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original article

Long-Term Cognitive Impairment

after Critical Illness
P.P. Pandharipande, T.D. Girard, J.C. Jackson, A. Morandi, J.L. Thompson,
B.T. Pun, N.E. Brummel, C.G. Hughes, E.E. Vasilevskis, A.K. Shintani,
K.G. Moons, S.K. Geevarghese, A. Canonico, R.O. Hopkins, G.R. Bernard,
R.S. Dittus, and E.W. Ely, for the BRAIN-ICU Study Investigators*

A BS T R AC T
BACKGROUND
The authors full names, degrees, and affiliations are listed in the Appendix. Address
reprint requests to Dr. Pandharipande at
1211 21st Ave. S, MAB Ste. 526, Nashville,
TN 37212, or at pratik.pandharipande@
vanderbilt.edu.
*The Bringing to Light the Risk Factors and
Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) Study
Investigators are listed in the Supplementary Appendix, available at NEJM.org.
N Engl J Med 2013;369:1306-16.
DOI: 10.1056/NEJMoa1301372
Copyright 2013 Massachusetts Medical Society.

Survivors of critical illness often have a prolonged and disabling form of cognitive
impairment that remains inadequately characterized.
METHODS

We enrolled adults with respiratory failure or shock in the medical or surgical intensive
care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition
and executive function 3 and 12 months after discharge with the use of the Repeatable
Battery for the Assessment of Neuropsychological Status (population age-adjusted
mean [SD] score, 10015, with lower values indicating worse global cognition) and the
Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score,
5010, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were
assessed with the use of linear regression, with adjustment for potential confounders.
RESULTS

Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had
global cognition scores that were 1.5 SD below the population means (similar to
scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD
below the population means (similar to scores for patients with mild Alzheimers
disease). Deficits occurred in both older and younger patients and persisted, with
34% and 24% of all patients with assessments at 12 months that were similar to
scores for patients with moderate traumatic brain injury and scores for patients
with mild Alzheimers disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001
and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004
and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months.
CONCLUSIONS

Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global
cognition and executive function scores at 3 and 12 months. (Funded by the National
Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.)

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Long-Term Cognitive Impairment after Critical Illness

urvivors of critical illness frequently have a prolonged and poorly understood

form of cognitive dysfunction,1-4 which is
characterized by new deficits (or exacerbations of
preexisting mild deficits) in global cognition or executive function. This long-term cognitive impairment after critical illness may be a growing public
health problem, given the large number of acutely ill
patients being treated in intensive care units (ICUs)
globally.5 Among older adults, cognitive decline is
associated with institutionalization,6 hospitalization,7 and considerable annual societal costs.8,9 Yet
little is known about the epidemiology of longterm cognitive impairment after critical illness.
Delirium, a form of acute brain dysfunction
that is common during critical illness, has consistently been shown to be associated with
death,10,11 and it may be associated with longterm cognitive impairment.12 In addition, factors that have been associated with delirium,
including the use of sedative and analgesic
medications, may independently contribute to
long-term cognitive impairment.13,14
Data on the prevalence of long-term cognitive
impairment after critical illness have largely come
from small cohort studies restricted to single
disease processes (e.g., the acute respiratory distress syndrome)1,15,16 or from large, longitudinal
cohort studies lacking details of in-hospital risk
factors for long-term cognitive impairment.3,4 We
conducted a multicenter, prospective cohort study
of a diverse population of critically ill patients to
estimate the prevalence of long-term cognitive
impairment after critical illness and to test our
hypothesis that a longer duration of delirium in
the hospital and higher doses of sedative and analgesic agents are independently associated with
more severe cognitive impairment up to 1 year
after hospital discharge.

ME THODS
STUDY POPULATION AND SETTING

The Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU
Survivors (BRAIN-ICU) study was conducted at
Vanderbilt University Medical Center and Saint
Thomas Hospital in Nashville. Detailed definitions of the inclusion and exclusion criteria are
provided in the Supplementary Appendix, available
with the full text of this article at NEJM.org.

Briefly, we included adults admitted to a medical or surgical ICU with respiratory failure, cardiogenic shock, or septic shock. We excluded patients
with substantial recent ICU exposure (i.e., receipt
of mechanical ventilation in the 2 months before the current ICU admission, >5 ICU days in
the month before the current ICU admission, or
>72 hours with organ dysfunction during the
current ICU admission); patients who could not
be reliably assessed for delirium owing to blindness, deafness, or inability to speak English;
patients for whom follow-up would be difficult
owing to active substance abuse, psychotic disorder, homelessness, or residence 200 miles or
more from the enrolling center; patients who
were unlikely to survive for 24 hours; patients
for whom informed consent could not be obtained; and patients at high risk for preexisting
cognitive deficits owing to neurodegenerative
disease, recent cardiac surgery (within the pre
vious 3 months), suspected anoxic brain injury, or
severe dementia. Specifically, patients who were
suspected to have preexisting cognitive impairment on the basis of a score of 3.3 or more on
the Short Informant Questionnaire on Cognitive
Decline in the Elderly (IQCODE; on a scale from
1.0 to 5.0, with 5.0 indicating severe cognitive
impairment)17 were assessed by certified evaluators with the use of the Clinical Dementia Rating
(CDR) scale (with scores ranging from 0 to 3.0,
and higher scores indicating more severe dementia).18 Patients with a CDR score of more than
2.0 were excluded (additional information on the
IQCODE and CDR is provided in the Supplementary Appendix).
At enrollment, we obtained written informed
consent from all the patients or their authorized
surrogates; if consent was initially obtained
from a surrogate, we obtained consent from the
patient once he or she was deemed to be mentally competent. The study protocol was approved
by each local institutional review board.
RISK FACTORS, OUTCOMES, AND COVARIATES

We examined two primary independent risk factors: duration of delirium (defined as the number
of hospital days with delirium) and use of sedative or analgesic medications during hospitalization. Trained research personnel evaluated patients
for delirium and level of consciousness daily until hospital discharge or study day 30. Delirium

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was assessed with the use of the Confusion Assessment Method for the ICU (CAM-ICU), a diagnostic algorithm for determining the presence or
absence of delirium on the basis of four features:
acute change or a fluctuation in mental status,
inattention, disorganized thinking, and altered
level of consciousness.19 Level of consciousness
was assessed with the use of the Richmond AgitationSedation Scale (RASS), on which scores
range from 5 to 4, with lower scores indicating
less arousal, higher scores indicating more agitation, and 0 indicating an alert and calm state.20
Throughout the hospitalization, we used medication-administration records to collect information
on daily doses of benzodiazepines (converted to
midazolam dose equivalents), opiates (converted
to fentanyl dose equivalents), propofol, and dexmedetomidine. Conversion factors are described
in the Supplementary Appendix.
Trained psychology professionals, who were
unaware of the patients in-hospital course, assessed patients global cognition 3 and 12 months
after hospital discharge using the Repeatable Battery for the Assessment of Neuropsychological
Status (RBANS), a comprehensive and validated
neuropsychometric battery for the evaluation of
global cognition, including individual domains of
immediate and delayed memory, attention, visuospatial construction, and language.21 The population age-adjusted mean (SD) for the RBANS
global cognition score and for the individual domains is 10015 (on a scale ranging from 40 to
160, with lower scores indicating worse performance). In addition, executive function (specifically, cognitive flexibility and set shifting) was
assessed with the use of the Trail Making Test,
Part B (Trails B)22; the age-, sex-, and educationadjusted mean T score is 50 (on a scale ranging
from 0 to 100, with lower scores indicating worse
executive function). All follow-up assessments are
described in detail in the Supplementary Appendix.
All covariates were chosen a priori on the
basis of clinical judgment and previous research,
owing to their expected associations with the
outcomes and with delirium, and thus their potential to be confounders. Details of the covariates and the range and clinical significance of
specific scores are provided in the Supplementary
Appendix. Briefly, covariates that were determined
at enrollment included age, years of education,
chronic disease burden according to the Charl-

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son comorbidity index (on a scale ranging from

0 to 33, with higher scores indicating a greater
burden of coexisting conditions),23 preexisting
cognitive impairment according to the Short
IQCODE,17 cerebrovascular disease as assessed by
means of the Framingham Stroke Risk Profile,24
and apolipoprotein E genotype. Covariates that
were measured daily until ICU discharge or study
day 30 included severity of illness as assessed by
means of the Sequential Organ Failure Assessment
(SOFA; scores range from 0 to 24 [from 0 to 4 for
each of six organ systems], with higher scores
indicating more severe organ dysfunction),25 mean
daily dose of haloperidol, and duration of severe
sepsis, hypoxemia, and coma.
MANAGEMENT OF MISSING DATA

Because missing data rarely occur entirely at random,26 we assessed the associations between characteristics of the patient and status with respect to
missing data according to recommendations.27
Table S1 in the Supplementary Appendix shows
the frequency of missing outcomes, and Table S2
in the Supplementary Appendix shows that patients
with at least one missing outcome value were different from those with complete outcomes data in
small but potentially meaningful ways. The exclusion of such patients may have biased our results,
so we used multiple imputation to assign values to
missing risk factors and outcomes in regression
modeling. However, we did not impute data for
patients who had no cognitive-outcomes data (e.g.,
owing to death or withdrawal from the study).
We used single imputation for missing delirium and coma assessments. Of 10,558 patient-days
during which delirium or coma assessments were
expected, only 3% were missing and required
imputation.
STATISTICAL ANALYSIS

To determine whether the duration of delirium

and the doses of sedative or analgesic agents (including benzodiazepines, propofol, dexmedetomidine, and opiates) were independent risk factors for the primary outcome variable (RBANS
global cognition score), we used multiple linear
regression with adjustment for all aforementioned covariates in separate models for the outcomes at 3 and 12 months. Similarly, we used
multiple linear regression to determine whether
the duration of delirium and the doses of seda-

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Long-Term Cognitive Impairment after Critical Illness

tive or analgesic agents were independently associated with secondary outcomes (Trails B score
and RBANS scores for immediate memory, delayed memory, and attention) at 3 and 12 months.
Because we hypothesized that delirium and coma
may interact in their association with long-term
cognitive impairment, we assessed the data for
such interactions in all regression models.
In all models, drug doses were transformed
with the use of their cube root to reduce the
influence of extreme outliers, and continuous
variables were modeled with the use of restricted
cubic splines to allow for nonlinear associations
(with the exception of dexmedetomidine and
haloperidol doses, which were used so infrequently that the number of unique doses was too
small for splines).28 We also conducted sensitivity
analyses that were restricted to data for patients
who underwent all outcome assessments (i.e., a
complete case analysis). To determine whether an
altered level of consciousness confounded the association between delirium and long-term cognitive impairment, we conducted a sensitivity analysis with adjustment for duration of an altered
level of consciousness. Since days of delirium
and coma were already accounted for in our regression models, we included as a separate covariate the number of days without delirium and
without coma but with an altered level of consciousness (defined as a RASS score other than 0).
We also examined ICU type (medical vs. surgical)
as a potential confounder by including this variable in models in a separate sensitivity analysis.
We examined model diagnostics using residual
plots versus predicted plots and quantilequantile plots. All model assumptions were met adequately. Variance inflation due to multiple imputation was not problematic. We used R software,
version 3.0.1 (www.r-project.org), for all statistical analyses.

R E SULT S
CHARACTERISTICS OF THE PATIENTS

Between March 2007 and May 2010, we enrolled

826 patients (Fig. S1 in the Supplementary Appendix). A total of 5 patients withdrew consent
and permission to use their collected data; thus,
we included 821 patients, who had a median age
of 61 years and a high severity of illness (Table 1).
Only 51 patients (6%) had evidence of preexisting

cognitive impairment (Table 1). Delirium affected 606 patients (74%) during their hospital stay,
with a median duration of delirium of 4 days.
Between enrollment and the 3-month followup, 252 patients (31%) died; 448 of the 569 surviving patients (79%) underwent cognitive testing
3 months after discharge. Another 59 patients (7%
of the original cohort) died before the 12-month
follow-up, and 382 of the 510 surviving patients
(75%) were tested 12 months after discharge
(Fig. S1 in the Supplementary Appendix).
PREVALENCE AND SEVERITY OF LONG-TERM
COGNITIVE IMPAIRMENT

Median RBANS global cognition scores at 3 and

12 months were 79 (interquartile range, 70 to 86)
and 80 (interquartile range, 71 to 87), respectively.
These scores were approximately 1.5 SD below the
age-adjusted population mean of 10015 and were
similar to scores for patients with mild cognitive
impairment.29 At 3 months, 40% of the patients
had global cognition scores that were worse than
those typically seen in patients with moderate
traumatic brain injury,30 and 26% had scores 2 SD
below the population means, which were similar
to scores for patients with mild Alzheimers disease (Fig. 1).31 Deficits of this severity were also
common at 12 months, with 34% and 24% of
patients having scores similar to those for patients with moderate traumatic brain injury and
those for patients with mild Alzheimers disease,
respectively.30,31
Cognitive impairment was not limited to older
patients or to patients with coexisting conditions
at baseline. Patients who were 49 years of age or
younger, for example, had median global cognition scores of 78 and 80 at 3 and 12 months,
respectively (Fig. 1, and Table S3 in the Supplementary Appendix). In addition, global cognition scores were low regardless of the burden of
coexisting conditions (Fig. S2 in the Supplementary Appendix). Even among patients 49 years of
age or younger with no coexisting conditions at
baseline, 34% had global cognition scores at the
12-month follow-up that were commensurate with
moderate traumatic brain injury, and approximately 20% had results similar to those for patients
with mild Alzheimers disease. Unlike Alzheimers
disease, however, which affects delayed memory
much more than other domains, long-term cognitive impairment after critical illness tended

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Table 1. Demographic and Clinical Characteristics of the Patients.*

In-Hospital Cohort
(N=821)

Characteristic

Follow-up Cohort
(N=467)

Age yr
Median
Interquartile range
White race no. (%)

61

59

5171

4969

740 (90)

413 (88)

Male sex no. (%)

420 (51)

234 (50)

Medical ICU no. (%)

559 (68)

298 (64)

Level of education yr
Median

12

12

1214

1214

Short IQCODE score 3.6 no. (%)

51 (6)

26 (6)

CDR score of 1 or 2 no. (%)

45 (5)

23 (5)

14

14

25

24

1931

1930

712

712

Interquartile range

Charlson comorbidity index

Median
Interquartile range
APACHE II score at enrollment
Median
Interquartile range
SOFA score at enrollment**
Median
Interquartile range
Diagnosis at admission no. (%)
Sepsis

244 (30)

136 (29)

Acute respiratory failure

135 (16)

71 (15)

Cardiogenic shock, myocardial ischemia, or arrhythmia

141 (17)

79 (17)

Upper-airway obstruction

87 (11)

49 (10)

Gastric or colonic surgery

63 (8)

29 (6)

Neurologic disease or seizure

11 (1)

7 (1)

Other surgical procedure

82 (10)

65 (14)

Other diagnosis

58 (7)

31 (7)

746 (91)

421 (90)

18

16

606 (74)

352 (75)

27

27

Mechanical ventilation
No. of patients %
No. of days
Median
Interquartile range
Delirium
No. of patients %
No. of days
Median
Interquartile range

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Long-Term Cognitive Impairment after Critical Illness

Table 1. (Continued.)
In-Hospital Cohort
(N=821)

Characteristic

Follow-up Cohort
(N=467)

Coma
No. of patients %

517 (63)

265 (57)

26

15

10

10

617

618

Benzodiazepine

509 (62)

274 (59)

Propofol

425 (52)

256 (55)

Dexmedetomidine

105 (13)

63 (13)

Opiate

641 (78)

362 (78)

No. of days
Median
Interquartile range
Duration of hospital stay days
Median
Interquartile range
Use of sedative or analgesic agent in ICU no. (%)

* Percentages may not sum to 100, owing to rounding. Of the 821 patients for whom in-hospital data and assessments
were available, 467 underwent follow-up assessments at 3 months, 12 months, or both. A total of 354 patients did
not undergo follow-up (252 patients died and 74 withdrew from the study before the 3-month assessment, and 28
were permanently lost to follow-up). ICU denotes intensive care unit.
Race was determined according to the medical record or was reported by the patients surrogate.
Scores on the Short Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) range from 1 to 5, with a
score of 3 indicating no change in cognition over the past 10 years, a score lower than 3 indicating improvement, and
a score higher than 3 indicating decline in cognition, as compared with 10 years before. A score of 3.3 or higher indicates an increased probability of cognitive impairment, and a score of 3.6 or higher indicates preexisting cognitive
impairment (see the Supplementary Appendix).
Scores on the Clinical Dementia Rating (CDR) scale range from 0 to 3.0, with 0 indicating no impairment, 0.5 very
mild impairment, 1.0 mild impairment, 2.0 moderate impairment, and 3.0 severe impairment.
Scores on the Charlson comorbidity index range from 0 to 33, with higher scores indicating a greater burden of illness;
a score of 1 or 2 is associated with mortality of approximately 25% at 10 years.
Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0 to 71, with higher scores
indicating worse outcomes.
** Scores on the Sequential Organ Failure Assessment (SOFA) range from 0 to 24 (from 0 to 4 for each of six organ
systems), with higher scores indicating more severe organ dysfunction. We used a modified SOFA score in our regression models, which excluded the Glasgow Coma Scale components, since coma was included separately in our
models.
Acute respiratory failure included the acute respiratory distress syndrome, acute exacerbations of chronic obstructive
pulmonary disease or asthma, pulmonary edema, embolus, and fibrosis.
Other surgical procedures included hepatobiliary surgery, liver transplantation, and orthopedic, obstetrical or gynecologic, vascular, otolaryngologic, and urologic surgery.

to affect multiple cognitive domains (Fig. S3 in

the Supplementary Appendix). The Trails B executive-function scores were also low at 3 and
12 months; median scores of 41 and 42, respectively, were below population norms, regardless
of the patients age (Table S3 in the Supplementary Appendix).

cognition scores at both 3 and 12 months after

discharge (P=0.001 and P=0.04, respectively)
(Table 2 and Fig. 2). However, the duration of
coma was not associated with RBANS scores at
either 3 or 12 months after discharge (P=0.87
and P=0.79, respectively), although it did modify the association between delirium and global
cognition scores at 3 months (P=0.05 for interDELIRIUM, SEDATIVE and ANALGESIC medications, action) (Fig. S4 in the Supplementary Appenand long-term cognitive impairment
dix). A longer duration of delirium was also
A longer duration of delirium was an inde anindependent risk factor for worse executive
pendent risk factor for worse RBANS global function at 3 and 12 months (P=0.004 and

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RBANS Global Cognition Score

an altered level of consciousness and surgical

versus medical ICU did not qualitatively change
our findings.
120

DISCUSSION
100

Normal

80

MCI
TBI
Alzheimers
disease

60

40
0

3 Mo
(N= 97)

12 Mo
(N= 89)

49 Yr

3 Mo
12 Mo
(N= 147) (N= 138)

5064 Yr

3 Mo
(N= 130)

12 Mo
(N= 98)

65 Yr

Figure 1. Global Cognition Scores in Survivors of Critical Illness.

The box-and-whisker plots show the age-adjusted global cognition scores on
the Repeatable Battery for the Assessment of Neuropsychological Status
(RBANS; with a population age-adjusted mean [SD] of 10015, and lower
scores indicating worse global cognition) at 3 months (light-gray boxes) and
12 months (dark-gray boxes), according to age. For each box-and-whisker
plot, the horizontal bar indicates the median, the upper and lower limits of
the boxes the interquartile range, and the ends of the whiskers 1.5 times the
interquartile range. Outliers are shown as black dots. The green dashed line
indicates the age-adjusted population mean (100) for healthy adults, and the
green band indicates the standard deviation (15). Also shown are the expected
population means for mild cognitive impairment (MCI), moderate traumatic
brain injury (TBI), and mild Alzheimers disease on the basis of other cohort
studies. Expected population means for MCI and Alzheimers disease are
shown only for patients 65 years of age or older, since RBANS population
norms for these disorders have been generated only in that age group.

P = 0.007, respectively) (Table 2, and Fig. S4 and

S5 in the Supplementary Appendix). A longer
duration of delirium was also a risk factor for
worse function in several individual RBANS domains (see the Supplementary Appendix).
We did not observe an independent association between higher doses of benzodiazepines
and worse long-term cognitive scores, except that
higher benzodiazepine doses were an independent risk factor for worse executive-function scores
at 3 months (P = 0.04) (Table 2). None of the
other medications examined, including propofol, dexmedetomidine, and opiates, were consistently associated with global cognition or
executive-function outcomes.
Sensitivity analyses that included only patients
for whom complete outcome data were available
yielded similar results (Table S4 in the Supplementary Appendix). In addition, adjustments for
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In this multicenter, prospective cohort study involving a diverse population of patients in general medical and surgical ICUs, we found that one out of
four patients had cognitive impairment 12 months
after critical illness that was similar in severity to
that of patients with mild Alzheimers disease,
and one out of three had impairment typically
associated with moderate traumatic brain injury.
Impairments affected a broader array of neuropsychological domains than is characteristically
seen in Alzheimers disease, but the impairments
were very similar to those observed after moderate traumatic brain injury. A validated instrument
that assessed baseline cognitive status showed
that only 6% of patients had evidence of mild-tomoderate cognitive impairment before ICU admission, indicating that these profound cognitive
deficits were new in the majority of patients.
Long-term cognitive impairment affected both
old and young patients, regardless of the burden
of coexisting conditions at baseline.
A longer duration of delirium was associated
with worse long-term global cognition and executive function, an association that was independent of sedative or analgesic medication use,
age, preexisting cognitive impairment, the burden
of coexisting conditions, and ongoing organ failures during ICU care. Although the mechanisms
by which delirium may predispose patients to
long-term cognitive impairment after critical illness have not yet been elucidated, delirium is associated with inflammation and neuronal apoptosis, which may lead to brain atrophy.32,33 Delirium
has previously been associated with cerebral atrophy34 and reduced white-matter integrity35; both
atrophy and white-matter disruption are associated with cognitive impairment.34,35 It is also
possible that patients who are vulnerable to delirium owing to severe critical illness are also
vulnerable to long-term cognitive impairment and
that delirium does not play a causal role in the
development of persistent cognitive impairment.
After adjustment for delirium, we did not find
any consistent associations between the use of
sedative or analgesic medications and long-term
cognitive impairment. The significant association

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Dexmedetomidine (g)
1238.8

3826

804

7.88

75th

3.5 (0.1 to 6.9)

4.0 (11.7 to 3.7)

0.5 (2.2 to 3.3)

0.3 (2.9 to 3.5)

1.5 (7.0 to 4.1)

6.3 (10.3 to 2.3)

0.14

0.31

0.83

0.20

0.12

0.001

1.7 (2.1 to 5.4)

5.7 (14.1 to 2.8)

0.4 (3.4 to 2.7)

0.4 (3.9 to 3.0)

1.2 (3.3 to 5.7)

5.6 (9.5 to 1.8)

difference (95% CI)

difference (95% CI)

P value

At 12 Mo

At 3 Mo

RBANS Global Cognition Score

0.04

0.19

0.96

0.17

0.87

0.04

P value

5.2 (1.4 to 9.1)

2.5 (11.2 to 6.1)

1.4 (4.6 to 1.7)

2.9 (6.9 to 1.0)

1.6 (6.1 to 2.9)

5.1 (9.2 to 1.1)

difference (95% CI)

At 3 Mo

0.06

0.57

0.44

0.04

0.70

0.004

P value

4.6 (0.4 to 8.8)

0.4 (9.5 to 8.7)

1.7 (5.1 to 1.7)

0.5 (4.4 to 3.5)

0.9 (3.8 to 5.6)

0.09

0.93

0.61

0.19

0.79

6.0 (10.2 to 1.9) 0.007

difference (95% CI) P value

At 12 Mo

Trails B Executive-Function Score

* Results shown are from linear regression models in which outcome variables were global cognition scores on the Repeatable Battery for the Assessment of Neuropsychological Status
(RBANS; on a scale from 40 to 160, with lower scores indicating worse performance) or the Trail Making Test, Part B (Trails B; with scores ranging from 0 to 100, and lower scores
indicating worse executive function), the independent variables were duration of delirium, duration of coma, and mean dose of sedative or analgesic medications (all included simultaneously in the model), and the covariates were the following potential confounders, which were selected a priori: age, educational level, coexisting conditions, preexisting cognitive
impairment, apolipoprotein E genotype, stroke risk, and ICU variables, including the mean scores for the severity of illness, mean haloperidol dose, duration of severe sepsis, duration
of hypoxemia, and an interaction between delirium and coma.
Differences (point estimates) in the RBANS and the Trails B scores in the linear regression analyses reflect a comparison between the 25th and the 75th percentile values for each variable among all 821 patients in the original cohort (with the exception of dexmedetomidine dose; because more than 85% of patients received no dexmedetomidine, we used the minimum and maximum doses instead). For example, in a comparison of patients with no delirium and those with 5 days of delirium, with all other covariates held constant, patients with
5 days of delirium had RBANS global cognition scores that were 5.6 points lower at 12 months than did those with no delirium. This represents a decrease of approximately 0.5 SD,
which is considered to be a clinically significant decline (see the Supplementary Appendix). A similar comparison of executive-function scores at 3 and 12 months showed a decrease of
0.5 SD in the scores for patients with 5 days of delirium, which is a clinically significant decline according to the neuropsychology literature. CI denotes confidence interval.
We used restricted cubic splines for all continuous variables, which allows for a nonlinear relationship between covariates and outcomes but requires multiple beta coefficients to estimate
the effect. The most appropriate P value is one that takes into consideration all these beta coefficients together. Although the P value may indicate significance (and is correct), the comparison of the 25th and 75th percentiles may yield a point estimate with a confidence interval that crosses zero, or vice versa.

13.3

Propofol (mg)

Opiate (mg)

Benzodiazepine (mg)

Mean daily dose of sedative

or analgesic agent

Duration of coma (days)

25th

Percentile

Duration of delirium (days)

Independent Variable

Table 2. Effect of Duration of Delirium, Duration of Coma, and Exposure to Sedative or Analgesic Agents on Global Cognition and Executive Function.*

Long-Term Cognitive Impairment after Critical Illness

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1313

The

n e w e ng l a n d j o u r na l

Adjusted RBANS Global Cognition Score

at 12 Mo

90

80

70

60

N=382
P=0.04

10

Days of Delirium

Figure 2. Duration of Delirium and Global Cognition Score at 12 Months.

Longer durations of delirium were independently associated with worse
RBANS global cognition scores at 12 months. Point estimates and the 95%
confidence interval for these relationships are shown by the blue line and the
gray band, respectively. RBANS global cognition scores have age-adjusted
population norms, with a mean (SD) score of 10015. Rug plots show the
distribution of the durations of delirium. Although delirium could be assessed
for up to 30 days in the study, the x axis is truncated at 10 days because 90%
of the patients had delirium for 10 days or less; all available data were used in
the multivariable modeling. As one example, in a comparison of patients with
no delirium and those with 5 days of delirium (the 25th and 75th percentile
values of delirium duration in our cohort), with all other covariates held constant (at the median or mode of the covariate), patients with 5 days of delirium had RBANS global cognition scores at 12 months that were an average
of 5.6 points lower than the scores for patients with no delirium.

between benzodiazepines and executive function

at 3 months should be interpreted cautiously,
owing to multiple testing and the nonsignificant
associations between benzodiazepines and global cognition scores at 12 months. However, the
lack of a consistent association should not be
taken to suggest that large doses of sedatives are
safe, given studies showing that oversedation is
associated with adverse outcomes.36
Since delirium is associated with long-term
cognitive impairment, interventions directed at
reducing delirium may mitigate brain injury associated with critical illness. Although the judicious use of sedative agents and routine monitoring for delirium recommended components
of care for all patients in the ICU37 are increasingly applied, only a few interventions (e.g.,
early mobilization and sleep protocols) have been
shown to reduce the risk of delirium among pa1314

n engl j med 369;14

of

m e dic i n e

tients in the ICU,38-40 and it is not known whether

any preventive or treatment strategies can reduce
the risk of long-term cognitive impairment after
critical illness.
These results complement those of earlier
cohort studies that exposed the problem of cognitive deficits in survivors of critical illness.1-4
Some important differences, however, exist between previous investigations and the BRAIN-ICU
study. First, we enrolled a large sample of patients with a diverse set of admission diagnoses
and a broad age range. Second, we collected and
analyzed detailed data about delirium and sedative exposure as risk factors for long-term cognitive impairment. Two longitudinal studies3,4 have
advanced the field, but one was limited to patients
with severe sepsis,4 and neither study collected detailed data on in-hospital exposures, such as
delirium and psychoactive medications. In addition, the previous studies assessed cognitive
outcomes with the use of abbreviated screening
tools, which do not allow comparisons with
other populations, such as patients with traumatic brain injury or Alzheimers disease.
An important limitation of the BRAIN-ICU
study was our inability to test patients cognition
before their emergent illness. We addressed this
limitation in three ways. First, we excluded patients who were found to have severe dementia
with the use of a rigorous and well-validated approach that relied on two validated surrogate assessment tools, the widely used Short IQCODE17
and the reference standard CDR scale.18 Second,
we used the Short IQCODE to estimate preexisting cognitive function in all patients 50 years of
age or older and in those younger than 50 years
of age with memory problems, and we adjusted
for this measure as a continuous variable in our
regression models. Third, we stratified cognitive
outcomes according to age and burden of coexisting illness and found that even young patients
with no coexisting conditions that is, patients
who were highly unlikely to have any preexisting
cognitive impairment were also at high risk
for long-term cognitive impairment (Fig. S2 in
the Supplementary Appendix).
Another limitation of our study is that, despite
high follow-up rates, some patients were unable to
complete all cognitive tests. We used imputation
strategies in our main analysis to reduce potential
bias due to missing data and conducted sensitivity
analyses that were restricted to data from patients
with complete assessments, with similar results.

nejm.org

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Long-Term Cognitive Impairment after Critical Illness

We were not able, however, to address the possibility of confounding by death or withdrawal. Finally,
as with any observational study, the possibility of
bias due to unmeasured confounders cannot be
excluded.
In conclusion, cognitive impairment after
critical illness is very common and in some patients persists for at least 1 year. Patients with a
longer duration of delirium are more likely than
those with a shorter duration of delirium to have
cognitive deficits.

Supported by grants from the National Institutes of Health

(AG027472; HL111111, to Drs. Pandharipande, Hughes, Dittus,
and Ely; AG035117, to Drs. Pandharipande, Bernard, Dittus, and
Ely; AG034257, to Dr. Girard; AG031322, to Dr. Jackson;
AG040157, to Dr. Vasilevskis; and NHLBI 2 T32 HL087738-06,
to Drs. Brummel and Bernard) and the Veterans Affairs (VA)
Clinical Science Research and Development Service (to Drs.
Pandharipande, Dittus, and Ely), a Mentored Research Training
Grant from the Foundation for Anesthesia Education and Research (to Dr. Hughes), and the VA Tennessee Valley Geriatric
Research Education and Clinical Center (to Drs. Girard, Vasilevskis, Dittus, and Ely).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

APPENDIX
The authors full names, degrees, and affiliations are as follows: Pratik P. Pandharipande, M.D., M.S.C.I., the Department of Anesthesiology, Division of Critical Care, Vanderbilt University School of Medicine, and the Anesthesia Service, Department of Veterans Affairs,
Tennessee Valley Healthcare System both in Nashville; Timothy D. Girard, M.D., M.S.C.I., the Department of Medicine, Division of
Allergy, Pulmonary, and Critical Care Medicine, and the Center for Health Services Research, Vanderbilt University School of Medicine,
and the Geriatric Research Education and Clinical Center (GRECC), Department of Veterans Affairs, Tennessee Valley Healthcare System
both in Nashville; James C. Jackson, Psy.D., the Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine,
the Center for Health Services Research, and the Department of Psychiatry, Vanderbilt University School of Medicine, and the Research
Service, Department of Veterans Affairs, Tennessee Valley Healthcare System both in Nashville; Alessandro Morandi, M.D., M.P.H.,
the Rehabilitation and Aged Care Unit, Hospital Ancelle, Cremona, and the Geriatric Research Group, Brescia both in Italy; Jennifer
L. Thompson, M.P.H., the Department of Biostatistics, Vanderbilt University School of Medicine, Nashville; Brenda T. Pun, R.N.,
M.S.N., the Center for Health Services Research, Vanderbilt University School of Medicine, Nashville; Nathan E. Brummel, M.D.,
M.S.C.I., the Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and the Center for Health Services
Research, Vanderbilt University School of Medicine, Nashville; Christopher G. Hughes, M.D., the Department of Anesthesiology, Division of Critical Care, Vanderbilt University School of Medicine, and the Anesthesia Service, Department of Veterans Affairs, Tennessee
Valley Healthcare System both in Nashville; Eduard E. Vasilevskis, M.D., M.P.H., the Center for Health Services Research and the
Department of Medicine, Division of General Internal Medicine and Public Health, Vanderbilt University School of Medicine, and the
GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System both in Nashville; Ayumi K. Shintani, Ph.D., M.P.H.,
the Department of Biostatistics, Vanderbilt University School of Medicine, Nashville; Karel G. Moons, Ph.D., the Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, and the Julius Center for Health Sciences and Primary Care, University
Medical Center, Utrecht, the Netherlands; Sunil K. Geevarghese, M.D., M.S.C.I., the Department of Surgery, Division of Hepatobiliary
Surgery and Liver Transplantation, Vanderbilt University School of Medicine, Nashville; Angelo Canonico, M.D., Saint Thomas Hospital,
Nashville; Ramona O. Hopkins, Ph.D., the Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical
Center, Murray, and the Psychology Department and Neuroscience Center, Brigham Young University, Provo both in Utah; Gordon
R. Bernard, M.D., the Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School
of Medicine, Nashville; Robert S. Dittus, M.D., M.P.H., the Center for Health Services Research and the Department of Medicine, Division
of General Internal Medicine and Public Health, Vanderbilt University School of Medicine, and the GRECC, Department of Veterans
Affairs, Tennessee Valley Healthcare System both in Nashville; and E. Wesley Ely, M.D., M.P.H., the Department of Medicine, Division
of Allergy, Pulmonary, and Critical Care Medicine, and the Center for Health Services Research, Vanderbilt University School of Medicine,
and the GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System both in Nashville.
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