1 the importance of diagnosing and managing icu delirium

DOI 10.1378/chest.06-1795 2007;132;624-636Chest

Brenda T. Pun and E. Wesley Ely

*ICU DeliriumThe Importance of Diagnosing and Managing

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The Importance of Diagnosing andManaging ICU Delirium*

Brenda T. Pun, RN, MSN; and E. Wesley Ely, MD, MPH, FCCP

ICU delirium represents a form of brain dysfunction that in many cohorts has been diagnosed in 60 to 85%of patients receiving mechanical ventilation. This organ dysfunction is grossly underrecognized because amajority of patients have hypoactive or quiet delirium characterized by negative symptoms (eg,inattention and a flat affect) not alarming the treating team. Hyperactive delirium, formerly called ICUpsychosis, stands out because of symptoms such as agitation that may cause harm to self or staff, but isactually rare relative to hypoactive delirium and associated with a better prognosis. Delirium is oftenincorrectly thought to be transient and of little consequence. After adjusting for numerous covariates,delirium is a strong, independent predictor of prolonged length of stay, reintubation, higher mortality,and cost of care. Expanded work on patient safety and recommendations by professional societies haveestablished the importance of delirium monitoring and recommended it as standard practice in ICUs allover the world. This evidence-based review for physicians, nurses, respiratory therapists, and pharmacistswill outline why it is imperative that patients be routinely monitored for delirium. This review will discussmodifiable risk factors for delirium, such as metabolic disturbances or potent sedative and analgesicmedications. Attention to mitigating risk factors, along with recommended pharmacologic approachessuch as antipsychotic medications, may provide resolution of delirium in some patients, while others willpersist with refractory brain dysfunction and long-term cognitive impairment following critical illness.

(CHEST 2007; 132:624636)

Key words: aging; analgesia; cognitive impairment; critical care; delirium; encephalopathy; mechanical ventilation; protocols;respiratory failure; sedation

Abbreviations: ASE Attention Screening Examination; CAM-ICU Confusion Assessment Method for the ICU; GABA -aminobutyric acid; PAR Psychological Assessment Resources; RASS Richmond Agitation-Sedation Scale; SCCM Society ofCritical Care Medicine; VUMC Vanderbilt University Medical Center; York-VA Veterans Affairs TN Valley HealthcareSystem-York Campus

I n an executive summary published by the AmericanAssociation of Retired Persons and the HarvardSchools of Medicine and Public Health,1 delirium wasconsidered one of six-leading causes of preventableinjury in those 65 years old. Delirium is an acuteconfusional state defined by fluctuating mental status,inattention, and either disorganized thinking or analtered level of consciousness. This review will focus on

advances in our understanding of delirium in criticalcare. This update is organized according to key ques-tions that answer the why, what, and how of moni-toring and managing delirium in critical illness.

Why Should We Monitor for Delirium?

For many years, the critical care community hasfocused on assessing, preventing, and reversing mul-tiorgan dysfunction syndrome. However, the brain*From Vanderbilt University and the Tennessee Valley VA GeriatricResearch Education and Clinical Center, Nashville, TN.

Dr. Ely was supported by National Institutes of Health grants RO1 AG072701A1 and AG 0102301A1 and the VA Merit Review ClinicalScience Research and Development, the Measuring the Incidence andDetermining Risk Factors for Neuropsychological Dysfunction in ICUSurvivors study.Ms. Pun has received honoraria from Hospira, Inc. and CardinalHealth and serves as a consultant on research project for Hospira,Inc. Dr. Ely has received grant support and honoraria from Hospira,Pfizer, and Eli Lilly.

Manuscript received July 19, 2006; revision accepted February 7, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Brenda T. Pun, RN, MSN, Center for HealthServices Research, Vanderbilt Medical Center, Nashville, TN 37232-8300; e-mail: [email protected] or www.ICUdelirium.orgDOI: 10.1378/chest.06-1795

CHEST Recent Advances in Chest Medicine

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has been subjected to relatively little formal studyuntil recently. ICU patients, especially older persons,are among the most vulnerable hospitalized patientsfor the development of delirium. Studies27 havefound that delirium develops in 20 to 50% of lower-severity ICU patients or those not receiving mechan-ical ventilation, and in 60 to 80% of ICU patientsreceiving mechanical ventilation. Speaking further tothe high prevalence of this organ dysfunction, astudy8 enrolling only nondelirious patients had toexclude 80% of screened ICU patients due to delir-ium. This problem is neither benign nor self-limit-ing. ICU delirium is predictive of a threefold-higherreintubation rate and 10 additional days in thehospital.913 Additionally, ICU delirium is associatedwith higher ICU and in-hospital mortality.14 Evenafter controlling for preexisting comorbidities, sever-ity of illness, coma, and the use of sedatives andanalgesics, patients with ICU delirium have morethan a threefold-increased risk of 6-month mortalitycompared to those without delirium (Fig 1).5,9 It isunknown if delirium is the cause of these outcomesor just a marker of an unidentified covariate. How-ever, delirium risks are cumulative; for example,each additional day spent in delirium is associatedwith a 20% increased risk of prolonged hospitaliza-tion and a 10% increased risk of death.9 It is notsurprising that delirium is independently associatedwith higher ICU costs ($22,346 vs $13,332, respec-tively) and hospital costs ($41,836 vs $27,106, re-

spectively) compared to those without delirium (Fig2).15 Between 10% and 24% of patients experiencepersistent delirium that may be related to long-termcognitive impairment.3,16

While it is well known that patients with preexist-ing dementia are at risk for delirium (ie, delirium ondementia [Fig 3]),4,17,18 data are emerging thatindicate delirium may lead to or even accelerate theacquisition of a dementia-like entity (ie, dementiafollowing delirium).19 Approximately one third ofICU patients receiving mechanical ventilation havelong-term cognitive impairment that has been doc-

Figure 2. The impact of ICU delirium on costs: median ICUand hospital cost per patient. This histogram shows cost accord-ing to clinical categorization of ever delirium vs never delir-ium. Delirium was significantly and independently associatedwith increased ICU and hospital cost. Used with permission fromMilbrandt et al.15

Figure 1. Delirium in ICU patients is a risk factor for 6-month mortality. Kaplan-Meier curves ofsurvival to 6 months among ICU patients. Patients with delirium in the ICU had a significantly highermortality rate than patients without delirium. Used with permission from Ely et al.9 H.R. hazardratio. Data in parenthesis indicate confidence interval.

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umented up to 6 years after hospital dis-charge.10,1924 Several studies19,25 have found a linkbetween delirium and declining function. Rockwoodet al26 studied cognitively intact geriatric medicalpatients over 3 years and found that patients withdelirium had significantly higher dementia incidencethan those without delirium (18.1% vs 5.6%). Dolanet al27 studied geriatric hip surgery patients andfound that patients with delirium were twice as likelyto have dementia diagnosed at 2 years. McCusker etal22 evaluated hospitalized geriatric patients andfound that the 1-year mini-mental status examinationscores of delirious patients were 5 points lower thanpatients without delirium. Last, Nelson et al28 foundthat the number of days spent in delirium or comawas significantly associated with an increased likeli-hood of discharge to a post-acute care facility asopposed to home and poorer functional status at 3months and 6 months. This post-ICU long-termcognitive impairment involves memory, attention,and executive function problems (Fig 4) and leads toinability to return to work, impaired activities of dailyliving, increased risk of institutionalization, and de-creased quality of life.2932 The causes of this ac-quired cognitive impairment are being investigatedin two large cohort studies funded by the VeteransAdministration (Measuring the Incidence and De-

termining Risk Factors for Neuropsychological Dys-function in ICU Survivors [or MIND ICU] study)and the National Institutes of Health (Bringing toLight the Risk Factors and Incidence of Neuropsy-chological Dysfunction in ICU Survivors [or BRAINICU] study).

Given the poor outcomes associated with delirium,it can no longer be considered a benign problem thatwill clear when the patient is transferred from theICU. Considering that 9 of 10 seriously ill patientsdeclared they would rather die than survive withsevere cognitive impairment,33 it is imperative thatwe begin to incorporate brain dysfunction into ourprognostication schemes and discharge discussions.This form of organ dysfunction mandates attentionand prioritization in the assessment and care ofcritically ill patients.

What Is Delirium?

Delirium is defined by the Diagnostic and Statis-tical Manual of Mental Disorders34 as a disturbanceof consciousness with inattention accompanied by achange in cognition or perceptual disturbance thatdevelops over a short period (hours to days) andfluctuates over time. Although there are many hy-pothesized pathophysiologic mechanisms involved inthe development of delirium, most are thoughtrelated to imbalances in neurotransmitters that mod-ulate cognition, behavior, and mood. Varied termshave been used to describe the spectrum of acutecognitive impairment in critically ill patients, includ-ing ICU psychosis, ICU syndrome, acute confusionalstate, septic encephalopathy, and acute brain fail-ure.20,35,36 The current consensus is to consistentlyuse the unifying term delirium and subcategorizeaccording to psychomotor symptoms (hyperactive,hypoactive, or mixed).37 Hyperactive delirium, in thepast referred to as ICU psychosis, is rare in the pureform and is associated with a better overall progno-sis.38 It is characterized by agitation, restlessness,attempting to remove catheters, and emotional labil-ity.37,39 Hypoactive delirium, which is very commonand often more deleterious for the patient in the longterm,38 remains unrecognized in 66 to 84% of hos-pitalized patients.40,41 Amid a busy emergency de-partment ICU shift, hypoactivity on the part of apatient does not seem like a problem and may bemissed.4244 This subtype is characterized by with-drawal, flat affect, apathy, lethargy, and decreasedresponsiveness.38,44,45 In terms of nosology, somerefer to the hypoactive delirium as encephalopathyand restrict delirium to hyperactive patients. How-ever, using separate terms proves difficult sincepatients may present with a mixed clinical picture or

Figure 3. Delirium on dementia: cumulative rates of delirium inICU patients 70 years old with and without preexisting demen-tia. The graph depicts the cumulative rates of delirium stratifiedby dementia status in three separate periods: on hospital admis-sion or baseline, by the end of the ICU period, and by the end ofthe post-ICU period up to 7 days. *Indicates statistical signifi-cance with p 0.05 for comparison of groups with and withoutdementia. Used with permission from McNicoll et al.4




sequentially experience both subtypes. Peterson etal46 reported the rates of these subtypes in the ICUto be 1.6% hyperactive, 43.5% hypoactive, and54.1% mixed (Fig 5). Many critical care providersbelieve hyperactive delirium is more common, but itis merely because these patients attract attention dueto their immediate threat to self and others. Thesedata underscore the importance of regular deliriummonitoring because many delirium episodes will beinvisible otherwise because of negative symptomatol-ogy. For quiet or hypoactive delirium, it is worthemphasizing that if you dont look, you wont find.

How Do We Monitor for Delirium?

The Society of Critical Care Medicine (SCCM)guidelines47 recommend monitoring delirium rou-tinely in patients receiving mechanical ventilation.There are currently two validated tools for monitor-ing delirium in ICU patients: the Intensive CareDelirium Screening Checklist48 and the ConfusionAssessment Method for the ICU (CAM-ICU).47 TheIntensive Care Delirium Screening Checklist (Table1) is an eight-item checklist with a sensitivity of 99%and specificity of 64% and interrater reliability of

0.94.48 Each of the eight items is scored as absent orpresent (1 or 0, respectively) and summed. A score 4 indicates delirium. The CAM-ICU was adaptedfor use in nonverbal ICU patients from the original

Figure 4. Cognitive impairment with the Rey-O Copy complex figure, a test of visuoconstruction inwhich the patient is asked to copy a complex geometric design while looking at the original. This figureshows the original Rey-O and the examples of two patients tested 3 months after hospital discharge(neither had any detectable baseline cognitive deficits). These images serve as a striking example ofneuropsychological deficits that impair the visuospatial and executive abilities of patients long after ICUstay. Reproduced by special permission of the Publisher, Psychological Assessment Resources (PAR),Inc., 16204 North Florida Ave, Lutz, FL 33549, from the Rey Complex Figure Test and RecognitionTrial by John E. Meyers, Kelly R. Meyers. Copyright 1989, 1992, 1995 by PAR, Inc. Furtherreproduction is prohibited without permission of PAR, Inc.

Figure 5. Hypoactive and mixed delirium predominate in olderand younger ICU patients: percentage of ICU patients withdelirium by motoric subtypes (hyperactive, hypoactive, andmixed) stratified by age. Used with permission from Peterson etal.46




Confusion Assessment Method,49 and includes a four-feature assessment (Fig 6). Sensitivity and specificityvalues of the CAM-ICU are both 90%. The CAM-ICU is translated into over a dozen languages, easy toadminister, takes on average 1 min to complete, andrequires minimal training.2,50 CAM-ICU implementa-tion projects within different types of hospitals havereported high compliance and accuracy51 (Fig 7). Acomplete description of the CAM-ICU and trainingmaterials including videos and translations can befound at www.ICUdelirium.org.

Case Study

The following case study demonstrates deliriumassessment using the CAM-ICU. A brief description

of CAM-ICU features is needed to guide the readerin these examples. Feature 1 (change in mentalstatus from baseline or fluctuating course) is assessedby comparing current mental status to the patientsprehospital baseline or to the changes in the mentalstatus over the previous 24 h. The patient has feature1 if his or her mental status is altered compared toprehospital baseline, or is normal but has fluctuatedin the past 24 h. Feature 2 (inattention) is assessedusing the Attention Screening Examination (ASE).The ASE has two versions: auditory and visual. Toconduct the auditory ASE (random letter A), thepatient is asked to squeeze the testers hand whenthe letter A is said in a series of 10 letters. The visualversion is only needed when a patient is unable tophysically squeeze (eg, the patient is a quadriplegicor has severe critical illness myoneuropathy). For thevisual ASE, the patient is shown 5 pictures and thenasked to nod yes or no if he/she just saw the original5 among 10 subsequent pictures. Inattention isdeemed to present (ie, feature 2 positive) when thepatient scores less than eight correct answers oneither the auditory or visual ASE tests. Feature 3(disorganized thinking) is assessed by asking four yesor no questions and having the patient follow asimple command to hold up two fingers with bothhands (5 points total). If the patient gets three orfewer correct, he/she has disorganized thinking andis feature 3 positive. Feature 3 is technically onlyneeded for alert and calm patients because they arefeature 4 negative. Feature 4 (altered level of con-sciousness) is measured using a sedation scale suchas the Richmond Agitation-Sedation Scale(RASS)52,53 [Table 2]. If a patient is anything butalert and calm (eg, RASS score other than 0), he/sheis feature 4 positive. Delirium is present whenfeatures 1 and 2 and either 3 or 4 are positive (Fig 6,Table 3).

Examination 1: Mr. A (day 1) is a 57-year-oldpatient admitted to the ICU in respiratory distresssecondary to pneumonia and was placed on mechan-ical ventilation. Later that evening, he was foundagitated, pulling at his gown, and attempting to getout of bed. At baseline, his family reported that hefunctioned at a high level and was an engineer. Thenurse assessed him to be hyperalert with a RASS of 3. Attention was assessed by performing the ASEauditory (letter) test; he scored 6 of 10. According tothis assessment, features 1, 2, and 4 were positive,and the patient was considered CAM-ICU positivewith hyperactive delirium (Table 3). It was notnecessary to assess for feature 3 in order to make theoverall assessment.

Figure 6. CAM-ICU. The diagnosis of delirium requires thepresence of acute onset of changes or fluctuations in the courseof mental status (feature 1) and inattention (feature 2), pluseither disorganized thinking (feature 3) or an altered level ofconsciousness (feature 4). Used with permission from Ely et al.3See www.ICUdelerium.org for step-by-step training materialsand a short demonstration video.

Table 1ICU Delirium Screening Checklist*

Items

Altered level of consciousness (if A or B, do not completepatient evaluation for the period)

A: No response, score: noneB: Response to intense and repeated simulation (loud

voice and pain), score: noneC: Response to mild or moderate stimulation, score: 1D: Normal wakefulness, score: 0E: Exaggerated response to normal stimulation, score: 1

Inattention (score: 0 to 1)Disorientation (score: 0 to 1)Hallucination-delusion-psychosis (score: 0 to 1)Psychomotor agitation or retardation (score: 0 to 1)Inappropriate speech or mood (score: 0 to 1)Sleep/wake cycle disturbance (score: 0 to 1)Symptom fluctuation (score: 0 to 1)Total (score: 0 to 8)

*The scale is completed based on information collected from eachentire 8-h shift or from the previous 24 h. Adapted from Bergeronet al,48 with the kind permission of Springer Science and BusinessMedia. Obvious manifestation of an item 1 point; no manifesta-tion of an item or no assessments possible 0 point.




Examination 2: Mr. A (same patient, day 2) wasadministered lorazepam twice during the night. Thefollowing day, his nurse assessed him and found thathe opened his eyes to a verbal stimulus with sus-

tained eye contact for 10 s (ie, RASS score 1).He scored only 3 of 10 correct responses on the ASEauditory (letter) test. As on the previous day, features1, 2, and 4 were positive, yet this time he was in

Figure 7. Large-scale implementation of sedation and delirium monitoring in the ICU: compliance andagreement within raters. These graphs are from two institutions: a university-based hospital (VanderbiltUniversity Medical Center [VUMC]) and community-based Veterans Affairs hospital (Veterans Affairs TNValley Healthcare System-York Campus, Nashville, TN). Top, A: compliance with the two scales over time.Bottom, B: agreement between bedside medical ICU nurses and expert reference standard raters using thetwo tools over time. The baseline values noted on the X-axis were obtained during a preimplementationphase to allow comparison with data obtained on subsequent months following educational in-services andhands-on feedback geared to improve the quality of bedside nurses performance. Used with permissionfrom Pun et al.51




hypoactive (quiet) delirium (Table 3). Although notnecessary, the nurse assessed for feature 3. Thepatient answered two of the four simple yes or noquestions incorrectly and was unable to follow thehold up two fingers command, thus displayingdisorganized thinking (feature 3 positive).

Examination 3: Mr. As (same patient, day 3)breathing improved, and he was successfully extu-bated. In the previous 24 h, he was assessed withRASS scores 3 and 2, but at the current timethe patient was sitting calmly in his bed with his eyesopen (ie, RASS score 0). He scored 10 of 10 on theASE auditory (letter). This examination revealed thatalthough feature 1 was positive due to fluctuatingmental status, features 2 and 4 were not. This patientwas no longer delirious (Table 3).

Additional Pearls to Delirium Diagnosis: Someonewho is attentive is not delirious. Inattention is pivotalin the diagnosis of delirium. Those meeting somefeatures but not full criteria may have subsyndromaldelirium, which is currently being investigated toestablish its relationship to intermediate outcomes.

Risk Factors/Etiology: What Are theModifiable Risk Factors?

One key strategy to prevent or diminish delirium isto identify and modify risk factors that lead to

delirium. Inouye et al54,55 developed a predictivemodel for delirium in the elderly non-ICU patientsthat classified risk factors into two categories: pre-disposing (baseline vulnerability) and precipitating(hospital related or iatrogenic).55 Numerous riskfactors have been identified in non-ICU popula-tions7,5457 that fall into these categories, and ICUpatients have an average of 11 4 (mean SD)10 ofthese reported risk factors (Table 4).

Baseline risk factors that predispose patients to thedevelopment of delirium include dementia, apoli-poprotein E4 phenotype, advanced age, comorbidity,and depression.4,36,55,56,58 Dubois et al59 found thatpreexisting hypertension and smoking (presumablydue to relative hypoperfusion and nicotine with-drawal, respectively) were significantly associatedwith the development of ICU delirium. Similarly,Ouimet et al14 reported that hypertension and alco-holism were associated with ICU delirium. Pan-dharipande et al60 reported in medical ICU patientsthat increasing age and severity of illness scores weresignificant independent predictors of transitioning todelirium. Another investigation4 reported that pre-existing dementia was a significant risk factor fordelirium. Precipitating and iatrogenic risk factorsrepresent areas of potential modification and thusintervention for delirium prevention and/or treat-ment. Precipitating factors include hypoxia, meta-bolic disturbances, electrolyte imbalances, with-

Table 3Summary of the Delirium Assessments (See Case Presentation)

Features Day 1 Day 2 Day 3

Feature 1: does the patient have anacute change in mental statusfrom baseline or fluctuation?

Positive Positive Positive (due to RASS fluctuation)

Feature 2: is the patientinattentive?

Positive Positive Negative

Feature 3: does the patient havedisorganized thinking?

No need to test Positive No need to test

Feature 4: does the patient have analtered level of consciousness?

Positive (agitated, RASS 3) Positive (lethargic, RASS 1) Negative (awake and alert, RASS 0)

Overall CAM-ICU: is this patientdelirious?

Positive (hyperactive delirium) Positive (hypoactive delirium) Negative (not delirious)

Table 2The RASS*

Scale Definitions Description

4 Combative Combative, violent, immediate danger to staff3 Very agitated Pulls or removes tubes or catheters; aggressive2 Agitated Frequent nonpurposeful movement, fights ventilator1 Restless Anxious and apprehensive, but movements not aggressive or vigorous0 Alert and calm 1 Drowsy Not fully alert but has eye opening to voice and sustained eye contact ( 10 s) 2 Light sedation Briefly awakens to voice with eye opening and eye contact ( 10 s) 3 Moderate sedation Movement or eye opening to voice (but no eye contact) 4 Deep sedation No response to voice, but movement or eye opening to physical stimulation 5 Not arousable No response to voice or physical stimulation

*Adapted from Sessler et al52 and Ely et al.53




drawal syndromes, acute infection (systemic andintracranial), seizures, dehydration, hyperthermia,head trauma, vascular disorders, immobilization,sleep deficiency, psychiatric medications, and intra-cranial space-occupying lesions.36,55,56

Medications are perhaps the most prevalent mod-ifiable risk factor for ICU delirium. Sedatives andanalgesics primarily work by altering neurotransmit-ter levels throughout the brain, which may be theprimary mechanism in delirium development. Forexample, morphine and high-dose benzodiaz-epines (up to 15 mg) were also linked to delirium inunadjusted analysis.59 Ouimet et al14 reported thatsedatives and analgesics increased risk of deliriumthreefold when used to induce coma. Pandharipandeet al60 reported that lorazepam was an independentrisk factor for daily transition to delirium (Fig 8),whereas fentanyl, morphine, and propofol trendedtoward delirium development but were not statisti-cally significant. In a subsequent study61 of 100surgical and trauma ICU patients, midazolam (oddsratio, 2.75; p 0.002) and fentanyl (odds ratio, 1.87;p 0.05) exposures were the strongest independentpredictors of transitioning to delirium.

Sleep deprivation or loss of circadian rhythm isanother potentially modifiable risk factor. Criticallyill patients have severe sleep deprivation and disrup-tion of sleep architecture, averaging about 2 h ofsleep every 24 h. The causes of sleep deprivation inthe ICU consist of excessive noise and lighting,patient care activities, metabolic consequences ofcritical illness, mechanical ventilation, and sedativeand analgesic medications.62 It is known that distur-bance in duration and quality of sleep has detrimen-tal effects on protein synthesis, cellular immunity,and energy expenditure resulting in cardiopulmo-nary and cognitive effects, yet the relationship be-tween sleep and ICU delirium has not been wellcharacterized.62,63 Studies are under way to under-stand how bedside care may be altered to reduce thisorgan dysfunction and improve immediate and long-term outcomes of ICU patients.

How Should We Approach ThisMultifaceted Problem?

Nonpharmacologic Prevention and Treatment

In the non-ICU setting, risk factor modificationhas resulted in a 40% relative reduction in thedevelopment of delirium.64 Modifications includerepeated reorientation of patients, repetitive provi-sion of cognitively stimulating activities for the pa-tients, nonpharmacologic sleep protocol, early mobi-lization, range-of-motion exercises, timely removal ofcatheters and physical restraints, use of eye glassesand magnifying lenses, hearing aids and earwax

Figure 8. Lorazepam is an independent risk factor for transi-tioning to delirium in the ICU. The probability of transitioning todelirium increased with the dose of lorazepam administered inthe previous 24 h. This incremental risk was large at low dosesand plateaued at approximately 20 mg/d. Used with permissionfrom Pandharipande et al.60

Table 4Risk Factors Associated With ICU Delirium

Preexisting risk factors (baseline vulnerability)DementiaApolipoprotein E4 phenotypeChronic illness (including hypertension)Advanced ageDepressionSmokingAlcoholismSeverity of illness on hospital admission

Precipitating risk factors (hospital related or iatrogenic)HypoxiaMetabolic disturbancesElectrolyte imbalancesSleep deficits*Congestive heart failureSepsisProlonged restraint use and immobilityWithdrawal syndromesAcute infections (systemic and intracranial)SeizuresDehydrationHyperthermiaHead traumaVascular disordersIntracranial space-occupying lesionsMedications

BenzodiazepinesMorphine/fentanylMeperdinePropofol

*Sleep deficits in ICU patients are hypothesized to cause delirium,although this area is currently in its infancy, and ongoing studies areforthcoming.

Most consistently associated with non-ICU delirium.




disimpaction, adequate hydration, use of scheduledpain protocol, and minimization of unnecessarynoise/stimuli. Additionally, delirium-specific multi-disciplinary education and nurse-led interventionprograms have resulted in a decrease in the durationand severity of delirium.65,66 However, the success ofsuch strategies will depend on the specific plan, thepatient population, and compliance with implemen-tation.66,67 For example, Lundstrom et al66 reportedthat patients on a ward where the staff receivedspecific delirium education and bedside nursing carewas reorganized to provide more patient care conti-nuity experienced shorter duration of delirium,shorter hospital stay, and lower mortality.66 How-ever, Cole et al67 found no difference in deliriumrates in patients observed by an intervention nursewhen compared to patients who received standardcare. To date, nonpharmacologic protocolization-of-care studies have focused on non-ICU populations,but they clearly need to be done in the ICU setting,where the margin for improvement is great due tohigher baseline prevalence rates and longer dura-tions of delirium. Currently, investigators are work-ing to determine the most important modifiable riskfactors to include in such trials.

Pharmacologic Prevention and Treatment

Coupled with a general lack of awareness ofdelirium, the absence of level I evidence has resultedin a great deal of indifference regarding ICU delir-ium and wide variations in pharmacologic treat-ment.68,69 Pharmacologic strategies center on eitherof the following: (1) optimizing the quantity and typeof sedative and analgesic medications delivered topatients, or (2) instituting currently recommendedmedications such as antipsychotics.

Benzodiazepines and propofol work primarily as-aminobutyric acid (GABA) agonists, an inhibitoryneurotransmitter that affects wakefulness and isthought to be one of the major neurotransmittersinvolved in delirium etiology. The sedation andamnesia produced by GABA-mimetic drugs result ina decreased level of consciousness but impair slow-wave sleep, which over time may predispose patientsto delirium. While these medications have an impor-tant role in patient comfort, clinicians must strive toachieve balance in their administration. Daily inter-ruption of sedatives and analgesics and protocolizingtheir delivery have both been shown to improvepatient outcomes.7073 The SCCM guidelines47 rec-ommend that ICU teams set clinically appropriatetarget sedation levels using well-validated sedationscales and readdress these target levels daily toensure medication titration to the desired clinicalend point.

Novel GABA-receptorsparing sedative agentsmay also reduce cognitive dysfunction seen in ICUpatients. 2-Receptor agonists such as dexmedeto-midine for short-term sedation in the ICU74 havestimulated research in this area. Dexmedetomidineinhibits the release of norepinephrine.74,75 Norepi-nephrine inhibition and the subsequent downstreamaffects on neurotransmitters such as histamine,orexin, GABA, and serotonin are similar to that seenin non-rapid eye movement sleep, and are responsi-ble for the sedative property of this drug.76 Maldo-nado et al77 conducted a prospective, unblinded,randomized trial in which cardiac surgery patientssedated intraoperatively at sternal closure were ran-domized to either dexmedetomidine, propofol, ormidazolam. The dexmedetomidine patients had dra-matically lower incidence of delirium postoperatively(8%) as compared to those sedated with propofol(50%) or midazolam (50%). These findings should beconfirmed in larger trials to determine whetherdifferent sedatives (eg, benzodiazepines vs dexme-detomidine) are related to a reduced prevalence andduration of delirium, and other important outcomes.

There are currently no drugs with regulatoryapproval for the treatment of delirium. SCCMguidelines47,78 recommend haloperidol as the pre-ferred agent for the treatment of delirium based oncase series and anecdotal reports. Adverse effectsassociated with haloperidol include extrapyramidalsymptoms, prolongation of the QTc, torsades depointes, neuroleptic malignant syndrome, and aka-thisia. All patients receiving antipsychotic agentsshould be monitored for these.47 Few rigorous stud-

Table 5Summary Points on Management of Deliriumin the ICU

Monitor delirium regularly in ICU patients using a valid, reliabletool (eg, The Delirium Screening Checklist or the CAM-ICU).Remember that the most is hypoactive and will be missed if notactively looked for (Fig 9).

Discuss results of delirium assessments on all patients daily oninterdisciplinary rounds.

Identify patients with high number of risk factors for thedevelopment or persistence of delirium (eg, electrolyteimbalance, fever, addition of new medications; especially thosewith anticholinergic properties, uncontrolled pain, new onset ofcongestive heart failure or nosocomial infection, prolongedimmobility and restrain use, sleep/wake cycle disturbance).

Review sedation and analgesia therapy, and ensure that the patientis receiving the minimum doses needed to achieve comfort,realizing that narcotics are often used for the double effect ofanalgesia and sedation. Implement strategies for tighttitration (eg, nurse-driven, patient-targeted sedation delivery withdaily sedation vacations).

Consider the benefit and risk profile of adding medications thatmight spare the use of sedatives and avoid respiratorysuppression (eg, haloperidol or atypical antipsychotics).




ies have been done to evaluate the efficacy ofhaloperidol or other antipsychotics in delirious pa-tients.79 One report80 found that prophylactic treat-ment with low-dose haloperidol in elderly hip sur-gery patients reduced the duration and severity ofdelirium but not its incidence. A retrospectivestudy81 found that patients who received haloperidolwithin 2 days of initiation of mechanical ventilationhad a significantly lower hospital mortality rate whencompared to patients who did not receive haloperi-dol.

The atypical antipsychotics (eg, aripiprazole, olan-zapine, quetiapine, and ziprasidone) may also behelpful in treating delirium. Their mechanisms of

action are similar to haloperidol, but in addition todopamine they affect a variety of neurotransmitters,including norepinephrine, serotonin, histamine, andacetylcholine.79,8284 Skrobik et al83 reported thatolanzapine and haloperidol had similar affects ondelirium in medical and surgical ICU patients, butthat olanzapine was associated with fewer adverseevents. The results of this initial study83 should beconfirmed in placebo-controlled trials. Kato et al85reported a case study suggesting that genotyping mayimpact the treatment effect of antipsychotic drugs. Apatient with a CYP2D6 poor metabolizer genotypehad persistent delirium and severe extrapyramidalsymptoms when treated with risperidone, which is

Figure 9. Delirium treatment algorithm. This empiric protocol, which is largely based on the currentSCCM clinical practice guidelines,47 is the algorithm the authors use to treat delirium in their ICU.Some aspects are evidence based, while others represent expert opinion and are awaiting refinementthrough clinical trials. Such protocols need to be updated regularly with new data and also personalizedat each medical center according to thought-leaders at that center. Specific recommendations about thechoice of antipsychotics to treat delirium have not been described because there are limited dataavailable regarding the preferential use of these medications in ICU patients. The nonpharmacologicinterventions recommended in this protocol have shown beneficial results in non-ICU patients;however, extrapolation to the ICU populations is speculative at this time. H2 histamine type 2;max maximum; dx diagnosis; CHF congestive heart failure; CPAP continuous positive airwaypressure; PEEP positive end-expiratory pressure; Sats oxygen saturation. This figure is available as afull landscape PDF file at http://icudelirium.org/delirium/training-pages/DeliriumProto%2001_30_07.pdf.




metabolized by CYP2D6. The patient was switchedto quetiapine (metabolized by CYP3A4), and thedelirium cleared within 2 days without side effects.Considering individual-patient metabolic enzymeprofiles may be a tool in guiding safer and moreefficacious pharmacotherapy, but this is a controver-sial topic that is in its infancy.

In early 2005, the Food and Drug Administrationissued an alert86 that atypical antipsychotic medica-tions are associated with mortality risk among elderlypatients. This warning was supported by a largemetaanalysis of demented outpatients who receivedantipsychotic medications for treatment of psychoticsymptoms.87,88 Subsequently, Wang et al89 reportedthat haloperidol had an even higher mortality risk innon-ICU elderly patients than atypical antipsychot-ics. No placebo-controlled trials involving haloperi-dol and/or atypical antipsychotics have been done inthe ICU. Milbrandt et al81 reported on a retrospec-tive chart review in which haloperidol use in the ICUwas associated with improved survival. The dataabove emphasize the need for more research in thisarea and underscore the importance of exercisingcaution when treating delirium.

Conclusions

Although delirium research in critical care is rap-idly maturing, the weight of evidence already dem-onstrates that critical care clinicians cannot afford toignore this form of organ dysfunction in our patients(Table 5). If we are to be comprehensive in ourapproach to monitoring and managing organ dys-function, the brain should be a very active compo-nent of our daily discussion at the bedside in theICU. This article has outlined key reasons to tipdelirium onto the physicians radar screen and hassupported each reason with evidence. Where evi-dence is emerging or not yet existent, we have alsoacknowledged this and offered timely solutions forthe clinician.

How might the physician begin this process ofchange in practice? First, one can start by making itclear that as a climate of patient safety is instilled inthe institution, delirium will be a priority. Second, asrecommended by the clinical practice guidelines,implement goal-directed sedation and delirium mon-itoring, frequent charting, and discussion on roundsas part of a daily ICU routine. Third, the physicianshould discuss preventive strategies that make sensefor patients in the ICU setting. In addition to thespecific recommendations for the management ofpain, sedation, and delirium, the 2002 SCCM guide-lines47 include a treatment algorithm. Additionally,we have included a sample delirium treatment algo-

rithm (Fig 9). This article has reviewed severalnon-ICU randomized trials with positive findingsthat, coupled with obvious issues such as correctionof metabolic disturbances, avoiding overuse of psy-choactive medications and prolonged restraints, andattempts at improving sleep, may offer an initialprotocolized approach while awaiting results of ICU-specific investigations. As pointed out by Poldermanand Smit,90 Inattention may be a basic feature ofdelirium, but it should not be a component of ourattitude toward delirium in the ICU.

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DOI 10.1378/chest.06-1795 2007;132; 624-636Chest

Brenda T. Pun and E. Wesley Ely*The Importance of Diagnosing and Managing ICU Delirium

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