Car Gade Delirium e Nuc I

PLOS ONE
RESEARCH ARTICLE
ICU delirium burden predicts functional

neurologic outcomes
Luis Paixao1,2¤a, Haoqi Sun ID1,2, Jacob Hogan ID1¤b, Katie Hartnack3, Mike Westmeijer ID1,
Anudeepthi Neelagiri1, David W. Zhou ID2,4,5, Lauren M. McClain1,2, Eyal Y. Kimchi ID1,2,
Patrick L. Purdon2,4, Oluwaseun Akeju2,4, M. Brandon Westover1,2*
1 Department of Neurology, Massachusetts General Hospital, Boston, MA, United States of America,
2 Harvard Medical School, Boston, MA, United States of America, 3 Antioch University New England, Keene,
NH, United States of America, 4 Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts
General Hospital, Boston, MA, United States of America, 5 Department of Brain and Cognitive Sciences,
a1111111111 Massachusetts Institute of Technology, Cambridge, MA, United States of America
a1111111111
a1111111111 ¤a Current address: Department of Neurology, Washington University School of Medicine in St. Louis,
a1111111111 St. Louis, MO, United States of America
¤b Current address: Department of Biology, Brigham Young University, Provo, UT, United States of America
a1111111111
* [email protected]
Abstract
OPEN ACCESS
Citation: Paixao L, Sun H, Hogan J, Hartnack K,

Westmeijer M, Neelagiri A, et al. (2021) ICU Background
delirium burden predicts functional neurologic We investigated the effect of delirium burden in mechanically ventilated patients, beginning
outcomes. PLoS ONE 16(12): e0259840. https://
in the ICU and continuing throughout hospitalization, on functional neurologic outcomes up
doi.org/10.1371/journal.pone.0259840
to 2.5 years following critical illness.
Editor: Aleksandar R. Zivkovic, Heidelberg
University Hospital, GERMANY
Methods
Received: May 22, 2021
Prospective cohort study of enrolling 178 consecutive mechanically ventilated adult medical
Accepted: October 28, 2021
and surgical ICU patients between October 2013 and May 2016. Altogether, patients were
Published: December 2, 2021 assessed daily for delirium 2941days using the Confusion Assessment Method for the ICU
Copyright: © 2021 Paixao et al. This is an open (CAM-ICU). Hospitalization delirium burden (DB) was quantified as number of hospital days
access article distributed under the terms of the with delirium divided by total days at risk. Survival status up to 2.5 years and neurologic out-
Creative Commons Attribution License, which
comes using the Glasgow Outcome Scale were recorded at discharge 3, 6, and 12 months
permits unrestricted use, distribution, and
reproduction in any medium, provided the original post-discharge.
author and source are credited.
Data Availability Statement: All relevant data are Results

available in the manuscript and its Supporting Of 178 patients, 19 (10.7%) were excluded from outcome analyses due to persistent coma.
Information files.
Among the remaining 159, 123 (77.4%) experienced delirium. DB was independently asso-
Funding: This research was conducted while MBW ciated with >4-fold increased mortality at 2.5 years following ICU admission (adjusted haz-
was a Breakthroughs in Gerontology Grant
recipient, supported by the Glenn Foundation for
ard ratio [aHR], 4.77; 95% CI, 2.10–10.83; P < .001), and worse neurologic outcome at
Medical Research and the American Federation for discharge (adjusted odds ratio [aOR], 0.02; 0.01–0.09; P < .001), 3 (aOR, 0.11; 0.04–0.31;
Aging Research. MBW also received funding from P < .001), 6 (aOR, 0.10; 0.04–0.29; P < .001), and 12 months (aOR, 0.19; 0.07–0.52; P =
grants from the NIH (NIH-NINDS 1K23NS090900,
.001). DB in the ICU alone was not associated with mortality (HR, 1.79; 0.93–3.44; P = .082)
1R01NS102190-01, 1R01NS102574,
1R01NS107291, 1RF1AG064312) and the and predicted neurologic outcome less strongly than entire hospital stay DB. Similarly, the
American Academy of Sleep Medicine through an number of delirium days in the ICU and for whole hospitalization were not associated with
PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 1 / 20

PLOS ONE Mortality and functional neurological outcomes in delirium
AASM Foundation Strategic Research Award. LP mortality (HR, 1.00; 0.93–1.08; P = .917 and HR, 0.98; 0.94–1.03, P = .535) nor with neuro-
and HS received funding from the Glenn logical outcomes, except for the association between ICU delirium days and neurological
Foundation for Medical Research and the American
Federation for Aging Research. EYK received
outcome at discharge (OR, 0.90; 0.81–0.99, P = .038).
funding from grants from the NIH
(K08MH116135). JH, KH, MW, AN, DWZ, LMM, Conclusions
PLP and OA report no disclosures. The funders had
no role in study design, data collection and
Delirium burden throughout hospitalization independently predicts long term neurologic out-
analysis, decision to publish, or preparation of the comes and death up to 2.5 years after critical illness, and is more predictive than delirium
manuscript. burden in the ICU alone and number of delirium days.
Competing interests: The authors have declared
that no competing interests exist.
Introduction
Delirium, a condition of an acute and fluctuating change in mental status, impaired attention,
and disorganized thinking, occurs in 30–60% of patients admitted to an intensive care unit
(ICU) [1, 2]. In the past delirium was considered transient and reversible [3]. Delirium is now
known to be associated with prolonged ICU and hospital stay, increased mortality, long-term
disability and cognitive impairment [4–32].
However, few studies have tracked the course of ICU delirium throughout the entire hospi-
tal stay, thus little is known about the impact of the overall burden of delirium. In this prospec-
tive observational cohort study, we aimed to determine the independent impact of the burden
of delirium throughout hospitalization on long-term functional neurological outcome among
mechanically ventilated ICU patients. To measure delirium burden, we introduce a normal-
ized metric of delirium burden (DB): the fraction of days patients were delirious during hospi-
talization. Unlike delirium days, DB is not confounded by survival status nor length of hospital
stay and hence may be a strong independent predictor of mortality and functional neurological
outcomes at discharge and long-term.
Materials and methods

This prospective observational cohort study was conducted at Massachusetts General Hospital
(MGH).
Patients
The Mass General Brigham (MGB) Institutional Review Board (IRB) approved this retrospec-
tive study and waived the requirement for written consent. Inclusion criteria: any adult (�18
years) mechanically ventilated patient in a medical or surgical ICU at MGH between October
29, 2013 and May 19, 2016 (S1 Fig). Exclusion criteria: history of dementia, stroke or other pri-
mary neurologic disease; inability to be reliably assessed for delirium (e.g. owing to deafness).
Patients comatose throughout the entire hospitalization were also excluded because they could
not be evaluated for delirium.
Explanatory variables
Study physicians enrolled patients each morning. Delirium and coma status in the ICU and
hospital ward areas were assessed daily by staff using the CAM-ICU [33]. CAM-ICU includes
four categories: 1, acute onset of mental status changes or fluctuating course; 2, inattention; 3,
disorganized thinking; 4, altered level of consciousness. The CAM-ICU assessment is positive
if categories 1 and 2 plus either 3 or 4 are present. Level of consciousness was assessed using

the Richmond Agitation-Sedation Scale (RASS) [34, 35], which ranges from -5 to 4, with lower
scores indicating reduced arousal, higher scores indicating increased agitation; and 0, an alert
calm state. The explanatory variable in this study was delirium burden (DB) during hospitali-
zation (i.e. ICU and floor).
Delirium. Patients were defined as delirious if they had a RASS score of -3 or higher and
had positive CAM-ICU; and comatose if RASS was -4 or -5. Patients were defined as normal if
they were not delirious or comatose. Two groups of patients were defined a priori: 1) “delir-
ium” group: patients who developed delirium during hospitalization, 2) “no delirium group”:
all others. “Delirium” group patients were further categorized as “delirium-only” or “delirium-
coma” (i.e. developed separated episodes of both delirium and coma). Patients in the “no delir-
ium” group were classified as “normal” (i.e. never developed delirium nor coma) or “coma-
normal” (i.e. had episodes of coma and consistently normal examinations but no delirium).
ICU patients discharged to the floor continued to be assessed until hospital discharge.
Delirium burden. In this study we introduce a novel normalized measure of delirium
burden called delirium burden (DB) which ranges from 0 to 1 and represents the fraction of
days patients were delirious during hospitalization (i.e. ICU + hospital wards). Unlike number
of hospital days with delirium, which has been utilized as a measure of delirium burden in pre-
vious studies [7, 21, 36–38], DB is unaffected by survival status and overall length of stay. In
addition, this metric is relatively insensitive to missing assessment days if they occur at random
(rather than preferentially on either days with or without delirium. Coma days were not
included in the analysis of delirium burden as patient’s level of consciousness was too low (e.g.
RASS of -4 or -5) to enable delirium assessment which per definition requires a RASS score of
-3 or higher.
No: delirium days in ICU and wards
Delirium Burden in ICU&wards ¼
No: days assessed for delirium in ICU&wardsy
† the denominator only includes days at risk of developing delirium: “normal days” (i.e.
days when pts were not delirious nor comatose) plus delirium days. It excludes coma days
(RASS of -4 or -5) as the level of arousal is too low to assess for delirium.
Acute brain dysfunction burden. This normalized metric represents the fraction of days
patients were delirious and/or comatose during hospitalization. One of the limitations of the
above delirium burden model is that it is does not take into account coma days. Acute brain
dysfunction burden is adjusted for both delirium and coma both of which can be associated
with significant morbidity, cognitive dysfunction and mortality. Similarly, to delirium burden,
this is unaffected by survival status and overall length of stay.
No: delirium&coma days in ICU&wards
Acute Brain Dysfunction Burden� ¼
No: days assessed for delirium&coma in ICU&wardsx
�
In the ICU and wards
§ the denominator includes days at risk of developing delirium and coma: “normal days”
(i.e. days when pts were not delirious nor comatose), delirium days and coma days.
Outcome variables
Outcome variables were the covariate-adjusted mortality rate 2.5 years after ICU admission
and functional neurological status measured by the Glasgow Outcome Scale (GOS) at hospital
discharge, 3, 6, and 12 months following hospital discharge. GOS is an ordinal scale, where a
score of 1 corresponds to death; 2, persistent vegetative state; 3, severe neurological disability /
dependency; 4, moderate neurological deficit but with ability to live independently; and 5

return to original functional level with no neurological deficit [39, 40]. The GOS scale is a
widely used scale with high inter-rater reliability, validity, stability, and flexibility of adminis-
tration and GOS ratings have been shown to be associated with cognitive test scores [40–43].
Deaths were identified through chart review of hospital records and community obituaries.
GOS was obtained by neurological examination before discharge and chart review following
discharge by staff physicians blinded to patients’ delirium status. For GOS assessments after
discharge, the study physician conducted GOS assessments via chart review inspection twice
at different time points. Incongruences in the GOS scores were evaluated by a second study
physician who was board certified in neurology and final GOS score was dictated by agree-
ment between first and second study physicians.
Covariates
Covariates obtained at enrollment included demographics; Charlson Comorbidity Index
(range 0 to 37; a proxy for chronic disease burden; higher scores indicate greater burden of
preexisting comorbid conditions) [44]; the Acute Physiology and Chronic Health Evaluation
II (APACHE II) score (range 0 to 71; measures severity of illness during the first 24 ICU
hours; higher scores indicate greater severity) [45]; pre-existing dementia; principal ICU
admission diagnosis; and administrations of sedative and analgesic agents including dexmede-
tomidine (mcg/kg), opiates (mcg/kg) (hydromorphone, morphine, oxycodone, and/or fenta-
nyl, converted to fentanyl dose equivalents, henceforth referred to as opiates), propofol (mg/
kg), and benzodiazepines (mg/kg) (lorazepam, diazepam, and/or midazolam; converted to
midazolam dose equivalents, henceforth referred to as benzodiazepines).
Conversion factors are provided in the S1 Text. Mean daily dose and cumulative dose were
used as summary drug measures. We also recorded ICU length of stay and total length of hos-
pital stay.
Management of missing data

5 (3.1%) of 159 subjects had missing drug data. These patients were excluded from the covari-
ate adjusted models.
Statistical analysis
Baseline characteristics for the delirium vs. no delirium groups were compared using Chi-
square tests for categorical variables with >5 patients in each group, Fisher’s exact test with
<5, and Wilcoxon rank sum tests for continuous variables. Comparison of drug exposure
between the two groups was assessed using the Wilcoxon rank sum test. To assess correlations
between variables, a correlation matrix was computed using Spearman’s correlation (S2 Fig).
All multivariate models (Cox proportional hazard regression, ordinal logistic regression, and
logistic regression models; described below), were adjusted for covariates chosen a priori based
on previous literature [3, 7, 12, 26]: age at ICU admission, Charlson Comorbidity Index,
APACHE II score, and weight-normalized mean daily doses of Dexmedetomidine, Opiate,
Propofol, and Benzodiazepines. Statistical analyses were performed using R software, version
3.5.1 (www.r-project.org/) [46]. A level of 0.05 was used for statistical significance. The cumu-
lative dose of a drug represents the drug amount received during the entire hospital stay. Mean
daily drug doses were calculated by dividing cumulative dose by the length of hospital stay. All
doses were normalized by body weight. The effect of outliers was reduced by log-transforming
using sin(x)� log(|x|+1) and standardizing (Z-score) drug doses.
Mortality during 2.5 years of follow-up was analyzed using time-to-event analyses with
right censoring for patients alive at the study end. Follow-up time was measured in years from

ICU admission to date of censoring (up to 2.5 years after ICU admission) or death. Cox pro-
portional hazard regression models were used to obtain adjusted hazard ratios (aHRs) for the
impact of delirium, delirium burden (DB) and acute brain dysfunction burden on mortality,
adjusted for covariates. Log-rank statistics were used to assess for differences by overall delir-
ium status; delirium and coma status (“delirium-coma” / “delirium only” / “coma-normal” /
“normal”); and delirium burden (categorized into low, medium, and high-tertile DB groups).
Effects of delirium, delirium burden, and acute brain dysfunction burden on functional
outcome (GOS) at discharge, 3, 6, and 12 months were evaluated using univariate and multi-
variate proportional odds ordered logistic regression analysis [47–50]. The multivariate model
was adjusted for the same covariates used in the Cox regression model. Since neurological out-
come is progressively worse as one goes down the GOS scale (i.e. from 5 to 1), proportional
odd ratios >1 indicate increased odds of favorable neurological outcomes; and <1 indicate
unfavorable outcomes.
There was no loss to follow-up or patient withdrawal from the study regarding data pertain-
ing to mortality and GOS.
Results
Patient characteristics
Between October 29, 2013 and May 19, 2016, we enrolled 178 adult mechanically ventilated
ICU patients (S2 Fig). 19 (10.7%) remained in coma throughout hospitalization and were
excluded from outcome analyses (S1 Fig); the remaining 159 patients were included. Baseline
characteristics of patients with vs. without delirium are reported in Table 1. Patients in the
delirium group were older (mean ± standard deviation [SD], 59.0 ± 14.3 vs. 53.6 ± 14.1; P =
.033) and had higher severity of illness during the first 24 ICU hours as measured by APACHE
II scores (22.9 ± 9.1 vs. 19.4 ± 7.1; P = .036) compared to patients without delirium.
Sedative and analgesic agents use

Mean cumulative and daily dose of sedative and analgesic medications are shown in S1 Table.
Mean cumulative and daily doses of Dexmedetomidine (P = .025; P = .039), Opiates (P = .001;
P = NS), Propofol (P < .001; P = NS), and Benzodiazepines (P = .002; P = .008) were higher in
patients with delirium vs. patients without delirium, although this trend did not reach signifi-
cance for the mean daily dose of opiates (P = .096) and propofol (P = .053).
Prevalence of delirium, coma, length of stay, and mortality

Of 159 patients, 123 (77.4%) had delirium at some point during hospitalization (Table 2). The
median duration of delirium was 4 days (IQR, 2–7) including a median of 2 (1–5) ICU days.
Delirious patients had a median DB of 0.36(0.17–0.75) during hospitalization, and for the ICU
period alone, 0.55 (0.31–1.00).
The number of patients who developed coma in the delirium and non-delirium groups was
similar: 110 of 123 patients (89.4%) in the delirium group and in 30 of 36 patients (83.3%) in
the non-delirium group developed coma (P = .325). However, the number of coma days was
higher in the delirium group compared to the non-delirium group throughout hospitalization
(median, 4 [IQR 2–8] vs 2 [1–4] days; P = .002) and ICU stay (4 [2–7] vs 1.5 [1–4]; P < .001).
Propofol was received by the majority of patients who developed coma at some point in both
the delirium group (103 of 106 patients [97.2%]; drug data is missing in 4 of the 110 delirium
group patients) and non-delirium group (26 of 29 patients [89.7%); drug data is missing in 1 of
the 30 non-delirium group patients). Similarly, 105 of the 106 patients (99.1%) in the delirium

Table 1. Patients’ characteristics.

Characteristic Delirium (n = 123) No Delirium (n = 36) P value�
Age, y, mean ± SD 59.0 ± 14.3 53.6 ± 14.1 .033
Male, n (%) 82 (67) 23 (64) .913
White race, n (%) 105 (85) 33 (92) .412
Weight, kg, mean ± SD 92.8 ± 38.3 81.4 ± 23.0 .130
CCI at admission, mean ± SD§ 3.4 ± 2.4 2.9 ± 2.5 .140
APACHE II score, mean ± SD† 22.9 ± 9.1 19.4 ± 7.1 .036
Dementia, n (%) 0 (0) 0 (0) NA
ICU admission diagnosis, n (%)‡
Sepsis 25 (20) 5 (14) .531
Surgery 32 (26) 11 (31) .744
Acute Respiratory Failure 78 (63) 21 (58) .721
Cardiac Shock / Arrhythmia / MI 10 (8) 3 (8) 1.000
Pancreatitis 6 (5) 0 (0) .338
Liver Failure 12 (10) 1 (3) .301
Gastrointestinal bleeding 1 (1) 1 (3) .403
Renal Failure 25 (20) 3 (8) .135
Malignancy 4 (3) 0 (0) .575
Drug intoxication 4 (3) 1 (3) 1.000
Other 18 (15) 2 (6) .251
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CCI, Charlson Comorbidity Index; ICU, intensive care unit; MI, myocardial ischemia; SD,
standard deviation; y, years.
�
P value for Chi-square test in the case of categorical variables with large (�5) cell sizes; for Fisher’s Exact test in the case of categorical variables with small (<5) cell
sizes; and for Wilcoxon rank sum test in the case of continuous variables.
§ Scores on the CCI range from 0 to 37, with higher scores indicating a greater burden of illness and a higher 10-year mortality risk.
† The APACHE II measures the severity of disease for adult patients. It is applied within 24 hours of patient admission to an intensive care unit. Scores range from 0 to
71, with higher scores corresponding to more severe disease and d higher risk of death.
‡ Recorded by the patients´ medical team as the diagnoses most representative of the reason for ICU admission. Patients were sometimes given more than 1 admission
diagnosis by the medical team, resulting in column totals > 100%.
https://doi.org/10.1371/journal.pone.0259840.t001
group and 29 of the 29 patients (100%) in non-delirium group who developed coma received
either propofol or benzodiazepines.
Overall, the 159 patients spent 1,566 (53.2%) hospital (i.e. ICU and wards) days “normal”
(not delirious nor comatose), 675 (23.0%) delirious, and 700 (23.8%) comatose, including the
ICU period where they spent 602 (36.3%) ICU days normal, 426 (25.7%) ICU days delirious,
and 631 (38.0%) ICU days comatose. The total number of hospital days patients were assessed
for delirium and coma across the cohort was 2941, including 1659 ICU days. The length of
hospital stay from ICU admission to hospital discharge and total length of hospital stay was
4282 and 4548 days, respectively.
The median length of ICU stay and total hospital stay were higher for the delirium group
(15 [9–22] and 28 [19–42] days) compared to the non-delirium group (6 [3–9] and 13 [10–19]
days) (P < .001).
During hospitalization, 18.9% (30/159) of patients died (Table 2). Of the 30 who died in
hospital, 21 (13.2% of the total cohort) died in the ICU. The mortality rate at 2.5 years follow-
up was 37.7% (60/159).
Delirious patients compared to non-delirious patients had higher ICU (16.3% [20/123] vs.
2.8% [1/36]; P = .047), in-hospital (23.6% (29/123) vs. 2.8% (1/36); P = .003), and 2.5 year

Table 2. Patients delirium duration, coma, length of stay, mortality, and glasgow outcome scale� .
Delirium No Delirium P value§
(n = 123) (n = 36)
Delirium Duration
Delirium days in ICU and in hospital wards, d, median (IQR) 4.0 (5.0) - -
Days assessed for delirium in ICU and in hospital wards, d, 13.0 (14.5) 8.5 (9.0) .009
median (IQR)
Delirium burden (DB) in ICU and in hospital wards, median 0.36 (0.59) - -
(IQR)†
Delirium days in ICU, d, median (IQR) 2.0 (4.0) - -
Days assessed for delirium in ICU, d, median (IQR) 5.0 (5.5) 3.0 (3.0) .005
Delirium burden (DB) in ICU, median (IQR)† 0.55 (0.70) - -
Coma
Number of patients who developed coma, n (%) 110 (89.4) 30 (83.3) 0.325
Coma days in ICU and in hospital wards, d, median (IQR) 4.0 (6.0) 2.0 (3.0) .002
Coma days in ICU, d, median (IQR) 4.0 (5.0) 1.5 (3.0) < .001
Acute brain dysfunction burden in ICU and in hospital wards, 0.55 (0.60) 0.16 (0.21) < .001
median (IQR)¥
Acute brain dysfunction burden in ICU, median (IQR) 0.77 (0.50) 0.29 (0.36) < .001
ICU length of stay, d, median (IQR) 15.0 (13.0) 6.0 (6.0) < .001
Length of hospital stay after ICU admission, d, median (IQR)Δ 27.0 (20.5) 12.0 (10.3) < .001
‡
Total length of hospital stay, d, median (IQR) 28.0 (23.5) 13.0 (9.3) < .001
Follow-up time for patients who died within 2.5y post-ICU 0.09 (0.73) 0.72 (0.58) .157
admission, y, median (IQR)k
No. of Deaths within:
the ICU, n (%) 20 (16) 1 (3) .047
hospital stay, n (%) 29 (24 1 (3) .003
3m post-ICU admission, n (%) 32 (26) 1 (3) .002
6m post-ICU admission, n (%) 34 (28) 3 (8) .014
1y post-ICU admission, n (%) 42 (34) 6 (17) .062
2.5y post-ICU admission, n (%) 53 (43) 7 (19) .011
Glasgow Outcome Scale at:
discharge, median (IQR) 3 (0) 3 (1) < .001
3 months post-discharge, median (IQR) 3 (3) 4 (2) < .001
6 months post-discharge, median (IQR) 3 (4) 5 (2) < .001
1 year post-discharge, median (IQR) 3 (4) 4 (2) .015
Abbreviations: acc., according; ICU, intensive care unit; IQR, interquartile range; d, days; m, months; n, number; y,
years.
�
Glasgow Outcome Scale is a 5-point functional outcome scale, where score of 1 corresponds to death; 2, to
persistent vegetative state; 3, to severe disability; 4, to moderate disability; and 5 to good recovery39.
§ P value for Fisher’s Exact test in the case of categorical variables with small (<5) cell sizes; and for Wilcoxon rank
sum test in the case of continuous variables and ordinal variables.
† Delirium burden is quantified as the number of days of hospitalization with delirium divided by total days at risk.
The fraction of delirium days ranges from 0.00 to 1.00.
¥ Acute brain dysfunction burden is calculated as the number of days of hospitalization with delirium or coma
divided by total days at risk.
Δ Length of hospital stay after ICU admission represents the length of stay since ICU admission until hospital
discharge.
‡ Hospital stay represents the sum of ICU and hospital ward stays.
k Follow-up time defined as the length of time in years from ICU admission day to date of death.

Fig 1. Survival and delirium status. Cox adjusted survival curve for 2.5-years survival post-ICU admission according
to the presence or absence of delirium during hospitalization (ICU + hospital wards; N = 154). The estimated adjusted
survival rates at 2.5 years post-ICU admission were 77% for the no delirium cohort vs 54% for the delirium cohort,
equating to a 23% survival difference between the two cohorts. This dataset includes 154 patients only as medication
data is missing in five of the original 159 patients. Covariates adjusted for include age, the Charlson Comorbidity
Index, APACHE II score, and mean daily doses of dexmedetomidine (mcg/kg), opiate (mcg/kg), propofol (mg/kg),
and benzodiazepine (mg/kg).
https://doi.org/10.1371/journal.pone.0259840.g001
mortalities (43.1% [53/123] vs. 19.4% [7/36]; P = .011) (Table 2) in both unadjusted (S3 Fig)
and adjusted survival analyses (Fig 1). The estimated adjusted survival rates at 2.5 years post-
ICU admission were 54% for the delirium and 77% for non-delirium cohorts, corresponding
to a 23% 2.5 years survival difference. Patients with in-hospital delirium had a greater than
2-fold increased risk of death at 2.5 years (adjusted HR [aHR], 2.42; 95% CI, 1.08–5.42; P =
.032) (Table 3).
Patients in the delirium cohort who also developed coma during hospitalization had a
higher mortality during the 2.5 years follow-up compared to the delirium group without coma
(S4 Fig). Similarly, acute brain dysfunction was associated with higher mortality. The esti-
mated adjusted survival rates at 2.5 years post-ICU admission were 58% for the acute brain
dysfunction group and 86% for non-acute brain dysfunction group, corresponding to a 28%
2.5 years survival difference (S5 Fig). A greater than a 3-fold increased risk of death at 2.5 years
(aHR, 3.56; 95% CI, 0.47–27.11; P = .220) although with a p value that was non-significant was
observed in patients with in-hospital acute brain dysfunction.
Delirium burden and mortality

The median delirium burden (DB) was higher in patients who ultimately died (0.33; IQR,
0.11–0.85) compared to the surviving cohort (0.18; 0.00–0.49) (P = .007) (S6 Fig). Survival was
worse with increasing delirium burden in unadjusted (S7 Fig; P = .010) and Cox-adjusted sur-
vival analyses (Fig 2). When patients were categorized into low-, middle-, and high- tertile
groups for DB, representing the low, medium, and high DB groups, respectively, the estimated
adjusted survival rates at 2.5 years post-ICU admission were 67% for the low, 65% for the
medium, and 44% for the high tertile DB cohorts (Fig 2).
In the unadjusted analysis, DB during hospitalization (ICU + hospital ward) was associated
with mortality up to 2.5 years after ICU admission (HR 3.92; 95% CI, 1.93–7.95; P < .001)

Table 3. Univariate and multivariate Cox proportional hazards regression analysis: Predictors of mortality 2.5 years after ICU admission in mechanically ventilated
ICU patients (N = 159)� .
Univariate Multivariate–Delirium Multivariate–Delirium Burden
Factor HR 95% CI P value Adjusted HR 95% CI Adjusted P value Adjusted HR 95% CI Adjusted P value
Age, y 1.04 1.01–1.06 .001 1.01 0.99–1.04 .348 1.01 0.99–1.04 .370
Male 0.74 0.44–1.24 .253 - - - - - -
White race 1.47 0.63–3.42 .369 - - - - - -
Weight, kg 1.00 0.99–1.01 .624
Acute Respiratory Failure� � 1.46 0.84–2.54 .179 - - - - - -
Surgery� �
0.63 0.33–1.19 .152 - - - - - -
Charlson Comorbidity Index 1.20 1.10–1.32 < .001 1.15 1.00–1.32 .057 1.13 0.99–1.30 .076
APACHE II score 1.02 0.99–1.05 .236 1.00 0.97–1.03 .927 1.00 0.97–1.03 .852
Delirium in ICU and wards 2.69 1.22–5.92 .014 2.42 1.08–5.42 .032 - - -
Delirium days in ICU and wards, d 0.98 0.94–1.03 .535 - - - - - -
Delirium burden in ICU and wards¶ 3.92 1.93–7.95 < .001 - - - 4.77 2.10–10.83 < .001
Delirium days in ICU, d 1.00 0.93–1.08 .917 - - - - - -
Delirium burden in ICU¶ 1.79 0.93–3.44 .082 - - - - - -
ICU length of stay, d 1.00 0.98–1.02 .904 - - - - - -
Total length of hospital stay†, d 0.99 0.97–1.00 .073 - - - - - -
Dexmedetomidine Mean Cumulative Dose, mcg/kg│ 0.58 0.40–0.82 .003 - - - - - -
Dexmedetomidine Mean Daily Dose, mcg/kgk 0.64 0.44–0.94 .024 0.65 0.43–0.99 .046 0.69 0.45–1.06 .090
Opiate Mean Cumulative Dose, mcg/kg‡ │ 0.84 0.66–1.08 .167 - - - - - -
Opiate Mean Daily Dose, mcg/kg ‡ k 0.81 0.62–1.07 .140 0.95 0.66–1.35 .759 0.75 0.51–1.11 .145
Propofol Mean Cumulative Dose, mg/kg│ 1.04 0.80–1.35 .759 - - - - - -
Propofol Mean Daily Dose, mg/kgk 1.13 0.87–1.47 .356 1.28 0.92–1.78 .141 1.23 0.89–1.69 .215
Benzodiazepine Mean Cumulative Dose, mg/kg§ │ 0.74 0.50–1.11 .144 - - - - - -
Benzodiazepine Mean Daily Dose, mg/kg§ k 0.70 0.35–1.40 .318 1.09 0.63–1.88 .768 1.16 0.69–1.96 .569
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; d, days; HR, hazard ratio; ICU, intensive care unit; y, years.
�
Except for the drug variables where medication is missing in five of the 159 patients.
� �
Recorded by the patients´ medical team as the diagnosis most representative of the reason for ICU admission.
¶ Delirium burden during hospital stay is calculated by dividing the number of delirium days by the number of days assessed for delirium and it ranges from 0.00 to
1.00.
† Total length of hospital stay represents the summation of ICU and hospital ward days.
│Mean cumulative dose of a drug represents the drug amount patient received during the entire hospital stay.
k Mean daily dose of a drug was calculated by dividing the mean cumulative dose of the drug by the total length of hospital stay.
‡ Opiate exposure includes patients’ intake of hydromorphone, morphine, oxycodone, and/or fentanyl. It is expressed in fentanyl equivalents, such that 100mcg
fentanyl = 0.75mg hydromorphone = 5mg morphine = 3.33mg oxycodone [51, 52].
§ Benzodiazepine exposure summarizes patients’ intake of lorazepam, diazepam, and/or midazolam. It is expressed in midazolam equivalents, such that 2.5mg
midazolam = 1mg lorazepam = 5mg diazepam [53].
Note: HR of all drug doses are not interpretable since drug doses were log-transformed using (sin(x)� log(|x|+1)) and then standardized (Z-score).
(Table 3). In-hospital DB remained a significant predictor of mortality 2.5 years following ICU
admission after adjusting for covariates, showing a >4-fold increase in risk of death (aHR,
4.77; CI, 2.10–10.83; P < .001) (Table 3), unlike delirium burden in the ICU-only which was
not associated with mortality (HR, 1.79; 0.93–3.44; P = .082).
There was no significant association between mortality during the 2.5 years of follow-up
and delirium days during hospital stay in the univariate (HR, 0.98; 0.94–1.03; P = .535) and
multivariate (aHR, 0.97; 0.92–1.03; P = .338) analyses. Similarly, a significant association
between mortality up to 2.5 years of follow-up and ICU delirium days was not present in the
univariate (HR 1.00; 0.93–1.08; P = .917) and multivariate (aHR 1.01; 0.93–1.10; P = .741)
analyses.

Fig 2. Survival according to delirium burden (DB). Cox adjusted survival curve for 2.5-years survival post-ICU
admission according to DB during hospital stay (i.e. ICU + hospital wards) (N = 154). DB is categorized into low
(N = 53), medium (N = 50) and high (N = 51) DB groups, which in turn represent the low-, middle-, and high- tertile
groups for DB, respectively. DB ranges from 0.00 to 1.00 and is calculated by dividing the number of delirium days
patients experienced delirium over the number of days patients were assessed for delirium. Low, medium, and high DB
groups represent DB ranging from 0.00–0.111 (i.e. low tertile), >0.111–0.474 (middle-tertile), >0.474–1.000 (high-
tertile), respectively. The estimated adjusted survival rates at 2.5 years post-ICU admission were 67%, 65%, and 44% for
the low, medium, and high DB cohorts, respectively. This dataset includes 154 patients only as medication data is
missing in five of the original 159 patients. Covariates adjusted for include age, the Charlson Comorbidity Index,
APACHE II score, and mean daily doses of dexmedetomidine (mcg/kg), opiate (mcg/kg), propofol (mg/kg), and
benzodiazepine (mg/kg).
Delirium burden and functional neurological outcome

Fig 3E–3H and S2 Table show the association between DB categorized into low and high tertile
groups and functional outcome. The percentage of patients with poor GOS (1 to 3) was larger
in patients with high delirium burden: the high tertile delirium burden group had an extra
29%, 27%, 29% and 27% of patients with a lower GOS at discharge, 3, 6, and 12 months follow-
ing discharge compared to patients with low delirium burden representing the low tertile DB
group.
In the unadjusted ordinal regression analysis, increased DB during hospitalization was
associated with worse GOS at all follow up times (S3 Table). The effect of delirium burden dur-
ing hospitalization on worse GOS remained significant at all-time points, including discharge
(adjusted odds ratio [aOR], 0.02; 95% CI, 0.01–0.09; P < .001), 3 (aOR, 0.11; 0.04–0.31; P <
.001), 6 (aOR, 0.10; 0.04–0.29; P < .001), and 12 months (aOR, 0.19; 0.07–0.52; P = .001) after
adjusting for covariates (Table 4). Conducting a sub-analysis excluding patients who died (i.e.
patients with GOS score 1), increased in-hospital delirium burden was significantly associated
with worse GOS at discharge but did not reach statistical significance for GOS at 3, 6, and
12-months after adjusting for covariates (GOS at discharge [N = 129]: aOR, 0.03; 95% CI,
0.00–0.36; P = .015; 3 months [N = 124]: aOR, 0.90; 0.24–3.35; P = 0.880; 6 months [N = 121]:
aOR, 0.70; 0.18–2.47; P = .558); 12 months [N = 110]: aOR, 0.49; 0.12–1.94; P = .312).
Compared to DB accounting for the entire hospital stay, DB during ICU only was a weaker
predictor of functional neurologic outcomes after adjusting for covariates (GOS at discharge:

Fig 3. Distribution of scores on the Glasgow Outcome Scale (GOS). A measure of functional neurological outcome,
at hospital discharge and 3 months, 6 months, and 1 year after hospital discharge according to the presence or absence
of delirium during hospital stay (i.e. ICU + hospital wards) (N = 159) (A.—D.) and in-hospital delirium burden (DB)
(N = 107) (E.—H.) in mechanically ventilated intensive care unit patients. The GOS is a global 5-point scale for
functional neurological outcome that rates patient status into one of five categories: 1, Dead; 2, Persistent Vegetative
State; 3, Severe Disability; 4, Moderate Disability or 5, Good Recovery. In-hospital delirium burden ranges from 0.00 to
1.00 and is calculated by dividing the number of in-hospital (ICU + hospital wards) delirium days patients experienced
delirium over the number of days patients were assessed for delirium. Low and high DB groups correspond to the low-
tertile (N = 54, DB 0.000–0.111) and high-tertile (N = 53, DB >0.468–1.000) DB groups, respectively. The numbers in
the bars are percentages of patients who had each score. The percentages may not sum to 100 because of rounding. The
list of the number of patients according to their delirium status with each GOS score are provided in S2 Table.
aOR, 0.14; 0.05–0.40 P < .001; 3 months: aOR, 0.38; 0.16–0.88; P = .025; 6 months: aOR, 0.42;
0.18–0.98; P = .047; 12 months: aOR, 0.61; 0.26–1.41; P = .250).
There was no significant association between delirium days during hospitalization nor
between delirium days in the ICU and GOS at any time point, except for the association
between ICU delirium days and GOS at discharge which reached statistical significance (OR,
0.90; 0.81–0.99, P = .038) (S3 Table).
Acute brain dysfunction burden and mortality and functional neurological

outcomes
Coma days were not adjusted within delirium burden, potentially skewing the outcomes
observed. This is particularly relevant as patients in the delirium group had a higher number

Table 4. Multivariate ordinal regression analysis: Delirium burden and acute brain dysfunction Burden as predictors of functional neurological outcome, as
assessed by the Glasgow outcome scale¥, at discharge, and 3, 6, and 12 months post-discharge in mechanically ventilated ICU patients (N = 154).
Delirium Burden in ICU and wards Acute Brain Dysfunction Burden in-ICU and
wards†
Adjusted OR˟ 95% CI Adjusted P value Adjusted OR˟ 95% CI Adjusted P value
Discharge (N = 129) 0.02 0.01–0.09 < .001 0.02 0.00–0.09 < .001
3 months (N = 124) 0.11 0.04–0.31 < .001 0.11 0.03–0.31 < .001
6 months (N = 121) 0.10 0.04–0.29 < .001 0.09 0.03–0.27 < .001
1 year (N = 110) 0.19 0.07–0.52 .001 0.16 0.05–0.47 .001
Abbreviations: CI, confidence interval; OR, odds ratio.

¥
Glasgow Outcome Scale is a 5-point functional outcome scale, where score of 1 corresponds to death; 2, to persistent vegetative state; 3, to severe disability; 4, to
moderate disability; and 5 to good recovery [39].
˟ Variables with a proportional odds ratio (OR) >1 are associated with greater odds of a favorable functional neurological outcome whereas variables with a
proportional OR < 1 are associated with increased odds of an unfavorable functional neurological outcome.
¶ Delirium burden during hospital stay is calculated by dividing the number of delirium days by the number of days assessed for delirium and it ranges from 0.00 to
1.00.
† Acute Brain Dysfunction Burden is determined by dividing the number of delirium and coma days by the number of days assessed for delirium and coma and it
ranges from 0.00 to 1.00.
of coma days compared to the non-delirium group even though the two groups had a similar
proportion of patients who developed coma (Table 2). Hence, we tested the effect of acute
brain dysfunction burden which represents the fraction of hospital days patients were delirious
or comatose on mortality and functional neurological outcomes.
In-hospital acute brain dysfunction burden was associated with a >5-fold increase in the
risk of death at 2.5 years following ICU admission (aHR 5.59; 2.19–14.26; P < .001). In-hospi-
tal acute brain dysfunction burden was also a significant predictor of worse functional neuro-
logic outcomes at discharge after adjusting for confounders (aOR, 0.02; 0.00–0.09; P < .001), 3
months (aOR, 0.11; 0.03–0.31; P < .001), 6 months (aOR, 0.09; 0.03–0.27; P < .001) and 12
months (aOR, 0.16; 0.05–0.47; P = .001) (Table 4).
Discussion
In this prospective observational cohort study involving mechanically ventilated adult
ICU patients, we describe a novel normalized measure of delirium burden called delirium
burden (DB) which, unlike delirium days, is unaffected by patient’s survival status. We
found that in-hospital delirium burden independently predicts mortality at 2.5 years of
follow-up and worse long-term functional neurological outcomes after adjusting for age,
illness severity, medical comorbidities, and exposure to sedative and analgesic medica-
tions. In-hospital delirium burden was independently associated with >4-fold increase in
risk of death at 2.5 years, with a difference in mortality by 2.5 years between the high and
low delirium burden groups of 23%, and poorer neurologic outcomes. The high delirium
burden group had an extra 29%, 27%, 29% and 27% of patients with a lower GOS at dis-
charge, and 3, 6, and 12 months compared to patients with low delirium burden. Delirium
burden in the ICU-only was not significantly associated with mortality and predicted neu-
rologic outcomes less strongly than DB accounting for the entire hospital stay. Similarly,
delirium days in the ICU and for whole-hospitalization were not associated with mortality
nor with functional outcomes, except for the association between delirium days in ICU
and neurological outcome at discharge.

Delirium burden and mortality

Our results add to previous findings of strong associations of delirium with a range of adverse
clinical outcomes, including mortality, institutionalization after hospital discharge, and long-
term cognitive impairment [4–32, 37, 38, 54]. The delirium- and delirium burden-attributable
increase in mortality in our study (aHRs, 2.42 and 4.77 respectively) are similar to other studies
looking at the effect of delirium on mortality with a follow-up ranging from hospital/ICU dis-
charge to five years after discharge (adjusted HR, 1.7–4.8) [2, 7, 10, 13, 14, 17–20, 24–31, 54],
although two other studies reported an even higher increase in mortality (adjusted odds ratios
7.35 and 13.0) [15, 16]. These differences may be due to the differences in patient populations,
follow-up times, rates of loss to follow-up and withdrawal, and covariates used in the models.
The impact of ICU-only vs. whole hospital stay delirium on mortality and
neurological outcomes
In-hospital delirium burden was a significant predictor of mortality, unlike delirium burden in
the ICU-only which was not associated with mortality. Similarly, DB accounting for entire
hospital stay predicted neurologic outcome more strongly than DB during ICU stay alone.
This suggests that delirium persisting post-ICU discharge is associated with additional mor-
bidity and mortality compared to ICU delirium only. This finding fits with literature showing
that hospital delirium outside the ICU is prevalent [55]. Therefore, our study supports recom-
mendations to assess for delirium throughout the hospital stay.
Delirium’s effects on neurologic outcome persist by 12 months

In our study, in-hospital delirium burden independently predicted worse long-term functional
neurological outcomes at discharge, 3, 6, and 12 months following discharge even after adjust-
ing for confounders. This corroborates other studies that have shown an association between
delirium and worse cognitive function [4, 9, 11, 13, 22, 54, 56]. The gap between functional
neurological status in the high delirium burden and low delirium burden cohorts remained
markedly wide and relatively constant from hospital discharge to 12 months following dis-
charge. Specifically, the percentage of patients with poor GOS scores (1 to 3) was 30% at dis-
charge and 27% at 1 year follow-up. This was accounted for by two factors. First, the relative
proportion of patients in both groups with a poor GOS who recovered throughout the 12
months was similar. Second, while mortality in the delirium group was highest during the first
month and half after ICU admission, as in other studies [7, 15, 18–20, 28, 31, 32, 36, 57], high-
and low-delirium burden associated mortality continued to accrue at a proportional rate to
almost 2.5 years after enrollment. These findings suggest that in-hospital delirium continues to
have long-lasting functional effects long after hospital discharge.
Delirium burden vs. delirium days as predictors of mortality and

neurological outcomes
Previous studies have found that the number of days of ICU delirium is associated with mor-
tality [7, 21, 36–38, 57] and worse long-term global cognition and executive function at 3 and
12 months [4, 11]. Further, prolonged delirium has been associated with smaller brain volumes
and white matter disruption [58, 59]. Interestingly, in our cohort, delirium days in the ICU
and for whole-hospitalization were not associated with mortality. Similarly, ICU and in-hospi-
tal delirium days were generally not associated with functional outcomes, except for the associ-
ation between delirium days in ICU and GOS at discharge. By contrast, DB was strongly
associated with worse outcomes. This apparent discrepancy may be explained by the smaller

sample size of our cohort, in combination with the decreased sensitivity of delirium days as a
measure of delirium burden, confounded by survival status and hospital length of stay.
Acute brain dysfunction and mortality and neurological outcomes. The absence of a
significant association between the presence of acute brain dysfunction and mortality at 2.5
years post ICU admission might be related to the small sample (N = 6) of patients without
acute brain dysfunction. Differently, acute brain dysfunction burden was an independent pre-
dictor of overall mortality and functional neurological status outcomes at discharge, 3-, 6-, and
12-months follow-up. The hazard and odds ratio and P values in relation to mortality and
functional neurological outcomes for acute brain dysfunction burden and delirium burden
were overall similar. Hence, in this study, the added value of accounting for coma days when
assessing the relationship between delirium and mortality and functional neurological out-
comes appears to be minimal. This is possibly due to the fact that the many of the of coma days
were medically induced as demonstrated by the fact that 97% and 90% of patients from the
delirium and non-delirium cohorts, respectively, received propofol.
Conflicting results: Causality; potential explanations

Previous studies have yielded contradictory results regarding the impact of delirium on long-
term mortality. Namely, some studies identified delirium as an independent predictor of death
[2, 7, 10, 13–20, 24–32, 54], while others have shown no association with mortality [5, 6, 8, 21–
23, 60–62]. These inconsistencies may be partly explained by the differences in case mix, fol-
low-up time, rates of loss to follow-up, model misspecification, and confounding [21, 63].
Most of the previous studies had a follow-up time up to 1 year. The ability of our study to dem-
onstrate an effect of delirium on mortality may be related to the study’s longer follow-up, pro-
viding more time for the medical sequela of delirium to yield an impact; and our measurement
of delirium during the entire hospital stay rather than ICU stay only.
Since delirious and non-delirious patients had a similar burden of comorbid conditions at
baseline, our results suggest that in-hospital delirium may be a causal factor for the increased
mortality and worse functional neurological outcomes seen in delirious patients. This finding
corroborates the need for randomized controlled trials to evaluate whether prevention and
treatment of in-hospital delirium changes clinical outcomes including long-term mortality
and functional neurological outcomes among survivors of critical illness.
Clinical implications of our study

The common clinical perception is that delirium is often a transient condition with no long-
term serious adverse outcomes. The results of this study show that in-hospital delirium is a
strong independent predictor of 2.5 year survival and functional neurological status at dis-
charge and long-term follow-up. Thereby, guidelines should emphasize the importance of in-
hospital delirium prevention and treatment given the substantial public health relevance and
associated burden of delirium-related downstream complications and costs. Moreover,
patients experiencing in-hospital delirium should also be assessed for delirium burden as the
latter provides additional prognostic information in term of future survival and functional
neurological recovery to delirium status alone. Our study also shows that calculating delirium
burden using delirium burden measured as the fraction of hospital days spent in delirium is a
feasible and informative approach and a more sensitive metric of delirium burden compared
to delirium days. Finally, we recommend that for patients initially admitted to the ICU, the
assessment of delirium and delirium burden continues post-ICU discharge and in the hospital
wards rather than being limited to the ICU stay, as the former is a more accurate marker of the
effects of delirium on survival and functional neurological outcomes.

Limitations of our study

There are important limitations to our study. First, we performed only once-daily CAM-ICU
assessments; twice daily assessments might have detected a higher prevalence of delirium.
Second, the number of days patients were assessed for delirium was lower than the length
of hospital stay after ICU admission by 31% (1–2941 days/4282 days). This is partly due to the
fact that patients were not always enrolled on the first day of ICU admission, and partly
because at times study staff missed delirium assessment on days when patients were not in the
room when they came to evaluate the patients. The missing days from before ICU admission
might mean that the incidence of delirium is somewhat underestimated. The missing days
after enrollment, however, were essentially random (due to time of study staff visits) and
should have relatively little effect on our measure of delirium burden, since by design “days
with delirium divided by days assessed” omits days when assessments were not done.
Third, mortality and functional neurological outcomes as measured by the GOS after hospi-
tal discharge were abstracted from patient chart review which may be less accurate than
obtaining the data directly from patient or family members themselves.
Fourth, the presence of delirium on the floor before patients were admitted to the ICU was
not accounted for, thereby potentially under-estimating hospital delirium duration.
Fifth, we used the CAM-ICU to assess for delirium throughout our study. The CAM-ICU
has primarily been validated within the ICU, and although specificity is maintained in non-
ICU settings, it may be less sensitive outside of the ICU [64]. We continued to assess patients
once they left the ICU with the CAM-ICU, however, as it is algorithmically similar to the non-
ICU version, the Confusion Assessment Method [65], and to maintain consistency throughout
hospitalization.
Finally, it remains unknown whether delirium causes poor outcomes or is an epiphenome-
non. Recent evidence suggests that the brain, particularly microglia, produces its own inflam-
matory response to injury [66, 67], which may influence other organs and may influence
survival in delirium. Activated microglia cause phagocytosis and produce inflammatory medi-
ators, such as cytokines and proteases, that weaken astrocytic tight junctions and induce neural
loss and neurodegeneration [68, 69]. Delirium is known to be associated with neuronal apo-
ptosis, cerebral atrophy and reduced white-matter integrity. These neuroanatomical changes
are associated with long-term cognitive impairment [58, 59]. On the other hand, in support of
the epiphenomenon hypothesis, a recent meta-analysis failed to show that ICU interventions
that reduce delirium duration reduce short-term mortality [70]. Given the observational
nature of our study we cannot resolve this question.
Conclusion
Normalized delirium burden, measured as the fraction of hospital days spent in delirium, is
associated with higher mortality and worse long-term functional neurological outcomes
among mechanically ventilated ICU patients up to 2.5 years following critical illness, and more
strongly predicts mortality and neurologic outcomes than delirium burden in the ICU alone
and cumulative number of delirium days, even after adjusting for age, illness severity, comor-
bid conditions, and use of sedatives and analgesics in ICU patients receiving mechanical
ventilation.
Supporting information
S1 Fig. Flow of patients in study cohort.
(PDF)

S2 Fig. Correlation matrix of study variables.

(PDF)
S3 Fig. Kaplan-Meier curve for 2.5-years survival post-ICU admission according to the
presence of absence of delirium in the ICU and/or floor (N = 159).
(PDF)
S4 Fig. Cox-adjusted survival curve for 2.5-year survival post-ICU admission according to
delirium and coma status in the ICU and/or floor (N = 154).
(PDF)
S5 Fig. Cox-adjusted survival curve for 2.5-year survival post-ICU admission according to
the presence or absence of acute brain dysfunction in the ICU and/or floor (N = 154).
(PDF)
S6 Fig. Box-Plot comparison of delirium burden during hospital stay between the alive
and deceased cohort of patients at the end of the 2.5 years follow-up (N = 159).
(PDF)
S7 Fig. Kaplan-Meier curve for 2.5-year survival post-ICU admission according to delirium
burden in the ICU and/or floor (N = 159).
(PDF)
S1 Text. Calculation of conversion factors for opiate and benzodiazepine.
(PDF)
S2 Text. Characteristics of patients who remained in persistent coma during hospital stay
(N = 19).
(PDF)
S1 Table. Mean cumulative and daily doses of sedative and analgesic agents during hospital
stay (N = 154).
(PDF)
S2 Table. Patients’ Glasgow outcome scale at hospital discharge and 3 months, 6 months,
and 1 year after hospital discharge according to their in-hospital (ICU and hospital ward)
delirium status (N = 159).
(PDF)
S3 Table. Univariate ordinal regression analysis: Predictors of functional neurological out-
come, as assessed by the Glasgow outcome scale, at discharge and 3, 6, and 12 months
post-discharge in mechanically ventilated ICU patients (N = 159).
(PDF)
S1 Data.
(CSV)
Author Contributions
Conceptualization: Luis Paixao, Haoqi Sun, M. Brandon Westover.
Data curation: Luis Paixao, Haoqi Sun, Jacob Hogan, Katie Hartnack, Mike Westmeijer, Anu-
deepthi Neelagiri, David W. Zhou, Lauren M. McClain, Eyal Y. Kimchi, Patrick L. Purdon,
Oluwaseun Akeju, M. Brandon Westover.
Formal analysis: Luis Paixao, Haoqi Sun, Jacob Hogan, M. Brandon Westover.

Funding acquisition: M. Brandon Westover.

Investigation: Luis Paixao, Haoqi Sun, Katie Hartnack, Mike Westmeijer, Anudeepthi Neela-
giri, David W. Zhou, Lauren M. McClain, Eyal Y. Kimchi, Patrick L. Purdon, Oluwaseun
Akeju, M. Brandon Westover.
Methodology: Luis Paixao, Haoqi Sun, M. Brandon Westover.
Project administration: Luis Paixao, Haoqi Sun, M. Brandon Westover.
Resources: Luis Paixao, Haoqi Sun, M. Brandon Westover.
Software: Luis Paixao, Haoqi Sun, M. Brandon Westover.
Supervision: M. Brandon Westover.
Validation: Haoqi Sun, Jacob Hogan, M. Brandon Westover.
Visualization: Luis Paixao, Haoqi Sun, Jacob Hogan, M. Brandon Westover.
Writing – original draft: Luis Paixao, M. Brandon Westover.
Writing – review & editing: Luis Paixao, Haoqi Sun, Jacob Hogan, Katie Hartnack, Mike
Westmeijer, Anudeepthi Neelagiri, David W. Zhou, Lauren M. McClain, Eyal Y. Kimchi,
Patrick L. Purdon, Oluwaseun Akeju, M. Brandon Westover.
References
1. Van Den Boogaard M, Pickkers P, Slooter AJC, Kuiper MA, Spronk PE, Van Der Voort PHJ, et al.
Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium predic-
tion model for intensive care patients: Observational multicentre study. BMJ. 2012; 344:e420. https://
doi.org/10.1136/bmj.e420 PMID: 22323509
2. Salluh JI, Soares M, Teles JM, Ceraso D, Raimondi N, Nava VS, et al. Delirium epidemiology in critical
care (DECCA): An international study. Crit Care. 2010; 14(6):R210. https://doi.org/10.1186/cc9333
PMID: 21092264
3. Ely EW, Siegel MD, Inouye SK. Delirium in the intensive care unit: an under-recognized syndrome of
organ dysfunction. Semin Respir Crit Care Med. 2001; 22(2):115–26. https://doi.org/10.1055/s-2001-
13826 PMID: 16088667
4. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-Term Cogni-
tive Impairment after Critical Illness. N Engl J Med. 2013; 369(14):1306–16. https://doi.org/10.1056/
NEJMoa1301372 PMID: 24088092
5. Levkoff SE, Evans DA, Liptzin B, Cleary PD, Lipsitz LA, Wetle TT, et al. Delirium. The occurrence and
persistence of symptoms among elderly hospitalized patients. Arch Intern Med. 1992; 152(2):334–40.
https://doi.org/10.1001/archinte.152.2.334 PMID: 1739363
6. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990;
263(8):1097–101. PMID: 2299782
7. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FEJ, et al. Delirium as a Predictor of Mor-
tality in Mechanically Ventilated Patients in the Intensive Care Unit. JAMA. 2004; 291(14):1753–62.
https://doi.org/10.1001/jama.291.14.1753 PMID: 15082703
8. Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital
outcomes? A three-site epidemiologic study. J Gen Intern Med. 1998; 13(4):234–42. https://doi.org/10.
1046/j.1525-1497.1998.00073.x PMID: 9565386
9. Van Den Boogaard M, Schoonhoven L, Evers AWM, Van Der Hoeven JG, Van Achterberg T, Pickkers
P. Delirium in critically ill Patients: Impact on long-term health-related quality of life and cognitive func-
tioning. Crit Care Med. 2012; 40(1):112–8. https://doi.org/10.1097/CCM.0b013e31822e9fc9 PMID:
21926597
10. Witlox J, Eurelings LSM, de Jonghe JFM, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in
Elderly Patients and the Risk of Postdischarge Mortality, Institutionalization, and Dementia. JAMA.
2010; 304(4):443–51. https://doi.org/10.1001/jama.2010.1013 PMID: 20664045

11. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, et al. Delirium as a
Predictor of Long-Term Cognitive Impairment in Survivors of Critical Illness. Crit Care Med. 2010; 38
(7):1513–20. https://doi.org/10.1097/CCM.0b013e3181e47be1 PMID: 20473145
12. Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, et al. The impact of delirium in the intensive
care unit on hospital length of stay. Intensive Care Med. 2001; 27(12):1892–900. https://doi.org/10.
1007/s00134-001-1132-2 PMID: 11797025
13. Francis J, Kapoor WN. Prognosis after Hospital Discharge of Older Medical Patients with Delirium. J
Am Geriatr Soc. 1992; 40(6):601–6. https://doi.org/10.1111/j.1532-5415.1992.tb02111.x PMID:
1587979
14. Curyto KJ, Johnson J, TenHave T, Mossey J, Knott K, Katz IR. Survival of hospitalized elderly patients
with delirium: A prospective study. Am J Geriatr Psychiatry. 2001; 9(2):141–7. PMID: 11316618
15. Lin S-M, Liu C-Y, Wang C-H, Lin H-C, Huang C-D, Huang P-Y, et al. The impact of delirium on the sur-
vival of mechanically ventilated patients. Crit Care Med. 2004; 32(11):2254–9. https://doi.org/10.1097/
01.ccm.0000145587.16421.bb PMID: 15640638
16. Moskowitz EE, Overbey DM, Jones TS, Jones EL, Arcomano TR, Moore JT, et al. Post-operative delir-
ium is associated with increased 5-year mortality. Am J Surg. 2017; 214(6):1036–8. https://doi.org/10.
1016/j.amjsurg.2017.08.034 PMID: 28947274
17. van den Boogaard M, Peters SAE, van der Hoeven JG, Dagnelie PC, Leffers P, Pickkers P, et al. The
impact of delirium on the prediction of in-hospital mortality in intensive care patients. Crit Care. 2010; 14
(4):R146. https://doi.org/10.1186/cc9214 PMID: 20682037
18. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU
delirium. Intensive Care Med. 2007; 33(1):66–73. https://doi.org/10.1007/s00134-006-0399-8 PMID:
17102966
19. Leslie DL, Zhang Y, Holford TR, Bogardus ST, Leo-Summers LS, Inouye SK. Premature death associ-
ated with delirium at 1-year follow-up. Arch Intern Med. 2005; 165(14):1657–62. https://doi.org/10.1001/
archinte.165.14.1657 PMID: 16043686
20. McCusker J, Cole M, Abrahamowicz M, Primeau F, Belzile E. Delirium Predicts 12-Month Mortality.
Arch Intern Med. 2002; 162(4):457–63. https://doi.org/10.1001/archinte.162.4.457 PMID: 11863480
21. Klein Klouwenberg PMC, Zaal IJ, Spitoni C, Ong DSY, van der Kooi AW, Bonten MJM, et al. The attrib-
utable mortality of delirium in critically ill patients: prospective cohort study. BMJ. 2014; 349:g6652.
https://doi.org/10.1136/bmj.g6652 PMID: 25422275
22. Wolters AE, van Dijk D, Pasma W, Cremer OL, Looije MF, de Lange DW, et al. Long-term outcome of
delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study. Crit
Care. 2014; 18(3):R125. https://doi.org/10.1186/cc13929 PMID: 24942154
23. Thomason JWW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is
an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients.
Crit Care. 2005; 9(4):R375–81. https://doi.org/10.1186/cc3729 PMID: 16137350
24. Abelha FJ, Luı́s C, Veiga D, Parente D, Fernandes V, Santos P, et al. Outcome and quality of life in
patients with postoperative delirium during an ICU stay following major surgery. Crit Care. 2013; 17(5):
R257. https://doi.org/10.1186/cc13084 PMID: 24168808
25. Van Rompaey B, Schuurmans MJ, Shortridge-Baggett LM, Truijen S, Elseviers M, Bossaert L. Long
term outcome after delirium in the intensive care unit. J Clin Nurs. 2009; 18(23):3349–57. https://doi.
org/10.1111/j.1365-2702.2009.02933.x PMID: 19735334
26. de Jong L, van Rijckevorsel VAJIM, Raats JW, Klem TMAL, Kuijper TM, Roukema GR. Delirium after
hip hemiarthroplasty for proximal femoral fractures in elderly patients: Risk factors and clinical out-
comes. Clin Interv Aging. 2019; 14:427–35. https://doi.org/10.2147/CIA.S189760 PMID: 30880924
27. Pauley E, Lishmanov A, Schumann S, Gala GJ, Van Diepen S, Katz JN. Delirium is a robust predictor of
morbidity and mortality among critically ill patients treated in the cardiac intensive care unit. Am Heart J.
2015; 170(1):79–86. https://doi.org/10.1016/j.ahj.2015.04.013 PMID: 26093867
28. Israni J, Lesser A, Kent T, Ko K. Delirium as a predictor of mortality in US Medicare beneficiaries dis-
charged from the emergency department: A national claims-level analysis up to 12 months. BMJ Open.
2018; 8(5):e021258. https://doi.org/10.1136/bmjopen-2017-021258 PMID: 29730630
29. Chan KY, Cheng LS, Mak IW, Ng SW, Yiu MG, Chu CM. Delirium is a Strong Predictor of Mortality in
Patients Receiving Non-invasive Positive Pressure Ventilation. Lung. 2017; 195(1):115–25. https://doi.
org/10.1007/s00408-016-9955-3 PMID: 27787611
30. McAvay GJ, Van Ness PH, Bogardus ST, Zhang Y, Leslie DL, Leo-Summers LS, et al. Older adults dis-
charged from the hospital with delirium: 1-year outcomes. J Am Geriatr Soc. 2006; 54(8):1245–50.
https://doi.org/10.1111/j.1532-5415.2006.00815.x PMID: 16913993

31. Eeles EMP, Hubbard RE, White SV, O’Mahony MS, Savva GM, Bayer AJ. Hospital use, institutionalisa-
tion and mortality associated with delirium. Age Ageing. 2010; 39(4):470–5. https://doi.org/10.1093/
ageing/afq052 PMID: 20554540
32. Marcantonio ER, Flacker JM, Michaels M, Resnick NM. Delirium Is Independently Associated with Poor
Functional Recovery After Hip Fracture. J Am Geriatr Soc. 2000; 48(6):618–24. https://doi.org/10.1111/
j.1532-5415.2000.tb04718.x PMID: 10855596
33. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in Mechanically Ventilated
Patients: Validity and Reliability of the Confusion Assessment Method for the Intensive Care Unit
(CAM-ICU). JAMA. 2001; 286(21):2703–10. https://doi.org/10.1001/jama.286.21.2703 PMID:
11730446
34. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal P V., Keane KA, et al. The Richmond Agitation-
Sedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med.
2002; 166(10):1338–44. https://doi.org/10.1164/rccm.2107138 PMID: 12421743
35. Ely EW, Truman B, Thomason JWW, Wheeler AP, Gordon S, Francis J, et al. Monitoring Sedation Sta-
tus Over Time in ICU Patients: Reliability and validity of the Richmond Agitation-Sedation Scale
(RASS). JAMA. 2003; 289(22):2983–91. https://doi.org/10.1001/jama.289.22.2983 PMID: 12799407
36. Pisani MA, Kong SYJ, Kasl SV, Murphy TE, Araujo KLB, Van Ness PH. Days of delirium are associated
with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009; 180
(11):1092–7. https://doi.org/10.1164/rccm.200904-0537OC PMID: 19745202
37. Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW. Delirium duration and mortality
in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med. 2010; 38(12):2311–8.
https://doi.org/10.1097/CCM.0b013e3181f85759 PMID: 20838332
38. Kiely DK, Marcantonio ER, Inouye SK, Shaffer ML, Bergmann MA, Yang FM, et al. Persistent Delirium
Predicts Increased Mortality. J Am Geriatr Soc. 2009; 57(1):55–61. https://doi.org/10.1111/j.1532-
5415.2008.02092.x PMID: 19170790
39. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975; 1(7905):480–4.
https://doi.org/10.1016/s0140-6736(75)92830-5 PMID: 46957
40. McMillan T, Wilson L, Ponsford J, Levin H, Teasdale G, Bond M. The Glasgow Outcome Scale—40
years of application and refinement. Nat Rev Neurol. 2016; 12(8):477–85. https://doi.org/10.1038/
nrneurol.2016.89 PMID: 27418377
41. Brooks DN, Hosie J, Bond MR, Jennett B, Aughton M. Cognitive sequelae of severe head injury in rela-
tion to the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 1986; 49(5):549–53. https://doi.
org/10.1136/jnnp.49.5.549 PMID: 3711917
42. Wilson JTL, Pettigrew LEL, Teasdale GM. Structured interviews for the glasgow outcome scale and the
extended glasgow outcome scale: Guidelines for their use. J Neurotrauma. 1998; 15(8):573–80. https://
doi.org/10.1089/neu.1998.15.573 PMID: 9726257
43. Wilson JTL, Pettigrew LEL, Teasdale GM. Emotional and cognitive consequences of head injury in rela-
tion to the Glasgow outcome scale. J Neurol Neurosurg Psychiatry. 2000; 69(2):204–9. https://doi.org/
10.1136/jnnp.69.2.204 PMID: 10896694
44. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administra-
tive databases. J Clin Epidemiol. 1992; 45(6):613–9. https://doi.org/10.1016/0895-4356(92)90133-8
PMID: 1607900
45. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification
system. Crit Care Med. 1985. p. 13(10):818–29. PMID: 3928249
46. R Core Team. R: A language and environment for statistical computing. Team RC, editor. Vienna, Aus-
tria: R Foundation for Statistical Computing 2017. Available at: https://www.R-project.org/.
47. McHugh GS, Butcher I, Steyerberg EW, Marmarou A, Lu J, Lingsma HF, et al. A simulation study evalu-
ating approaches to the analysis of ordinal outcome data in randomized controlled trials in traumatic
brain injury: results from the IMPACT Project. Clin Trials. 2010; 7(1):44–57. https://doi.org/10.1177/
1740774509356580 PMID: 20156956
48. Altman DG, Royston P. The cost of dichotomising continuous variables. BMJ. 2006; 332(7549):1080.
https://doi.org/10.1136/bmj.332.7549.1080 PMID: 16675816
49. Torres-Reyna O. Logit, probit and multinomial logit models in R. v. 3.5. Princeton University. 2014.
Available at: https://www.princeton.edu/~otorres/LogitR101.pdf.
50. UCLA Institute for Digital Research & Education: Statistical Consulting Group. Ordinal Logistic Regres-
sion | R Data Analysis Examples. Available at: https://stats.idre.ucla.edu/r/dae/ordinal-logistic-
regression/.

51. Gammaitoni AR, Fine P, Alvarez N, McPherson ML, Bergmark S. Clinical application of opioid equianal-
gesic data. Clin J Pain. 2003; 19(5):286–97. https://doi.org/10.1097/00002508-200309000-00002
PMID: 12966254
52. Anderson R, Saiers JH, Abram S, Schlicht C. Accuracy in Equianalgesic Dosing: Conversion Dilemmas.
J Pain Symptom Manage. 2001 May; 21(5):397–406. https://doi.org/10.1016/s0885-3924(01)00271-8
PMID: 11369161
53. Dundee JW, McGowan WAW, Lilburn JK, McKay AC, Hegarty JE. Comparison of the actions of diazepam
and lorazepam. Br J Anaesth. 1979; 51(5):439–46. https://doi.org/10.1093/bja/51.5.439 PMID: 36117
54. Rockwood K, Cosway S, Carver D, Jarrett P, Stadnyk K, Fisk J. The risk of dementia and death after
delirium. Age Ageing. 1999; 28(6):551–6. https://doi.org/10.1093/ageing/28.6.551 PMID: 10604507
55. Pisani MA, Murphy TE, Araujo KLB, Van Ness PH. Factors associated with persistent delirium following
ICU admission in an older medical patient population. J Crit Care. 2010; 25(3):540.e1–7.
56. Jackson JC, Gordon SM, Girard TD, Thomason JWW, Pun BT, Dunn J, et al. Delirium as a risk factor
for long term cognitive impairment in mechanically ventilated ICU survivors. Am J Respir Crit Care Med.
2007; 175:A22.
57. Bellelli G, Mazzola P, Morandi A, Bruni A, Carnevali L, Corsi M, et al. Duration of postoperative delirium
is an independent predictor of 6-month mortality in older adults after hip fracture. J Am Geriatr Soc.
2014; 62(7):1335–40. https://doi.org/10.1111/jgs.12885 PMID: 24890941
58. Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, et al. The association
between brain volumes, delirium duration and cognitive outcomes in intensive care unit survivors: A pro-
spective exploratory cohort magnetic resonance imaging study. Crit Care Med. 2012; 40(7):2022–32.
https://doi.org/10.1097/CCM.0b013e318250acc0 PMID: 22710202
59. Morandi A, Rogers BP, Gunther ML, Merkle K, Pandharipande P, Girard TD, et al. The relationship
between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survi-
vors as determined by diffusion tensor imaging. Crit Care Med. 2012; 40(7):2182–9. https://doi.org/10.
1097/CCM.0b013e318250acdc PMID: 22584766
60. Hamilton GM, Wheeler K, Di Michele J, Lalu MM, McIsaac DI. A Systematic Review and Meta-analysis
Examining the Impact of Incident Postoperative Delirium on Mortality. Anesthesiology. 2017; 127
(1):78–88. https://doi.org/10.1097/ALN.0000000000001660 PMID: 28459734
61. Dubois M-J, Bergeron N, Dumont M, Dial S, Skrobik Y. Delirium in an intensive care unit: a study of risk
factors. Intensive Care Med. 2001; 27(8):1297–304. https://doi.org/10.1007/s001340101017 PMID:
11511942
62. Furlaneto ME, Garcez-Leme LE. Impact of delirium on mortality and cognitive and functional perfor-
mance among elderly people with femoral fractures. Clinics (Sao Paulo). 2007; 62(5):545–52. https://
doi.org/10.1590/s1807-59322007000500003 PMID: 17952313
63. Zhang Z, Pan L, Ni H. Impact of delirium on clinical outcome in critically ill patients: A meta-analysis.
Gen Hosp Psychiatry. 2013; 35(2):105–11. https://doi.org/10.1016/j.genhosppsych.2012.11.003 PMID:
23218845
64. De J, Wand APF. Delirium Screening: A Systematic Review of Delirium Screening Tools in Hospitalized
Patients. Gerontologist. 2015; 55(6):1079–99. https://doi.org/10.1093/geront/gnv100 PMID: 26543179
65. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying Confusion: The Confu-
sion Assessment Method. A New Method for Detection of Delirium. Ann Intern Med. 1990; 113
(12):941–8. https://doi.org/10.7326/0003-4819-113-12-941 PMID: 2240918
66. Woiciechowsky C, Asadullah K, Nestler D, Eberhardt B, Platzer C, Schöning B, et al. Sympathetic acti-
vation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med.
1998; 4(7):808–13. https://doi.org/10.1038/nm0798-808 PMID: 9662372
67. Woiciechowsky C, Schöning B, Daberkow N, Asche K, Stoltenburg G, Lanksch WR, et al. Brain-IL-1β
induces local inflammation but systemic anti-inflammatory response through stimulation of both hypo-
thalamic-pituitary-adrenal axis and sympathetic nervous system. Brain Res. 1999; 816(2):563–71.
https://doi.org/10.1016/s0006-8993(98)01238-4 PMID: 9878881
68. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and
acetylcholine collide. Lancet. 2010; 375(9716):773–5. https://doi.org/10.1016/S0140-6736(09)61158-2
PMID: 20189029
69. Cunningham C. Systemic inflammation and delirium: important co-factors in the progression of demen-
tia. Biochem Soc Trans. 2011; 39(4):945–53. https://doi.org/10.1042/BST0390945 PMID: 21787328
70. Al-Qadheeb NS, Balk EM, Fraser GL, Skrobik Y, Riker RR, Kress JP, et al. Randomized ICU Trials Do
Not Demonstrate an Association Between Interventions That Reduce Delirium Duration and Short-
Term Mortality: A Systematic Review and Meta-Analysis. Crit Care Med. 2014; 42(6):1442–54. https://
doi.org/10.1097/CCM.0000000000000224 PMID: 24557420

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PLOS ONE

ICU delirium burden predicts functional

Citation: Paixao L, Sun H, Hogan J, Hartnack K,

Data Availability Statement: All relevant data are Results

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 1 / 20

Materials and methods

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PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 3 / 20

Management of missing data

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Sedative and analgesic agents use

Prevalence of delirium, coma, length of stay, and mortality

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 5 / 20

Table 1. Patients’ characteristics.

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Delirium burden and mortality

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Delirium burden and functional neurological outcome

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 10 / 20

Acute brain dysfunction burden and mortality and functional neurological

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 11 / 20

Abbreviations: CI, confidence interval; OR, odds ratio.

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 12 / 20

Delirium burden and mortality

Delirium’s effects on neurologic outcome persist by 12 months

Delirium burden vs. delirium days as predictors of mortality and

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 13 / 20

Conflicting results: Causality; potential explanations

Clinical implications of our study

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Limitations of our study

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S2 Fig. Correlation matrix of study variables.

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 16 / 20

Funding acquisition: M. Brandon Westover.

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PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 18 / 20

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 19 / 20

PLOS ONE | https://doi.org/10.1371/journal.pone.0259840 December 2, 2021 20 / 20

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