Evidence-based Synthesis Progra

(ESP)

Delirium: Screening, Preven

and Di i a

gnosis

A Systematic Review of the Evi

Timothy Wilt, MD, MPH

ESP Program Director

Minneapolis VA Medical Cente

October 13, 2011
Evidence-based Synthesis Progra

(ESP)

Acknowledgements

CoAuthors/Collaborators

o Rebecca Rossom, MDo Pauline Anderson, RN

Expert Panel/Re

o Barbara Kam

, o Terri Monk, M

o Nancy Greer, PhDo Roderick McDonald, MSo Indulis Rutks, BS

, 

o Beverly Priefeo Marta Render

o Indulis Rutks, BS

o James Rudolp

o James Tacklind, BS

o James Rudolpo Nancy Schmido Marianne Shao Kenneth Shay 

Kenneth Shay
Evidence-based Synthesis Progra

(ESP)

Disclosure

This report is based on research conducted by the Evidence This report is based on research conducted by the Evidence

-b

Synthesis Program (ESP) Center located at the Minneapolis VCenter, Minneapolis, MN funded by the Department of Vetera

Veterans Health Administration Office of Research and DeveVeterans Health Administration, Office of Research and Deve

Health Services Research and Development. The findings anin this document are those of the author(s) who are responsi

contents; the findings and conclusions do not necessarily repcontents; the findings and conclusions do not necessarily rep

views of the Department of Veterans Affairs or the United Stagovernment. Therefore, no statement in this article should b

as an official position of the Department of Veterans Affairs as an official position of the Department of Veterans Affairs. 

investigators have any affiliations or financial involvement (e.employment, consultancies, honoraria, stock ownership or op

t ti t t t i d di lti testimony, gran

ts or pa

ten

ts receive

d or pending, or royalties

with material presented in the report.
Evidence-based Synthesis Progra

(ESP)

VA Evidence-based Synthesis (E

Program Overview Program Overview

• Sponsored by VA Office of R&D and HSR&D.• Established to provide timely and accurate Established to provide timely and accurate

syntheses/reviews of healthcare topics identified clinicians, managers and policy-makers, as they wimprove the health and healthcare of Veterans improve the health and healthcare of Veterans. 

• Builds on staff and expertise already in place at th

Evidence-based Practice Centers (EPC) designate

Four of these EPCs are also ESP Centers: 

o Durham VA Medical Center; VA Greater Los Angeles 

System; Portland VA Medical Center; and MinneapoliSystem; Portland VA Medical Center; and Minneapoli

Center.
Evidence-based Synthesis Progra

(ESP)

• Provides evidence syntheses on important clinica

topics relevant to Veterans, and these reports hel

o d l li i l li i i f d b id develop cli

nical poli

cies in

forme

d

by evidence, 

o the implementation of effective services to impro

outcomes and to support VA clinical practice gui

performance measures, and 

o guide the direction for future research to addres

clinical knowled

ge.

• Broad topic nomination process – e.g. VACO, VISN

facilitated by ESP Coordinating Center (Portland) 

online process: online process:

http://www.hsrd.research.va.gov/publications/esp/TopicNom
Evidence-based Synthesis Progra

(ESP)

• Steering Committee representing research and op

(PCS, OQP, ONS, and VISN) provides oversight an

program di ti rec on.

• Technical Advisory Panel (TAP)

o Recruited for each to

pp p ic to 

provide content ex

pe

o Guides topic development; refines the key questo Reviews data/draft report.

• External Peer Reviewers & Policy Partners External Peer Reviewers

& Policy Partners

o Reviews and comments on draft report

• Final reports posted on VA HSR&D website and di

widely through the VA. 

http://www.hsrd.research.va.gov/publications/esp/repor
Evidence-based Synthesis Progra

(ESP)

Current Report

Delirium: Screening, Prevention, 

Diagnosis

– A Systematic Review o

A Systematic Review o

Evidence

(September, 2011)

Full-length report available on ESP website:

http://www.hsrd.research.va.gov/publications/esp/repor
Evidence-based Synthesis Progra

(ESP)

Background

• Common syndrome

o 10-30% of all hospital admissionso Over 80% in at Over 80% in at

-risk populations (e g elderly IC

risk populations (e.g., elderly, IC

• Associated with serious outcomes

o Mortality, y, g y, morbidity, len

gth of stay, institutionaliz

• Under-recognized• Many precipitating factors Many precipitating factors

o Medications, diseases, surgical procedures, and 

environmental factors
Evidence-based Synthesis Progra

(ESP)

Delirium definition

• Disturbance in a person's mental abilities 

results in a decreased awareness of one's envi t d f d thi ki ironmen

t an

d con

fuse

d thi

nking 

o Onset usually sudden-hours to few days (not gradua

decline-dementia

)
Evidence-based Synthesis Progra

(ESP)

Delirium Signs and Symptoms

• Reduced awareness of the environment

o Inability to stay focused, wandering attention, stuck 

easily distracted

• Cognitive impairment or poor thinking sk

Cognitive impairment or poor thinking sk

o Poor memory, particularly of recent events o Disorientationo Difficulty reading, writing, speaking, recalling or und

• Other common s

y p m

ptoms 

o Seeing things that don't exist (hallucinations) o Agitation, irritability, fear, anger, depression, combao Little or no activity or response to environment o Disturbed sleep
Evidence-based Synthesis Progra

(ESP)

Key Questions

Key Question 1• What is the What is the effectiveness effectiveness of screening screening for de

for de

adult inpatients?

o Do these results vary by medical unit, age, gen

comorbid conditions? 

o D i f d li i i li i l t 

Does screenin

g

for 

d

eli

rium improve cli

nical ou

t
Evidence-based Synthesis Progra

(ESP)

Key Questions

Key Question 2• What are the effectiveness and harms of del

prevention strategies in acute elderly inpatie

o Do these results vary by medical unit, age, gen

comorbid conditions?
Evidence-based Synthesis Progra

(ESP)

Key Questions

Key Question 3• What is the comparative diagnostic accuracy 

tools used to detect delirium:

a. In elderly medical and surgical inpatients?b. In elderly medical or surgical intensive care uninpatients?
Evidence-based Synthesis Progra

(ESP)

Screening

• Definition:

o

Test intended to detect a condition in an individual withou

symptoms of the index condition

• Criteria for effective screening Criteria for effective screening

o Disease is common, results in substantial morbidity and mo Detection tools have sufficient accuracy (sensitivity, specio

Effective interventions exist

o Detection in asymptomatic phase results in better health o

detection in symptomatic (benefits outweigh harms)

3⁄4 Evidence required to recommend screening is general

for tests or treatment of individuals with DZ signs or s

– Patients asy p m

ptomatic

– Benefits to few, harms to many
Evidence-based Synthesis Progra

(ESP)

Assessing Net Benefit

Benefit – Harms = N

(g q y Ma

gnitude X Fre

quenc

y

f

Timing)

–

(g q 

Ma

gnitude X Fre

qu
Evidence-based Synthesis Progra

(ESP)

A l ti F k

KQ1 - Screening

Analytic 

Framewor

k

I t di t

CL

KQ2 –Preventive Intervention Treatment

Hospitalized Adult Patient:AgeRace

Diagnosis of Delirium (KQ3)

Intermedi

ate 

Outcomes:Change in mental status

L

(HVMTA

GenderMedications Comorbidities

No Delirium T

In

KQ2 – Preventive Intervention

Harms of TreatmResource utilizatioUnnecessary trea

Harms of Screening: False positive (labeling) or false negative diagnosis

Harms of Preventive Interventions:Resource utilizationUnnecessar

y intervention negative diagnosis, 

resource utilization 

y
Methods

• Literature Search: MEDLINE, CINAHL, PsycINFO; 19

Novemb 20 0 l h l ber 2010; English language

• Exclusion criteria for screening/diagnosis questio

Exclusion criteria for screening/diagnosis questio

Age <16 yrs Alcohol-related delirium Not hospitalNo reference standard Index and reference test Case series (

E l i it i f ti ti

No reference standard(e.g., DSM-IV)

Index and reference test by same individual

Case series (case report

• Exclusion criteria for prevention question:

Age <16 yrs Nursing home resident Case series o

report
Methods, continued Methods, continued

• Study Quality/Strength of Evidence:

RCTs

a. quality - allocation concealment, blinding, intent

analysis, reporting of withdrawals/drop-outs (Higgins, 2

b. strength of evidence – risk of bias, consistency, 

precision (Owens, 2010)

Diagnostic Accuracy Studies

a. quality – independent, blinded, criterion standar

sampl f ti i di id l ( le o

f consecutive indi

viduals 

(Si l me , 2008)

b. strength of evidence – not evaluated due to het

approaches
Literature Search Results Literature Search Results

S i creen ng: 1 889 b t t i d ( l 

1,889 a

b

s

trac

ts reviewe

d

(excl

111 full text articles reviewed:

Included: 0

Prevention: 1,175 abstracts reviewed (exc228 full text articles reviewed (excluded 197228 full text articles reviewed (excluded 197

search added 8; 

Included: 39 

Diagnosis (ICU only): 76 abstracts review(excluded 40); 36 full text articles reviewed (excluded 21); (excluded 21);

Included: 15 
Key Question 1 – Effectiveness o

S i creen

n

g

• No studies compared patient outcomes in 

h it li d ti t d l ( hospit

alize

d patien

ts ran

domly 

(or non-r

assigned to screening or no screening fo

• Potential harms of screening: 

o misclassification (inappropriate treatment or no trea

misclassification (inappropriate treatment or no trea

psychological harm to patient and family), opportun(screening and follow-up)
Key Question 2 Key Question 2 – Prevention Prevention

• 39 studies, 7935 total patients

Randomized Non-Rand

Pharmacologic 16 4

• Mean age: 78 years Gender: 44% male

Non-pharmacologic 5 14

Mean age: 78 years Gender: 44% male

• Orthopedics/orthopedic surgery: 33% of enrolled pat• Cardiac surgery: 19%• Other surgery: 8% 

• Internal medicine/geriatrics: 40%• 16 studies (53% of enrolled patients) in United States 

16 studies (53% of enrolled patients) in United States 
Key Question 2 – Prevention –

Ph l i RCT Pharmacologic RCT

s

Pharmacologic Studies

Intervention* RCTs Risk Ratio (95%C

Cholinesterase inhibitor 3 0.93 (0.51-1.69) Atypical antipsychotic 2 0.35 (0.25-0.50) Typical antipsychotic with consultation 1 0.91 (0.59-1.42) Typical antipsychotic 1 0.32 (0.12-0.91) Fascia iliaca block 1 0.45 (0.24 0.45 (0.24-0.87) Continuous epidural vs. continuous intravenous 1 0.87 (0.45-1.69) Deep vs. light sedation 1 0.48 (0.26-0.89) Ketamine bolus 1 0.11 

(0.02-0.82

) 

Regional vs. general anesthesia 1 0.74 (0.21-2.59) Epidural vs. general anesthesia 1 1.32 (0.73-2.39) Dexmedetomidine vs. propofol or midazolam 1 0.23 (0.08-0.61) (P

0.24 (0.09-0.64) (M

Delirium free protocol vs. usual care 1 0.14 (0.02-1.06) 

Melatonin 1 0.37 (0.17-0.81) *versus placebo except where indicated
Key Question 2 – Prevention –

Ch li t I hibit RCT Ch

olines

terase Inhibitor RCTs - P l

oo

e

Study or Subgroup1.1.1 Donepezil versus placeboLiptzin 2005

Events

8

Total

39

Events

7

Total

41

Weight

30 4%

M-H, Random, 95% CI

1 20 [0 48 3 00]

Pharmacologic Placebo Risk Ratio 

M-H

Liptzin 2005Sampson 2007Subtotal (95% CI)Total eventsHeterogeneity: Tau2 = 0 59; Chi2 = 2 50 df = 1 (P = 0 11); I2 = 60%

82

10

3919

58

75

12

4114

55

30.4%14.0%

44.5%

1.20 [0.48, 3.00]0.29 [0.07, 1.30]

0.68 [0.17, 2.62]

Heterogeneity: Tau2

=

0.59; Chi2

=

2.50, df

= 1 (P

=

0.11); I2

= 60%

Test for overall effect: Z = 0.57 (P = 0.57)1.1.2 Rivastigimine versus placeboG b i i 2009 Gam

berini 2009 18 56 17 57 55 5% 1 08 [0 62 1 87]

Subtotal (95% CI)Total eventsHeterogeneity: Not applicable

1818

56

56

1717

57

57

55.5%

55.5%

1.08 [0.62, 1.87]

1.08 [0.62, 1.87]

Test for overall effect: Z = 0.27 (P = 0.79)Total (95% CI)Total events 28

114

29

112 100.0% 0.93 [0.51, 1.69]

Heterogeneity: Tau2 = 0.09; Chi2 = 2.83, df = 2 (P = 0.24); I2 = 29%

Test for overall effect: Z = 0.24 (P = 0.81)Test for sub

grou

p differences: Chi2 = 0.39, df = 1 (P = 0.53), I2 = 0%

0.1 0.2 0

Favors pharmaco
Key Question 2 – Prevention – Atypic

A ti h ti RCT A

ntipsyc

h

otic RCTs 

– P ld oo

e

d

Pharmacologic Placebo Risk Ratio 

Study or Subgroup1.5.2 Olanzapine (atypical antipsychotic) versus placebo: Orthopedic patientsLarsen 2010

Events

28

Total

196

Events

82

Total

204

Weight

81.0%

M-H, Random, 95% CI

0.36 [0.24, 0.52]

Pharmacologic Placebo Risk Ratio 

M-H, 

Subtotal (95% CI)Total eventsHeterogeneity: Not applicableTest for overall effect: Z

= 5.31 (P

< 0.00001)

28

196

82

204 81.0% 0.36 [0.24, 0.52]

Test for overall effect:

Z 5.31 (P 0.00001)

1.5.3 Risperidone (atypical antipsychotic) versus placebo: Cardiac surgery patientsPrakanrattana 2007Subtotal (95% CI)

7 63

63

20 63

63

19.0%

19 0%

0.35 [0.16, 0.77]

Subtotal (95% CI) 0 35 [0 16 0 77]Total eventsHeterogeneity: Not applicableTest for overall effect: Z = 2.62 (P = 0.009)

7

63

20

63 19.0%

0.35 [0.16, 0.77]

Total (95% CI)Total eventsHetero

geneit

y: Tau2 = 0.00; Chi2 = 0.00, df = 1 (P = 0.97); I2 = 0%

35

259

102

267 100.0% 0.35 [0.25, 0.50]

0 1 0 2 0 

g y ; , ( ); Test for overall effect: Z = 5.92 (P < 0.00001)

Test for sub

grou

p differences: Chi2 = 0.00, df = 1 (P = 0.97), I2 = 0%

0.1 0.2

0.

Favors pharmacol
Key Question 2 – Prevention –

Ph l i N Pharmacologic 

Non-RCT

s

• Cholinesterase Inhibitors – 2 studies, different m

(rivastigmine, physostigmine) geriatric medicine 

), geriatric medicine 

surgery patients, significant reduction in risk in b

•

Analgesia – 1 study, patient controlled femoral n

intravenous, orthopedic patients, significant redu

risk

• Anti-lipid therapy – 1 study, statin vs. no statin, c

surgery pati t en

ts, no si ifi t diff i i k ignifican

t difference in ris

k
Key Question 2 – Prevention –

Non-Ph l i St di Pharmacologic St

udies

Multi-component Intervention Studies

-

linary

Education

nt

sment

tation 

r Sensory 

rment

ng

Protocol

ization

onmental 

ication

Multidiscipl

Team

Staff E

Patien

Assess

Orien

and/or

Impai

Traini

Sleep

Early 

Mobili

Enviro

Modifi

RCTs ( 3)

1232121

(n=3)NonRCTs 8 9 12 7 5 10 6 

Studies not pooled due to heterogeneity of interven

(n=13)

Studies not pooled due to heterogeneity of interven
Key Question 2 – Prevention –

Non-Ph l i St di Pharmacologic St

udies

• 3 Multi-Component RCTs

o Si ifi tl l i id f d li i i 2 f 

Sig

nificantly lower incidence o

f

d

eli

rium in 

2 o

f

3⁄4 1 was moderate quality

o Relative risks: 2 of 3 studies had reduced risk Relative risks:

2 of

3 studies had reduced risk

3⁄4 moderate quality study was significant

• 13 Multi-Component Non-RCTs

o Significantly lower incidence of delirium in 10 o

Significantly lower incidence of delirium in 10 o

reporting significance 

o Relative risks: all studies had reduced risk; 7 s
Key Question 2 – Prevention -

Non-Ph l i St di Pharmacologic St

udies

• Single Component Studies• 2 RCTs – (low quality)

o Bright light:– non-significant reduction in delirium ino Music added to usual care Music added to usual care

– reduction in delirium in

reduction in delirium in

• 1 Non-RCT –

o Staff education 

–reduction delirium incidence
Key Question 2 – Prevention 

Harms

• Mortality

o Reported in 7 pharmacologic and 11 non-pharmacolo 1 study: significantly lower mortality in intervention 

• Adverse Events Adverse Events

o 13 pharmacologic and 7 non-pharmacologic studieso

F

e s g ca d e e ces w 

significant 

diffe

re

nces

o Pharmacologic studies (n=2): Mixed results for use o Non-pharmacologic studies (n=3): fewer bed soreso Non-pharmacologic studies (n=2): fewer fallso Non-pharmacologic study (1 each): reduced infectio

bedridden status restraint use bedridden status, restraint use
Confusion Assessment Method 

(CAM) Di ti Al ith (CAM) Di

a

gnostic Algorith

m

• Feature 1: Acute onset and fluctuating co

o Change in mental status from baseline; behavior fluct

past day

• Feature 2: Inattention

o Easily distracted; difficulty keeping track of what was 

Easily distracted; difficulty keeping track of what was 

• Feature 3: Disorganized thinking

o Speech disorganized or incoherent; illogical flow of ide

Speech disorganized or incoherent; illogical flow of ide

switching from subject to subject

• Feature 4: Altered level of consciousness

o Alert, vigilant, lethargic, stupor, coma

Diagnosis: present/abnormal rating for features 

and also for either feature 3 or 4
Key Question 3 – Diagnosis

Non-ICU P ti t ICU

P

atien

t

s

• Systematic review (Wong, JAMA 2010)

o Included 25 studies; 15 with elderly patients

3⁄4 Hospitalized patients (non-ICU)3⁄4 Appropriate reference standard (DSM-IV or similar) pe

specialist

3⁄4 Adult, non-alcohol related delirium

o CAM – most widely studied (12 studies, 1,036 patients)

3⁄4 Sensitivity 86% Specificity 93% (pooled) Sensitivity 86%, Specificity 93% (pooled)3⁄4 Likelihood ratios: positive test = 9.6 negative te3⁄4 Considerable heterogeneity (I

2 > 65%)

o Other tools with more than 1 study

3⁄4 Delirium Rating Scale (4 studies, 943 patients)3⁄4 Memorial Delirium Assessment Scale 

( ,p 

3 studies, 330 

p

3⁄4 Delirium Observation Screening Scale (2 studies, 178 
Key Question 3 – Diagnosis

ICU P ti t ICU

P

atien

t

s

• Diagnosis in Elderly ICU Patients

o 15 studies; 1 272 medical surgical or psychiatric patients

15 studies;

1,272 medical, surgical, or psychiatric patients

included intubated patients 

o 11 different tools/methods for diagnosiso CAM-ICU: (6 studies)

3⁄4 Sensitivity: 64-100% S

p y ecificity: 88-100%

o Intensive Care Delirium Screening Checklist (ICDSC): (2 s

3⁄4 Sensitivity: 43 Sensitivity: 43

-99% Specificity: 64 Specificity: 64

-95%

o Other tools (all 1 study)

3⁄4 Sensitivity: 30-100% Specificity: 64-96%
Summary & Conclusions Summary

& Conclusions

• SCREENING – Key Question 1

o No RCTs (or non-RCTs) of screening for 

in hospitalized patients

o Insu c e t e de ce ffi

cie

n

t

evide

nce about et be e t o net be

n

efi

t

o

screening hospitalized patients or subgro(g g a

ge, 

gender, comorbidities, ICU

)
Summary & Conclusions Summary

& Conclusions

• PREVENTION – Key Question 2

o Pharmacologic interventions: Low or mixed 

3⁄4 1 trial, small, inconsistent outcome repo

o Multi-component interventions: 

3⁄4

generally successful; few RCTs; difficult determine effective components

o Harms-fewo No studies stratified by age, gender, or com

conditions
Summary & Conclusions Summary

& Conclusions

• DIAGNOSIS – Key Question 3

o S ii ystematic review: 

3⁄4 CAM: suitable operating characteristics i

and surgical inpatients and surgical inpatients

– Administrator training and concurren

status testing may influence accuracstatus testing may influence accurac

o Fewer studies in ICU patientso Unknown whether operating characteristics 

Unknown whether operating characteristics 

diagnostic tests are robust across wide ran

populations and settings populations and settings
Future Research Needs Future Research Needs

• RCTs of delirium screening in hosp

patients

• Assessment of prevention strategie

o Pharmacologico Multi-component

• Assessment of bedside diagnostic t

broad clinical settin

gs 
Evidence-based Synthesis Progra

(ESP)

Questions?

If you have further questions, 

feel free to contact:

Timothy Wilt, MD

Timothy Wilt@va gov Timothy.Wilt@va.gov

The full report and cyberseminar presentation is available on the 

http // g /p / p ://www.hsrd.research.va.gov/publications/esp