Interventions For Preventing Delirium in Hospital Is Ed Patients

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 Library
2009, 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.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Analysis 1.1. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 1 Incidence of delirium in first 7
days after surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Analysis 1.2. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 2 Behavioural disturbance in 1st 7
days after surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Analysis 1.3. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 3 Length of admission. . . 31
Analysis 2.1. Comparison 2 Epidural anaesthesia v Halothane anaesthesia, Outcome 1 Incident delirium on day 1 or day 7
post surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Analysis 2.2. Comparison 2 Epidural anaesthesia v Halothane anaesthesia, Outcome 2 Physical morbidity. . . . . 32
Analysis 3.1. Comparison 3 Prophylactic citocoline v Placebo, Outcome 1 Incident delirium. . . . . . . . . 33
Analysis 4.1. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 1 Incident delirium post surgery. . . . 34
Analysis 4.2. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 2 Delirium duration. . . . . . . . . 34
Analysis 4.4. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 4 Length of admission. . . . . . . . 35
Analysis 4.5. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 5 Withdrawal from protocol. . . . . . 35
Analysis 4.6. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 6 Adverse effects. . . . . . . . . . 36
Analysis 5.1. Comparison 5 Prophylactic donepezil v Placebo, Outcome 1 Delirium incidence after surgery. . . . 36
Analysis 5.4. Comparison 5 Prophylactic donepezil v Placebo, Outcome 4 Withdrawal from protocol. . . . . . 37
Analysis 6.1. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 1 Cumulative delirium incidence. 37
Analysis 6.2. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 2 Delirium duration. . . . . 38
Analysis 6.3. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 3 Severity- cumulative incidence of
severe delirium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Analysis 6.4. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 4 Institutionalisation at discharge. 39
Analysis 6.5. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 5 Cognitive status- delirium prevalence
at discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Interventions for preventing delirium in hospitalised patients (Review) i

[Intervention Review]
Interventions for preventing delirium in hospitalised patients
Najma Siddiqi1 , Rachel Holt2 , Annette M Britton3 , John Holmes4
1
Academic Unit for Psychiatry and Behavioural Sciences, University of Leeds, Leeds, UK. 2 Leeds, UK. 3 Geriatric Unit, Royal Prince
Alfred Hospital, Sydney, Australia. 4 Academic 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. n.siddiqi@leeds.ac.uk.
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 Database
of Systematic Reviews 2007, Issue 2. Art. No.: CD005563. DOI: 10.1002/14651858.CD005563.pub2.
ABSTRACT
Background
Delirium is a common mental 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 strategy
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.
Interventions for preventing delirium in hospitalised patients (Review) 1
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.
PLAIN LANGUAGE SUMMARY
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.
BACKGROUND 1994) and ICD-10 (WHO 1992). This recent consensus has al-
Delirium, a disturbance of consciousness and cognition, with rapid lowed some standardisation of research, and greater comparability
onset, fluctuating course and underlying causation, has been vari- between studies.
ously termed acute organic brain syndrome, acute organic mental
disorder and toxic confusional state. Until the 19th century delir- Delirium is common in hospitalized patients. Ten to 30% of ad-
ium was used to describe a disorder of thinking and later descrip- missions to a general hospital develop delirium (Levkoff 1991;
tions included disturbances of perception, often with overactive Trzepacz 1996) and in general medical in-patients, occurrence
behaviour, or impaired consciousness. The publication of DSM- rates ranging from 11 to 42% have been reported (Siddiqi 2006).
III (APA 1987) in 1987 brought together these ideas, combining Delirium has a prevalence of up to 60% in frail elderly patients
disturbance of consciousness with impairment of cognition; the (Francis 1990), and 7 to 9.6% in elderly patients presenting
core features of delirium have been clarified in the DSM-IV (APA to emergency departments (Elie 2000; Hustey 2003). Following
coronary artery bypass grafting in the elderly, incidence has been Prevention of delirium is obviously desirable for both patients’ and
reported as 33.6% (Santos 2004), and after bilateral knee replace- carers’, and to reduce health service costs. A recent study found that
ments 41% (Williams-Russo 1992). Following hip fracture the the health care costs in patients who developed delirium in ICUs
overall prevalence is 43 to 61% (Holmes 2000). were 31% higher ($41,836 versus $27,106) (Milbrandt 2004).
A non-randomised study of a multi-component intervention for
Patients in intensive care units (ICU) are at high risk of developing
delirium demonstrated overall improved cost-effectiveness (Rizzo
delirium, with incidence rates of 40% reported (Roberts 2004).
2001).
Cancer also increases the risk of developing delirium. 18% of those
admitted to an oncology ward, and 26 to 44% of those admitted to Possible interventions for preventing delirium in hospitalized pa-
hospital or a hospice with a diagnosis of advanced cancer developed tients have been developed. Most of the current studies have taken
delirium (Centeno 2004; Ljubisavljevic 2003). In AIDS patients a multi-factorial approach, attempting to prevent several risk fac-
who are unwell enough to be admitted, incidence of delirium is tors by protocols, education or systems redesign, rather than fo-
also high, being reported as 46% (Uldall 1997). cusing on one risk factor in isolation (Cole 2002; Inouye 2000a;
Milisen 2001). Interventions include programmes of education
Delirium is serious, with significant short and long term outcomes.
for ward nursing staff (Rockwood 1999), non-pharmacological
Death rates are increased (McCusker 2002), functional abilities
intervention protocols targeting specific risk factors and imple-
reduced (Moller 1998), admission to long-term care increased (
mented by a trained interdisciplinary team (Inouye 1999a), and
Inouye 1998a), and length of stay increased (McCusker 2003a;
a specialist nursing intervention to educate nursing staff, assess
Stevens 1998). Impairment of cognitive function can persist for
and change medication, encourage mobilization and improve the
at least one year (McCusker 2001), as can the symptoms of delir-
environment of the patient (Wanich 1992).
ium, especially inattention, disorientation and impaired mem-
ory (McCusker 2003b). Increasingly recognised is the distress an It is currently unclear whether interventions for prevention of
episode of delirium produces in carers (Breitbart 2002). delirium are effective, whether they can be successfully delivered
in all environments, and whether different interventions are neces-
Research in the elderly has identified a multitude of risk factors.
sary for different groups of patients. Previous reviews (Cole 1999;
The condition clearly has a multi-factorial aetiology, and these
Milisen 2005) have suggested possible protocols for delirium pre-
risk factors interact (Inouye 1998b); the more risk factors that
vention, but have not been systematic or have employed less rig-
are present, the greater the likelihood that the patient will de-
orous selection criteria.
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 OBJECTIVES
(more than three new medications added), use of psychoactive
drugs, co-morbidities, severe illness (especially infection, fracture Primary objective: To determine the effectiveness of interventions
or stroke), prior cognitive impairment, temperature abnormality designed to prevent delirium in hospitalised patients.
(fever or hypothermia), dehydration, malnutrition and low serum
Secondary objective: To highlight the quality and quantity of
albumin (Inouye 1998b; Inouye 1999c).
research evidence to prevent delirium in hospitalised patients
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
METHODS
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 Criteria for considering studies for this review
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 Types of studies
these risk factors can be seen as hospital quality of care measures,
We included only original reports of randomised controlled tri-
e.g. malnutrition, dehydration, use of physical restraints, iatro-
als in the review. Because of the difficulties inherent in blinding
genic events. Occurrence of delirium can, therefore, be seen as a
of participants and researchers to certain types of interventions,
proxy measure of the quality of in-patient care (Inouye 1999b).
blinding was not a prerequisite for inclusion. The length of trial
did not influence selection of studies.

Types of participants • cost to health care services
We included patients aged 16 years or over, admitted to acute
We also included adverse events, although this was not specified
general hospitals, and at risk of developing delirium. We excluded
in the original published protocol.
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.
Search methods for identification of studies
Types of interventions CDCIG Specialised Register:
We included studies of any intervention(s) designed to prevent The Specialized Register of the Cochrane Dementia and Cognitive
delirium with controls receiving standard care. We also included Improvement Group was searched on 30 September 2006 using
trials comparing two types of intervention. Trials of co-ordinated the terms: delirium or “acute confusion” or “acute brain failure”
multi-strategy initiatives were included. Examples of interventions or “acute organic psychosyndrome” or “acute brain syndrome” or
we included are: regular screening of cognitive function or mental “metabolic encephalopathy” or “acute psycho-organic syndrome”
state, protocol driven medical review and investigation, medica- or “clouded state” or “clouding of consciousness” or “exogenous
tion review, medication, nursing interventions, education of staff psychosis” or “toxic psychosis” or “toxic confusion”.
or family. The Specialized Register at that time contained records from the
We defined standard care as the usual care available on that unit. following databases:
• CENTRAL: July 2005 (issue 3);

Types of outcome measures • MEDLINE: 1966 to 2005/08, week 2;
The primary outcomes of interest were: • EMBASE: 1980 to 2005/08, week 2;
• PsycINFO: 1887 to 2005/07;
• incident delirium (new onset) during admission • CINAHL: 1982 to 2004/07;
• death • SIGLE (Grey Literature in Europe): 1980 to 2004/06;
We only accepted studies in which delirium was identified using • ISTP (Index to Scientific and Technical Proceedings): to
a validated method for diagnosis, such as operationalised clinical May 2000;
criteria from ICD-10, DSM-III, DSM-IIIR, DSM-IV, (WHO • INSIDE (BL database of Conference Proceedings and
1992; APA 1987; APA 1994; APA 1999) or using diagnostic tools Journals): to June 2000;
based on these e.g. the Confusion Assessment Method (CAM) ( • Aslib Index to Theses (UK and Ireland theses): 1970 to
Inouye 2000b), Delirium Rating Scale (DRS) (Trzepacz 1988). March 2003;
All types of delirium (hypoactive, hyperactive and mixed) were • Dissertation Abstract (USA): 1861 to March 2003;
considered together. We included drug-induced delirium but not • http://clinicalstudies.info.nih.gov/;
delirium tremens. • National Research Register (issue 3/2005)
Secondary outcomes were: • ClinicalTrials.gov: last searched 1 September 2005;
• LILACS: Latin American and Caribbean Health Science
• duration of delirium Literature: last searched April 2003
• severity of delirium, measured by validated instruments • http://www.forestclinicaltrials.com/: last searched 1
including the Memorial Delirium Assessment Scale (MDAS) ( September 2005
Breitbart 1997) and DRS • ClinicalStudyResults.org: last searched 1 September 2005
• use of psychotropic medication • http://www.lillytrials.com/index.shtml: last searched 28
• behavioural disturbance August 2005
• length of admission • ISRCTN Register: last searched 1 September 2005
• activities of daily living • IFPMA Clinical Trials Register: http://www.ifpma.org/
• institutional care at discharge clinicaltrials.html: last searched September 2005
• cognitive status
• physical morbidity The search strategies used to identify relevant records in MED-
• psychological morbidity LINE, EMBASE, PsycINFO, CINAHL and LILACS can be
• quality of life found in the group’s module.
• carers’ psychological morbidity As the searches in MEDLINE, EMBASE, CINAHL and
• staff psychological morbidity PsycINFO for the Specialized Register would not necessarily have
• withdrawal from protocols by patients picked up all delirium prevention trials (it is primarily a register of
• cost of intervention trials with people with dementia or cognitive impairment), these

databases were searched again on 28th October 2005 with the fol- care” or “standard treatment” or “normal treatment”
lowing search strategies: 12 #10 or #11
MEDLINE (1966-2005) 13 #9 and #12
1.“Delirium”/all subheadings 14 “delirium-tremens”/all subheadings
2.deliri* 15 #13 not #14
3.“acute confusion” 16 nonhuman* in DER
4.“acute organic psychosyndrome” 17 (nonhuman* in DER) and (human* in DER)
5.“acute brain syndrome” 18 #16 or #17
6.“metabolic encephalopathy” 19 #15 not #17
7.“acute psycho-organic syndrome” PsycINFO (1887-2005)
8.“clouded state” 1 deliri*
9.“clouding of consciousness” 2 “acute psycho-organic syndrome” or “clouded state” or “cloud-
10.“exogenous psychosis” ing of consciousness” or “exogenous psychosis” or “toxic psychosis”
11.“toxic psychosis” or “toxic confusion”
12.“toxic confusion” 3 acute brain confusion“ or ”acute brain failure“ or ”acute organic
13.#1 or #2 psychosyndrome“ or ”acute brain syndrome“ or ”metabolic en-
14.#3 or #4 or #5 or #6 cephalopathy“
15.#7 or #8 or #9 or #10 4 ”Delirium-“ in MJ,MN
16.#11 or #12 5 #1 or #2 or #3 or #4
17.#13 or #14 or #15 or #16 6 explode ”Prevention“
18.explode “Primary-Prevention”/all subheadings 7 prevent* or avoid*
19.prevent* 8 #6 or #7
20.avoid* 9 #5 and #8
21.#18 or #19 or #20 10 random* or placebo* or control* or ”normal treatment“ or
22.#17 and #21 ”normal care“ or ”standard care“ or ”standard treatment“
23.random* or placebo* or control* 11 #9 and #10
24.“standard treatment” or “normal treatment” or “standard care” CINAHL (1982-2004)
or “normal care” 1 deliri*
25.#23 or #24 2 ”acute psycho-organic syndrome“ or ”clouded state“ or ”cloud-
26.#22 and #25 ing of consciousness“ or ”exogenous psychosis“ or ”toxic psy-
27.“Alcohol-Withdrawal-Delirium”/all subheadings chosis“ or ”toxic confusion“
28.“delirium tremens” in TI 3 ”acute brain confusion“ or ”acute brain failure“ or ”acute or-
29.#27 or #28 ganic psychosyndrome“ or ”acute brain syndrome“ or ”metabolic
30.#26 not #29 encephalopathy“
31.((TG=animals) not (TG=humans)) and (TG =animals) 4 ”Delirium“/without-subheadings
32.#30 not #31 5 #1 or #2 or #3 or #4
EMBASE (1980-2005) 6 ”Preventive-Trials“/without-subheadings
1 explode “delirium” tree: 1/ all subheadings 7 prevent* or avoid*
2 deliri* 8 #6 or #7
3 “acute psycho-organic syndrome” or “clouded state” or “cloud- 9 #5 and #8
ing of consciousness” or “exogenous psychosis” or “toxic psychosis” 10 random* or placebo* or control* or ”normal care“ or ”standard
or “toxic confusion” care“ or ”normal treatment“ or ”standard treatment“
4 “acute brain confusion” or “acute brain failure” or “acute or- 11 #9 and #10
ganic psychosyndrome” or “acute brain syndrome” or “metabolic 12 ”Alcohol-Withdrawal-Delirium“/without-subheadings
encephalopathy” 13 ”delirium tremens“ in TI
5 #1 or #2 or #3 or #4 14 #12 or #13
6 explode “prevention”/all subheadings 15 #11 not #14
7 prevent* or avoid* 16 (animal in DE) not ((human in DE) and (animal in DE))
8 #6 or #7 17 #15 not #16
9 #5 and #8 CENTRAL (issue 3/2005)
10 “randomized-controlled-trial”/all subheadings 1.(acute next confusion)
11 random* or placebo* or control* or “normal care” or “standard 2.(acute next brain next syndrome)

3.(acute next organic next psychosyndrome) The titles, abstracts and descriptors of citations identified by the
4.(clouding next consciousness) search were examined by two reviewers, NS and RS independently;
5.(acute next psychosis) those deemed to be clearly irrelevant were discarded. The aim was
6.(toxic next psychosis) to be over-inclusive at this stage to avoid losing potentially relevant
7.(toxic next confusion) studies. Full text copies of the remaining citations were retrieved
8.(acute next psychosyndrome) and assessed independently by NS and RS for inclusion using the
9.(acute next psycho-syndrome) criteria described above. Disagreements at any stage of study selec-
10.(#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9) tion were resolved by referral to JH (this was only necessary with
11.(#10 and (prevent* or avoid*) regard to one study). Reports were checked for multiple publica-
12.(#11 and (not delirium tremens)) tion of the same data.
We reviewed bibliographies of books and review articles on delir- Quality Assessment
ium, and also references from retrieved articles. Experts in this field The internal validity of trials relates to how successfully selection,
were contacted for further references and to locate unpublished performance, attrition and detection biases are eliminated (Clarke
trials. The Internet was searched using the search engines Google 1999). The quality of included trials was assessed independently
and Copernic to try to find further evidence of unpublished trials by NS, RS and AB using predetermined criteria adapted from
using the same terms as stated above. the U.S. Preventive Services Task Force (Harris 2001; Table 1). A
We did not apply any time restrictions or language constraints. consensus process was used to reach agreement. Reviewers were 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
Data collection and analysis C if one or more criteria were not met or if it was not possible to
Selection of Studies determine whether one or more criteria were met.
Table 1. Quality Assessment Tool (Adapted from US Preventive Services Task Force)
Validity Criteria Met Partially Met Unmet/Unknown
Initial assembly of comparable

groups (includes concealment
of treatment allocation and po-
tential confounders distributed
equally among groups)
Maintenance
of comparable groups (includes
attrition, crossovers, adherence,
contamination)
Clear definition of interven-

tions
All important outcomes consid-

ered and predefined
Outcome measurements equal,

reliable, and valid (includes
masking of outcome assess-
ment)

Table 1. Quality Assessment Tool (Adapted from US Preventive Services Task Force) (Continued)
No important differential loss

to follow-up or overall high loss
to follow-up (trials should have
losses less than 25%, unless due
to death)
Intention-to-treat analysis
Data Extraction Description of studies

A data extraction form was designed and piloted. Data were then See: Characteristics of included studies; Characteristics of excluded
independently extracted by three reviewers NS, RS and AB with studies; Characteristics of ongoing studies.
disagreements resolved by a consensus process. Six, very diverse studies met our selection criteria, all conducted
To allow an intention-to-treat analysis, data were sought for every in surgical settings (Aizawa 2002; Berggren 1987; Diaz 2001;
patient randomised to treatment or control group irrespective of Kalisvaart 2005; Liptzin 2005; Marcantonio 2001). One study
compliance or subsequent exclusion. Where data were only avail- was limited to patients operated on for gastric or colorectal can-
able for participants completing treatment, these were extracted cer (Aizawa 2002). Five included orthopaedic patients, three con-
and reported separately. When individual patient data were not ducted in patients requiring surgery for hip fracture, one in acute
available, data were extracted from summary statistics for each or elective hip surgery patients (Kalisvaart 2005) and one in elec-
study. tive hip or knee arthroplasty patients (Liptzin 2005). Most studies
were conducted in older people.
Data Analysis
All six studies tested markedly different interventions; one com-
Missing data and drop-out rates were assessed for each of the in- pared two anaesthetic approaches (Berggren 1987), one evaluated
cluded studies. We reported the number of participants included proactive geriatric consultation (Marcantonio 2001), and the oth-
in the final analysis as a proportion of all participants in the study. ers investigated administration of various pharmacological agents.
There were no studies of multi component interventions, and none
For binary outcomes, a standard estimation of the risk ratio with
conducted in non-surgical settings.
a 95% confidence interval was calculated.
Outcomes examined included incident delirium, duration and
Where means and standard deviations were available, we analysed severity of delirium, behavioural disturbance, length of admission,
continuous data with a normal distribution (or approximating to physical morbidity, cognitive status and institutionalisation at dis-
a normal distribution) using Revman Statistical analysis software. charge. Although all studies determined the incidence of delir-
Appropriate non-parametric tests were used to analyse data not ium, there was heterogeneity in both the statistical measures of
normally distributed. frequency, and diagnostic methods used.
We pre-determined that if there were sufficient data and it was Aizawa et al (Aizawa 2002) hypothesised that sleep disorders are
appropriate to do so, one or more meta-analyses would be per- one of the critical factors in the aetiology of postoperative delir-
formed. However, no such analyses were possible due to lack of ium in patients treated in the ICU after surgery and attempted to
comparability of interventions and comparators used in individual control disturbance of the sleep-wake cycle. They devised a ’Delir-
studies. ium Free Protocol’ (DFP) employing routine administration of
diazepam, flunitrazepam and pethidine. They compared the ef-
We planned to perform a subgroup analysis of outcomes in patients fect of this unusual intervention with care as usual on the primary
with and without dementia, but this was only possible for one outcome, delirium incidence in the first 7 days after surgery. A
outcome in one study. 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.
RESULTS

A Swedish study (Berggren 1987) compared the incidence of post- Several case reports have suggested that donepezil, an acetyl-
operative ’mental confusion’ in patients operated on for hip frac- cholinesterase inhibitor widely approved for treatment in
ture under epidural and under halothane anaesthesia. Again their Alzheimer’s disease, might also be helpful in delirium (Gleason
primary outcome was incident delirium, but this was defined as 2003; Wengel 1998). A study in patients undergoing elective knee
delirium present on day one and/or day seven after surgery. They and hip arthroplasty (Liptzin 2005), investigated the effectiveness
also determined length of admission and physical morbidity in- of donepezil 5 mg given for 14 days before and after surgery. Con-
cluding stroke, urinary tract infection and decubitus ulcer. Delir- trols were given placebo tablets. Outcomes measured were inci-
ium was diagnosed by DSM III criteria (APA 1987) using a mod- dent delirium after surgery, duration of delirium and length of
ified Organic Brain Syndrome Scale (OBS) (Jensen 1993) by two admission. DSM IV delirium was diagnosed on days 7 and 14
trained researchers. after surgery using daily administration of the Delirium Symptom
CDP-choline (cytidine 5’-diphosphocholine) is a precursor essen- Interview (DSI) (Albert 1992), CAM and medical records review.
tial for the synthesis of cell membrane components, and animal In the only study of non-pharmacological interventions, Marcan-
studies suggest that it may protect cell membranes, and may also tonio and colleagues (Marcantonio 2001) tested proactive geriatric
attenuate the progression of ischaemic cell damage (Fioravanti consultation against ’care as usual’. Patients were visited daily by
2006). A recent Cochrane review (Fioravanti 2006) concluded that a consultant geriatrician preoperatively or within 24 hours after
there was some evidence that CDP-choline has a positive effect on surgery. Targeted recommendations were made based on a struc-
memory and behaviour in at least the short/medium term in older tured protocol. They included measures to address 10 areas: i)
people, with cognitive deficits associated with chronic cerebral dis- maintenance of adequate CNS oxygen delivery, ii) correction of
orders of the brain. A study from Chile (Diaz 2001) compared fluid and electrolyte balance, iii) treatment of severe pain, iv) elim-
the effectiveness of citicoline (CDP-choline) with placebo in pre- ination of unnecessary medications, v) regulation of bowel/blad-
venting delirium in patients undergoing hip fracture surgery. In der function, vi) adequate nutritional intake, vii) early mobilisa-
addition to administration of the study drug, anticholinergics or tion and rehabilitation, viii) prevention, early detection and treat-
benzodiazepine use was stopped, and anaemia and haemodynamic ment of major postoperative complications, ix) appropriate envi-
disturbances corrected in both groups. The primary outcome of ronmental stimuli and x) treatment of agitated delirium. Recom-
interest was incident delirium; this was determined immediately mendations were prioritised, and no more than five were made at
after surgery and on days 1, 2 and 3 postoperatively, using the the initial consultation, and three at subsequent visits. The usual
Abbreviated Mental Test Score (AMT) (Hodkinson 1972) and care group received management by the orthopaedics team in-
CAM. Cognitive status after surgery was assessed using the Mini- cluding internal medicine or geriatric consultation, if required,
Mental State Examination (MMSE) (Folstein 1975). on a reactive basis. The primary outcome was total cumulative
Kalisvaart et al (Kalisvaart 2005) administered daily prophylactic CAM-defined delirium incidence during admission. The MMSE,
oral haloperidol (1.5 mg) to elective and non-elective hip surgery DSI, MDAS and CAM instruments were administered daily from
patients at intermediate to high risk of delirium. Controls were admission to discharge by a trained assessor. Delirium duration,
given placebo tablets identical in appearance to the study drug. severity, length of admission and institutionalisation at discharge
All patients were also offered proactive geriatric consultation. If were also determined. Severity was defined as an MDAS score of
delirium occurred, the dose of study drug was doubled. In addition 18/30 or more.
to the primary outcome, postoperative incident delirium, they also
documented delirium duration, severity, length of admission and
adverse effects. Delirium was diagnosed according to DSM IV and
Risk of bias in included studies
CAM criteria using the Delirium Rating Scale-Revised-98 (DRS- Studies varied in their methodological quality. Table 2 gives the
R-98) (Trzepacz 2001), MMSE and Digit span administered by overall quality assessments determined using the preset criteria
trained assessors. described above.
Table 2. Study Quality Assessment
Study Quality Assessment
Aizawa 2002 C
Berggren 1987 B
Diaz 2001 B

Table 2. Study Quality Assessment (Continued)
Kalisvaart 2005 A
Liptzin 2005 C
Marcantonio 2001 A
Only one study (Marcantonio 2001) clearly achieved adequate three studies, data were only available for patients completing treat-
power to test effectiveness of the intervention in prevention of ment.
delirium. Aizawa 2002, Berggren 1987 and Kalisvaart 2005 did
not include a power calculation; the latter comment that the study Validated delirium diagnostic criteria consistent with the selec-
was underpowered, given the relatively low delirium incidence tion criteria for this review were used in all studies, but in some
in their trial. Diaz 2001 and Liptzin 2005 did perform a power there was variability in training of assessors, or training was not
calculation, but used much higher estimates of delirium rates than described (Aizawa 2002; Diaz 2001). Moreover, in Aizawa 2002,
actually found in these studies. the intervention caused sedation in 8/20 patients and may have
interfered with delirium assessment.
Randomisation was used in all studies, but adequate allocation
concealment was only described in two studies (Kalisvaart 2005; In outcomes, although all studies assessed incident delirium as
Marcantonio 2001). Blinding of participants was used, except in the primary outcome, other important outcomes including death,
the three studies in which the nature of the intervention protocols costs and psychological morbidity were not examined.
precluded this (Aizawa 2002; Berggren 1987; Marcantonio 2001).
All studies included blinded assessment of outcomes. The study population in Aizawa 2002 included a very specialised
In three studies (Aizawa 2002; Diaz 2001; Liptzin 2005), only setting, restricting its generalisability. The other five studies have
limited information about baseline comparability between inter- relevance for management of patients with hip fracture, a com-
vention and control or comparative groups was given; in these, mon presentation amongst older people requiring hospitalisation
there were no statistically significant differences in age, sex, cogni- (although the study population in Liptzin 2005 was confined to
tive status or post surgery APACHE score (Knaus 1985). Berggren elective hip or knee arthroplasty patients).
1987 also recorded co-morbidity and psychotropic drug use. Effects of interventions
The number of patients taking anticholinergic drugs was signifi-
Studies could not be combined for meta-analysis due to hetero-
cantly greater in the intervention group. In Kalisvaart 2005 and
geneity in interventions tested, settings, participants and methods.
Marcantonio 2001 there were no baseline differences described in
Results for individual studies are, therefore, presented by outcome.
a range of important characteristics.
1. Post surgery administration of Del i rium-Free Protocol v
In investigating the effectiveness of interventions to prevent delir- Usual care (Aizawa 2002)
ium, clearly assessment for delirium at enrollment will be im-
portant. This was done in only three of the studies (Diaz 2001; Primary outcome:
Kalisvaart 2005; Marcantonio 2001); however, in Aizawa 2002 a) Incident delirium in the 7 days after surgery was significantly
and Berggren 1987, the exclusion criteria would in effect have lower in the intervention group with an Odds Ratio (OR) 0.10
excluded delirium. In Marcantonio 2001, patients with delirium [95% CI 0.01, 0.89] and Relative Risk (RR) of 0.14 [95% CI
were not excluded from enrollment, and despite being examined 0.02, 1.06].
for, delirium prevalence at intake assessment was not reported.
Secondary outcomes:
Comorbidity with physical illness was not assessed in Aizawa 2002,
b) Behavioural disturbance in the first 7 days after surgery was also
Kalisvaart 2005 or Liptzin 2005, and presence of dementia was
lower for the intervention group, but the difference failed to reach
only reported in one study (Marcantonio 2001).
statistical significance (RR 0.20 [95% CI 0.03, 1.56])
An intention to treat analysis was carried out in three studies ( c) In length of admission also, there was no significant difference
Berggren 1987; Kalisvaart 2005; Marcantonio 2001). In the other between groups.

Analyses were carried out in 40 study participants but do not [95% CI1.4, 2.3], p<0.001.
include two patients who dropped out of the study. e) Withdrawal from the protocol did not differ between the two
groups and occurred in 11% of enrolled patients.
2. Epidural anaesthesia v Halothane anaesthesia (Berggren f ) Adverse effects were reported in three patients in each group
1987) who withdrew from the protocol. However no drug related side
effects were seen.
Primary outcome: This large study included 430 participants, stratified to be at inter-
a) Incidence of delirium on day 1 or day 7 after surgery did not mediate or high risk of delirium. Intention to treat analyses were
differ significantly between treatment groups (RR 1.32 [95% CI performed for all outcomes.
0.73, 2.39]).
Secondary outcomes: 5. Prophylactic donepezil v Placebo (Liptzin 2005)
b) Length of admission was reported to show no significant dif-
ference, but no data for this were given. Primary outcome:
c) Physical morbidity; there were no differences in the incidence a) Incident delirium after surgery occurred in 18.8% patients and
of stroke, urinary tract infection or decubitus ulcers (RR 1.20 did not differ significantly between treatment and placebo groups
[95%CI 0.51, 2.81]) (RR 1.2 [95% CI 0.48, 3.00])
Intention to treat analyses were performed for all outcomes in 57 Secondary outcomes:
study participants. One year mortality was reported as 7% (4/57), b) Delirium duration
but was not given by treatment group. c) Length of admission
Duration of delirium and length of admission were not signifi-
3. Prophylactic citicoline v Placebo (Diaz 2001) cantly different in the two groups.
d) Withdrawal from protocol occurred in 11/ 39 intervention and
Primary outcomes: 11/41 control patients.
a) Incident delirium immediately after surgery 90 patients were enrolled and randomised. 10 were not operated on
b) Incident delirium on day 1 after surgery or took no study medication and were excluded from any analyses.
c) Incident delirium on day 2 after surgery 6. Proactive geriatric consultation v Usual care (Marcantonio
d) Incident delirium on day 3 after surgery 2001)
There was no significant difference between groups in incidence
of delirium assessed at any of the above time points. Primary outcome:
Secondary outcome: a) Total cumulative delirium incidence during admission was re-
e) Cognitive status; there was no significant difference between duced in the proactive geriatrics consultation group compared
intervention and control groups in the MMSE score after surgery with usual care. The difference was statistically significant (OR
. 0.48 [95% CI 0.23, 0.98]; RR 0.64 [95% CI 0.37, 0.98]), sug-
Results were reported for 81 participants. Seven patients who were gesting a ’number needed to treat’ of 6 patients to prevent one case
enrolled, but did not proceed with the study protocol, were not of delirium. However, baseline delirium prevalence at enrollment
included in the final analyses. was not reported, limiting interpretation of findings.
4. Prophylactic haloperidol v Placebo (Kalisvaart 2005) In logistic regression analyses adjusting for pre fracture dementia
and Activities of Daily Living impairment, the authors report no
Primary outcome : reduction in effect size, OR 0.6, but this no longer remained sig-
a) Incidence of delirium after surgery was 15.8% in the study nificant [95% CI 0.3,1.3].
population with a non-significant difference between treatment Secondary outcomes:
and control groups (RR 0.91 [95% CI 0.59, 1.42]). b) Delirium duration. There was little difference between the two
Secondary outcomes: groups in number of hospital days with delirium per episode,
b) Delirium duration suggesting the impact of the intervention on already established
c) Delirium severity delirium may be limited.
Both the duration and severity were reduced in the intervention c) Delirium severity; the intervention was particularly effective in
group compared with controls, and the differences reached statis- preventing severe delirium, demonstrated by a greater reduction in
tical significance (delirium duration RR -6.44 [95% CI -7.64, - cumulative incidence of this in the intervention group compared
5.24] and mean difference in maximum DRS-R-98 score of 4.0 to controls (RR 0.4 [95% CI 0.19, 0.89]).
[95% CI 2.0, 5.8], p<0.001). d) Length of admission was similar for both groups.
d) Length of admission was also significantly shorter in the in- e) Rates of institutionalisation at discharge did not differ between
tervention group, with a mean difference in hospital days of 5.5 groups.

f ) Cognitive status at discharge was assessed by prevalence of delir- operative delirium compared to other studies in similar popula-
ium, which was present in 15.9% patients (8/62 in the interventions. Further studies are needed to clarify the role of neuroleptics
tion group and 12/64 controls, RR 0.69 [95% CI 0.30, 1.57]). in delirium prevention.
Outcomes in dementia sub-group analysis:
3. The most encouraging evidence for successful delirium preven-
This was carried out in 50 patients with dementia diagnosed using
tion comes from one large study of proactive geriatric consulta-
the Blessed Dementia Rating Scale (Blessed 1968).
tion (Marcantonio 2001). Given the multifactorial aetiology of
There was no significant difference between treatment and control
delirium (Lindesay 2002), their approach targeting a range of risk
groups in cumulative delirium incidence during admission in this
factors may be more appropriate than strategies relying on admin-
sub-group (RR 0.9 [95% CI 0.59, 1.36]).
istration of a single pharmacological agent (Inouye 1999a; Milisen
The total study population (with and without dementia) num-
2005) . The recommendations made comprised measures that are
bered 126. Intention to treat analyses were performed for all out-
essentially basic aspects of good care, yet they were able reduce
comes.
delirium incidence by more than one third.
We identified no completed studies in hospitalised medical, care of
the elderly, general surgery or intensive care settings. In outcomes, 4. Dementia is the most important risk factor for delirium (
no studies examined for death, use of psychotropic medication, Lindesay 2002); targeting this population makes empirical sense
activities of daily living, psychological morbidity, quality of life, and may deliver important benefits, not least as many of the mea-
carers’ psychological morbidity, staff psychological morbidity, cost sures to prevent delirium should also be helpful in dementia. How-
of intervention and cost to health care services. Outcomes were ever, Marcantonio 2001 could not demonstrate effectiveness of
only reported up to discharge, with no studies reporting medium the intervention in preventing delirium in a subgroup analysis of
or longer-term effects. We did not perform a funnel plot to exam- 50 patients with dementia.
ine for publication bias due to the limited number of studies.
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
DISCUSSION have been described, and implicated in limiting effectiveness by
others (Cole 2002; Inouye 2003; Young 2003) leading to calls to
1. We found only a handful of RCTs of interventions to prevent include strategies to improve implementation and adherence (such
delirium in hospitalised patients. Of the six which met our se- as measures to increase ownership and interactive education and
lection criteria, no two studies tested the same, or even a similar training (EHC 1999; Grimshaw 2004)) as an integral part of any
intervention. Additionally, there was heterogeneity in methods, delirium intervention package.
participants and outcomes examined. Methodological limitations
of these studies have been described above; importantly only one 6. The study by Kalisvaart and colleagues (Kalisvaart 2005) showed
study was sufficiently powered to determine effectiveness of the accurate stratification of delirium risk was feasible based on the
intervention, and then only for bivariate analyses. presence of four predictive delirium risk factors. This corroborates
findings in Inouye’s study of predictive risk factors (Inouye 1993b)
2. Research evidence for effectiveness of interventions to prevent and provides important validation of this risk identification system
delirium in this population is limited. Although Aizawa 2002 re- which may be useful in both clinical practice and for delirium
port that their intervention reduced postoperative delirium, the research.
protocol caused sedation and may have interfered with delirium
7. Only immediate benefits (up to discharge) were examined in
assessment. The highly specific study population and small study
all six included studies. However, in Marcantonio 2001, the au-
size, as well as the nature of the intervention, limit generalisability
thors indicate that they will be publishing results of longer term
of findings from this study. Berggren 1987 found no difference in
outcomes in future.
delirium incidence following surgery under epidural or halothane
anaesthesia. Prophylactic administration of citicoline (Diaz 2001)
and donepezil (Liptzin 2005) did not prevent delirium compared
8. The most striking finding is the paucity of high quality pub-
with placebo.
lished research on delirium prevention, particularly given how
3. Prophylactic haloperidol was not effective in preventing delir- common the condition is in hospitalised patients and its seriously
ium but did reduce its severity and duration, and also decreased poor outcomes. Reasons for this may include historical difficulties
length of hospital stay (Kalisvaart 2005). Interestingly, proactive with case definition and detection, and the challenges of conduct-
geriatric consultation was also offered to all patients, both in the ing research in often frail and debilitated patients. Further studies
intervention and control group; the authors speculate that this on delirium prevention are urgently needed to guide clinical prac-
might have been responsible for the overall lower incidence of post tice. Future investigations should focus on multi-faceted ’pack-

ages’ of delirium care in a whole range of hospital settings, and strategies in hospitalised patients in a range of medical and surgical
should include short and longer term outcomes such as mortality, settings.
physical and psychological morbidity, impact on carers and costs
to health care services.
AUTHORS’ CONCLUSIONS
9. Our review has some limitations. Although a fairly extensive
search was performed, resource limitations did not allow searching Implications for practice
of non-English language databases. We can be confident, however,
that we identified most important relevant studies, as our search There is little evidence from delirium prevention studies to guide
retrieved all studies included in recent reviews of this topic and also clinical practice. Based on a single RCT, a programme for proactive
identified additional studies. Resource limitations also precluded geriatric consultation may reduce delirium incidence and sever-
blinding to authors and source institutions of studies, which could ity in patients undergoing surgery for hip fracture (Marcantonio
potentially bias selection and quality assessment. Given the nature 2001). Prophylactic low dose haloperidol may reduce the severity
of the interventions, blinding of study subjects or researchers was and duration of a delirium episode, and reduce length of hospital
not a prerequisite for inclusion. stay in hip surgery patients (Kalisvaart 2005). There is no trial
evidence available on the effectiveness of any other strategies to
10. A strength of our review is that all stages of screening citations, prevent delirium in hospitalised patients.
identification of studies for inclusion, data extraction and quality
appraisal were carried out by at least two of the authors indepen- Implications for research
dently, and agreement reached by consensus. There is a striking lack of research on delirium prevention. Further
studies are urgently needed to guide clinical practice. Given its
11. Our findings are consistent with those of existing reviews
diverse predisposing and precipitating factors, and how common
of delirium prevention (Britton 2004; Cole 1999; Milisen 2005;
it is in a range of settings, future investigations should focus on
Weber 2004). Previous reviews have included studies using un-
evaluating multi-faceted ’packages’ of delirium prevention in var-
validated methods to operationalise delirium or using terms such
ious hospital settings. Drug prevention studies e.g. of haloperidol
as ’confusional state’ (without a clear definition of what this term
are also needed. Studies should use validated delirium screening
encompassed). We agree with Milisen (Milisen 2005) that reliance
and diagnostic methods such as the CAM and DRS and should
on terms such as ’acute confusion’ contributes to the semantic am-
include assessment of short and longer term outcomes such as
biguity rife in delirium research and is not helpful in furthering
mortality, physical and psychological morbidity, impact on carers
our understanding of the condition; in clinical settings also, it is
and costs to health care services.
unhelpful to efforts to increase recognition of delirium by health
care professionals as a condition warranting an urgent response.
ACKNOWLEDGEMENTS
12. This review aimed to consider all interventions designed to pre-
We gratefully acknowledge the contribution of Dr Duncan
vent delirium rather than testing a specific hypothesis. It provides
Forsyth, Consultant Elderly Care Medicine, Addenbrookes Hos-
a robust update, highlighting the current scarcity of research evi-
pital, Cambridge, who provided feedback as the consumer editor
dence to guide clinical practice in delirium prevention. Although
for this review.
based on the findings of only one study, there is some evidence
to recommend implementation of proactive geriatric consulta- We also wish to thank Katherine Hicks, Dymphna Hermans and
tion in patients undergoing surgery for hip fracture. Further trials Leon Flicker from the Dementia and Cognitive improvement
are needed of this intervention, and of other delirium prevention Group for their support with preparing the review.

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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
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
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

Marcantonio 2001
Methods Randomisation: Adequate concealed allocation

Power calculation: Yes. Study adequately powered for bivariate analyses but not for the multivariate or stratified
analyses.
Blinding of participants: No, not possible given nature of intervention
Informed consent: Yes, or proxy assent if unable to consent
Delirium diagnostic criteria: CAM
Outcomes Measurement: Daily interviews from enrollment to discharge to complete MMSE, DSI, CAM, (MDAS)
by trained assessors
Drop outs from protocol 0
Incomplete follow up: 0
Study duration: Not given

USA
1 academic tertiary centre orthopaedic department
Admitted for primary surgical repair of hip fracture
At intermediate or high risk of delirium (presence of 1 or more delirium risk factors)
Age: 65 yrs or over; mean 78 and 80 yrs in intervention and controls respectively
Co-morbidity: High (Charlson index >/= 4) in 39% and 33% of intervention and control groups respectively
Dementia: 37% in intervention group and 51% in controls Delirium at enrollment: Assessed but not excluded
Exclusions: Metatstatic cancer or comorbid illness reducing life expectancy to less than 6 months; Unable to obtain
consent (or proxy assent) within 24 hrs of surgery, or 48 hrs of admission
Interventions Proactive consultation by Consultant Geriatrician, with daily visits starting preop or within 24 hrs post op for duration
of admission. Protocol based targeted recommendations over and above what was already being done by team, limited
to 5 at initial visit and 3 at follow-up visits
Controls: Usual care, consisting of management by orthopaedic team and consultation by internal medicine or
geriatrics on reactive rather than proactive basis
Outcomes 1. Delirium incidence- total cumulative during admission

2. Delirium duration
3. Severity- cumulative incidence of severe delirium during admission
5. Institutionalisation at discharge
Notes Funding source: Older Americans Independence Center; Charles Farnworth Trust;
Delirium examined but not reported at intake, making interpretation of results for primary outcome of cumulative
delirium incidence difficult

Characteristics of excluded studies [ordered by study ID]
Baldwin 2004 The intervention was not designed to prevent delirium. Cognitive impairment rather than delirium was used as
an outcome measure.
Budd 1974 A validated method for diagnosis of delirium was not used.
Cerchietti 2000 Not a delirium prevention study.
Cole 2002 Not a delirium prevention study.
Culp 2003 Randomisation not used and participants were long term care residents.
Inouye 1993a Not original research- review article.
Inouye 1999 Randomisation not used.
Kaneko 1999 A validated method for delirium diagnosis was not used. Although DSM IIIR diagnostic criteria used, data
obtained from retrospective chart review.
Landefeld 1995 Outcomes examined did not include delirium.
Lundstrom 2005 Randomisation not used.
Mentes 2003 Randomisation not used.
Milisen 2001 Before and after study.
Naughton 2005 Randomisation not used.
Tabet 2005 Randomisation not used.
Tokita 2001 Delirium diagnosis relied on retrospective records review.
Wanich 1992 Not a delirium prevention study.
Wong 2005 Randomisation not used. Before and after study.

Characteristics of ongoing studies [ordered by study ID]
Boustani 2005a
Trial name or title Donepezil in the Prevention of Post-Operative Cognitive Decline
Methods
Participants 30 adults aged 65 and older who have a baseline mild cognitive impairment (MCI) and are undergoing
elective hip or knee replacement
Interventions Donepezil or a matching placebo for 3-6 weeks, starting 4 weeks preoperatively
Outcomes Primary Outcomes: Changes in the International Study of Post-Operative Cognitive Decline (ISPOCD) and
the CogHealth computerized battery tests at 1 week and 12 weeks after surgery.
Secondary Outcomes: Delirium status measured by the CAM and the MDAS daily during the post-operative
period; Global Cognitive status assessed using the MMSE; Length of Stay in the hospital post-operatively;
Discharge site; Adverse effects
Starting date February 2005
Contact information smunger@regenstrief.org
Notes
Boustani 2005b
Trial name or title Enhancing Care for Hospitalized Older Adults with Cognitive Impairment
Methods
Participants 400 patients with cognitive impairment who have been hospitalized in a medical ward
Interventions A cognitive screening program coupled with a Computerized Decision Support System or usual care
Outcomes Primary Outcomes: Use of potentially inappropriate medications, urinary catheter or physical restraints, and
length of time in initiating a referral order, as recorded in the electronic medical record; Total number of
hospital acquired complications recorded in the medical record that may be related to Cognitive Impairment
(CI)
Secondary Outcomes: Length and cost of hospital stay from discharge records and billing system
Starting date July 2006
Contact information smunger@regenstrief.org
Notes

Boustani 2005c
Trial name or title Donepezil in Preventing Delirium in Hospitalized Elderly
Methods
Participants 30 adults aged 65 or older who are undergoing hip fracture surgery
Interventions Donepezil or a matching placebo within 24 hours prior to surgery and for 4 days after surgery
Outcomes Primary Outcomes: Postoperative cumulative incident cases of delirium, as defined by the CAM administered
at baseline prior to surgery and daily until discharge; delirium severity as measured by the MDAS
Secondary Outcomes: Cognitive Status as measured by the MMSE; behavioral status using the Rating Scale
for Aggressive Behavior in the Elderly (RAGE); length of stay in hospital postoperatively; discharge site;
adverse effects; use of psychotropic medications
Starting date July 2004
Contact information ClinicalTrials.gov identifier NCT00182884 smunger@regenstrief.org
Notes
Diehl 2005
Trial name or title Prevention of Postoperative Delirium with Donepezil
Methods
Participants Cognitively healthy, elective hip or knee replacement patients aged 70 or over
Interventions Donepezil or matching placebo before (over 5-7 days), during and after (over 7 days) surgery
Outcomes Primary Outcomes: Incidence of delirium

Secondary Outcomes: Cognitive performance
Starting date January 2006
Contact information janine.diehl@lrz.tum.de
Notes
Ely 2004a
Trial name or title 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
Methods

Ely 2004a (Continued)
Participants 100 adult mechanically ventilated patients
Interventions A sedation strategy of dexmedetomidine ± fentanyl versus lorazepam ± fentanyl,
Outcomes Primary Outcomes: Delirium

Secondary Outcomes: Efficacy of sedation
Starting date August 2004
Contact information wes.ely@vanderbilt.edu
Notes
Ely 2004b
Trial name or title Delirium in the ICU: a Prospective, Randomized, Trial of Placebo vs Haloperidol vs Ziprasidone.
Methods
Participants 102 adult mechanically ventilated patients
Interventions Placebo or Haloperidol or Ziprasidone
Outcomes Primary Outcomes: Incidence and duration of delirium

Secondary Outcomes: Severity of neuropsychological dysfunction at hospital discharge
Starting date December 2004
Contact information wes.ely@vanderbilt.edu
Notes
Harari 2005
Trial name or title Proactive intervention to improve post-operative outcomes in at risk older people undergoing surgery: a
randomised controlled trial.
Methods
Participants Patients at risk of post-operative complications aged 65 or over awaiting major surgery
Interventions Proactive multidisciplinary geriatric intervention or usual care
Outcomes Primary outcome: hospital bed-days Secondary: 30-day re-admission, delirium, other medical complications,
mortality, function, anxiety, depression, resource use.

Harari 2005 (Continued)
Contact information danielle.harari@gstt.sthames.nhs.uk
Notes
Steiner 2005
Trial name or title Rivastigmine for the Prevention of Postoperative Delirium in Patients Undergoing Cardiac Surgery
Methods
Participants 120 patients aged 65 or more undergoing cardiac surgery with use of extracorporeal circulation
Interventions Rivastigmine (oral solution), starting on the evening preceding the operation and for the first seven days
postoperatively or placebo
Outcomes Primary Outcomes: Development of postoperative delirium within 7 days after cardiac surgery
Secondary Outcomes: Severity of delirium occurring within 7 days after cardiac surgery; Length of stay (
intensive care and hospital); Amount of drugs used for rescue therapy of delirium
Contact information lsteiner@uhbs.ch
Notes
van der Burg 2005
Trial name or title Post-Operative Haloperidol Versus Placebo for Prevention of Post-Operative Delirium After Acute Hip
Surgery
Methods
Participants 206 patients aged 75 yrs and older undergoing surgery for hip fracture
Interventions Post-operative haloperidol or placebo
Outcomes Primary Outcomes: Incidence of post-operative delirium

Secondary Outcomes: Length of stay.; Mortality.; ADL dependence at 3 months
Starting date November 2005
Contact information Boke Linso Sjirk Borger van der Burg, MD boudewijn.borgervanderburg@gmail.com
Notes

DATA AND ANALYSES
Comparison 1. Post surgery administration of DFP v Usual care
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Incidence of delirium in first 7 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.02, 1.06]
days after surgery
2 Behavioural disturbance in 1st 7 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.2 [0.03, 1.56]
days after surgery
3 Length of admission 1 40 Mean Difference (IV, Fixed, 95% CI) -4.30 [-12.51, 3.91]
Comparison 2. Epidural anaesthesia v Halothane anaesthesia
No. of No. of
1 Incident delirium on day 1 or 1 57 Risk Ratio (M-H, Fixed, 95% CI) 1.32 [0.73, 2.39]
day 7 post surgery
2 Physical morbidity 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 Stroke 1 57 Risk Ratio (M-H, Fixed, 95% CI) 7.24 [0.39, 134.12]
2.2 Urinary Tract Infection 1 57 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.57, 3.09]
2.3 Decubitus ullcer 1 57 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.16, 2.36]
Comparison 3. Prophylactic citocoline v Placebo
No. of No. of
1 Incident delirium 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Incident delirium 1 81 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.16, 2.02]
immediately post surgery
1.2 Incident delirium day 1 1 81 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.22, 2.01]
post surgery
post surgery
post surgery
2 MMSE score post surgery Other data No numeric data

Comparison 4. Prophylactic haloperidol v Placebo
No. of No. of
1 Incident delirium post surgery 1 430 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.59, 1.42]
2 Delirium duration 1 430 Mean Difference (IV, Fixed, 95% CI) -6.44 [-7.64, -5.24]
3 Delirium severity Other data No numeric data
4 Length of admission 1 430 Mean Difference (IV, Fixed, 95% CI) -5.5 [-8.17, -2.83]
5 Withdrawal from protocol 1 430 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.43, 1.26]
6 Adverse effects 1 430 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.10, 1.43]
Comparison 5. Prophylactic donepezil v Placebo
No. of No. of
1 Delirium incidence after surgery 1 80 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.48, 3.00]
4 Withdrawal from protocol 1 80 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.52, 2.14]
Comparison 6. Proactive geriatric consultation v Usual care
No. of No. of
1 Cumulative delirium incidence 1 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Cumulative delirium 1 126 Odds Ratio (M-H, Fixed, 95% CI) 0.48 [0.23, 0.98]
incidence in all patients
1.2 Cumulative delirium 1 50 Odds Ratio (M-H, Fixed, 95% CI) 0.73 [0.22, 2.38]
incidence in dementia sub-
group
2 Delirium duration 1 126 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.95, 0.55]
3 Severity- cumulative incidence 1 126 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.18, 0.89]
of severe delirium
4 Institutionalisation at discharge 1 126 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.93, 1.18]
5 Cognitive status- delirium 1 126 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.30, 1.57]
prevalence at discharge

Analysis 1.1. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 1 Incidence of
delirium in first 7 days after surgery.
Review: Interventions for preventing delirium in hospitalised patients
Comparison: 1 Post surgery administration of DFP v Usual care
Outcome: 1 Incidence of delirium in first 7 days after surgery
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Aizawa 2002 1/20 7/20 100.0 % 0.14 [ 0.02, 1.06 ]
Total (95% CI) 20 20 100.0 % 0.14 [ 0.02, 1.06 ]

Total events: 1 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.91 (P = 0.057)
0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control
Analysis 1.2. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 2 Behavioural
disturbance in 1st 7 days after surgery.
Outcome: 2 Behavioural disturbance in 1st 7 days after surgery

Aizawa 2002 1/20 5/20 100.0 % 0.20 [ 0.03, 1.56 ]
Total (95% CI) 20 20 100.0 % 0.20 [ 0.03, 1.56 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.3. Comparison 1 Post surgery administration of DFP v Usual care, Outcome 3 Length of
admission.
Outcome: 3 Length of admission
Study or subgroup Treatment Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Aizawa 2002 20 25.6 (9.4) 20 29.9 (16.2) 100.0 % -4.30 [ -12.51, 3.91 ]
Total (95% CI) 20 20 100.0 % -4.30 [ -12.51, 3.91 ]

-10 -5 0 5 10
Analysis 2.1. Comparison 2 Epidural anaesthesia v Halothane anaesthesia, Outcome 1 Incident delirium on
day 1 or day 7 post surgery.
Comparison: 2 Epidural anaesthesia v Halothane anaesthesia
Outcome: 1 Incident delirium on day 1 or day 7 post surgery
Study or subgroup Epidural Halothane Risk Ratio Weight Risk Ratio

Berggren 1987 14/28 11/29 100.0 % 1.32 [ 0.73, 2.39 ]
Total (95% CI) 28 29 100.0 % 1.32 [ 0.73, 2.39 ]

Total events: 14 (Epidural), 11 (Halothane)
0.1 0.2 0.5 1 2 5 10


Analysis 2.2. Comparison 2 Epidural anaesthesia v Halothane anaesthesia, Outcome 2 Physical morbidity.
Comparison: 2 Epidural anaesthesia v Halothane anaesthesia
Outcome: 2 Physical morbidity
Study or subgroup Epidural Halothane Risk Ratio Weight Risk Ratio

1 Stroke
Berggren 1987 3/28 0/29 100.0 % 7.24 [ 0.39, 134.12 ]
Subtotal (95% CI) 28 29 100.0 % 7.24 [ 0.39, 134.12 ]

2 Urinary Tract Infection
Berggren 1987 9/28 7/29 100.0 % 1.33 [ 0.57, 3.09 ]
Subtotal (95% CI) 28 29 100.0 % 1.33 [ 0.57, 3.09 ]

3 Decubitus ullcer
Berggren 1987 3/28 5/29 100.0 % 0.62 [ 0.16, 2.36 ]
Subtotal (95% CI) 28 29 100.0 % 0.62 [ 0.16, 2.36 ]

0.1 0.2 0.5 1 2 5 10


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

1 Incident delirium immediately post surgery

Diaz 2001 3/35 7/46 100.0 % 0.56 [ 0.16, 2.02 ]
Subtotal (95% CI) 35 46 100.0 % 0.56 [ 0.16, 2.02 ]

2 Incident delirium day 1 post surgery
Diaz 2001 4/35 8/46 100.0 % 0.66 [ 0.22, 2.01 ]
Subtotal (95% CI) 35 46 100.0 % 0.66 [ 0.22, 2.01 ]

Diaz 2001 3/35 4/46 100.0 % 0.99 [ 0.24, 4.12 ]
Subtotal (95% CI) 35 46 100.0 % 0.99 [ 0.24, 4.12 ]

Diaz 2001 3/35 3/46 100.0 % 1.31 [ 0.28, 6.12 ]
Subtotal (95% CI) 35 46 100.0 % 1.31 [ 0.28, 6.12 ]

0.1 0.2 0.5 1 2 5 10

Analysis 3.2. Comparison 3 Prophylactic citocoline v Placebo, Outcome 2 MMSE score post surgery.
MMSE score post surgery
Diaz 2001 23.48 6.0 24.95 4.9 0.2, not significant;

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

Kalisvaart 2005 32/212 36/218 100.0 % 0.91 [ 0.59, 1.42 ]
Total (95% CI) 212 218 100.0 % 0.91 [ 0.59, 1.42 ]

0.1 0.2 0.5 1 2 5 10

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

Kalisvaart 2005 212 5.41 (4.91) 218 11.85 (7.56) 100.0 % -6.44 [ -7.64, -5.24 ]
Total (95% CI) 212 218 100.0 % -6.44 [ -7.64, -5.24 ]

Test for overall effect: Z = 10.50 (P < 0.00001)
-10 -5 0 5 10
Analysis 4.3. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 3 Delirium severity.

Delirium severity
Kalisvaart 2005 14.4 3.5 18.4 4.4 4.0, [95% CI 1.4, 2.3] P< 0.001)

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

Kalisvaart 2005 212 17.1 (11.1) 218 22.6 (16.7) 100.0 % -5.50 [ -8.17, -2.83 ]
Total (95% CI) 212 218 100.0 % -5.50 [ -8.17, -2.83 ]

-10 -5 0 5 10
Analysis 4.5. Comparison 4 Prophylactic haloperidol v Placebo, Outcome 5 Withdrawal from protocol.
Outcome: 5 Withdrawal from protocol

Kalisvaart 2005 20/212 28/218 100.0 % 0.73 [ 0.43, 1.26 ]
Total (95% CI) 212 218 100.0 % 0.73 [ 0.43, 1.26 ]

0.1 0.2 0.5 1 2 5 10


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

Kalisvaart 2005 3/212 8/218 100.0 % 0.39 [ 0.10, 1.43 ]
Total (95% CI) 212 218 100.0 % 0.39 [ 0.10, 1.43 ]

0.1 0.2 0.5 1 2 5 10

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

Liptzin 2005 8/39 7/41 100.0 % 1.20 [ 0.48, 3.00 ]
Total (95% CI) 39 41 100.0 % 1.20 [ 0.48, 3.00 ]

0.1 0.2 0.5 1 2 5 10


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

Liptzin 2005 11/39 11/41 100.0 % 1.05 [ 0.52, 2.14 ]
Total (95% CI) 39 41 100.0 % 1.05 [ 0.52, 2.14 ]

0.1 0.2 0.5 1 2 5 10

Analysis 6.1. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 1 Cumulative delirium
incidence.
Comparison: 6 Proactive geriatric consultation v Usual care
Outcome: 1 Cumulative delirium incidence
Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

1 Cumulative delirium incidence in all patients

Marcantonio 2001 20/62 32/64 100.0 % 0.48 [ 0.23, 0.98 ]
Subtotal (95% CI) 62 64 100.0 % 0.48 [ 0.23, 0.98 ]

2 Cumulative delirium incidence in dementia sub-group
Marcantonio 2001 13/21 20/29 100.0 % 0.73 [ 0.22, 2.38 ]
Subtotal (95% CI) 21 29 100.0 % 0.73 [ 0.22, 2.38 ]

0.1 0.2 0.5 1 2 5 10


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

Marcantonio 2001 62 2.9 (2) 64 3.1 (2.3) 100.0 % -0.20 [ -0.95, 0.55 ]
Total (95% CI) 62 64 100.0 % -0.20 [ -0.95, 0.55 ]

-10 -5 0 5 10
Analysis 6.3. Comparison 6 Proactive geriatric consultation v Usual care, Outcome 3 Severity- cumulative
incidence of severe delirium.
Outcome: 3 Severity- cumulative incidence of severe delirium

Marcantonio 2001 7/62 18/64 100.0 % 0.40 [ 0.18, 0.89 ]
Total (95% CI) 62 64 100.0 % 0.40 [ 0.18, 0.89 ]

0.1 0.2 0.5 1 2 5 10


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

Marcantonio 2001 57/62 56/64 100.0 % 1.05 [ 0.93, 1.18 ]
Total (95% CI) 62 64 100.0 % 1.05 [ 0.93, 1.18 ]

0.1 0.2 0.5 1 2 5 10

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

Marcantonio 2001 8/62 12/64 100.0 % 0.69 [ 0.30, 1.57 ]
Total (95% CI) 62 64 100.0 % 0.69 [ 0.30, 1.57 ]

0.1 0.2 0.5 1 2 5 10


WHAT’S NEW
Last assessed as up-to-date: 11 January 2007.
3 November 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 4, 2005
Review first published: Issue 2, 2007
12 January 2007 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Najma Siddiqi: All correspondence; drafting of protocol versions; searching for trials; selection of trials; extraction of data and critical
review of studies; entry of data; interpretation of data analyses; updating review
Rachel Stockdale: Drafting of protocol versions; searching for trials; selection of trials; extraction of data and critical review of studies;
entry of data; interpretation of data analyses
Annette Britton: Extraction of data and critical review of studies
John Holmes: Arbiter in selection of trials and interpretation of data analyses
Contact Editors: Leon Flicker and Lon Schneider
Consumer Editor: Duncan Forsyth
This review has been peer reviewed anonimously by two peer reviewers
DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT

Internal sources
• University of Leeds, UK.

• Leeds Mental Health NHS Teaching Trust, UK.
• Leeds Teaching Hospitals NHS Trust, UK.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)

∗ Hospitalization;
Anesthesia, Epidural; Anesthetics, Inhalation; Cytidine Diphosphate Choline [administration & dosage]; Delirium
[∗ prevention & control]; Halothane; Indans [administration & dosage]; Nootropic Agents [administration & dosage]; Piperidines
[administration & dosage]
MeSH check words

Humans


Interventions For Preventing Delirium in Hospital Is Ed Patients

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Interventions for preventing delirium in hospitalised patients

Siddiqi N, Holt R, Britton AM, Holmes J

Interventions for preventing delirium in hospitalised patients (Review)

Interventions for preventing delirium in hospitalised patients (Review) i

Interventions for preventing delirium in hospitalised patients

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

Editorial group: Cochrane Dementia and Cognitive Improvement Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

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

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

Interventions for preventing delirium in hospitalised patients (Review) 3

• CENTRAL: July 2005 (issue 3);

Interventions for preventing delirium in hospitalised patients (Review) 4

Interventions for preventing delirium in hospitalised patients (Review) 5

Validity Criteria Met Partially Met Unmet/Unknown

Initial assembly of comparable

Clear definition of interven-

All important outcomes consid-

Outcome measurements equal,

Interventions for preventing delirium in hospitalised patients (Review) 6

No important differential loss

Data Extraction Description of studies

Interventions for preventing delirium in hospitalised patients (Review) 7

Table 2. Study Quality Assessment

Study Quality Assessment

Interventions for preventing delirium in hospitalised patients (Review) 8

Interventions for preventing delirium in hospitalised patients (Review) 9

Interventions for preventing delirium in hospitalised patients (Review) 10

Interventions for preventing delirium in hospitalised patients (Review) 11

Interventions for preventing delirium in hospitalised patients (Review) 12

Interventions for preventing delirium in hospitalised patients (Review) 15

Interventions for preventing delirium in hospitalised patients (Review) 16

Characteristics of included studies [ordered by study ID]

Participants Number in study: 42

Outcomes 1. Incident delirium in 7 days postop

Interventions for preventing delirium in hospitalised patients (Review) 17

Methods Randomisation: Method not described

Participants Number in study: 57

Interventions Epidural anaesthesia

Outcomes 1. Incident delirium on postop day 1 or 7

Interventions for preventing delirium in hospitalised patients (Review) 18

Methods Randomisation: Method not described

Participants Number in study: 88

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

Interventions for preventing delirium in hospitalised patients (Review) 19

Methods Randomisation: Adequate concealed allocation

Participants Number in study: 430

Outcomes 1. Incident delirium post op

Notes Funding source: Medical Center Alkmaar

Interventions for preventing delirium in hospitalised patients (Review) 20

Methods Randomisation: By research pharmacist but method not described

Participants Number in study: 90

Outcomes 1. Incident delirium postop

Notes Funding source: Unrestricted research grant from Pfizer

Interventions for preventing delirium in hospitalised patients (Review) 21

Methods Randomisation: Adequate concealed allocation

Participants Number in study: 126

Outcomes 1. Delirium incidence- total cumulative during admission

Interventions for preventing delirium in hospitalised patients (Review) 22

Cerchietti 2000 Not a delirium prevention study.

Cole 2002 Not a delirium prevention study.