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8/6/2019 Interventions for Preventing Delirium in Hospital is Ed Patients
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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 1http://www.thecochranelibrary.com
Interventions for preventing delirium in hospitalised patients (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/8/6/2019 Interventions for Preventing Delirium in Hospital is Ed Patients
2/43
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28DATA 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
39WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iInterventions for preventing delirium in hospitalised patients (Review)
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[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 Reviews2007, Issue 2. Art. No.: CD005563. DOI: 10.1002/14651858.CD005563.pub2.
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
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 andbooks. Expertsin this field were contacted andthe Internet searched for furtherreferences andto 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.
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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).
Canceralso increasesthe risk of developingdelirium. 18%of those
admittedto anoncology ward, and 26to 44% ofthose admitted to
hospitalor a hospice with a diagnosisof advanced cancerdeveloped
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 andlong term outcomes.
Death rates are increased (McCusker 2002), functional abilitiesreduced (Moller 1998), admission to long-term care increased (
Inouye 1998a), and length of stay increased (McCusker 2003a;
Stevens 1998). Impairment of cognitive function can persist for
at least one year (McCusker 2001), as can the symptoms of delir-
ium, especially inattention, disorientation and impaired mem-
ory (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 (Ljubisavljevic2003).
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 reducehealthservice costs.A recentstudyfound thatthe 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-pharmacologicalintervention 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 whetherdifferentinterventions 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: To determine the effectivenessof 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.
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Types of participants
We included patients aged 16 years or over, admitted to acutegeneral 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, (WHO1992; 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 Specialized Register of the Cochrane Dementia and Cognitive
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 exogenouspsychosis 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 andJournals): 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 28August 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
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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 confusion13.#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 care25.#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 consciousnessor exogenous psychosis or toxic psychosisor 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 #1113 #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*
2 acute psycho-organic syndrome or clouded state or cloud-
ingof consciousnessor exogenous psychosis or toxic psychosis
or toxic confusion
3 acute brain confusion or acute brain failure or acute organicpsychosyndrome or acute brain syndrome or metabolic en-
cephalopathy
4 Delirium- in MJ,MN
5 #1 or #2 or #3 or #4
6 explode Prevention
7 prevent* or avoid*
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*2 acute psycho-organic syndrome or clouded state or cloud-
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
7 prevent* or avoid*
8 #6 or #7
9 #5 and #8
10 random* or placebo* or control* or normal care or standardcare 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)
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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, andalsoreferences from retrievedarticles.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 trialsusing 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 tworeviewers,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 fromthe U.S. Preventive Services Task Force (Harris 2001; Table 1). A
consensusprocess was usedto 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.
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 importantoutcomes consid-
ered and predefined
Outcome measurements equal,
reliable, and valid (includes
masking of outcome assess-
ment)
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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
A data extraction form was designed and piloted. Data were then
independently extracted by three reviewers NS, RS and AB withdisagreements 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 individualstudies.
We planned to perform a subgroup analysisof 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: Characteristicsof included studies; Characteristicsof 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 of multicomponent 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 ofdiazepam, 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.
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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 recentCochranereview(Fioravanti 2006) concluded thatthere 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
delirium occurred,the dose of study drug wasdoubled.In addition
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
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 inAlzheimers 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 the Delirium Symptom
Interview (DSI) (Albert 1992), CAM and medical records review.
In the only study of non-pharmacological interventions, Marcan-
tonio and colleagues (Marcantonio 2001) testedproactivegeriatric
consultation against care as usual. Patients were visited daily by
a consultant geriatrician preoperatively or within 24 hours aftersurgery. 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. The MMSE,
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.
Table 2. Study Quality Assessment
Study Quality Assessment
Aizawa 2002 C
Berggren 1987 B
Diaz 2001 B
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Table 2. Study Quality Assessment (Continued)
Kalisvaart 2005 A
Liptzin 2005 C
Marcantonio 2001 A
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 powercalculation, 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
precludedthis (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 deliriumwere not excluded from enrollment, and despite being examined
for, delirium prevalence at intake assessment was not reported.
Comorbidity withphysical illness wasnot 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
threestudies,data wereonly availablefor patientscompletingtreat-
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 toelective 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 and methods.
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% CI0.02, 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.
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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 incidenceof 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 treatmentand 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
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f) Cognitive status at discharge was assessed by prevalence of delir-
ium, which was present in 15.9% patients (8/62 in the interven-tion group and 12/64 controls, RR 0.69 [95% CI 0.30, 1.57]).
Outcomes in dementia sub-group analysis:
This was carried out in 50 patients with dementia diagnosed using
the Blessed Dementia Rating Scale (Blessed 1968).
There was no significant difference between treatment and control
groups in cumulative delirium incidence during admission in this
sub-group (RR 0.9 [95% CI 0.59, 1.36]).
The total study population (with and without dementia) num-
bered 126. Intention to treat analyses were performed for all out-
comes.
We identified no completedstudies in hospitalised medical, care of
the elderly, general surgery or intensive care settings. In outcomes,
no studies examined for death, use of psychotropic medication,activities of daily living, psychological morbidity, quality of life,
carers psychological morbidity, 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. We did not perform a funnel plot to exam-
ine for publication bias due to the limited number of studies.
D I S C U S S I O N
1. We found only a handful of RCTs of interventions to prevent
delirium in hospitalised patients. Of the six which met our se-
lection criteria, no two studies tested the same, or even a similar
intervention. Additionally, there was heterogeneity in methods,
participants and outcomes examined. Methodological limitations
of these studies have been described above; importantly only one
study was sufficiently powered to determine effectiveness of the
intervention, and then only for bivariate analyses.
2. Research evidence for effectiveness of interventions to prevent
delirium in this population is limited. Although Aizawa 2002 re-
port that their intervention reduced postoperative delirium, the
protocol caused sedation and may have interfered with delirium
assessment. The highly specific study population and small study
size, as well as the nature of the intervention, limit generalisabilityof findings from this study. Berggren 1987 found no difference in
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 neurolepticsin 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 senseand may deliver important benefits, not least as many of the mea-
sures to prevent delirium shouldalso be helpfulin 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 strategiesto improve implementation and adherence (suchas 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 importantvalidation of this riskidentification 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-
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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 wasperformed, resource limitations didnot allow searching
of non-English language databases. We can be confident, however,
that we identified most important relevant studies, as our search
retrievedall studies included in recentreviews of this topic andalso
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 with Milisen (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.Thisreview aimed to consider allinterventions designed to pre-
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. Basedon a singleRCT, a programmefor proactive
geriatric consultation may reduce delirium incidence and sever-
ity 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 trialevidence 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 asmortality, physical and psychological morbidity, impact on carers
and costs to health care services.
A C K N O W 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 andLeon Flicker from the Dementia and Cognitive improvement
Group for their support with preparing the review.
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R E F E R E N C E S
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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
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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: YesInformed 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 cancerAge: More than 70 yrsand less than 86 yrs; mean age75.9 and76.2 yrs in intervention andcontrol groupsrespectively
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 postop3. 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
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Berggren 1987
Methods Randomisation: Method not described
Power calculation: No
Blinding of participants: No, not possible because of the type of interventions
Outcomes assessments blind: Yes
Informed consent: Yes
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
Proportion of participants reported in final analysis: 100%Study duration: 20 months
Participants Number in study: 57
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
2. Length of admission
3. Physical morbidity
Notes Funding source: Swedish Medical Council; King Gustav V Birthday Foundation; Umea University Research Foun-
dation
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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
Outcomes assessments blind: Yes
Informed consent: 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
Proportion of participants reported in final analysis: 92%Study duration: Not given
Participants Number in study: 88
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
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Kalisvaart 2005
Methods Randomisation: Adequate concealed allocation
Power calculation: No but discussion states study under powered
Blinding of participants: Yes
Outcomes assessments blind: Yes
Informed consent: Yes
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
Proportion of participants reported in final analysis: 100%Study duration: 24 months
Participants Number in study: 430
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
Co-morbidity: Not given
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
4. Length of admission
5. Withdrawal from protocol
6. Adverse effects
Notes Funding source: Medical Center Alkmaar
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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
Blinding of participants: Yes
Outcomes assessments blind: Yes
Informed consent: Yes
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 interven