Cochrane SCA sindrome confusional agudo

Interventions for preventing delirium in hospitalised patients

(Review)

Siddiqi N, Holt R, Britton AM, Holmes J

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Interventions for preventing delirium in hospitalised patients (Review)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 1 Incidence of delirium in first 7

days after surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 1.2. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 2 Behavioural disturbance in 1st 7

days after surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 1.3. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 3 Length of admission. . . 30

Analysis 2.1. Comparison 2 Epidural anaesthesia v Halothane anaesthesia, Outcome 1 Incident delirium on day 1 or day 7

post surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Analysis 2.2. Comparison 2 Epidural anaesthesia v Halothane anaesthesia, Outcome 2 Physical morbidity. . . . . 31

Analysis 3.1. Comparison 3 Prophylactic citocoline v Placebo, Outcome 1 Incident delirium. . . . . . . . . 32

Analysis 4.1. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 1 Incident delirium post surgery. . . . 33

Analysis 4.2. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 2 Delirium duration. . . . . . . . . 33

Analysis 4.4. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 4 Length of admission. . . . . . . . 34

Analysis 4.5. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 5 Withdrawal from protocol. . . . . . 34

Analysis 4.6. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 6 Adverse effects. . . . . . . . . . 35

Analysis 5.1. Comparison 5 Prophylactic donepezil v Placebo, Outcome 1 Delirium incidence after surgery. . . . 35

Analysis 5.4. Comparison 5 Prophylactic donepezil v Placebo, Outcome 4 Withdrawal from protocol. . . . . . 36

Analysis 6.1. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 1 Cumulative delirium incidence. 36

Analysis 6.2. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 2 Delirium duration. . . . . 37

Analysis 6.3. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 3 Severity- cumulative incidence of

severe delirium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Analysis 6.4. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 4 Institutionalisation at discharge. 38

Analysis 6.5. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 5 Cognitive status- delirium prevalence

at discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

38ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iInterventions for preventing delirium in hospitalised patients (Review)


[Intervention Review]

Interventions for preventing delirium in hospitalised patients

Najma Siddiqi1, Rachel Holt2, Annette M Britton3, John Holmes4

1Academic Unit for Psychiatry and Behavioural Sciences, University of Leeds, Leeds, UK. 2Leeds, UK. 3Geriatric Unit, Royal Prince

Alfred Hospital, Sydney, Australia. 4Academic Unit of Psychiatry, University of Leeds, Leeds, UK

Contact address: Najma Siddiqi, Academic Unit for Psychiatry and Behavioural Sciences, University of Leeds, 15 Hyde Terrace, Leeds,

LS2 9LT, UK. [email protected].

Editorial group: Cochrane Dementia and Cognitive Improvement Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.

Review content assessed as up-to-date: 11 January 2007.

Citation: Siddiqi N, Holt R, Britton AM, Holmes J. Interventions for preventing delirium in hospitalised patients. Cochrane Databaseof Systematic Reviews 2007, Issue 2. Art. No.: CD005563. DOI: 10.1002/14651858.CD005563.pub2.


A B S T R A C T

Background

Delirium is a commonmental disorder with serious adverse outcomes in hospitalised patients. It is associated with increases in mortality,

physical morbidity, length of hospital stay, institutionalisation and costs to healthcare providers. A range of risk factors has been

implicated in its aetiology, including aspects of the routine care and environment in hospitals. Prevention of delirium is clearly desirable

from patients and carers perspectives, and to reduce hospital costs. Yet it is currently unclear whether interventions for prevention of

delirium are effective, whether they can be successfully delivered in all environments, and whether different interventions are necessary

for different groups of patients.

Objectives

Our primary objective was to determine the effectiveness of interventions designed to prevent delirium in hospitalised patients. We

also aimed to highlight the quality and quantity of research evidence to prevent delirium in these settings.

Search methods

We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 30 September 2006. As the

searches in MEDLINE, EMBASE, CINAHL and PsycINFO for the Specialized Register would not necessarily have picked up all

delirium prevention trials, these databases were searched again on 28th October, 2005. We also examined reference lists of retrieved

articles, reviews and books. Experts in this field were contacted and the Internet searched for further references and to locate unpublished

trials.

Selection criteria

Randomised controlled trials evaluating any interventions to prevent delirium in hospitalised patients.

Data collection and analysis

Data collection and quality assessment were performed by three reviewers independently and agreement reached by consensus.

1Interventions for preventing delirium in hospitalised patients (Review)


Main results

Six studies with a total of 833 participants were identified for inclusion. All were conducted in surgical settings, five in orthopaedic

surgery and one in patients undergoing resection for gastric or colon cancer.

Only one study of 126 hip fracture patients comparing proactive geriatric consultation with usual care was sufficiently powered to

detect a difference in the primary outcome, incident delirium. Total cumulative delirium incidence during admission was reduced in

the intervention group (OR 0.48 [95% CI 0.23, 0.98]; RR 0.64 [95% CI 0.37, 0.98]), suggesting a number needed to treat of 5.6

patients to prevent one case. The intervention was particularly effective in preventing severe delirium. In logistic regression analyses

adjusting for pre fracture dementia and Activities of Daily Living impairment, there was no reduction in effect size, OR 0.6, but this

no longer remained significant [95% CI 0.3,1.3]. There was no effect on the duration of delirium episodes, length of hospital stay, and

cognitive status or institutionalisation at discharge. There was also no significant difference in cumulative delirium incidence between

treatment and control groups in a sub-group of 50 patients with dementia (RR 0.9 [95% CI 0.59, 1.36]).

In another trial of low dose haloperidol prophylaxis, there was no difference in delirium incidence but the severity and duration of a

delirium episode, and length of hospital stay were all reduced.

We identified no completed studies in hospitalised medical, care of the elderly, general surgery, cancer or intensive care patients. In

outcomes, no studies examined for death, use of psychotropic medication, activities of daily living, psychological morbidity, quality of

life, carers or staff psychological morbidity, cost of intervention and cost to health care services. Outcomes were only reported up to

discharge, with no studies reporting medium or longer-term effects.

Authors conclusions

Research evidence on effectiveness of interventions to prevent delirium is sparse. Based on a single study, a programme of proactive

geriatric consultation may reduce delirium incidence and severity in patients undergoing surgery for hip fracture. Prophylactic low dose

haloperidol may reduce severity and duration of delirium episodes and shorten length of hospital admission in hip surgery. Further

studies of delirium prevention are needed.

P L A I N L A N G U A G E S U M M A R Y

There is a lack of robust information on delirium prevention in hospitalised patients

We were only able to identify one trial with adequate power to demonstrate effectiveness of any preventive strategies. Based on this

single study, proactive consultation by a consultant geriatrician before, or within 24 hours of operation may reduce the incidence and

severity of delirium in patients undergoing surgery for hip fracture. Low dose haloperidol prophylaxis may be effective in reducing the

severity and duration of a delirium episode and may shorten length of hospital admission. Given what is already known about how

common delirium is, and how poor its outcomes are, further trials of delirium prevention are urgently needed.

B A C K G R O U N D

Delirium, a disturbance of consciousness and cognition,with rapid

onset, fluctuating course and underlying causation, has been vari-

ously termed acute organic brain syndrome, acute organic mental

disorder and toxic confusional state. Until the 19th century delir-

ium was used to describe a disorder of thinking and later descrip-

tions included disturbances of perception, often with overactive

behaviour, or impaired consciousness. The publication of DSM-

III (APA 1987) in 1987 brought together these ideas, combining

disturbance of consciousness with impairment of cognition; the

core features of delirium have been clarified in the DSM-IV (APA

1994) and ICD-10 (WHO 1992). This recent consensus has al-

lowed some standardisation of research, and greater comparability

between studies.

Delirium is common in hospitalized patients. Ten to 30% of ad-

missions to a general hospital develop delirium (Levkoff 1991;

Trzepacz 1996) and in general medical in-patients, occurrence

rates ranging from 11 to 42% have been reported (Siddiqi 2006).

Delirium has a prevalence of up to 60% in frail elderly patients



(Francis 1990), and 7 to 9.6% in elderly patients presenting

to emergency departments (Elie 2000; Hustey 2003). Following

coronary artery bypass grafting in the elderly, incidence has been

reported as 33.6% (Santos 2004), and after bilateral knee replace-

ments 41% (Williams-Russo 1992). Following hip fracture the

overall prevalence is 43 to 61% (Holmes 2000).

Patients in intensive care units (ICU) are at high risk of developing

delirium, with incidence rates of 40% reported (Roberts 2004).

Cancer also increases the risk of developing delirium. 18%of those

admitted to an oncology ward, and 26 to 44% of those admitted to

hospital or a hospicewith a diagnosis of advanced cancer developed

delirium (Centeno 2004; Ljubisavljevic 2003). In AIDS patients

who are unwell enough to be admitted, incidence of delirium is

also high, being reported as 46% (Uldall 1997).

Delirium is serious, with significant short and long term out-

comes. Death rates are increased (McCusker 2002), functional

abilities reduced (Moller 1998), admission to long-term care in-

creased (Inouye 1998a), and length of stay increased (McCusker

2003a; Stevens 1998). Impairment of cognitive function can per-

sist for at least one year (McCusker 2001), as can the symptoms

of delirium, especially inattention, disorientation and impaired

memory (McCusker 2003b). Increasingly recognised is the distress

an episode of delirium produces in carers (Breitbart 2002).

Research in the elderly has identified a multitude of risk factors.

The condition clearly has a multi-factorial aetiology, and these

risk factors interact (Inouye 1998b); the more risk factors that

are present, the greater the likelihood that the patient will de-

velop delirium. Risk factors that have so far been identified in-

clude: increased age, sensory deprivation (visual or hearing im-

pairment), sleep deprivation, social isolation, physical restraint,

use of bladder catheter, iatrogenic adverse events, poly-pharmacy

(more than three new medications added), use of psychoactive

drugs, co-morbidities, severe illness (especially infection, fracture

or stroke), prior cognitive impairment, temperature abnormality

(fever or hypothermia), dehydration, malnutrition and low serum

albumin (Inouye 1998b; Inouye 1999c).

Studies in oncology patients have identified a range of different

risk factors for the development of delirium, for example bone

metastases, the presence of haematological malignancy, advanced

age, cognitive impairment, and low albumin level (Ljubisavljevic

2003).

The identification of such a varied list of aetiological factors sug-

gests several things. Firstly, we may be able to identify patients at

high risk of developing delirium, and by modifying these risk fac-

tors could attempt to prevent it; differing groups of patients may

require a different set of preventative measures. Secondly, many of

these risk factors can be seen as hospital quality of care measures,

e.g. malnutrition, dehydration, use of physical restraints, iatro-

genic events. Occurrence of delirium can, therefore, be seen as a

proxy measure of the quality of in-patient care (Inouye 1999b).

Prevention of delirium is obviously desirable for both patients and

carers, and to reduce health service costs. A recent study found that

the health care costs in patients who developed delirium in ICUs

were 31% higher ($41,836 versus $27,106) (Milbrandt 2004).

A non-randomised study of a multi-component intervention for

delirium demonstrated overall improved cost-effectiveness (Rizzo

2001).

Possible interventions for preventing delirium in hospitalized pa-

tients have been developed.Most of the current studies have taken

a multi-factorial approach, attempting to prevent several risk fac-

tors by protocols, education or systems redesign, rather than fo-

cusing on one risk factor in isolation (Cole 2002; Inouye 2000a;

Milisen 2001). Interventions include programmes of education

for ward nursing staff (Rockwood 1999), non-pharmacological

intervention protocols targeting specific risk factors and imple-

mented by a trained interdisciplinary team (Inouye 1999a), and

a specialist nursing intervention to educate nursing staff, assess

and change medication, encourage mobilization and improve the

environment of the patient (Wanich 1992).

It is currently unclear whether interventions for prevention of

delirium are effective, whether they can be successfully delivered

in all environments, and whether different interventions are neces-

sary for different groups of patients. Previous reviews (Cole 1999;

Milisen 2005) have suggested possible protocols for delirium pre-

vention, but have not been systematic or have employed less rig-

orous selection criteria.

O B J E C T I V E S

Primary objective:Todetermine the effectiveness of interventions

designed to prevent delirium in hospitalised patients.

Secondary objective: To highlight the quality and quantity of

research evidence to prevent delirium in hospitalised patients

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included only original reports of randomised controlled tri-

als in the review. Because of the difficulties inherent in blinding

of participants and researchers to certain types of interventions,

blinding was not a prerequisite for inclusion. The length of trial

did not influence selection of studies.



Types of participants

We included patients aged 16 years or over, admitted to acute

general hospitals, and at risk of developing delirium. We excluded

studies conducted in community settings e.g. in nursing homes.

We excluded studies in mixed settings unless data could be ex-

tracted separately for hospitalised in-patients.

Types of interventions

We included studies of any intervention(s) designed to prevent

delirium with controls receiving standard care. We also included

trials comparing two types of intervention. Trials of co-ordinated

multi-strategy initiatives were included. Examples of interventions

we included are: regular screening of cognitive function or mental

state, protocol driven medical review and investigation, medica-

tion review, medication, nursing interventions, education of staff

or family.

We defined standard care as the usual care available on that unit.

Types of outcome measures

The primary outcomes of interest were:

incident delirium (new onset) during admission

death

We only accepted studies in which delirium was identified using

a validated method for diagnosis, such as operationalised clinical

criteria from ICD-10, DSM-III, DSM-IIIR, DSM-IV, (WHO

1992; APA 1987; APA 1994; APA 1999) or using diagnostic tools

based on these e.g. the Confusion Assessment Method (CAM)

(Inouye 2000b), Delirium Rating Scale (DRS) (Trzepacz 1988).

All types of delirium (hypoactive, hyperactive and mixed) were

considered together. We included drug-induced delirium but not

delirium tremens.

Secondary outcomes were:

duration of delirium

severity of delirium, measured by validated instruments

including the Memorial Delirium Assessment Scale (MDAS)

(Breitbart 1997) and DRS

use of psychotropic medication

behavioural disturbance

length of admission

activities of daily living

institutional care at discharge

cognitive status

physical morbidity

psychological morbidity

quality of life

carers psychological morbidity

staff psychological morbidity

withdrawal from protocols by patients

cost of intervention

cost to health care services

We also included adverse events, although this was not specified

in the original published protocol.

Search methods for identification of studies

CDCIG Specialised Register:

The SpecializedRegister of theCochraneDementia andCognitive

Improvement Group was searched on 30 September 2006 using

the terms: delirium or acute confusion or acute brain failure

or acute organic psychosyndrome or acute brain syndrome or

metabolic encephalopathy or acute psycho-organic syndrome

or clouded state or clouding of consciousness or exogenous

psychosis or toxic psychosis or toxic confusion.

The Specialized Register at that time contained records from the

following databases:

CENTRAL: July 2005 (issue 3);

MEDLINE: 1966 to 2005/08, week 2;

EMBASE: 1980 to 2005/08, week 2;

PsycINFO: 1887 to 2005/07;

CINAHL: 1982 to 2004/07;

SIGLE (Grey Literature in Europe): 1980 to 2004/06;

ISTP (Index to Scientific and Technical Proceedings): to

May 2000;

INSIDE (BL database of Conference Proceedings and

Journals): to June 2000;

Aslib Index to Theses (UK and Ireland theses): 1970 to

March 2003;

Dissertation Abstract (USA): 1861 to March 2003;

http://clinicalstudies.info.nih.gov/;

National Research Register (issue 3/2005)

ClinicalTrials.gov: last searched 1 September 2005;

LILACS: Latin American and Caribbean Health Science

Literature: last searched April 2003

http://www.forestclinicaltrials.com/: last searched 1

September 2005

ClinicalStudyResults.org: last searched 1 September 2005

http://www.lillytrials.com/index.shtml: last searched 28

August 2005

ISRCTN Register: last searched 1 September 2005

IFPMA Clinical Trials Register: http://www.ifpma.org/

clinicaltrials.html: last searched September 2005

The search strategies used to identify relevant records in MED-

LINE, EMBASE, PsycINFO, CINAHL and LILACS can be

found in the groups module.

As the searches in MEDLINE, EMBASE, CINAHL and

PsycINFO for the Specialized Register would not necessarily have

picked up all delirium prevention trials (it is primarily a register of

trials with people with dementia or cognitive impairment), these

databases were searched again on 28th October 2005 with the fol-

lowing search strategies:

MEDLINE (1966-2005)



1.Delirium/ all subheadings

2.deliri*

3.acute confusion

4.acute organic psychosyndrome

5.acute brain syndrome

6.metabolic encephalopathy

7.acute psycho-organic syndrome

8.clouded state

9.clouding of consciousness

10.exogenous psychosis

11.toxic psychosis

12.toxic confusion

13.#1 or #2

14.#3 or #4 or #5 or #6

15.#7 or #8 or #9 or #10

16.#11 or #12

17.#13 or #14 or #15 or #16

18.explode Primary-Prevention/ all subheadings

19.prevent*

20.avoid*

21.#18 or #19 or #20

22.#17 and #21

23.random* or placebo* or control*

24.standard treatment or normal treatment or standard care

or normal care

25.#23 or #24

26.#22 and #25

27.Alcohol-Withdrawal-Delirium/ all subheadings

28.delirium tremens in TI

29.#27 or #28

30.#26 not #29

31.((TG=animals) not (TG=humans)) and (TG =animals)

32.#30 not #31

EMBASE (1980-2005)

1 explode delirium tree: 1/ all subheadings

2 deliri*

3 acute psycho-organic syndrome or clouded state or cloud-

ing of consciousness or exogenous psychosis or toxic psychosis

or toxic confusion

4 acute brain confusion or acute brain failure or acute or-

ganic psychosyndrome or acute brain syndrome or metabolic

encephalopathy

5 #1 or #2 or #3 or #4

6 explode prevention/ all subheadings

7 prevent* or avoid*

8 #6 or #7

9 #5 and #8

10 randomized-controlled-trial/ all subheadings

11 random* or placebo* or control* or normal care or standard

care or standard treatment or normal treatment

12 #10 or #11

13 #9 and #12

14 delirium-tremens/ all subheadings

15 #13 not #14

16 nonhuman* in DER

17 (nonhuman* in DER) and (human* in DER)

18 #16 or #17

19 #15 not #17

PsycINFO (1887-2005)

1 deliri*


ing of consciousness or exogenous psychosis or toxic psychosis

or toxic confusion

3 acute brain confusion or acute brain failure or acute organic

psychosyndrome or acute brain syndrome or metabolic en-

cephalopathy

4 Delirium- in MJ,MN

5 #1 or #2 or #3 or #4

6 explode Prevention


8 #6 or #7

9 #5 and #8

10 random* or placebo* or control* or normal treatment or

normal care or standard care or standard treatment

11 #9 and #10

CINAHL (1982-2004)

1 deliri*


ing of consciousness or exogenous psychosis or toxic psy-

chosis or toxic confusion

3 acute brain confusion or acute brain failure or acute or-

ganic psychosyndrome or acute brain syndrome or metabolic

encephalopathy

4 Delirium/ without-subheadings

5 #1 or #2 or #3 or #4

6 Preventive-Trials/ without-subheadings


8 #6 or #7

9 #5 and #8

10 random* or placebo* or control* or normal care or standard

care or normal treatment or standard treatment

11 #9 and #10

12 Alcohol-Withdrawal-Delirium/ without-subheadings

13 delirium tremens in TI

14 #12 or #13

15 #11 not #14

16 (animal in DE) not ((human in DE) and (animal in DE))

17 #15 not #16

CENTRAL (issue 3/2005)

1.(acute next confusion)

2.(acute next brain next syndrome)

3.(acute next organic next psychosyndrome)

4.(clouding next consciousness)

5.(acute next psychosis)



6.(toxic next psychosis)

7.(toxic next confusion)

8.(acute next psychosyndrome)

9.(acute next psycho-syndrome)

10.(#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9)

11.(#10 and (prevent* or avoid*)

12.(#11 and (not delirium tremens))

We reviewed bibliographies of books and review articles on delir-

ium, and also references from retrieved articles. Experts in this field

were contacted for further references and to locate unpublished

trials. The Internet was searched using the search engines Google

and Copernic to try to find further evidence of unpublished trials

using the same terms as stated above.

We did not apply any time restrictions or language constraints.

Data collection and analysis

Selection of Studies

The titles, abstracts and descriptors of citations identified by the

searchwere examined by two reviewers, NS andRS independently;

those deemed to be clearly irrelevant were discarded. The aim was

to be over-inclusive at this stage to avoid losing potentially relevant

studies. Full text copies of the remaining citations were retrieved

and assessed independently by NS and RS for inclusion using the

criteria described above. Disagreements at any stage of study selec-

tion were resolved by referral to JH (this was only necessary with

regard to one study). Reports were checked for multiple publica-

tion of the same data.

Quality Assessment

The internal validity of trials relates to how successfully selection,

performance, attrition and detection biases are eliminated (Clarke

1999). The quality of included trials was assessed independently

by NS, RS and AB using predetermined criteria adapted from

the U.S. Preventive Services Task Force (Harris 2001; Table 1). A

consensus processwas used to reach agreement. Reviewerswere not

blinded to author and source institution. A was used to indicate

a trial in which all the quality criteria were met, B to indicate that

one or more criteria were partially met and the rest fully met, and

C if one or more criteria were not met or if it was not possible to

determine whether one or more criteria were met.

Data Extraction

A data extraction form was designed and piloted. Data were then

independently extracted by three reviewers NS, RS and AB with

disagreements resolved by a consensus process.

To allow an intention-to-treat analysis, data were sought for every

patient randomised to treatment or control group irrespective of

compliance or subsequent exclusion. Where data were only avail-

able for participants completing treatment, these were extracted

and reported separately. When individual patient data were not

available, data were extracted from summary statistics for each

study.

Data Analysis

Missing data and drop-out rates were assessed for each of the in-

cluded studies. We reported the number of participants included

in the final analysis as a proportion of all participants in the study.

For binary outcomes, a standard estimation of the risk ratio with

a 95% confidence interval was calculated.

Where means and standard deviations were available, we analysed

continuous data with a normal distribution (or approximating to

a normal distribution) using Revman Statistical analysis software.

Appropriate non-parametric tests were used to analyse data not

normally distributed.

We pre-determined that if there were sufficient data and it was

appropriate to do so, one or more meta-analyses would be per-

formed. However, no such analyses were possible due to lack of

comparability of interventions and comparators used in individual

studies.

Weplanned toperforma subgroup analysis of outcomes in patients

with and without dementia, but this was only possible for one

outcome in one study.

R E S U L T S

Description of studies

See:Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

Six, very diverse studies met our selection criteria, all conducted

in surgical settings (Aizawa 2002; Berggren 1987; Diaz 2001;

Kalisvaart 2005; Liptzin 2005; Marcantonio 2001). One study

was limited to patients operated on for gastric or colorectal can-

cer (Aizawa 2002). Five included orthopaedic patients, three con-

ducted in patients requiring surgery for hip fracture, one in acute

or elective hip surgery patients (Kalisvaart 2005) and one in elec-

tive hip or knee arthroplasty patients (Liptzin 2005). Most studies

were conducted in older people.

All six studies tested markedly different interventions; one com-

pared two anaesthetic approaches (Berggren 1987), one evaluated

proactive geriatric consultation (Marcantonio 2001), and the oth-

ers investigated administration of various pharmacological agents.

Therewere no studies ofmulti component interventions, andnone

conducted in non-surgical settings.

Outcomes examined included incident delirium, duration and

severity of delirium, behavioural disturbance, length of admission,

physical morbidity, cognitive status and institutionalisation at dis-

charge. Although all studies determined the incidence of delir-

ium, there was heterogeneity in both the statistical measures of

frequency, and diagnostic methods used.

Aizawa et al (Aizawa 2002) hypothesised that sleep disorders are

one of the critical factors in the aetiology of postoperative delir-

ium in patients treated in the ICU after surgery and attempted to



control disturbance of the sleep-wake cycle. They devised a Delir-

ium Free Protocol (DFP) employing routine administration of

diazepam, flunitrazepam and pethidine. They compared the ef-

fect of this unusual intervention with care as usual on the primary

outcome, delirium incidence in the first 7 days after surgery. A

single psychiatrist performed a screening interview twice daily and

diagnosed delirium according to DSM IV criteria (APA 1994).

In secondary outcomes, behavioural disturbance in the same time

period and length of admission were examined.

A Swedish study (Berggren 1987) compared the incidence of post-

operative mental confusion in patients operated on for hip frac-

ture under epidural and under halothane anaesthesia. Again their

primary outcome was incident delirium, but this was defined as

delirium present on day one and/or day seven after surgery. They

also determined length of admission and physical morbidity in-

cluding stroke, urinary tract infection and decubitus ulcer. Delir-

ium was diagnosed by DSM III criteria (APA 1987) using a mod-

ified Organic Brain Syndrome Scale (OBS) (Jensen 1993) by two

trained researchers.

CDP-choline (cytidine 5-diphosphocholine) is a precursor essen-

tial for the synthesis of cell membrane components, and animal

studies suggest that it may protect cell membranes, and may also

attenuate the progression of ischaemic cell damage (Fioravanti

2006). A recentCochrane review (Fioravanti 2006) concluded that

there was some evidence that CDP-choline has a positive effect on

memory and behaviour in at least the short/medium term in older

people, with cognitive deficits associated with chronic cerebral dis-

orders of the brain. A study from Chile (Diaz 2001) compared

the effectiveness of citicoline (CDP-choline) with placebo in pre-

venting delirium in patients undergoing hip fracture surgery. In

addition to administration of the study drug, anticholinergics or

benzodiazepine use was stopped, and anaemia and haemodynamic

disturbances corrected in both groups. The primary outcome of

interest was incident delirium; this was determined immediately

after surgery and on days 1, 2 and 3 postoperatively, using the

Abbreviated Mental Test Score (AMT) (Hodkinson 1972) and

CAM. Cognitive status after surgery was assessed using the Mini-

Mental State Examination (MMSE) (Folstein 1975).

Kalisvaart et al (Kalisvaart 2005) administered daily prophylactic

oral haloperidol (1.5 mg) to elective and non-elective hip surgery

patients at intermediate to high risk of delirium. Controls were

given placebo tablets identical in appearance to the study drug.

All patients were also offered proactive geriatric consultation. If

deliriumoccurred, the dose of study drugwas doubled. In addition

to the primary outcome, postoperative incident delirium, they also

documented delirium duration, severity, length of admission and

adverse effects. Deliriumwas diagnosed according toDSM IV and

CAM criteria using the Delirium Rating Scale-Revised-98 (DRS-

R-98) (Trzepacz 2001), MMSE and Digit span administered by

trained assessors.

Several case reports have suggested that donepezil, an acetyl-

cholinesterase inhibitor widely approved for treatment in

Alzheimers disease, might also be helpful in delirium (Gleason

2003;Wengel 1998). A study in patients undergoing elective knee

and hip arthroplasty (Liptzin 2005), investigated the effectiveness

of donepezil 5 mg given for 14 days before and after surgery. Con-

trols were given placebo tablets. Outcomes measured were inci-

dent delirium after surgery, duration of delirium and length of

admission. DSM IV delirium was diagnosed on days 7 and 14

after surgery using daily administration of theDelirium Symptom

Interview (DSI) (Albert 1992), CAM and medical records review.

In the only study of non-pharmacological interventions, Marcan-

tonio and colleagues (Marcantonio 2001) tested proactive geriatric

consultation against care as usual. Patients were visited daily by

a consultant geriatrician preoperatively or within 24 hours after

surgery. Targeted recommendations were made based on a struc-

tured protocol. They included measures to address 10 areas: i)

maintenance of adequate CNS oxygen delivery, ii) correction of

fluid and electrolyte balance, iii) treatment of severe pain, iv) elim-

ination of unnecessary medications, v) regulation of bowel/blad-

der function, vi) adequate nutritional intake, vii) early mobilisa-

tion and rehabilitation, viii) prevention, early detection and treat-

ment of major postoperative complications, ix) appropriate envi-

ronmental stimuli and x) treatment of agitated delirium. Recom-

mendations were prioritised, and no more than five were made at

the initial consultation, and three at subsequent visits. The usual

care group received management by the orthopaedics team in-

cluding internal medicine or geriatric consultation, if required,

on a reactive basis. The primary outcome was total cumulative

CAM-defined delirium incidence during admission. TheMMSE,

DSI, MDAS and CAM instruments were administered daily from

admission to discharge by a trained assessor. Delirium duration,

severity, length of admission and institutionalisation at discharge

were also determined. Severity was defined as an MDAS score of

18/30 or more.

Risk of bias in included studies

Studies varied in their methodological quality. Table 2 gives the

overall quality assessments determined using the preset criteria

described above.

Only one study (Marcantonio 2001) clearly achieved adequate

power to test effectiveness of the intervention in prevention of

delirium. Aizawa 2002, Berggren 1987 and Kalisvaart 2005 did

not include a power calculation; the latter comment that the study

was underpowered, given the relatively low delirium incidence

in their trial. Diaz 2001 and Liptzin 2005 did perform a power

calculation, but used much higher estimates of delirium rates than

actually found in these studies.

Randomisation was used in all studies, but adequate allocation

concealment was only described in two studies (Kalisvaart 2005;

Marcantonio 2001). Blinding of participants was used, except in

the three studies in which the nature of the intervention protocols



precluded this (Aizawa 2002; Berggren 1987;Marcantonio 2001).

All studies included blinded assessment of outcomes.

In three studies (Aizawa 2002; Diaz 2001; Liptzin 2005), only

limited information about baseline comparability between inter-

vention and control or comparative groups was given; in these,

there were no statistically significant differences in age, sex, cogni-

tive status or post surgery APACHE score (Knaus 1985). Berggren

1987 also recorded co-morbidity and psychotropic drug use.

The number of patients taking anticholinergic drugs was signifi-

cantly greater in the intervention group. In Kalisvaart 2005 and

Marcantonio 2001 there were no baseline differences described in

a range of important characteristics.

In investigating the effectiveness of interventions to prevent delir-

ium, clearly assessment for delirium at enrollment will be im-

portant. This was done in only three of the studies (Diaz 2001;

Kalisvaart 2005; Marcantonio 2001); however, in Aizawa 2002

and Berggren 1987, the exclusion criteria would in effect have

excluded delirium. In Marcantonio 2001, patients with delirium

were not excluded from enrollment, and despite being examined

for, delirium prevalence at intake assessment was not reported.

Comorbiditywith physical illnesswas not assessed inAizawa 2002,

Kalisvaart 2005 or Liptzin 2005, and presence of dementia was

only reported in one study (Marcantonio 2001).

An intention to treat analysis was carried out in three studies

(Berggren 1987; Kalisvaart 2005;Marcantonio 2001). In the other

three studies, datawere only available for patients completing treat-

ment.

Validated delirium diagnostic criteria consistent with the selec-

tion criteria for this review were used in all studies, but in some

there was variability in training of assessors, or training was not

described (Aizawa 2002; Diaz 2001). Moreover, in Aizawa 2002,

the intervention caused sedation in 8/20 patients and may have

interfered with delirium assessment.

In outcomes, although all studies assessed incident delirium as

the primary outcome, other important outcomes including death,

costs and psychological morbidity were not examined.

The study population in Aizawa 2002 included a very specialised

setting, restricting its generalisability. The other five studies have

relevance for management of patients with hip fracture, a com-

mon presentation amongst older people requiring hospitalisation

(although the study population in Liptzin 2005 was confined to

elective hip or knee arthroplasty patients).

Effects of interventions

Studies could not be combined for meta-analysis due to hetero-

geneity in interventions tested, settings, participants andmethods.

Results for individual studies are, therefore, presented by outcome.

1. Post surgery administration of Del i rium-Free Protocol v

Usual care (Aizawa 2002)

Primary outcome:

a) Incident delirium in the 7 days after surgery was significantly

lower in the intervention group with an Odds Ratio (OR) 0.10

[95% CI 0.01, 0.89] and Relative Risk (RR) of 0.14 [95% CI

0.02, 1.06].

Secondary outcomes:

b) Behavioural disturbance in the first 7 days after surgery was also

lower for the intervention group, but the difference failed to reach

statistical significance (RR 0.20 [95% CI 0.03, 1.56])

c) In length of admission also, there was no significant difference

between groups.

Analyses were carried out in 40 study participants but do not

include two patients who dropped out of the study.

2. Epidural anaesthesia v Halothane anaesthesia (Berggren

1987)

Primary outcome:

a) Incidence of delirium on day 1 or day 7 after surgery did not

differ significantly between treatment groups (RR 1.32 [95% CI

0.73, 2.39]).

Secondary outcomes:

b) Length of admission was reported to show no significant dif-

ference, but no data for this were given.

c) Physical morbidity; there were no differences in the incidence

of stroke, urinary tract infection or decubitus ulcers (RR 1.20

[95%CI 0.51, 2.81])

Intention to treat analyses were performed for all outcomes in 57

study participants. One year mortality was reported as 7% (4/57),

but was not given by treatment group.

3. Prophylactic citicoline v Placebo (Diaz 2001)

Primary outcomes:

a) Incident delirium immediately after surgery

b) Incident delirium on day 1 after surgery

c) Incident delirium on day 2 after surgery

d) Incident delirium on day 3 after surgery

There was no significant difference between groups in incidence

of delirium assessed at any of the above time points.

Secondary outcome:

e) Cognitive status; there was no significant difference between

intervention and control groups in the MMSE score after surgery

.

Results were reported for 81 participants. Seven patients who were

enrolled, but did not proceed with the study protocol, were not

included in the final analyses.

4. Prophylactic haloperidol v Placebo (Kalisvaart 2005)

Primary outcome :

a) Incidence of delirium after surgery was 15.8% in the study

population with a non-significant difference between treatment



and control groups (RR 0.91 [95% CI 0.59, 1.42]).

Secondary outcomes:

b) Delirium duration

c) Delirium severity

Both the duration and severity were reduced in the intervention

group compared with controls, and the differences reached statis-

tical significance (delirium duration RR -6.44 [95% CI -7.64, -

5.24] and mean difference in maximum DRS-R-98 score of 4.0

[95% CI 2.0, 5.8], p

delirium incidence following surgery under epidural or halothane

anaesthesia. Prophylactic administration of citicoline (Diaz 2001)

and donepezil (Liptzin 2005) did not prevent delirium compared

with placebo.

3. Prophylactic haloperidol was not effective in preventing delir-

ium but did reduce its severity and duration, and also decreased

length of hospital stay (Kalisvaart 2005). Interestingly, proactive

geriatric consultation was also offered to all patients, both in the

intervention and control group; the authors speculate that this

might have been responsible for the overall lower incidence of post

operative delirium compared to other studies in similar popula-

tions. Further studies are needed to clarify the role of neuroleptics

in delirium prevention.

3. The most encouraging evidence for successful delirium preven-

tion comes from one large study of proactive geriatric consulta-

tion (Marcantonio 2001). Given the multifactorial aetiology of

delirium (Lindesay 2002), their approach targeting a range of risk

factors may be more appropriate than strategies relying on admin-

istration of a single pharmacological agent (Inouye 1999a;Milisen

2005) . The recommendations made comprised measures that are

essentially basic aspects of good care, yet they were able reduce

delirium incidence by more than one third.

4. Dementia is the most important risk factor for delirium

(Lindesay 2002); targeting this population makes empirical sense

and may deliver important benefits, not least as many of the mea-

sures to prevent delirium should also be helpful in dementia.How-

ever, Marcantonio 2001 could not demonstrate effectiveness of

the intervention in preventing delirium in a subgroup analysis of

50 patients with dementia.

5. A high 77% adherence to recommendations was achieved in

this study, but the authors argue that this could be further im-

proved if geriatric consultation were systematically integrated into

care. Problems with adherence to recommendations and protocols

have been described, and implicated in limiting effectiveness by

others (Cole 2002; Inouye 2003; Young 2003) leading to calls to

include strategies to improve implementation and adherence (such

as measures to increase ownership and interactive education and

training (EHC 1999; Grimshaw 2004)) as an integral part of any

delirium intervention package.

6. The study byKalisvaart and colleagues (Kalisvaart 2005) showed

accurate stratification of delirium risk was feasible based on the

presence of four predictive delirium risk factors. This corroborates

findings in Inouyes study of predictive risk factors (Inouye 1993b)

and provides important validation of this risk identification system

which may be useful in both clinical practice and for delirium

research.

7. Only immediate benefits (up to discharge) were examined in

all six included studies. However, in Marcantonio 2001, the au-

thors indicate that they will be publishing results of longer term

outcomes in future.

8. The most striking finding is the paucity of high quality pub-

lished research on delirium prevention, particularly given how

common the condition is in hospitalised patients and its seriously

poor outcomes. Reasons for this may include historical difficulties

with case definition and detection, and the challenges of conduct-

ing research in often frail and debilitated patients. Further studies

on delirium prevention are urgently needed to guide clinical prac-

tice. Future investigations should focus on multi-faceted pack-

ages of delirium care in a whole range of hospital settings, and

should include short and longer term outcomes such as mortality,

physical and psychological morbidity, impact on carers and costs

to health care services.

9. Our review has some limitations. Although a fairly extensive

search was performed, resource limitations did not allow searching

of non-English language databases. We can be confident, however,

that we identified most important relevant studies, as our search

retrieved all studies included in recent reviews of this topic and also

identified additional studies. Resource limitations also precluded

blinding to authors and source institutions of studies, which could

potentially bias selection and quality assessment. Given the nature

of the interventions, blinding of study subjects or researchers was

not a prerequisite for inclusion.

10. A strength of our review is that all stages of screening citations,

identification of studies for inclusion, data extraction and quality

appraisal were carried out by at least two of the authors indepen-

dently, and agreement reached by consensus.

11. Our findings are consistent with those of existing reviews

of delirium prevention (Britton 2004; Cole 1999; Milisen 2005;

Weber 2004). Previous reviews have included studies using un-

validated methods to operationalise delirium or using terms such

as confusional state (without a clear definition of what this term

encompassed). We agree withMilisen (Milisen 2005) that reliance

on terms such as acute confusion contributes to the semantic am-

biguity rife in delirium research and is not helpful in furthering

our understanding of the condition; in clinical settings also, it is

unhelpful to efforts to increase recognition of delirium by health

care professionals as a condition warranting an urgent response.

12.This review aimed to consider all interventions designed topre-

vent delirium rather than testing a specific hypothesis. It provides

a robust update, highlighting the current scarcity of research evi-

dence to guide clinical practice in delirium prevention. Although

based on the findings of only one study, there is some evidence

to recommend implementation of proactive geriatric consulta-

tion in patients undergoing surgery for hip fracture. Further trials

are needed of this intervention, and of other delirium prevention

strategies in hospitalised patients in a range of medical and surgical

settings.



A U T H O R S C O N C L U S I O N S

Implications for practice

There is little evidence from delirium prevention studies to guide

clinical practice. Based on a single RCT, a programme for proactive

geriatric consultation may reduce delirium incidence and severity

in patients undergoing surgery for hip fracture (Marcantonio

2001). Prophylactic low dose haloperidol may reduce the severity

and duration of a delirium episode, and reduce length of hospital

stay in hip surgery patients (Kalisvaart 2005). There is no trial

evidence available on the effectiveness of any other strategies to

prevent delirium in hospitalised patients.

Implications for research

There is a striking lack of research on delirium prevention. Further

studies are urgently needed to guide clinical practice. Given its

diverse predisposing and precipitating factors, and how common

it is in a range of settings, future investigations should focus on

evaluating multi-faceted packages of delirium prevention in var-

ious hospital settings. Drug prevention studies e.g. of haloperidol

are also needed. Studies should use validated delirium screening

and diagnostic methods such as the CAM and DRS and should

include assessment of short and longer term outcomes such as

mortality, physical and psychological morbidity, impact on carers

and costs to health care services.

A C K N OW L E D G E M E N T S

We gratefully acknowledge the contribution of Dr Duncan

Forsyth, Consultant Elderly Care Medicine, Addenbrookes Hos-

pital, Cambridge, who provided feedback as the consumer editor

for this review.

We also wish to thank Katherine Hicks, Dymphna Hermans and

Leon Flicker from the Dementia and Cognitive improvement

Group for their support with preparing the review.

R E F E R E N C E S

References to studies included in this review

Aizawa 2002 {published data only}

Aizawa K, Kanai T, Saikawa Y, Takabayashi T, Kawano

Y, Miyazawa N, Yamamoto T. A novel approach to the

prevention of postoperative delirium in the elderly after

gastrointestinal surgery.. Surgery today 2002;32(4):3104.

Berggren 1987 {published data only}

Berggren D, Gustafson Y, Eriksson B, et al.Postoperative

confusion after anesthesia in elderly patients with femoral

neck fractures. Anesthesia & Analgesia 1987;66(6):497504.

Diaz 2001 {published data only}

Diaz V, Rodriguez J, Barrientos P, Serra M, Salinas H,

Toledo C, Kunze S, Varas V, Santelices E, Cabrera C,

Farias J, Gallardo J, Beddings MI, Leiva A, Cumsille MA.

[Use of procholinergics in the prevention of postoperative

delirium in hip fracture surgery in the elderly A randomized

controlled trial]. Revista de Neurologia 2001;33(8):7169.

Kalisvaart 2005 {published data only}

Kalisvaart KJ, de Jonghe JF, Bogaards MJ, et al.Haloperidol

prophylaxis for elderly hip-surgery patients at risk for

delirium: a randomized placebo-controlled study. J Am

Geriatr Soc 2005;53(10):165866.

Liptzin 2005 {published data only}

Liptzin B, Laki A, Garb J, Fingeroth R, Krushell R.

Donepezil in the Prevention and Treatment of Post-Surgical

Delirium. American Journal of Geriatric Psychiatry 2005;13:

11001106.

Marcantonio 2001 {published data only}

Marcantonio ER, Flacker JM, Wright RJ, Resnick NM.

Reducing delirium after hip fracture: a randomized trial.

Journal-of-the-American-Geriatrics-Society 2001;49(5):

51622.

References to studies excluded from this review

Baldwin 2004 {published data only}

Baldwin R, Pratt H, Goring H, Marriott A, Roberts C.

Does a nurse-led mental health liaison service for older

people reduce psychiatric morbidity in acute general medical

wards? A randomised controlled trial. Age and ageing 2004;

33(5):4728.

Budd 1974 {published data only}

Budd, S, Brown, W. Effect of a reorientation technique on

postcardiotomy delirium. Nursing Research 1974;23(4):

3418.

Cerchietti 2000 {published data only}

Cerchietti L, Navigante A, Sauri A, Palazzo F.

Hypodermoclysis for control of dehydration in terminal-

stage cancer.. International journal of palliative nursing

2000;6(8):3704.

Cole 2002 {published data only}

Cole MG, McCusker J, Bellavance F, Primeau FJ, Bailey

RF, Bonnycastle MJ, Laplante J. Systematic detection

and multidisciplinary care of delirium in older medical

inpatients: a randomized trial. CanadianMedical Association

Journal 2002;167(7):7539.

Culp 2003 {published data only}

Culp K, Mentes J, Wakefield B. Hydration and acute

confusion in long-term care residents. Western journal of

nursing research 2003;25(3):251-66; discussion 267-73.



Inouye 1993a {published data only}

Inouye SK. A controlled trial of a nursing-centered

intervention in hospitalized elderly medical patients: the

Yale Geriatric Care Program. Journal of the American

Geriatrics Society. 1993;41(12):1353.

Inouye 1999 {published data only}

Bogardus Jr ST, Desai MM, Williams CS, Leo Summers

L, Acampora D, Inouye SK. The effects of a targeted

multicomponent delirium. American Journal of Medicine

2003;114(5):38390.

Inouye SK, Bogardus Jr ST, Williams CS, Leo-Summers

L, Agostini JV. The role of adherence on the effectiveness

of nonpharmacologic interventions: Evidence from the

delirium prevention trial. Archives of Internal Medicine

2003;163(8):958964. Inouye SK, Bogardus STJr, Charpentier PA, Leo-

Summers L, Acampora D, Holford TR, Cooney LMJr.

A multicomponent intervention to prevent delirium in

hospitalized older patients see comments. New England

Journal of Medicine 1999;340(9):669.

Leslie DL, Zhang Y, Bogardus ST, Holford TR, Leo-

Summers LS, Inouye SK. Consequences of preventing

delirium in hospitalized older adults on nursing home costs.

JAGS 2005;53(3):4059.

Rizzo JA, Bogardus ST, Leo-Summers L, Williams CS,

Acampora D, Inouye SK. Multicomponent targeted

intervention to prevent delirium in hospitalized older

patients: what is the economic value?. Medical care 2001;

39(7):74052.

Kaneko 1999 {published data only}

Kaneko T, Cai J, Ishikura T, Kobayashi M, Naka T, Kaibara

N. Prophylactic consecutive administration of haloperidol

can reduce the occurrence of postoperative delirium in

gastrointestinal surgery. Yonago Acta Medica 1999;42(3):

17984.

Landefeld 1995 {published data only}

Landefeld CS, Palmer RM, Kresevic DM, Fortinsky RH,

Kowal J. A randomized trial of care in a hospital medical

unit especially designed to improve the functional outcomes

of acutely ill older patients. New England Journal of

Medicine 1995;332(20):133844.

Lundstrom 2005 {published data only}

Lundstrom M, Edlund A, Karlsson S, Brannstrom B, Bucht

G, Gustafson Y. A multifactorial intervention program

reduces the duration of delirium, length of hospitalization,

and mortality in delirious patients. Journal of the American

Geriatrics Society 2005;53(4):6228.

Mentes 2003 {published data only}

Mentes JC, Culp K. Reducing hydration-linked events in

nursing home residents. Clinical Nursing Research 2003;12

(3):210-25; discussion 226-8.

Milisen 2001 {published data only}

Milisen K, Foreman MD, Abraham IL, De Geest

S, Godderis J, Vandermeulen E, et al.A nurse-led

interdisciplinary intervention program for delirium in

elderly hip-fracture patients. Journal of the American


Naughton 2005 {published data only}

Naughton BJ, Saltzman S, Ramadan F, Chadha N, Priore

R, Mylotte JM. A multifactorial intervention to reduce

prevalence of delirium and shorten hospital length of stay.

Journal of the American Geriatrics Society 2005;53(1):1823.

Tabet 2005 {published data only}

Tabet N, Hudson S, Sweeney V, Sauer J, Bryant C,

Macdonald A, Howard R. An educational intervention can

prevent delirium on acute medical wards. Age and Ageing

2005;34(2):1526.

Tokita 2001 {published data only}

Tokita K, Tanaka H, Kawamoto M, Yuge O. [Patient-

controlled epidural analgesia with bupivacaine and fentanyl

suppresses postoperative delirium following hepatectomy].

Masui; Japanese journal of anesthesiology, The 2001;50(7):

7426.

Wanich 1992 {published data only}

Wanich CK, Sullivan-Marx EM, Gottlieb GL, Johnson

JC. Functional status outcomes of a nursing intervention

in hospitalized elderly. Image - the Journal of Nursing

Scholarship 1992;24(3):2017.

Wong 2005 {published data only}

Wong Tin Niam DM, Bruce JJ, Bruce DG. Quality project

to prevent delirium after hip fracture. Australasian Journal

on Ageing 2005;24(3):174177.

References to ongoing studies

Boustani 2005a {published data only}

Boustani M. Donepezil in the Prevention of Post-Operative

Cognitive Decline. ClinicalTrials.gov 2005.

Boustani 2005b {published data only}

Boustani M. Enhancing Care for Hospitalized Older Adults

with Cognitive Impairment. ClinicalTrials.gov 2005.

Boustani 2005c {published data only}

Boustani M. Preventing Delirium in Hospitalized Elderly.

ClinicalTrials.gov 2005.

Diehl 2005 {published data only}

Diehl J. Prevention of Postoperative Delirium with

Donepezil. ClinicalTrials.gov 2005.

Ely 2004a {published data only}

Ely EW. A Randomized, Double-blind Trial in Ventilated

ICU Patients Comparing Treatment with an Alpha2 Agonist

versus a Gamma Aminobutyric Acid (GABA)-Agonist to

Determine Delirium Rates, Efficacy of Sedation, Analgesia

and Discharge Cognitive Status. ClinicalTrials.Gov 2004a.

Ely 2004b {published data only}

Ely EW. Delirium in the ICU: a Prospective, Randomized,

Trial of Placebo vs Haloperidol vs Ziprasidone.

ClinicalTrials.gov 2004b.

Harari 2005 {published data only}

Harari D. Proactive intervention to improve post-operative

outcomes in at risk older people undergoing surgery: a



randomised controlled trial.. National Research Register

2005, issue issue 3.

Steiner 2005 {published data only}

Steiner L. Rivastigmine for the Prevention of Postoperative

Delirium in Patients Undergoing Cardiac Surgery.

ClinicalTrials.gov 2005.

van der Burg 2005 {published data only}

van der Burg BL. Post-Operative Haloperidol Versus

Placebo for Prevention of Post-Operative Delirium After

Acute Hip Surgery. ClinicalTrials.gov 2005.

Additional references

Albert 1992

Albert MS, Levkoff SE, Reilly C, Liptzin B, Pilgrim D,

Cleary PD, Evans D, Rowe JW. The delirium symptom

interview: an interview for the detection of delirium

symptoms in hospitalized patients. Journal of Geriatric

Psychiatry & Neurology 1992;5(1):1421.

APA 1987

American Psychiatric Association. Diagnostic and Statistical

Manual of Mental Disorders. Third Edition. Washington

DC: American Psychiatric Association, 1987.

APA 1994

American Psychiatric Association. Diagnostic and Statistical

Manual of Mental Disorders. Fourth. Washington DC:

American Psychiatric Association, 1994.

APA 1999

American Psychiatric Association. Practice guideline for the

treatment of patients with delirium. American Psychiatric

Association. American Journal of Psychiatry 1999;156:120.

Blessed 1968

Blessed G, Tomlinson BE, Roth M. The association between

quantitative measures of dementia and of senile change in

the cerebral grey matter of elderly subjects. British Journal

Psychiatry 1968;114(512):797811.

Breitbart 1997

Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K,

Passik S. The Memorial Delirium Assessment Scale. Journal

of Pain & Symptom Management 1997;13(3):12837.

Breitbart 2002

Breitbart W, Gibson C, Tremblay A. The delirium

experience: delirium recall and delirium-related distress in

hospitalized patients with cancer, their spouses/caregivers,

and their nurses. Psychosomatics 2002;43(3):18394.

Britton 2004

Britton A, Russell R. Multidisciplinary team interventions

for delirium in patients with chronic cognitive

impairment. Cochrane Database of Systematic Reviews

2004, Issue 2.[Art. No.: CD000395. DOI: 10.1002/

14651858.CD000395.pub3]

Centeno 2004

Centeno C, Sanz A, Bruera E. Delirium in advanced cancer

patients. Palliative Medicine 2004;18(3):184194.

Clarke 1999

Clarke M, Oxman AD, editors. Cochrane Reviewers

Handbook 4.0 [updated July 1999]. In: Review Manager

(RevMan) [Computer program] Version 4.0. The Cochrane

Collaboration, 1999.

Cole 1999

Cole MG. Delirium: effectiveness of systematic

interventions. Dementia & Geriatric Cognitive Disorders

1999 SepOct;10(5):406-11 1999.

EHC 1999

EHC. Getting evidence into practice. Effective Health Care

1999;5:1.

Elie 2000

Elie M, Rousseau F, Cole M, Primeau F, McCusker J,

Bellavance F. Prevalence and detection of delirium in elderly

emergency department patients. CMAJ Canadian Medical

Association Journal 2000;163(8):97781.

Fioravanti 2006

Fioravanti M, Yanagi M The Cochrane Database of

Systematic Reviews 2006 Issue 2 Copyright 2006 The

Cochrane Collaboration. Published by John Wiley &

Sons, Ltd. Cytidinediphosphocholine (CDP-choline) for

cognitive and behavioural disturbances associated with

chronic cerebral disorders in the elderly Fioravanti M,

Yanagi M. Cytidinediphosphocholine (CDP-choline) for

cognitive and behavioural disturbances associated with

chronic cerebral disorders in the elderly Fioravanti M,

Yanagi M. Cochrane Database of Systematic Reviews 2006,

Issue 2.

Folstein 1975

Folstein MF, Folstein SE, McHugh PR. Mini-mental

state. A practical method for grading the cognitive state

of patients for the clinician. J Psychiatr Res 1975;12(3):

18998.

Francis 1990

Francis J, Kapoor WN. Delirium in hospitalized elderly.

Journal of General Internal Medicine 1990;5(1):6579.

Gleason 2003

Gleason OC. Donepezil for postoperative delirium.

Psychosomatics 2003;44(5):4378.

Grimshaw 2004

Grimshaw JM, Thomas RE, MacLennan G, Fraser C,

Ramsay CR, Vale L, Whitty P, EcclesMP, Matowe L, Shirran

L, Wensing M, Diikstra R, Donaldson C. Effectiveness and

efficiency of guideline dissemination and implementation

strategies. Health. Health Technology Assessment 2004;8(6):

172.

Harris 2001

Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD,

Teutsch SM, et al.Current methods of the US Preventive

Services Task Force: a review of the process. Am J Prev Med

2001;20(3 Suppl):2135.

Hodkinson 1972

Hodkinson HM. Evaluation of a mental test score for

assessment of mental impairment in the elderly. Age Ageing

1972;1(4):2338.



Holmes 2000

Holmes JD, House AO. Psychiatric illness in hip fracture.

Age & Ageing 2000;29(6):53746.

Hustey 2003

Hustey FM, Meldon SW, Smith MD, Lex CK. The effect

of mental status screening on the care of elderly emergency

department patients. Annals of Emergency Medicine 2003;

41(5):678684.

Inouye 1990

Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP,

Horwitz RI. Clarifying confusion: the confusion assessment

method. A new method for detection of delirium. Annals of

Internal Medicine 1990;113(12):9418.

Inouye 1993b

Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti

ME. A predictive model for delirium in hospitalized elderly

medical patients based on admission characteristics. Annals

of Internal Medicine 1993;119(6):47481.

Inouye 1998a

Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei

P. Does delirium contribute to poor hospital outcomes? A

three-site epidemiologic study. Journal of General Internal

Medicine 1998;13:23442.

Inouye 1998b

Inouye SK. Delirium in hospitalized older patients:

recognition and risk factors. Journal of Geriatric Psychiatry

& Neurology 1998;11(3):118-25; discussion 157-8.

Inouye 1999a

Inouye SK, Bogardus ST, Jr, Charpentier PA, Leo-Summers

L, Acampora D, Holford TR, et al.A multicomponent


patients. New England Journal of Medicine 1999;340(9):

66976.

Inouye 1999b

Inouye SK, Schlesinger MJ, Lydon TJ. Delirium: A

Symptom of How Hospital Care Is Failing Older Persons

and a Window to Improve Quality of Hospital Care. The

American Journal of Medicine 1999;106(5):565573.

Inouye 1999c

Inouye SK. Predisposing and precipitating factors for

delirium in hospitalized older patients. Dementia &

Geriatric Cognitive Disorders 1999;10(5):393400.

Inouye 2000a

Inouye SK, Bogardus ST, Jr, Baker DI, Leo-Summers L,

Cooney LM, Jr. The Hospital Elder Life Program: a model

of care to prevent cognitive and functional decline in older

hospitalized patients. Journal of the American Geriatrics

Society 2000;48(12):1697706.

Inouye 2000b

Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP,

Horwitz RI. Clarifying confusion: the confusion assessment

method. A new method for detection of delirium. Annals of


Inouye 2003

Inouye SK, Bogardus Jr ST, Williams CS, Leo-Summers

L, Agostini JV. The role of adherence on the effectiveness

of nonpharmacologic interventions: Evidence from the

delirium prevention trial. Archives of Internal Medicine

2003;163(8):95864.

Jensen 1993

Jensen E, Dehlin O, Gustafson L. A comparison between

three psychogeriatric rating scales. International Journal of

Geriatric Psychiatry 1993;8(3):215229.

Knaus 1985

Knaus WA, Draper EA, Wagner DP, Zimmerman JE.

APACHE II: a severity of disease classification system.

Critical Care Medicine 1985;13(10):81829.

Levkoff 1991

Levkoff S, Cleary P, Liptzin B, Evans DA. Epidemiology

of delirium: an overview of research issues and findings.

International Psychogeriatrics 1991;3(2):14967.

Lindesay 2002

Lindesay J, Rockwood K, Rolfson D. The epidemiology of

delirium. In: Lindesay J, Rockwood K, Macdonald A editor

(s). Delirium in Old Age. New York: Oxford University

Press, 2002:2750.

Ljubisavljevic 2003

Ljubisavljevic V, Kelly B. Risk factors for development of

delirium among oncology patients. Gen Hosp Psychiatry

2003;25(5):34552.

McCusker 2001

McCusker J, Cole M, Dendukuri N, Belzile E, Primeau

F. Delirium in older medical inpatients and subsequent

cognitive and functional status: a prospective study. CMAJ

Canadian Medical Association Journal 2001;165(5):57583.

McCusker 2002

McCusker J, Cole M, Abrahamowicz M, Primeau F, Belzile

E. Delirium predicts 12-month mortality. Archives of


McCusker 2003a

McCusker J, Cole MG, Dendukuri N, Belzile E. Does

delirium increase hospital stay?. Journal of the American


McCusker 2003b

McCusker J, Cole M, Dendukuri N, Han L, Belzile E. The

course of delirium in older medical inpatients: a prospective

study. J Gen Intern Med 2003;18(9):696704.

Milbrandt 2004

Milbrandt EB, Deppen S, Harrison PL, Shintani AK,

Speroff T, Stiles RA, et al.Costs associated with delirium in

mechanically ventilated patients. Critical Care Medicine

2004;32(4):955962.

Milisen 2005

Milisen K, Lemiengre J, Braes T, Foreman MD.

Multicomponent intervention strategies for managing

delirium in hospitalized older people: systematic review.

Journal of Advanced Nursing 2005;52(1):7990.

Moller 1998

Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen

H, Canet J, et al.Long-term postoperative cognitive

dysfunction in the elderly ISPOCD1 study. ISPOCD



investigators. International Study of Post-Operative

Cognitive Dysfunction. Lancet 1998;351(9106):85761.

Rizzo 2001

Rizzo JA, Bogardus ST, Jr, Leo-Summers L, Williams

CS, Acampora D, Inouye SK. Multicomponent targeted


patients: what is the economic value?. Medical Care 2001;

39(7):74052.

Roberts 2004

Roberts B. Screening for delirium in an adult intensive care

unit. Intensive Crit Care Nurs 2004;20(4):20613.

Rockwood 1999

Rockwood K. Educational interventions in delirium.

Dementia & Geriatric Cognitive Disorders 1999;10(5):

4269.

Santos 2004

Santos FS, Velasco IT, Fraguas R, Jr. Risk factors for

delirium in the elderly after coronary artery bypass graft

surgery. Int Psychogeriatr 2004;16(2):17593.

Siddiqi 2006

Siddiqi N, House AO, Holmes JD. Occurrence and

outcome of delirium in medical in-patients: a systematic

literature review. Age Ageing 2006;35:350364.

Stevens 1998

Stevens LE, de Moore GM, Simpson JM. Delirium in

hospital: does it increase length of stay?. Australian & New

Zealand Journal of Psychiatry 1998;32(6):8058.

Trzepacz 1988

Trzepacz PT, Baker RW, Greenhouse J. A symptom rating

scale for delirium. Psychiatry Res 1988;23(1):8997.

Trzepacz 1996

Trzepacz PT. Delirium. Advances in diagnosis,

pathophysiology, and treatment. Psychiatric Clinics of North

America 1996;19(3):42948.

Trzepacz 2001

Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J,

Jimerson N. Validation of the Delirium Rating Scale-

revised-98: comparison with the delirium rating scale and

the cognitive test for delirium. Journal of Neuropsychiatry &

Clinical Neurosciences 2001;13(2):22942.

Uldall 1997

Uldall KK, Berghuis JP. Delirium in AIDS patients:

recognition and medication factors. AIDS Patient Care &

Stds 1997;11(6):43541.

Weber 2004

Weber JB, Coverdale JH, Kunik ME. Delirium: Current

trends in prevention and treatment. Internal Medicine

Journal 2004;34(3):115121.

Wengel 1998

Wengel SP, Roccaforte WH, Burke WJ. Donepezil improves

symptoms of delirium in dementia: implications for future

research. Journal of Geriatric Psychiatry & Neurology 1998;

11(3):15961.

WHO 1992

World Health Organisation. International classification of

diseases, 10th revision. Geneva: World Health Organisation,

1992.

Williams-Russo 1992

Williams-Russo P, Urquhart BL, Sharrock NE, Charlson

ME. Post-operative delirium: Predictors and prognosis

in elderly orthopedic patients. Journal of the American


Young 2003

Young LJ, George J. Do guidelines improve the process and

outcomes of care in delirium?. Age and Ageing 2003;32(5):

5258.

References to other published versions of this review

Siddiqi 2007

Siddiqi N, Stockdale R, Britton AM, Holmes J.

Interventions for preventing delirium in hospitalised

patients. Cochrane Database of Systematic Reviews 2007,

Issue 2. [DOI: 10.1002/14651858.CD005563.pub2] Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Aizawa 2002

Methods Randomisation: Allocation immediately after surgery but method not described

Power calculation: No and small number in study

Blinding of participants: No

Outcomes assessments blind: Yes

Informed consent: Yes

Delirium diagnostic criteria: DSM IV

Outcomes Measurement: Twice daily screening interview after surgery by one psychiatrist for 7 consecutive days

Intention to treat analysis: No

Drop outs from protocol: 2 from intervention group

Incomplete follow up: 2/42 - excluded after randomisation and no data presented on these

Proportion of participants reported in final analysis: 95%

Study duration: 29 months

Participants Number in study: 42

Japan

One surgical department

Post resection of gastric or colorectal cancer

Age:More than 70 yrs and less than 86 yrs; mean age 75.9 and 76.2 yrs in intervention and control groups respectively

Co-morbidity: Not given

Dementia: Not mentioned specifically but mental disorders excluded (although method not described)

Delirium at enrollment: As for dementia, not mentioned specifically

Exclusions: Liver, renal or respiratory dysfunction, mental disorders, visual impairment, resection of other organs,

emergency surgery

Interventions Delirium Free Protocol (DFP): Post surgery, Diazepam 0.1 mg/kg IM at 20.00, Flunitrazepam 0.04 mg/kg IV and

Pethidine 1mg/kg IV infusions 20.00-04.00 for 3 nights

Controls: Treatment as usual. No placebo

Outcomes 1. Incident delirium in 7 days postop

2. Behavioural disturbance in 7 days postop

3. Length of admission

Notes Intervention used likely to sedate (morning lethargy due to DFP in 8/20), and perhaps interfere with assessment for

delirium

Very specific study population, limiting generalisability

Funding Source: Not given



Berggren 1987

Methods Randomisation: Method not described

Power calculation: No

Blinding of participants: No, not possible because of the type of interventions



Delirium diagnostic criteria: DSM III

Outcomes Measurement: Modified Organic Brain Syndrome Scale (OBS) by 2 researchers with good (over 90%)

inter-rater reliability. Assessments on postop day 1 and 7

Intention to treat analysis: Yes

Drop outs from protocol: 0

Incomplete follow up: 0




Sweden

Orthopaedic wards of one University hospital

Patients requiring surgery for femoral neck fracture

Age range: 65-86 yrs; mean age 78 and 77 yrs respectively in epidural and halothane groups respectively

Co-morbidity (number): Ischaemic heart disease(29), hypertension(13), diabetes(9), cerebrovascular disease(6), res-

piratory disease(5), depression(10), parkinsons(5), severely impaired hearing(11), severe visual impairment(10)

Dementia: Not mentioned specifically but would in effect be excluded by exclusion criteria

Delirium at enrollment: Not excluded specifically, but lucidity requirement for inclusion

Exclusions: Score more than 6/36 on 12 item disorientation subscale of OBS assessed within 3 hours of admission

Interventions Epidural anaesthesia

Comparison with Halothane anaesthesia

Outcomes 1. Incident delirium on postop day 1 or 7


3. Physical morbidity

Notes Funding source: Swedish Medical Council; King Gustav V Birthday Foundation; Umea University Research Foun-

dation



Diaz 2001

Methods Randomisation: Method not described

Power calculation: Yes, indicates needed to enrol 88 patients, but results for 81 reported

Blinding of participants: Yes



Delirium diagnostic criteria: American Psychiatric Association 1987

Outcomes Measurement: Abbreviated Mental Test Score (AMT) and Confusion Assessment Method (CAM) preop,

immediately postop, and on day 1, 2 and 3 postop. Training and number of assessors not described

Intention to treat analysis: No. Details of 7 subjects who dropped out not given

Drop outs from protocol: 7

Incomplete follow up: 7/88


Study duration: Not given


Chile

Multicentre, Orthopaedic or Trauma departments

Patients requiring surgery for hip fracture

Anaesthetic risk ASA I, II or III

Surgery under regional anaesthesia

Age: Over 70 yrs; mean 79.45 and 79.97 yrs in intervention and controls respectively

Comorbidity: Specific conditions not described. Present in 28/35 in Intervention group and 39/46 in Control group

Dementia: Excluded

Delirium at enrollment: Excluded using MiniMental State Examination (MMSE), AMT, CAM

Exclusions: Organic brain disorder, major cerebrovascular disease, anaesthetic risk ASA IV

Interventions Citicoline 400 mg orally 8 hrly, given between 24 hrs before and 4 days after surgery.

Controls: Placebo matched for colour, consistency and flavour

Authors state that if anticholinergics and benzodiazepines were being used they were stopped, and anaemia and

haemodynamic variables corrected in both groups

Outcomes 1. Incident delirium immediately, day 1, day 2 and day 3 post op

2. Cognitive status

Notes Study underpowered, as incidence of delirium much lower than the 20% used in power calculation

Funding Source: Not given



Kalisvaart 2005

Methods Randomisation: Adequate concealed allocation

Power calculation: No but discussion states study under powered




Delirium diagnostic criteria: DSM IV and CAM

Outcomes Measurement: Daily Delirium Rating Scale Revised 98 (DRS-R-98), MMSE, Digit span by trained

assessors

Intention to treat analysis: Yes

Drop outs from protocol: 48, 20 in intervention group and 28 controls

Incomplete follow up: 11/ 212 in intervention group and 24/218 controls




Netherlands

2 surgical and 3 orthopaedic wards in 1 Teaching hospital

Admitted for acute or elective hip surgery

At intermediate or high risk of delirium (presence of 1 or more delirium risk factors)

Age: More than 70 yrs; mean 78.71 and 79.57 yrs in intervention and control groups respectively


Dementia: Not given Delirium at enrollment: Excluded, but method not described

Exclusions: Haloperidol allergy, prolonged QTc interval, use of cholinesterase inhibitors or levodopa, parkinsonism,

epilepsy, inability to participate in interviews, delay in surgery more than 72 hrs from admission

Interventions Haloperidol 0.5 mg orally three times daily on admission until 3 days post op

Controls: Placebo tablets identical in appearance

Proactive geriatric consultation offered to all patients in both groups

If delirium occurred, patients treated with haloperidol or lorazepam (or both) 3 times daily in increasing doses

depending on symptoms

Outcomes 1. Incident delirium post op

2. Duration of delirium

3. Delirium severity


5. Withdrawal from protocol

6. Adverse effects

Notes Funding source: Medical Center Alkmaar



Liptzin 2005

Methods Randomisation: By research pharmacist but method not described

Power calculation: Yes, but used a higher estimate of delirium incidence than in study




Delirium diagnostic criteria: DSM IV

Outcomes Measurement: Delirium Symptom Interview (DSI) and CAM daily pre and postop, and postop daily

medical records review by experienced research assistant; Delirium presence determined from this information at day

7 and 14 postop

Intention to treat analysis: No

Drop outs from protocol: 11 in intervention group and 11 controls

Incomplete follow up: 10/90




USA

One academic medical centre

Scheduled for elective admission for hip or knee arthroplasty

Age Range: 52-90 yrs; mean 67.2 and 69.4 yrs respectively


Dementia: Not given Delirium at enrollment: Not assessed

Exclusions: Gastro-oesophageal reflux disease, sick sinus syndrome, using donepezil or intolerant to it, non-English

speaking

Interventions Donepezil 5 mg once daily for 14 days before and after surgery, doubled to 10 mg if developed any symptoms of

delirium

Placebo identical in appearance

Outcomes 1. Incident delirium postop

2. Duration of delirium


4. Withdrawal from protocol

Notes Funding source: Unrestricted research grant from Pfizer


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