delirium as a predictor of mortality em pacientes com ventilação mecânica

7/28/2019 Delirium as a Predictor of Mortality em Pacientes com Ventilao Mecnica

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CARING FOR THE

CRITICALLY ILL PATIENT

Delirium as a Predictor of Mortalityin Mechanically Ventilated Patientsin the Intensive Care UnitE. Wesley Ely, MD, MPH

Ayumi Shintani, PhD, MPH

Brenda Truman, RN, MSN

Theodore Speroff, PhDSharon M. Gordon, PsyD

Frank E. Harrell, Jr, PhD

Sharon K. Inouye, MD, MPH

Gordon R. Bernard, MD

Robert S. Dittus, MD, MPH

IN THE UNITED STATES, 55000 PA-tients arecared for daily inmorethan6000 intensive care units (ICUs).1

The most common reason for ICUadmission is respiratory failure and the

need for a mechanical ventilator.2

Al-though hospital mortality for such pa-tients ranges from 30% to 50%,3 only16% of patients receiving mechanicalventilation diedirectlyof respiratory fail-ure.4 In fact, nonpulmonary acute or-gan dysfunction contributes impor-tantly to mortality.5,6 Delirium is one ofthesenonpulmonary considerations yetremains understudiedin critically ill pa-tients. Although scoring systems for se-verity of illness have included theGlasgow Coma Scale7,8 as an important

predictor of outcome,there hasbeen noin-depth analysis focusing on the directcontribution of delirium to clinical out-comes in critically ill ICU patients.

Management of patients with sepsisand multiorgan failure has tradition-

Author Affiliations are listed at the end of this article.Corresponding Author: E. Wesley Ely, MD, MPH,Division of Allergy/Pulmonary/Critical Care Medi-cine, Center for Health Services Research, Sixth FloorMedical Center East #6109, Vanderbilt UniversityM e d ica l Ce n te r, Na sh v i l le , T N 3 7 2 3 2 -8 3 0 0

([email protected]; www.icudelirium.org).Caring for the Critically Ill Patient Section Editor:Deborah J. Cook, MD, Consulting Editor, JAMA.Advisory Board: David Bihari, MD; Christian Brun-Buisson,MD; Timothy Evans, MD; JohnHeffner, MD;Norman Paradis, MD; Adrienne Randolph, MD.

Context In the intensive care unit (ICU), delirium is a common yet underdiagnosedform of organ dysfunction, and its contribution to patient outcomes is unclear.

Objective To determine if delirium is an independent predictor of clinical outcomes,including 6-month mortality and length of stay among ICU patients receiving me-chanical ventilation.

Design, Setting, and Participants Prospective cohort study enrolling 275 con-secutive mechanically ventilated patients admitted to adult medical and coronaryICUs of a US university-based medical center between February 2000 and May 2001.Patients were followed up for development of delirium over 2158 ICU days using theConfusion Assessment Method for the ICU and the Richmond Agitation-SedationScale.

Main Outcome Measures Primary outcomes included 6-month mortality, overallhospital length of stay, and length of stay in the post-ICU period. Secondary out-comes were ventilator-free days and cognitive impairment at hospital discharge.

Results Of 275 patients, 51 (18.5%) had persistent coma and died in the hospital.Among the remaining 224 patients, 183 (81.7%) developed delirium at some pointduring the ICU stay. Baseline demographics including age, comorbidity scores, de-

mentia scores, activities of daily living, severity of illness, and admission diagnoses weresimilar between those with and without delirium (P.05 for all). Patients who devel-oped delirium had higher 6-month mortality rates (34% vs 15%, P=.03) and spent10 days longer in the hospital than those who never developed delirium (P.001).After adjusting for covariates (including age, severity of illness, comorbid conditions,coma, and use of sedatives or analgesic medications), delirium was independently as-sociated with higher 6-month mortality (adjusted hazard ratio [HR], 3.2; 95% confi-dence interval [CI], 1.4-7.7; P=.008), and longer hospital stay (adjusted HR, 2.0; 95%CI, 1.4-3.0; P.001). Delirium in the ICU was also independently associated with alonger post-ICU stay (adjusted HR, 1.6; 95% CI, 1.2-2.3; P=.009), fewer median daysalive and without mechanical ventilation (19 [interquartile range, 4-23] vs 24 [19-26]; adjusted P=.03), and a higher incidence of cognitive impairment at hospital dis-charge (adjusted HR, 9.1; 95% CI, 2.3-35.3; P=.002).

Conclusion Delirium was an independent predictor of higher 6-month mortality andlonger hospital stay even after adjusting for relevant covariates including coma, seda-

tives, and analgesics in patients receiving mechanical ventilation.JAMA. 2004;291:1753-1762 www.jama.com

See also Patient Page.

2004 American Medical Association. All rights reserved. (Reprinted) JAMA, April 14, 2004Vol 291, No. 14 1753

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ally been centeredon dysfunction in theheart, lungs, or kidneys rather than thebrain, though the brain is one of theor-gans most commonly involved.9-13 De-lirium has received little attention inICU settings because it is (1) rarely a

primary reason for admission, (2) of-ten believed to be iatrogenic due tomedications, (3) frequently explainedaway as ICU psychosis, and (4) be-lieved to have no adverse conse-quences in terms of patients ultimateoutcome.14-16 Last, there is a paucity ofpublished trials of prevention or treat-ment of delirium showing altered out-comes17 and none in ICU patients.

Even among clinicians whoexhibit anoverall appreciation for delirium as animportantform oforgan dysfunction,re-

cent data point to a general disconnectbetween its perceived importance andcurrent monitoring practices. Despite re-cent guidelines suggesting that ICU pa-tients be monitored daily for de-lirium,18 only 6.4% (58/912) of criticalcare professionals surveyed in 2001-2002 reportedobjectivelymonitoring forthis condition.19 Indeed, delirium, es-

pecially the hypoactivesubtype,20,21 goesunrecognized in more than two thirdsof the patients in clinical practice.22-25

The original Confusion AssessmentMethod of Inouye et al26 popularizedmonitoring of delirium by nonpsychia-

trists. In non-ICU hospital settings, de-lirium has been associated with pro-longed stay, greater dependency,subsequent institutionalization, and in-creased mortality.17,27-34 However, only re-cently have valid and reliable instru-m ents to m easur e b o th l ev el o f arousal35-37 and delirium38-40 in ICU pa-tients become available. Using these in-struments, our pilot study showed thatdelirium intheICU was an importantde-terminant oflengthof hospitalstay.41Weundertook the current study to test thehypothesis that delirium in the ICU isan

independentpredictor of 6-monthmor-tality and length of stay among patientsreceiving mechanical ventilation evenaf-ter adjusting for other covariates.

METHODS

Patients

The Vanderbilt University institu-tional review board approved thisstudy,and written informed consent was ob-tained from patients or their surro-gates. Enrollment criteria included anyadult, mechanically ventilated patient

admitted to medical or coronary ICUsof the 631-bed Vanderbilt UniversityMedical Center between February 2000to May 2001. While no outcomes datafrom this report have been previouslypublished, other data from this cohorthave been published.37,39,42 Exclusioncriteria, defined a priori, are outlinedin thepatient flow diagram(FIGURE 1).

Study Protocol

Study nurses enrolled patients eachmorning and recorded baseline demo-

graphic information. Information col-lected at enrollment included patientdemographics and severity of illness us-ing the most abnormal values ob-tained during the first 24 hours of ICUstay to calculate Acute Physiology andChronic Health EvaluationII (APACHEII) (scale range, 0-71)7 and SequentialOrgan Failure Assessment (SOFA)

(scale range, 0-24) scores.8 The Charl-son Comorbidity Index, which repre-sents the sum of a weighted index thattakes into account the number and se-riousness of preexisting comorbid con-ditions, was calculated as per Deyo et

al.

43

Surrogate assessments were usedfor baseline activities of daily living(scale range, 0-12),44 visual and hear-ing deficits, and the modified BlessedDementia Rating Scale (mBDRS) (scalerange, 0-17),45 an instrument vali-dated against brain pathological speci-mens to measure a patients baselinelikelihood of dementia.

Terminology

Delirium has more than 25 synonyms,including acute encephalopathy, sep-tic encephalopathy, toxic psychosis,

ICU psychosis, and acute confusionalstate.10,11,14,46,47 Delirium will be thetermused herein, because the neurologicmonitoring instrument used in this in-vestigation (described below) was de-veloped and validated using Diagnos-tic and Statistical Manual of MentalDisorders, Fourth Edition criteria for de-lirium.48

Explanatory Variable

Definitions and Patient Assess-ments. Patients neurologic status was

assessed daily by the study nurses anddefined as normal, delirious, or coma-tose using a 1- to 2-minute neurologicassessment that objectively measuredpatients arousal and delirium status.Arousal was measured using theRichmond Agitation-Sedation Scale(RASS).3 6 , 3 7 T he R AS S i s a w ell -validated and highly reliable 10-pointscale with scores from +1 to +4 as-signed for levels of agitation throughcombativeness, 0 assigned for alert andcalm state, and 1 to 5 assigned for

successive levels of depressed arousalor coma.37 Delirium, the independentvariable, was measured using a well-validated and highly reliable instru-ment, the Confusion AssessmentMethod for the ICU (CAM-ICU).39,40

The CAM-ICU assessment was posi-tive if patients demonstrated an acutechange or fluctuation in the course of

Figure 1. Flow of Patients in Study Cohort

224 Included in OutcomesAnalyses

51 Persistently Comatose andUnable to Be Evaluated for

the Primary IndependentVariable (Delirium)

280 Excluded

86 Had Stroke Syndrome orOther Primary NeurologicDisease

13 Were Deaf or Were Unableto Speak or UnderstandEnglish

69 Were Extubated Priorto Enrollment

27 Had Been PreviouslyEnrolled

41 Patient or FamilyRefused to Participate

44 Died Before StudyNurses Assessments

275 Enrolled

555 Mechanically VentilatedPatients Admitted tothe ICU

ICU indicates intensive care unit.

DELIRIUM IN MECHANICALLY VENTILATED PATIENTS

1754 JAMA, April 14, 2004Vol 291, No. 14 (Reprinted) 2004 American Medical Association. All rights reserved.



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their mental status (as determined byabnormalities or fluctuations in theRASS scores), plus inattention andeither disorganized thinking or an al-teredlevel of consciousness.39,40 By defi-nition, patients weredelirious if they re-

sponded to verbal stimulation with eyeopening (RASS scores of 3 to +4) andhadpositive CAM-ICUassessments. Pa-tients were defined as comatose if theyresponded only to physical/painfulstimulation with movement but had noeye opening (RASS score, 4) or if theyhad no response to verbal or physicalstimulation (RASS score, 5). Patientswere definedas normal if they were notdelirious or comatose.

Categorizationby Explanatory Vari-able. Using daily assessments de-scribedabove,it wasdetermined a priori

that patients would be included in a de-lirium group if they ever had deliriumwhile in the ICU, and all others wouldbe included in a no delirium group.To understand the phenomenology ofthese groups, patients in the deliriumgroup were further categorized as de-lirium only (ie, delirium but no epi-sodes of coma) or as delirium-coma(ie, delirium and coma). Likewise, pa-tientsin theno delirium group were cat-egorized as normal (ie, no episodes ofdelirium or coma) or as coma-

normal (ie, transient coma [eg, comadue to sedative medications] followedby consistently normal examinations).Patients who were comatose on all ICUevaluations during the study were cat-egorized as persistent coma.

Outcome Variables

The primary outcome variables in-cluded 6-month mortality, overall hos-pital length of stay, and length of stayin the post-ICU period. In addition, weincluded 2 secondary outcome vari-

ables: ventilator-free days and cogni-tiveimpairment at discharge.Ventilator-free days were defined as the number ofdays alive and free of mechanical ven-tilation between study enrollment andday 28.49 Cognitive impairment at dis-charge was defined as a Mini-MentalStateExaminationscore50 ofless than 24out of a possible 30 points.51-53

Statistical Analysis

Patientsbaselinedemographic andclini-cal variables were assessed using Wil-coxon rank sum tests for continuousvariables; Fisher exact tests were usedfor comparing proportions. For analy-

sis of analgesics (morphine, fentanyl)and sedatives (lorazepam, propofol),mean daily ICU dose and cumulativedose per patient during the ICU staywere used as summary measures. Ad-ministered benzodiazepineswereeitherlorazepam or midazolam, and mid-azolam dose was converted to loraze-pam equivalents (henceforth referredto as lorazepam) by dividing by 3 toachieve equipotent dose.54 Wilcoxonrank sumtestswereused to comparedis-tributions of the drugs between the nodelirium and delirium groups.

Six-month mortality, overall hospi-tal length of stay, and length of stay af-ter first ICUdischargewere analyzed us-ing time-to-eventanalyses.Patients werefollowed up from time of enrollment un-til hospitaldischarge. All survivors werethen followed up using the hospitalselectronic record system, monthly tele-phone calls, and in-person visits for sur-vival status. Kaplan-Meier survivalcurves were used for graphical presen-tation of time to death or hospital dis-charge, andlog-rank statisticswere used

to assess difference by overall deliriumstatus.55 For 6-month mortality analy-ses, patients were censored at the timeof last contact alive or at 6 months fromenrollment, whichever was first. Cen-soring for length-of-stay analyses oc-curred at time of hospital death.

Cox proportional hazard regressionmodels with time-dependent covari-ates56-58 were used to obtain hazard ra-tios(HRs)of death up to 6 months fromenrollment and HRs of remaining inhospital. Details of the model construc-

tion are described below. The 11 co-variates in the multivariable Coxregression models included a time-dependent coma variable, 6 additionalbaseline covariateschosena priori basedon clinical relevance (patient age at en-rollment, Charlson Comorbidity In-dex,43 mBDRS score,45 APACHE IIscore,7 SOFA score,8,59,60 admitting

diagnoses of sepsis or acute respira-tory distress syndrome), andthe4 seda-tive and analgesic medications used inthis cohort (lorazepam, propofol, mor-phine, and fentanyl). Patients neuro-logic status (normal, delirious, coma-

tose) was updated daily in the ICU,and time-dependent variables wereused for delirium and coma sepa-rately.This time-dependent delirium in-cidence variable was coded as 0 for thedays prior to the first delirious event,and coded as 1 thereafter. The time-dependent coma incidence variablewascoded similarly.

In addition, we performed a similaranalysis that considered the duration ofdelirium using cumulative number ofdays of delirium, coding the time-dependent delirium duration variable

as 0 until a deliriumevent occurred, andthen incrementally adding 1 when eachadditional day of delirium occurred.The time-dependent coma durationvariable was created similarly for thisadditional analysis.

The time-dependent delirium inci-dence variable was used as the main in-dependent variable in all Cox modelswith adjustment for time-dependentcoma incidence variable. Cox regres-sion models were then used to furthercontrol for the additional 6 baseline co-

variates mentioned above and the 4sedative and analgesic medications.Dummy coding was used for missingobservations with the mBDRS. Be-cause coma was already being handledas a covariate in the model, theAPACHE II and SOFA scores were cal-culated without inclusion of theGlasgow Coma Scale. To incorporatesedative (lorazepam, propofol) and an-algesic (morphine, fentanyl) medica-tions in a time-dependent fashion, dailyuse of medication was coded as 1 for

each of 4 drug variables separately if anyamount wasadministered prior to dailyassessment of neurologicstatus and wascoded as 0 otherwise. In an additionalanalysis, time-dependent cumulativedose of sedatives and narcotics were in-corporated into the model. Collinear-ity among all independent variables wasevaluated by examining the variancein-





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flation factor.61 Assumptions of pro-portional hazard for the final modelswere evaluated by examining interac-tions between time and each variable

in the model. When significant inter-actions were found, those interactionterms were included in the finalmodel.

Ventilator-free days were calculatedas described in the Dependent Vari-ables section above and compared be-tween the delirium and no deliriumgroups. A Poisson regression modelwithoverdispersion correction was usedto control for theset of covariates statedabove. Presence or absence of cogni-tive impairment at hospital dischargewas assessed as described in the De-

pendent Variables section and com-pared between the delirium and no de-lirium groups using Fisher exact tests,anda logistic regressionmodel wasusedto adjust for the set of 11 covariates. Alldataanalyseswereperformed using SAS8.02 (SAS Institute, Cary, NC); a sig-nificance level of .05 was used for sta-tistical inferences.

RESULTS

Patients Baseline Characteristics

During the study period, 555 mechani-

cally ventilated ICU patients were ad-mitted, of whom 275 (49.5%) were en-rolled within a mean and median of 1dayand 280 met exclusion criteria (Fig-ure 1). On enrollment, 23 (8.4%) pa-tients were defined as normal, 89(32.4%) as delirious, and 163 (59.3%)as comatose. FIGURE 2 shows the pro-portion of patients in each neurologic

category (as well as death or ICU dis-charge) over thefirst 14 days from studyenrollment. Of the 275 enrolled pa-tients, 51 (18.5%) never woke up from

coma and experienced100% ICU mor-tality after a median of 3 (interquartilerange [IQR], 1-5) days. These 51 pa-tients with persistent coma hada meanage of 55 (SD, 16) years and similarbaseline characteristics compared withtheremaining 224 patients, with theex-ception of greater severity of illness atenrollment as measured by meanAPACHE II scores (29.5 [SD, 9]) andSOFA scores (12.1 (SD, 3.8]) and bygreater rates of malignancy (14%) andsepsis/acute respiratory distress syn-

drome (63%) as admission diagnoses(P.05 for all). Due to their 100% mor-tality and theinability to evaluate themfor the independent variable (delirium),patients categorized as experiencingpersistent coma were not included inoutcomes analyses. The remaining 224patients were used for these analyses;their baseline characteristics are shownin TABLE 1. The cohort was divided into2 groupsaccording to whether they everdeveloped delirium in the ICU. Therewere no significant differences be-

tween the delirium and no deliriumgroups for demographicvariables, base-line comorbidities,activities of daily liv-ing,severity-of-illness scores, organdys-function scores, or admissiondiagnoses.

Prevalence of Delirium and Coma

All224 patients were followed up forde-velopment of delirium over 2158 ICU

days. Forty-one patients (18.3%) neverdemonstrated delirium in the ICU (ie,the no delirium group); of those, 24(58.5%) were in a comafor a median of

1.5 (IQR, 1-3) days, during which time21 (87.5%) received sedative or analge-sicmedications. Delirium in the ICUde-veloped in 183 (81.7%) patients (ie, thedelirium group) for a median of 2 (IQR,1-3) days, of whom 123 also were in acoma for a median of 2 (IQR, 1-4) days.Delirium occurred in 77.9% (60/77) ofthose without coma and in 83.7% (123/147)of those with coma(P=.29). Over-all, patients spent 21.6% of their ICUdays as normal, 43.1% as delirious, and35.3% as comatose. Of patients who

were alert or easily arousable as mea-sured by a RASS score of 0 or 1, morethan half (54.5%) were delirious.

Sedative and Analgesic

Medication Use

Mean daily dose and cumulative ad-ministered dose of sedative and nar-cotic medications (ie, lorazepam, pro-pofol, morphine, and fentanyl) used inthis cohort are presented in TABLE 2.Both mean daily and cumulative dosesof these medications were higher in pa-

tients in the delirium group, but onlylorazepam was significantly different be-tween the 2 groups.

Delirium and Associated

Clinical Outcomes

Six-Month Mortality. During the6-month follow-up period, 34% (63/183)ofthepatientsin thedelirium group

Figure 2. Daily Neurologic Status of 275 Patients in the ICU, Through the First 14 Days of the Study

Days After Enrollment

Percenta

ge

Normal

131197531

60

40

50

20

30

10

0


Delirium

131197531


Coma

131197531


Discharged From ICU

131197531


Death

131197531

Denominator is identical (N = 275) for all 14 days. ICU indicates intensive care unit.





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died vs 15% (6/41) of the patients in theno delirium group (P=.03) (TABLE 3).FIGURE 3A shows Kaplan-Meier curvesof survival to 6 months among the pa-tients in both groups, with significantlyhigher mortality among patientswithde-

lirium in the ICU. Figure 3B further de-picts the patients survival according toboth delirium and coma status.

Using a time-dependent multivari-able Cox proportional hazards modelto adjust for all 11 of the covariates (in-cluding coma incidence and adminis-tration of sedative and analgesicmedications), delirium was associatedwith a more than 3-times higher riskof dying by 6 months (Table 3). In anadditional analysis (data not shown),time-dependent cumulative doses ofsedatives and narcotics were incorpo-

rated into the model, with similar re-sults compared with the primary analy-sis. No collinearity was identifiedamong the covariates used in theseanalyses (all variance inflation factorswere 2, well below the thresholdof 10 used to indicate potentialcollinearity). To complement the mor-tality analysis presented in Table 3, asimilar analysis that considered the du-ration of delirium found that after ad-justing for the covariates, each addi-tional day an ICU patient spent in

delirium was associated with a 10% in-creased risk of death (HR, 1.1; 95% con-fidence interval [CI], 1.0-1.3; P =.03).

Hospital Lengths of Stay. Com-pared with patients in the no deliriumgroup, those who did develop deliriumspent a median of 10 days longer in the

hospital overall (Table 3). FIGURE 4Ashows Kaplan-Meier curves of the prob-ability of remaining in the hospital ac-cording to the clinical distinction of nodelirium vs delirium. Figure 4B showstheno delirium anddeliriumgroups fur-

ther categorized by coma status, as inFigure 3B. At any given time during the

hospitalstay, patientsdiagnosed withde-lirium had an adjusted risk of remain-ing in thehospital that was twiceas highas those who never developed deliriumand a 60% greater risk of remaining inthewards after ICU discharge (Table 3).

In a separate analysis, time-dependentcumulative doses of sedatives and nar-

Table 1. Baseline Characteristics of the Patients*

Characteristic

No. (%)

No Delirium(n = 41)

Delirium(n = 183)

Age, mean (SD), y 54 (17) 56 (17)

Men 18 (44) 95 (52)

RaceWhite 32 (78) 145 (79)

Black 9 (22) 38 (21)

Charlson Comorbidity Index, mean (SD) 3.2 (2.8) 3.2 (2.8)

Vision deficits, No./total (%) 23/33 (70) 104/153 (68)

Hearing deficits, No./total (%) 5/32 (16) 29/152 (19)

mBDRS score, mean (SD) 0.14 (0.6) 0.23 (0.8)

Activities of daily living, mean (SD) 0.81 (2.4) 0.91 (2.3)

APACHE II score, mean (SD) 23.2 (9.6) 25.6 (8.1)

SOFA score, mean (SD) 9.5 (2.9) 9.6 (3.4)

ICU admission diagnosisSepsis and/or acute respiratory distress syndrome 24 (59) 78 (43)

Pneumonia 6 (15) 35 (19)

Myocardial infarction/congestive heart failure 4 (10) 15 (8)

Hepatic or renal failure 0 11 (6)

Chronic obstructive pulmonary disease 2 (5) 18 (10)

Gastrointestinal bleeding 2 (5) 18 (10)

Malignancy 0 7 (4)

Drug overdose 3 (7) 8 (4)

Other 14 (34) 53 (29)

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; mBDRS, modi-fied Blessed Dementia Rating Scale; SOFA, Sequential Organ Failure Assessment.

*All comparisons between the no delirium and delirium groups were nonsignificant (P.05).See Methods section fordescriptions of scales and for scale ranges.

Except where noted otherwise.Denominators indicate number of patients with available information.Recordedby thepatients medical team as thediagnoses most representative of thereason foradmission to theICU.

Patients were sometimes given more than 1 admission diagnosis by the medical team, resulting in column totals100%.

Table 2. Daily and Cumulative Doses of Sedative and Analgesic Medications

Drug

Daily ICU Dose, Mean (SD), mg Cumulative ICU Dose, Mean (SD), mg*

No Delirium(n = 41)

Delirium(n = 183) P Value

No Delirium(n = 41)

Delirium(n = 183) P Value

Lorazepam 1.12 (2.2) 4.8 (12.8) .01 9.0 (20.0) 49.2 (131.3) .001

Propofol 36.6 (258.6) 48.4 (172.9) .19 362.1 (1265.4) 591.2 (3942.2) .20Morphine 5.8 (17.0) 17.3 (163.8) .79 48.0 (147.0) 168.1 (1321.9) .66

Fentanyl 0.53 (1.7) 0.78 (1.7) .22 3.1 (10.3) 8.7 (22.9) .12

Abbreviation: ICU, intensive care unit.*In the persistently comatose patients, the mean (SD) cumulative doses of these medications were: lorazepam, 15 (27) mg; propofol, 318 (1434) mg; morphine, 107 (345) mg; and

fentanyl, 3 (12) mg.By Wilcoxon rank sum test for no delirium vs delirium.Fentanyl is commonly reported to be 100 times more potent than morphine.54 Therefore, using a dose conversion factor of 0.01, the median cumulative morphine equivalent

dose of fentanyl given to patients in the no delirium and delirium groups would equate to 310 mg and 870 mg, respectively. While this mathematical conversion may be flawedor confounded in vivo, such large values are plausible considering fentanyls initially short duration of action, 18 the potential for rapid tolerance to fentanyl, 62-64 and the adminis-tration of fentanyl as a continuous infusion rather than an intermittent bolus.





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cotics wereincorporatedinto the modelwith similar results (data not shown)compared with theprimary analysis. Tocomplement the length-of-stay analy-ses presented in Table 3, similar analy-ses that considered the duration of de-

lirium found that after adjusting for thecovariates, each additional day spent indelirium by an ICU patient was associ-atedwitha 20% and a 10% increased risk

of remaining in the hospital or in thewards, respectively (hospital length ofstay: adjusted HR, 1.2; 95% CI, 1.1-1.3;P =.002; post-ICU length of stay: ad-justed HR, 1.1;95% CI, 1.0-1.2; P=.04).

Secondary Outcomes. Secondary

outcomes included ventilator-free daysin the ICU and neurologic impairmentat discharge. There were significantlyfewer days alive and free of the ventila-

toramong patients in thedelirium group(median, 19; IQR, 4-23) vs those in theno delirium group (median, 24; IQR, 19-26)(P.001). After adjusting for the11covariates, this difference remained sig-nificant (P =.03). Cognitive assess-

ments were not available at the time ofhospital discharge for 51 of 179 survi-vors, due either to inability to completetesting or to unexpected discharge. Onehundred twenty-eight survivors weretested, of whom 63 (49.2%) had dis-charge cognitive impairment as definedintheMethods section. Ofthose tested,twice as many patients in the deliriumgroup vs the no delirium group exhib-itedcognitive impairment at hospitaldis-charge (54.9% [56/102]vs 26.9% [7/26],respectively; P=.01), and multivariableanalysisrevealedthat the patients in the

delirium group were 9 times more likelyto be discharged with cognitive impair-ment than were those in the no de-lirium group (adjusted HR, 9.1; 95% CI,2.3-35.3; P=.002).

COMMENT

The development of delirium in thesemechanically ventilated patientswasas-sociated with a 3-fold increase in risk ofdeath aftercontrolling for preexisting co-morbidities, severityofillness,coma, andthe use of sedative and analgesic medi-

Table 3. Delirium Status and Clinical Outcomes Including 6-Month Mortality and Lengths ofStay

No Delirium Delirium Adjusted P Value

6-Month Mortality

No. 41 183

Rate, No. (%) 6 (15) 63 (34)

Adjusted HR (95% CI)* Reference 3.2 (1.4-7.7) .008

Hospital Stay

No. 41 183

Median (IQR), d 11 (7-14) 21 (19-25)


Post-ICU Stay

No. 40 156

Median (IQR), d 5 (2-7) 7 (4-15.5)


Abbreviations: CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; IQR, interquartile range.

*Multivariable model incorporating baseline covariates including patient age at enrollment, Charlson Comorbidity In-dex,43 modified Blessed Dementia Rating Scalescore,45Acute Physiology and Chronic Health Evaluation II (APACHEII) score,7 SequentialOrgan Failure Assessment(SOFA) score,59,60 admittingdiagnosesof sepsis or acuterespiratorydistress syndrome, and time-varying covariates for coma and use (yes/no) of lorazepam, propofol, morphine, andfentanyl. Assumptions of proportional hazard for the final models were evaluated by examining interactions betweentime and each variable in the model. Interaction terms were included in the model whenever nonproportionality ofhazards was observed.For analysis of hospital length of stay,interactions weredetectedbetweentime and APACHEII scores, SOFA scores, presence of coma, and use of lorazepam. No other significant interactions were observed.

Twenty-eight patients died in the ICU (1 in the no delirium group and 27 in the delirium group, P= .03) and weretherefore not included in the post-ICU length-of-stay analysis.

Figure 3. Kaplan-Meier Analysis of Delirium in the Intensive Care Unit and 6-Month Survival

100

30

60

50

40

70

80

90

20

10

0

No. at Risk

No Delirium

Delirium

0

41

183

1 32 5 64

34

138

25

111

28

116

21

98

19

88

22

104

Months After Enrollment

ProbabilityofSurvival,%

No Delirium

Delirium

A

Delirium Only

DeliriumNo Delirium

Delirium-Coma

Normal

Coma-Normal

100

30

60

50

40

70

80

90

20

10

0

No. at Risk

No Delirium

0 1 32 5 64

Normal

Coma-Normal

Delirium

Delirium Only

Delirium-Coma

17

24

60

123

15

19

51

87

11

15

39

72

11

17

42

74

10

11

33

65

10

9

29

59

10

12

34

70

Months After Enrollment

ProbabilityofSurvival,%

B





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cations. While development of coma iswell recognized as a risk factor fordeath,7,8,10,11 this investigation is the firstto document a strong relationship be-tween delirium andclinical outcomes af-ter adjusting for coma. These data

showed not only that ever developingthis type oforgan dysfunction was a pre-dictor of death by 6 months after ICUdischarge, but also that the number ofdays spent in a delirious state pre-dicted mortality. In addition, deliriumwas not simply a transition state fromcoma to normal, as delirium occurredjustas often among those who never de-veloped comaas it did among those whodiddevelopcomaat somestage,and per-sisted in 11% of patients at the time ofhospital discharge.

Monitoring for Delirium in the ICUIn the absence of data linking de-lirium to outcomes, few ICUs rou-tinely monitor for delirium. Monitor-ing for delirium with the CAM-ICU,which is easily incorporated by nursesinto their daily work and takes only 1to 2 minutes, could allow the medicalteam to consider causes and modifica-tions in their treatment of the patientexperiencing this organ dysfunc-tion65,66 (downloadable materials anddiscussion available at http://www

.icudelirium.org). We have found dur-ing a year-long implementation studyincorporating more than 22000 pa-tient observations that nursing staffreadily incorporated such measure-ments into routine care,67 in keeping

with recently issued guidelines of theSociety of Critical Care Medicine.18

Perhaps the greatest benefit of incor-porating delirium monitoring would bethe enhanced detection of the hypoac-tive delirium subtype,often calledquietdelirium because it is characterized bya flat affect or apathy and often presentinotherwise calm andseemingly alert pa-tients.68 This is in contrast to the readilydetected hyperactive delirium that ischaracterized by agitation, restlessness,attempting to removecatheters or tubes,hitting, biting, and emotional lability.68

In this study, hypoactive delirium waspresent in over 50% of patients with nor-malor near-normal arousal. This typeofbrain dysfunction may portend a worseprognosisthan hyperactivedelirium, ac-counts for the majority of delirium ob-servations, and is the most commonlymissed subtype of delirium.21,47,68-70

Potentially Modifiable Risk Factors

Our findings suggest that an impor-tant opportunity for improving the careof critically ill patients may be the de-

termination of modifiable risk factorsfor delirium in the ICU. Numerous riskfactors for delirium have been identi-fied, including preexistingcognitive im-pairment; advanced age; use of psycho-active drugs; mechanical ventilation;

untreated pain; and a variety of medi-calconditionssuch as heart failure, pro-longedimmobilization, abnormal bloodpressure, anemia,sleep deprivation, andsepsis.17,34,71-81

Some of the most readily imple-mented opportunities for improvingcare could be to correct brain ischemia/hypoxemia,82 to modify the adminis-tration of psychoactive medications,78

and to aggressively treat both under-lying infection and the manifestationsof severe sepsis, especially in elderly pa-tients.11,17,83-86 Regarding hypoxemia,

Hopkins et al82 found in 55 mechani-cally ventilated patients with acute lunginjury that mean oxygen saturationswere below 90% for 122 hours and be-low 85% for 13 hours per patient. Re-garding use of psychoactive drugs, re-cent studies87-89 have shown thatreducing unnecessary use of sedativesand analgesics may improve patientsoutcomes. Another approach to inter-vention would be to treat delirious pa-tients with procognitive medicationssuch as haloperidol, as recommended

Figure 4. Kaplan-Meier Analysis of Delirium in the Intensive Care Unit and Hospital Length of Stay

100

30

60

50

40

70

80

90

20

10

0

No. at Risk

No Delirium

Delirium

0

41

183

10 3020 50 6040

23

137

3

43

8

82

1

13

0

4

3

20


ProbabilityofBeingintheHospital,% No Delirium

Delirium

A

Delirium Only

Delirium

Delirium-Coma

No Delirium

Normal

Coma-Normal

100

30

60

50

40

70

80

90

20

10

0

No. at Risk

No Delirium

0 10 3020 50 6040

Normal

Coma-Normal

Delirium

Delirium Only

Delirium-Coma

17

24

60

123

8

15

38

99

2

1

17

26

3

5

25

57

1

0

5

8

0

0

2

2

2

1

8

12


ProbabilityofBeingintheHospital,%

B





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by the Society of Critical Care Medi-cine guidelines.18 However, such inter-ventions need to be tested in future re-search. Our multivariable analysis diddemonstrate that delirium influencedoutcomes even after adjusting for these

medications.

89

Thus, the developmentof delirium was of clinical relevanceabove and beyondthat attributed to iat-rogenic administration of sedative andanalgesic medications.

Long-term Cognitive Impairment

At the time of hospital discharge, therewas substantial cognitive impairment in1 out of every 2 survivors tested, whichwas significantly more common amongpatients who ever developed deliriumcompared with those who did not. Animportant limitation regarding this ob-

servation is that the patients were nottested for the presence of preexisting(ie,prior to ICU admission) cognitive im-pairment (a problem not easily re-solved due to the emergent nature ofthese patients illnesses). However, wedidusea well-validated surrogate assess-ment of dementia to estimate and ad-just for this possible confounder.

While long-term neuropsychologicalimpairment following mechanical ven-tilation is now recognized with increas-ing frequency,42,82 its relationship with

delirium during ICU stay is not knownand deserves further study. Ongoing de-lirium has been observed by others, in-cluding Levkoff et al,32 who found thatthe majority of hospitalized elderly pa-tients didnot experience complete reso-lutionof delirium symptomsprior to dis-charge. More recently, McNicoll andcolleagues90 reported that 40% of olderICU patientshad ongoing delirium dur-ing thepost-ICUperiod, and Kiely et al91

found that almost 20% of elderly pa-tientshaddelirium at thetime of admis-

sion to postacute facilities.

Limitations and Future Directions

Four limitations of this study shouldbenoted. Thefirst limitation has to do withthe delirium coding and the fact thatstudy protocol mandated only once-daily CAM-ICU assessments. Assess-ing patients more often with the

CAM-ICU will help to improve ourunderstanding of the phenomenologyof delirium in these patients. In theyear-long implementation study men-tioned above,67 nurses adopted de-lirium monitoring so readily that they

assessed patients more often than thetwice-daily requirement.Our coding ofpatients as having or not having de-lirium for a given day has to do withthe Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition defi-nition of this disorder. However, it isimportant to remember that delirium,by definition, fluctuates over time. Dueto the fluctuating nature of this disor-der, it is consideredpresent until clearedfor 24 hours. It would be feasible tocode the patients in 12-hour intervals.Even using such a schema, the de-

lirium episode will be considered asongoing until there are 2 consecutive12-hour shifts with negative CAM-ICU assessments. Second, we did notexamine the impact from the broadrange of psychoactive medicationsother thansedativesand analgesics, pa-tients pharmacological interindi-vidual variability in transport and me-tabolism of medications, or geneticpredisposition to this form of brain in-jury. Third, while our cohort did in-corporate a broad range of diagnoses in

themedical ICUpopulation, other typesof critically ill patients should be in-vestigated, includingpatients in traumaand surgical ICUs as well as those withbaseline neurologic comorbidities.

Lastly, this observational study wasnot designed to prove a cause-and-effect relationship between deliriumand clinical outcomes. However, thereare data to support a pathophysiologicrationale for the brain as a potentiator(rather than merely a marker) of total-body injury during critical illness. The

brain responds to systemic infectionsand injury with an inflammatoryresponse of its own that also includesthe production of cytokines, cellinfiltration, and tissue damage.92,93

Reports also indicate that local inflam-mation in the brain and subsequentactivation of the central nervous sys-tems immune responses are accompa-

nied by peripheral manifestations ofsystemic inflammation, including pro-duction of large amounts of peripher-ally produced tumor necrosis factor ,interleukin 1, and interferon .92,94-96

Such centrally mediated inflammation

could influence the development orresolution of multiple organ dysfunc-tion syndrome. Direct injury to thecentral nervous system induced byintracerebral endotoxin has also beenshown to result in loss of the liversability to metabolize drugs indepen-dent of intraperitoneally administeredendotoxin.97-99 Thus, the brain pro-duces its own signaling that likelyinfluences the overall outcome of thepatient. The exact nature of the signal-ing between the brain and other sys-temic organs remains to be elucidated.

In the meantime, this study has dem-onstrated an important clinical asso-ciation as well as the need for furtherexamination, including etiologic andinterventional studies.

CONCLUSIONS

In this single-center observationalstudy, we found that delirium amongmechanically ventilated patients in theICU was associated with higher6-month mortality and longer lengthsof stay even after adjusting for numer-

ous covariates. This study raises thequestion of how diligently deliriumshould be monitored in acutely illpatients, especially considering thatvalidated instruments can be imple-mented with a high degree of repro-ducibility andratesof complianceat thebedside by those routinely caring for pa-tients in the ICU. Some recent system-atic reviews of sedation practices andtheir consequences in the ICU have notmentioned delirium,100,101 while oth-ers have suggested that missing de-

lirium in acutely ill patients should beconsidered a medical error.25 Futurestudies are needed to determinewhether prevention or treatment of de-lirium would change clinical out-comes including mortality, length ofstay, cost of care, and long-term neu-ropsychological outcomes among sur-vivors of critical illness.





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Author Affiliations: Department of Medicine, Divi-sion ofGeneral Internal Medicine andCenter forHealthServices Research and the Veterans Affairs Tennes-see Valley Geriatric Research, Education and ClinicalCenter (GRECC) (Drs Ely, Shintani, Speroff, Gordon,Inouye, Dittus, and Ms Truman), Division of Allergy/P u l m o na r y / C ri t i c a l C a r e M e d i c in e ( D r s E l yand Bernard, Ms Truman), Department of Biostatis-tics (Drs Shintani, Speroff, and Harrell), and Depart-

ment of Psychiatry (Dr Gordon), Vanderbilt Univer-sity School of Medicine, Nashville, Tenn; andDepartment of Medicine, Yale University School ofMedicine, New Haven, Conn (Dr Inouye)Author Contributions: Drs Ely,Shintani, Speroff,andDittus and Ms Truman had full access to the all of thedata in the study and take responsibility for the integ-rity of the data and the accuracy of the data analyses.Study concept and design: Ely, Shintani, Truman,Gordon, Bernard, Dittus.Acquisition of data: Ely, Truman.Analysis and interpretation of data: Ely, Shintani,Truman, Speroff, Gordon, Harrell, Inouye, Bernard,Dittus.Drafting of the manuscript: Ely, Shintani, Truman.Critical revision of the manuscript for important in-tellectual content: Ely, Truman, Speroff, Gordon,Harrell, Inouye, Bernard, Dittus.Statistical expertise: Ely, Shintani, Speroff, Harrell,Dittus.Obtained funding; study supervision: Ely, Bernard,Dittus.Administrative, technical, or material support: Ely,Truman, Gordon, Inouye, Bernard, Dittus.Funding/Support: Dr Elyis a recipient ofthe PaulBee-son Faculty Scholar Award from the Alliance for Ag-ing Research and of a K23 from the National Insti-tutes of Health (AG01023-01A1) and the VeteransAffairs Tennessee Valley Geriatric Research, Educa-tion, and Clinical Center. Dr Inouye is a recipient of aMidcareer Award (K24AG00949) from the NationalInstitute onAging anda Donaghue InvestigatorAward(DF98-105) from the Patrick and Catherine WeldonDonaghue Medical Research Foundation.Role of the Sponsor: The Alliance for Aging Re-search, National Institutes of Health, National Insti-tute on Aging, and the Patrick and Catherine Wel-don Donaghue Medical Research Foundationhad norole in the design or conduct of the study; in the col-

lection,management, analysis, or interpretation of thedata; or in thepreparation, review, or approval of themanuscript.Acknowledgment: We thankall ofthe dedicatedandopen-minded ICU staff and Meredith Gambrell, whocontributed to this work. In addition,we thank GeetaMehta, MD; Derek Angus, MB, MPH; Craig Wein-ert,MD, MPH; andJean-Louis Vincent, MD,PhD, whoprovided important early feedback on the manu-script.

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delirium as a predictor of mortality em pacientes com ventilação mecânica

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