prolongation was greatest in the thioridazinegroup followed in descending order by ziprasidone, haloperi-dol, quetiapine, risperidone, and olanzapine. QTc prolongation>75 ms occurred in the ziprasidone arm; however, no cases of

torsades de pointes were reported. The risk of sudden cardiacdeath is highest in patients with underlying cardiac diseasealready taking medications known to prolong QTc. 20

All antipsychotics have the potential to induce extrapyrami-dal symptoms including akathisia, dyskinesia, and pseudo-par-kinsonism. 21 It is hypothesized that the newer antipsychoticsare distinguished by their decreased propensity to inducemovement disorders secondary to their specificity for limbicD2 receptors and high 5HT 2A receptor binding.

49 This dose-dependent relationship has been identified with risperidone and quetiapine in doses >6 and 20 mg/day, respectively. The risk of EPS appears to be minimal with a rapidly escalating regimen of quetiapine up to 200 mg twice daily. 35

Due to their antagonism at the H 1 receptor, sedation is acommon side effect of these agents. Olanzapine displays themost potent H 1 receptor antagonism correlating to its highincidence of sedation with up to 30 % of patients reportingsuch symptoms in clinical trials. 49,50 Quetiapine and risper-idone are less sedating followed by ziprasidone and aripiprazole. 51 This property may be beneficial in the patientsadmitted to ICU requiring large amounts of sedating benzo-diazepines as a mechanism to utilize alternative pharmaco-logic targets.

The major metabolic effects of atypical antipsychoticsinclude weight gain and development of diabetes mellitus.These are effects that would generally be out of the contextof the ICU population. The underlying mechanism of hypergly-cemia may be more relevant with the data supporting glycemiccontrol in critically ill patients. 52-54 These agents are thought toinduce hyperglycemia by affecting the secretion and action of hormones involved in glucose and lipid metabolism. 55,56 Todate, there are no randomized trials evaluating the effect of atypical antipsychotics on glycemic control in the patients admit-ted to ICU. This information may prove to be useful indetermining the optimal agents to use in this class.

Less common but potentially serious adverse effectsinclude seizures and NMS. Neither of these adverse effectswas observed during the clinical trials discussed in this arti-

cle; however, each has been reported in a number of published case reports. Antipsychotics as a class may increase the risk of seizures with an incidence of less the 2 % .47 Of the atypicalagents, clozapine appears to be the biggest offender in aconcentration-dependent manner. Doses greater than 600mg have been reported to have a high incidence (4.4 % ) of seizures compared to lower doses (300-600 mg/day 2.7 % ;


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NMS was not observed in safety studies of atypicalantipsychotics in the management of critically ill delirious patients previously described in this article.

Drug InteractionsThe atypical antipsychotics generally do not affect themetabolism of other drugs, as do the typical antipsychotics.

Atypical antipsychotics are neither inducers nor inhibitors of the CYP isoenzymes, a major enzymatic family responsible for the metabolism of many pharmacologic agents including antipsychotics. Drug-drug interactions involving atypical antipsy-chotics generally result from the effect of other drugs ontheir metabolism. Drugs such as ketoconazole, a potent CYP3A4 inhibitor, have led to the decreased metabolism of ziprasidone, resulting in increased serum concentrations and pro-longed QTc intervals. 46 An extensive review of antipsychoticdrug-drug interactions has been previously reported includingcoadministration of antipsychotics with antidepressants,antiepileptics, anticholinergics, and individual enzyme-alteringmedications. 63 A practical approach to minimize toxicity from

drug-drug interactions would be using clinical decision supportsoftware to detect the interactions, 64,65 minimize the exposuretime and adjust the dose(s) of medications that interact, 66 and consider alternative therapies which do not affect metabolizingenzyme activity.

Clinicians may observe adverse effects of drugs acting at thesame pharmacologic receptors. Previous discussion in the arti-cle described the propensity of this class of drugs to prolong theQTc interval; however, in a much less-significant amount thantypical antipsychotics, with the exception of ziprasidone.Table 3 lists the commonly prescribed medications in the ICUsetting which are associated with QTc prolongation. It is themultiple combinations of these agents in critically ill patientsthat create an increased risk for this adverse effect. Prescribersshould consider the multiple receptors that atypical antipsycho-tics affect to avoid additive toxicity.

ConclusionDelirium is a common clinical finding in critically ill patients,which requires accurate clinical assessment and appropriate pharmacologic therapy to reduce prolonged ICU and hospitalstay. Antipsychotic medications should be considered as part of the pharmacologic regimen for the treatment of

ICU-associated delirium. Limited data suggest that atypicalantipsychotics are more effective than placebo in decreasingthe duration of delirium and degree of agitation that patientsmay experience. In addition, this therapy may lead to increased discharges home or to a rehabilitation facility. Comparison tohaloperidol therapy has shown similar efficacy but with

reduced incidence of adverse effects. Clinicians should consider atypical antipsychotics as safe and effective in thetreatment of ICU delirium with short-term therapy. Further studies will be needed to determine the cost-effectiveness of using these agents in place of haloperidol therapy.

AcknowledgmentThe authors recognize the contributions of Angela T. Gilchrist,PharmD, for the review and preparation of the text.

Declaration of Conflicting InterestsThe authors declared no conflicts of interest with respect to the author-ship and/or publication of this article.

FundingThe authors received no financial support for the research and/or authorship of this article.

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Table 3. Commonly Prescribed ICU Medications Associated withQTC Prolongation 72-74

Amiodarone LevofloxacinMethadone CiprofloxacinMetocloperamide FluconazoleSotalol Voriconazole

Dofetilide ErythromycinHaloperidol Clarithromycin

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