Articles

Eect of preoperative pain and depressive symptoms on the

risk of postoperative delirium: a prospective cohort study
Cyrus M Kosar*, Patricia A Tabloski*, Thomas G Travison, Richard N Jones, Eva M Schmitt, Margaret R Puelle, Jennifer B Inloes, Jane S Saczynski,
Edward R Marcantonio, David Meagher, M Carrington Reid*, Sharon K Inouye*

Summary
Background Preoperative pain and depression predispose patients to delirium. We investigated whether pain and Lancet Psychiatry 2014;
depressive symptoms interact to increase the risk of delirium. 1: 43136
Published Online
October 28, 2014
Methods We enrolled 459 people without dementia, who were aged 70 years or older and were scheduled for elective
http://dx.doi.org/10.1016/
orthopaedic surgery between June, 2010, and August, 2013. At baseline, participants reported their current pain and S2215-0366(14)00006-6
the average and worst pain in the previous 7 days, on a scale of 010. Depressive symptoms before surgery were See Comment page 404
assessed with the 15-item geriatric depression scale and chart. Delirium after surgery was assessed with the confusion *CMK, PAT, MCR, and SKI
assessment method and chart. We used multivariable analysis to assess the relation between preoperative pain and contributed equally to the
postoperative delirium stratied by the presence of depressive symptoms. writing of the paper
Aging Brain Center, Institute
Findings Delirium was reported in 106 (23%) of patients, and was signicantly more frequent in those with depressive for Aging Research, Hebrew
SeniorLife, Boston, MA, USA
symptoms at baseline than in those without (relative risk [RR] 16, 95% CI 1223). Preoperative pain was associated (C M Kosar MA, P A Tabloski PhD,
with an increased adjusted risk of delirium across all pain measures (RR 107108 per 1-point increase in pain). In T G Travison PhD, R N Jones ScD,
stratied analyses, patients with depressive symptoms had a 21% increased risk of delirium for each 1-point increase E M Schmitt PhD, M R Puelle BS,
in worst pain score, which indicated a signicant interaction (pinteraction=0049). Similarly, a 13% increased risk of J B Inloes BS, J S Saczynski PhD,
Prof E R Marcantonio MD,
delirium was seen per 1-point increase in average pain score, but the interaction was not signicant. Prof S K Inouye MD); Boston
College, William F Connell
Interpretation Preoperative pain and depressive symptoms are associated with increased risk of delirium, School of Nursing, Chestnut
independently and with substantial interaction, which suggests a cumulative eect. These factors should be assessed Hill, MA, USA (P A Tabloski);
Department of Psychiatry and
before surgery. Human Behavior, Brown
University Warren Alpert
Funding US National Institute on Aging. Medical School, Providence, RI,
USA (R N Jones); Division of
Geriatric Medicine and Meyers
Introduction In view of the associations between pain and Primary Care Institute,
Delirium is characterised by acute decline in attention depression, delirium and depression, and delirium and University of Massachusetts
and cognitive function, and is a common complication of acute pain, an in-depth investigation of the inter- Medical School, Worcester, MA,
surgery in elderly adults (age 65 years and older), among relationship between preoperative pain, depression, and USA (J S Saczynski); Department
of Medicine, Beth Israel
whom incidence is 1151%.1 Adverse outcomes associated delirium seemed warranted. We did a prospective study Deaconess Medical Center,
with postoperative delirium include prolonged length of to assess whether preoperative pain and depression at Boston, MA, USA (T G Travison,
hospital stay, institutionalisation, mortality, functional baseline were risk factors for delirium, and to characterise Prof E R Marcantonio,
Prof S K Inouye); Harvard
decline, and long-term cognitive impairment.1,2 As the their respective contributions.12,13 We tested the hypothesis
Medical School, Boston, MA,
population of older adults undergoing surgical that the combination of severe pain and depression USA (T G Travison,
procedures continues to grow,3 improved understanding symptoms before surgery would be associated with an Prof E R Marcantonio,
of risk factors for delirium becomes increasingly increased risk of postoperative delirium. Prof S K Inouye); Department of
Adult Psychiatry, University
important.
Hospital Limerick and
Depression is a well recognised risk factor for Methods University of Limerick Medical
delirium, with risk in some studies having been Study population School, Limerick, Ireland
increased by two to three times.4,5 Comorbid depression This study is a secondary analysis of data collected for the (Prof D Meagher MD); and
Divisions of Geriatrics and
and delirium are associated with worse outcomes than Successful Aging After Elective Surgery (SAGES) study,14
Gerontology, and Geriatrics
with either syndrome alone.6 Depression also correlates which is a prospective cohort study of 566 patients who and Palliative Medicine, Weill
with increased pain, 7 which is underdiagnosed and underwent elective surgery, and is designed to assess the Cornell Medical College, New
undertreated in elderly people despite being linked to relation between delirium and outcomes. The methods York, NY, USA
(M Carrington Reid MD)
poor outcomes. 8 The relation between pain and have been described previously.14 Briey, eligible
Correspondence to:
delirium has mostly been described in studies of acute participants were aged 70 years or older, had no clinically
Mr Cyrus M Kosar, Aging Brain
pain experienced during hospital stay, with reports of documented evidence of previous delirium or dementia, Center, Institute for Aging
risk of delirium being increased by up to nine times in and were scheduled for major elective surgery at Beth Research, Hebrew SeniorLife,
patients with severe pain.9 Only two studies have Israel Deaconess Medical Center or Brigham and 1200 Centre Street, Boston,
MA 02131, USA
assessed the association between preoperative pain and Womens Hospital, Boston, MA, USA. Enrolment began
cyruskosar@hsl.harvard.edu
delirium.10,11 in June, 2010, and ended in August, 2013. Patients were

www.thelancet.com/psychiatry Vol 1 November 2014 431

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excluded if any evidence of dementia was found at
baseline screening or in their medical records, or if they
self-reported a previous clinical diagnosis, did not pass a
capacity assessment for providing informed consent, or
scored less than 69 (or its education-adjusted equivalent)
on the modied mini-mental state examination (3MS)15
completed before surgery. We further restricted the cohort
for this study to participants scheduled for orthopaedic
procedures (hip or knee replacement and laminectomy),
predominantly for painful conditions. Informed consent
was obtained from all patients according to procedures
approved by the institutional review boards of the study
centres and Hebrew SeniorLife, Boston, MA, USA, which
was the study coordinating centre.
Preoperative assessments
All patients were assessed in structured interviews and
medical records were reviewed around 2 weeks before
surgery. Interviews were administered by experienced
research associates who underwent 4 weeks of intensive
training in interview techniques and standardisation that
was repeated every 6 months. A trained physician
abstractor reviewed medical records according to
standardised procedures.
Information on sex, ethnic origin, years in education,
marital status, and physical function were self-reported
by patients. Cognitive function was assessed with the
3MS and a comprehensive neuropsychological battery.14
Physical function was assessed with basic and
instrumental activities of daily living scales.16,17 Age and
comorbidities were conrmed from patients medical
records. The Charlson comorbidity index was used to
dene comorbidity burden.18
The severity of preoperative pain was assessed with
three items from the brief pain inventory,19 which has
been validated previously. Patients were asked to rate on
a scale of 0 (no pain) to 10 (worst pain imaginable) their
current level of pain and the average and worst pain
within the previous 7 days. Degree of pain was categorised
according to the WHO classication scheme, in which a
rating of 0 corresponds to no pain, ratings of 13
correspond to mild pain, 46 to moderate pain, and 710
to severe pain.20
Depressive symptoms were assessed with the short
form of the geriatric depression scale. 21 Scores range
from 0 to 15, with higher scores reecting a greater
severity of depressive symptoms. We adopted the
commonly used threshold of a score of 6 to indicate
severe depressive symptoms.22 Information on
depression before surgery was obtained from patients
lists of medical diagnoses and conditions in their
medical records, documentation of active depression by
a physician or nurse practitioner during preadmission
screening, and available outpatient and psychiatric
notes. The screening questionnaires and medical
records were used as evidence of preoperative depressive
symptoms, as recommended by previous studies. 23
432
Postoperative delirium
Delirium was rated according to the confusion assessment
method (CAM) criteria, which denes delirium as being
present if a patient exhibits an acute change or uctuation
in mental status, inattention, and either disorganised
thinking or an altered level of consciousness.24 The CAM
is the most widely used bedside method for detecting
delirium, and has shown high sensitivity (94100%),
specicity (9095%), and reliability (=070100) when
compared with psychiatrists diagnoses.25,26 The CAM
assessment was done at baseline and once daily from the
day after surgery. Scoring was informed by comprising
brief cognitive testing of patients (orientation, recall, and
sustained attention tasks), conversations with caregivers
and nursing sta, and patients results on the delirium
symptom interview.27 Reliability of the CAM ratings was
checked in 71 paired ratings (including those from 16
delirious patients) and yielded excellent overall
identication (=092). A validated chart-based method
was also used to identify the signs and symptoms of
delirium between interviews or at times when structured
assessments were unfeasible (eg, at night).28 Patients were
classied as being delirious if CAM or the chart-based
criteria were satised on any postoperative day. Patients
were not judged to be delirious if symptoms of inattention,
disorganized thinking, or degree of consciousness did not
change from those at baseline. No delirium interventions
were used during the entire study.
Statistical analysis
All analyses were done with Stata MP (version 13.0). The
characteristics of patients with and without depressive
symptoms were described with standard statistics,
including means and SDs, medians and IQRs, and
frequency (%). The distributions of worst, average, and
current pain were described, and dierences between
patients with depressive symptoms and those without
were compared by analysis of variance.
Robust Poisson regression was used to estimate the
associations between each measure of preoperative pain
and delirium. To facilitate clinical interpretation, we
present relative risks (RRs) and 95% CIs for comparisons
of delirium risk between patients with moderate and
severe pain and those with mild or no pain. The Cochran-
Armitage test was used to assess trends in the rates of
delirium as a function of degree of pain.
To assess whether depressive symptoms and pain interact
in their associations with delirium, we stratied analyses
by presence (score of 6 or higher or evidence on medical
records) or absence of depressive symptoms. We calculated
the incidence of delirium for each point of pain on the
10-point rating scale and estimated the adjusted relative
risk for delirium associated with a 1-point dierence in
pain between individuals. Eect modications by
depressive symptoms were estimated by assessing the
multiplicative interaction term between the pain score and
depressive symptoms in models without stratication.
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Full sample Depressive No depressive Full sample Depressive No depressive

(n=459) symptoms symptoms (n=459) symptoms symptoms
(n=113) (n=346) (n=113) (n=346)
Age (years) 76 (7380) 76 (7381) 76 (7380) Worst pain in previous 7 days
Female sex 274 (60%) 73 (65%) 201 (58%) Mean (SD) 66 (26) 71 (22) 65 (27)
Non-white ethnic origin 38 (8%) 10 (9%) 28 (8%) Median (IQR) 7 (58) 7 (69) 7 (48)
Education (years) 14 (1218) 14 (1218) 15 (1218) Level of worst pain
Married 266 (58%) 58 (51%) 208 (60%) None/mild 71 (15%) 6 (5%) 65 (19%)
Charlson comorbidity 09 (12) 11 (13) 08 (11) Moderate 104 (23%) 26 (23%) 78 (23%)
score Severe 284 (62%) 81(72%) 203 (59%)
Type of surgery Average pain in previous 7 days
Hip replacement 115 (25%) 24 (21%) 91 (26%) Mean (SD) 47 (24) 53 (20) 45 (25)
Knee replacement 209 (46%) 44 (39%) 165 (48%) Median (IQR) 5 (36) 5 (47) 5 (36)
Laminectomy 135 (29%) 45 (40%) 90 (26%) Level of average pain
3MS score 934 (54) 927 (58) 937 (53) None/mild 145 (32%) 20 (18%) 125 (36%)
Any impairment in Moderate 205 (45%) 60 (54%) 145 (42%)
activities of daily living*
Severe 105 (23%) 32 (29%) 73 (21%)
Basic 38 (8%) 12 (11%) 26 (8%)
Current pain
Instrumental 137 (30%) 40 (35%) 97 (28%)
Mean (SD) 23 (26) 27 (28) 22 (25)
Delirium during hospital 106 (23%) 37 (33%) 69 (20%)
stay Median (IQR) 2 (04) 2 (05) 1 (04)
Level of current pain
Data are median (IQR), number (%), or mean (SD). 3MS=modied mini-mental state None/mild 331 (72%) 73 (65%) 258 (75%)
examination. *Dened as any impairment in one or more activity. The relative risk
for delirium associated with depressive symptoms is 16 (95% CI 1223, p=0004). Moderate 85 (19%) 26 (23%) 59 (17%)
Severe 43 (9%) 14 (12%) 29 (8%)
Table 1: Baseline characteristics and rate of delirium
*Pain is rated on a scale of 010: score of 0=no pain, scores of 13=mild, of
46=moderate pain, and of 710=severe pain. No and mild pain were combined
Multivariate models were adjusted for age, sex, ethnic because few patients rated worst or average pain with scores of 0. Excludes three
participants unable to recall their average pain and one who refused to answer.
origin, college education, and comorbidity, which have
been deemed to be important confounders by experts Table 2: Distribution of preoperative pain scores*
and in previous studies.10,11 Complete data on medication
use were not available. Null hypotheses were tested with procedures and one patient had no rating for depressive
a two-tailed level of 005. symptoms. These patients were excluded and, therefore,
To investigate the robustness of our delirium outcome, the nal sample for this study was 459. The baseline
we did sensitivity analyses that included only patients characteristics and rates of delirium for the whole cohort
with severe delirium, on the peak CAM-S (long form).29 and for patients with and without depressive symptoms
All analyses were repeated, including only patients with are presented in table 1. Overall, the sample was well
peak CAM-S scores of 5 or higher. Our primary goal was educated and had a low comorbidity burden. Delirium
to assess baseline risk factors and to avoid controlling for was reported in 106 (23%) of patients after surgery.
intermediate variables that might contribute to the causal 113 (25%) had depressive symptoms, more of whom
pathway for delirium30,31 and, therefore, we did not were women and unmarried and had laminectomy,
analyse any hospital-based precipitating factors. In functional impairment, and comorbidity burden than
another sensitivity analysis to verify the robustness of those without depressive symptoms. Delirium rates were
our ndings, however, we added either the count of days signicantly higher in patients with depressive symptoms
patients were taking opioids (by class) or treatment with than in those without (33% vs 20%, RR 16, 95% CI 12-23).
opioids for 3 days or longer. As expected, scores for worst pain in the 7 days before
baseline were higher than those for average pain in the
Role of the funding source previous 7 days and current pain at baseline (table 2). In
The funder had no role in the study design, data patients with depressive symptoms, mean pain intensity
collection, data analysis, data interpretation, or writing scores were higher for all three pain measures than in
of the report. The corresponding author had full access those without depressive symptoms (worst pain, p=0017,
to all the data in the study and had nal responsibility average pain p=0003, and current pain p=005; table 2).
for the decision to submit for publication. Worst and average pain scores were more variable in
patients without depressive symptoms than in those with
Results depressive symptoms, with larger SDs and wider IQR
Of the 566 patients in the original SAGES study cohort, spans, although the median scores did not dier between
106 were scheduled for vascular or general surgical subgroups (table 2).

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signicant association was with severe current pain

Worst pain Average pain* Current pain
(RR 20, 95% CI 1430).
n/total with Adjusted RR n/total with Adjusted RR n/total with Adjusted RR We found a relation between pain and delirium in the
delirium (%) (95% CI) delirium (%) (95% CI) delirium (%) (95% CI)
presence of depressive symptoms (gure). The rate of
None/Mild 13/71 (18%) 29/145 (20%) 71/331 (21%) delirium increased with increasing pain in a curvilinear
Moderate 21/104 (20%) 11 (06-20) 44/205 (21%) 10 (07-16) 16/85 (19%) 09 (05-14) fashion in patients with depressive symptoms, from 0 in
Severe 72/284 (25%) 13 (08-22) 33/105 (31%) 14 (09-23) 19/43 (44%) 20 (14-30) patients with worst pain scores of 02, to 47% in those
p value for 0146 0045 0013 with scores of 10. By contrast, in patients without
trend
depressive symptoms, the rate of delirium increased only
RR=relative risk. *Excludes three participants unable to recall their average pain and one who refused to answer. Pain marginally, from 15% to 26%.
is modelled as a three-level categorical variable. Risk estimates are adjusted for age, sex, ethnic origin, college In the overall cohort, preoperative pain was associated
education, and comorbidity. No and mild pain were combined because few patients rated worst or average pain with
scores of 0. p005 indicates that the rate of delirium changes linearly across increasing levels of pain.
with an increased adjusted risk of delirium across all pain
measures (table 4). Among patients with depressive
Table 3: Adjusted associations between preoperative pain levels and risk of delirium symptoms, the risk of delirium increased multiplicatively
by 21% for each 1-point increase in worst pain, contrasting
with a 3% increase per 1-point increase in patients
06 Depressive symptoms
No depressive symptoms without depressive symptoms (table 4). This risk
05
dierence corresponds to a 26 times increase in risk of
delirium for a 5-point dierence in worst pain in patients
Proportion with delirium

04 with depressive symptoms. The interaction between

worst pain score and depressive symptoms was signicant
03 (pinteraction=0049), which suggests that the association
between pain and delirium diered signicantly between
02 patients with and without depressive symptoms, and that
pain had a greater eect on the risk of delirium in patients
01 with depressive symptoms. For patients with depressive
symptoms, delirium risk increased by 13% for each
0
02 3 4 5 6 7 8 9 10 1-point increase in average pain, compared with 5% for
Worst pain score patients without depressive symptoms (table 4). Although
Number of patients this risk dierence suggests possible eect modication
Depressive symptoms 3 3 10 10 6 26 23 17 15 by depressive symptoms, the interaction was not
No depressive symptoms 39 26 23 25 30 47 77 29 50
signicant. Current pain was not signicantly associated
with delirium.
Figure: The relation between pain and delirium by presence of depressive symptoms
No participants with depressive symptoms reported worst pain scores of 1 and, therefore, scores of 02 are When analyses were repeated including only patients
combined. Trend lines are calculated with a generalised additive model with a Poisson error distribution and cubic with severe delirium, the results altered little. The
smoothing splines. proportion of delirious patients across measures of
pain remained similar, as did tests for trend. The
Worst pain Average pain* Current pain adjusted associations between pain and delirium
Overall (n=459) 108 (101116) 108 (101116) 107 (101113)
depicted were unchanged. Similarly, when repeating
Depressive symptoms (n=113) 121 (105140) 113 (101129) 107 (098117)
analyses adding either the count of days patients were
No depressive symptoms (n=346) 103 (095112) 105 (097115) 106 (098114)
taking opioids or treatment with opioids for 3 days or
more, the results remain virtually unchanged (results
Data are adjusted RR (95% CI). RR=Relative risk for delirium. Pain is modeled as a continuous variable. Relative risks not shown).
refer to a 1-point change in pain rating. Risk estimates are adjusted for age, sex, ethnic origin, college education,
and comorbidity. CIs were rounded to the nearest hundredth. To avoid confusion, values that were signicant
before rounding are indicated as 101. *Excludes three participants unable to recall average pain and one who Discussion
refused to answer. The results from this prospective cohort of elderly adults
show preoperative pain and depressive symptoms are
Table 4: Adjusted associations between preoperative pain and delirium stratied by presence of
depressive symptoms independently associated with the development of
postoperative delirium. These two factors also seemed to
have an interaction, as pain notably increased the risk of
The incidence of delirium across degree of pain delirium in patients with depressive symptoms. Our
categories increased from 18% to 25% for worst pain, ndings corroborate previous research into the separate
from 20% to 31% for average pain, and from 21% to 44% associations between pain and delirium and depression
for current pain (table 3). The test for trend was signicant and delirium, but extend the ndings by describing this
for average and current pain but not for worst pain. interaction (panel).
Notably, the estimated risk of delirium was increased with As in other studies,4,5 patients in our study who had
severe pain for all three pain measures, but the only depressive symptoms at baseline were more likely to

434 www.thelancet.com/psychiatry Vol 1 November 2014


report more severe pain than those without depressive
symptoms, and more likely to develop delirium. We
found, however, that while the between-group dierences
in reported degree of pain were small, even a 1-point
dierence in worst pain score in patients with depressive
symptoms was associated with a 21% increase in the risk
of delirium. The nding that current pain is associated
with delirium irrespective of depressive symptom status
is consistent with the ndings in previous studies
(panel).10,11 Depressive symptoms did not seem to alter
this association, potentially because the reporting of
current pain might be less aected by mood disorders.
Strengths of our study include the prospective design
and large sample size, which enabled a stratied analysis
of pain and delirium by depressive symptoms. The
measurement of pain and depressive symptoms before
the onset of delirium assured temporal precedence and
improved assessment of these variables as risk factors.
The use of state-of-the-art epidemiological methods for
identication of delirium and well established approaches
for measuring pain and depressive symptoms, along
with minimum missing data (<1%), strengthen the
validity of our results.
Several limitations of this study deserve comment. We
did not have available comprehensive data on individual
analgesics, only the class of opioids, or on anti-
depressants. We were, therefore, unable to evaluate
whether the increased risk of delirium was driven by
medication use or withdrawal. We also did not
investigate the role of postoperative pain, which has
been associated with delirium.11 An important area of
future investigation will be whether postoperative pain,
analgesics, and other precipitating factors interact with
preoperative pain and depression on risk of delirium.
Although we used widely applied epidemiological
methods to detect delirium and depressive symptoms,
our results are not based on formal diagnosis for either
condition, such as by a psychiatrists evaluation. We also
acknowledge that the geriatric depression scale might
be limited as a depression screening instrument in older
people with somatic complaints and multimorbidity.33
Our sample predominantly comprised white, well
educated, high-functioning participants recruited from
two academic medical centres in one geographic region,
which could potentially limit the generalisability of our
ndings. Our results, therefore, require validation in
population-based samples. Finally, our estimated risk of
delirium might not reect causal eects of preoperative
pain or depressive symptoms. We believe, however, that
our ndings are important to the identication of
patients at high risk of delirium and whose surgical
course merits close monitoring.
The mechanisms underlying the association between
preoperative pain and delirium are likely to be
multifactorial and complex. For example, patients with
severe preoperative pain might experience a high degree
of postoperative pain and be overtreated with agents that
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Articles
Panel: Research in context
Systematic review
Our exploration of the inter-relation between pain,
depressive symptoms, and delirium was motivated by the
publication of delirium prevention guidelines by the UK
National Institute for Health and Care Excellence, which
identify pain as a modiable risk factor32 and the fact that
depression is a well established risk factor for delirium.4,5 Our
aim was to identify studies of persistent, non-acute pain and
delirium. We systematically searched PubMed for reports
published in English with no date restrictions, with the
combined search terms pain and delirium and
confusion. We eliminated studies where the combination of
terms did not appear in the study title, abstract, or key terms.
Most studies of pain and delirium focused on acute pain that
developed during hospital stay (eg, after hip fracture) or
during postoperative periods. Two earlier studies reported an
association between preoperative pain (resting pain and pain
with movement) and postoperative delirium.10,11 The role of
depression was not investigated in of these studies.
Interpretation
By assessing multiple measures and degrees of pain, we
have conrmed previous ndings that preoperative pain
increases the risk of postoperative delirium and discovered
that this risk is exacerbated in patients with preoperative
depressive symptoms. Our results highlight the need for
increased assessment of pain and depressive symptoms
before surgery. This research provides groundwork for
future studies on the factors, and the pathways underlying
postoperative delirium. Areas to explore will include the role
of medication used before and after surgery and
postoperative pain as mediating factors, and whether better
treatment of preoperative pain and depressive symptoms
would lower the risk of delirium.
could induce delirium. Alternatively, the burden of severe
pain and depressive symptoms might lead to an
underlying cerebral dysfunction, such as through
abnormal stress response or triggering of brain
inammatory responses, that predisposes patients to an
exaggerated risk of postoperative delirium.34 Disturbances
in circadian function due to pain, depression, or
analgesia might also have important roles. Clarication
of the mechanisms underlying the association between
preoperative pain, depression, and delirium is a much-
needed area of future research.
Our data provide evidence for a combined eect of
preoperative pain and depressive symptoms on delirium.
Our results highlight the need for increased assessment
of both factors before surgery, with particular attention
given to patients in whom both are severe.
Contributors
CMK, PAT, MCR, and SKI conceived and designed the study. CMK,
EMS, ERM, and SKI acquired and assembled the data. CMK, PAT, TGT,
RNJ, and SKI analysed the data. CMK, PAT, TGT, RNJ, MRP, JBI, JSS,
435
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ERM, DM, MCR, and SKI interpreted the data. CMK and SKI drafted the
report. All authors provided critical revisions to the report for intellectual
content and provided nal approval. Funding was obtained by SKI.
Declaration of interests
We declare no competing interests.
Acknowledgments
This study was funded by the US National Institute on Aging (JSS,
grants K01AG33643 and U01HL105268; ERM, grants R01AG030618 and
K24AG035075; and SKI, grants P01AG031720 and K07AG041835). SKI
holds the Milton and Shirley F Levy Family Chair at Hebrew SeniorLife/
Harvard Medical School. We thank the patients, family members,
nurses, and physicians who participated in the study, and the study sta
at Beth Israel Deaconess Medical Center, Brigham and Womens
Hospital and Hebrew SeniorLife. This work is dedicated to the memory
of Joshua Bryan Inouye Helfand.
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