Long-Term Self-Reported Cognitive Problems After Delirium in
the Intensive Care Unit and the Effect of Systemic Inflammation
Annemiek E. Wolters, MD, MSc,* Linda M. Peelen, PhD,*
†
Dieuwke S. Veldhuijzen, PhD,*
‡
Irene J. Zaal, MD, PhD,* Dylan W. de Lange, MD, PhD,* Wietze Pasma, DVM,*
Diederik van Dijk, MD, PhD,* Olaf L. Cremer, MD, PhD,* and Arjen J. C. Slooter, MD, PhD*
OBJECTIVES: To describe the association between inten-
sive care unit (ICU) delirium and self-reported cognitive
problems in 1-year ICU survivors, and investigate whether
this association was altered by exposure to systemic
inflammation during ICU stay.
DESIGN: Prospective cohort study.
SETTING: Dutch medical-surgical ICU.
PARTICIPANTS: One-year ICU survivors, admitted to
the ICU ≥48 hours.
MEASUREMENTS: Self-reported cognitive problems
were measured with the Cognitive Failures Questionnaire
(CFQ). Cumulative exposure to systemic inflammation was
based on all daily C-reactive protein (CRP) measurements
during ICU stay, expressed as the area under the curve
(AUC). Multivariable linear regression was conducted to
evaluate the association between delirium and the CFQ.
The effect of inflammation on the association between
delirium and CFQ was assessed, comparing the effect esti-
mate (B) of delirium and CFQ between models with and
without inclusion of the AUC of CRP.
RESULTS: Among 567 1-year ICU survivors, the CFQ
was completed by 363 subjects. Subjects with multiple
days of delirium during ICU stay reported more self-
reported cognitive problems (Badj = 5.10, 95% CI 1.01–
9.20), whereas a single day delirium was not associated
with higher CFQ scores (Badj = 0.72, 95% CI 5.75 to
4.31). Including the AUC of CRP did not change the asso-
ciation between delirium and the CFQ (ratio for a single
and multiple days were respectively: 1.00, 95%CI 0.59–
1.44 and 0.86, 95% CI 0.47–1.16).
CONCLUSION: Multiple days of delirium was associated
with long-term self-reported cognitive problems. The
cumulative exposure to systemic inflammation did not
alter this association, suggesting that delirium in the con-
text of little inflammation is also detrimental. J Am Geriatr
Soc 65:786–791, 2017.
Key words: delirium; long-term self-reported cognitive
problems; systemic inflammation; C-reactive protein;
intensive care unit
I
ntensive care unit (ICU) survivors experience a substan-
tial amount of long-term morbidity, including problems
in cognitive functioning.
1,2
A pivotal risk factor for long-
term cognitive problems after ICU stay seems to be the
occurrence of delirium during critical illness.
3–6
Delirium
has a multifactorial pathophysiology, and it is usually not
possible to ascertain one specific cause of delirium in ICU
patients. Previous studies found acute systemic inflamma-
tion to be a risk factor for delirium
7–9
and also for
long-term cognitive impairment.
2,10
In rodent studies, neu-
roinflammation and neuronal loss was seen up to
10 months after systemic inflammation, induced by one
peripheral injection of lipopolysaccharide.
11
Persistent
neuroinflammation may thus explain why patients with
exposure to acute systemic inflammation and resulting
delirium develop long-term cognitive impairment.
8
Delir-
ium is, however, not exclusively associated with exposure
to acute systemic inflammation and can also result from
other causes, such as metabolic disturbances. Up until
now, it was unclear whether the association between delir-
ium and long-term self-reported cognitive problems was
mediated by the degree of exposure to acute systemic
inflammation.
8,9
Recent literature shows that rapidly-reversible seda-
tion-related delirium has a better outcome than persistent
From the *Department of Intensive Care Medicine, University Medical
Center Utrecht, Heidelberglaan 100, 3508 GA, Utrecht, The
Netherlands;
†
Department of Epidemiology, Julius Center for Health
Sciences and Primary Care, University Medical Center Utrecht, Utrecht,
The Netherlands; and
‡
Institute of Psychology, Health, Medical, and
Neuropsychology Unit, Leiden University, Leiden, The Netherlands.
Related paper presentations: Results of this study have been presented at
the 10th EDA/BGS Meeting, September 2015.
Address correspondence to Annemiek E. Wolters, Department of Intensive
Care Medicine, Room F.06.149, 3508 GA Utrecht, the Netherlands.
E-mail: a.e.wolters@umcutrecht.nl
DOI: 10.1111/jgs.14660
JAGS 65:786–791, 2017
© 2017, Copyright the Authors
Journal compilati on © 2017, The American Geriatrics Society 0002-8614/17/$15.00
delirium.
12
Although unstudied, it is plausible, that the
outcome of a very brief episode of delirium is also favor-
able, as compared to more delirium days in terms of cogni-
tion. The aim of this study was to investigate the
association of a single day or multiple days of ICU delir-
ium with long-term self-reported cognitive problems in
1-year ICU survivors, and to assess whether this associa-
tion was mediated by exposure to systemic inflammation
during ICU stay.
METHODS
Setting and Study Population
This prospective, observational study was conducted in
consecutively admitted adults, who stayed for at least
48 hours in the 32-bed mixed medical-surgical ICU of the
University Medical Center Utrecht (UMCU) between Jan-
uary 2011 and June 2013, and who were alive 1 year after
discharge. Survival status was determined by a query of
the Dutch municipal register. Excluded were subjects who
were transferred from an ICU of another hospital, as well
as subjects with an acute neurological illness or another
condition that could hamper delirium assessment. The
Medical Research Ethics Committee of the UMCU waived
the need for informed consent (protocols 12/421, 10/056
and 10/006).
Data Collection
A detailed description of the daily assessment of mental
status was recently published.
13
In brief, an algorithm was
used to evaluate daily mental status of each patient during
the preceding 24 hours (awake without delirium, delirium,
or coma). For this assessment, the Richmond Agitation
Sedation Scale (RASS)
14
and Confusion Assessment
Method for the ICU (CAM-ICU)
15
scores from the bedside
nurses were used, next to initiation of treatment with neu-
roleptic drugs in the previous 24 hours, chart review, and
an additional CAM-ICU by trained research nurses.
13
All subjects who were alive 1 year after ICU discharge
received a survey by mail containing multiple question-
naires, including the validated Dutch translation of the
Cognitive Failures Questionnaire (CFQ),
16,17
which has
been used as a long term outcome in postoperative care
and critical illness populations before.
18,19
The CFQ con-
sists of 25 questions, scored on a 5-point Likert scale, and
measures self-reported frequencies of failures in attention,
memory, and action. The total score on the CFQ ranges
from 0 to 100, with a higher score indicating more self-
reported cognitive problems.
17
A reminder was sent and
follow-up phone calls were made when subjects did not
respond.
Acute systemic inflammation during ICU stay was
quantified by daily C-reactive protein (CRP) levels (in mil-
ligrams per liter [mg/L]). CRP is an acute-phase reactant
found to be elevated in blood in inflammatory and infec-
tious conditions.
20
CRP levels in the ICU were measured
at admission and daily thereafter. Daily CRP levels were
used to calculate the area under the curve (AUC in
mg*days/L), as a measure of total exposure to acute sys-
temic inflammation during ICU stay.
21
At ICU admission, we recorded data on age, gender,
chronic disease burden according to the Charlson Comor-
bidity Index (CCI),
22
and the Acute Physiology And
Chronic Health Evaluation IV (APACHE IV) as a measure
for severity of illness in the first 24 hours of ICU admis-
sion.
23
Severity of illness on subsequent days was assessed
by the Sequential Organ Failure Assessment (SOFA)
24
score.
Statistical Methodology
To assess whether delirium during ICU stay was an inde-
pendent risk factor for long-term self-reported cognitive
problems, multivariable linear regression models were
used. Results of these analyses were presented as unstan-
dardized regression coefficients (B), with accompanying
95% confidence intervals (95% CI). The presence of delir-
ium was classified into three groups: (1) subjects with no
delirium during ICU admission (used as the reference
group), (2) subjects with a single day of ICU delirium, and
(3) subjects with multiple days of delirium during ICU
stay. In multivariable linear regression models, adjustments
were made for covariables with the potency to be a con-
founder in the association between delirium and long-term
self-reported cognitive problems. These covariables were
chosen a priori based on clinical judgment and a recent
systematic review,
25
and were age, gender, CCI and the
APACHE IV. Further, the maximal total SOFA score
(leaving out the central nervous system component to pre-
vent indirect adjustment for the presence of delirium) was
entered in the models as a measure for severity of illness
during ICU stay. Trend imputation was used for missing
values of daily measured variables, including the missing
levels of CRP, given the availability of longitudinal data
both preceding and following each measurement.
26
Additional analyses were conducted to assess to which
extent the degree of acute systemic inflammation con-
tributed to the association between delirium and long-term
self-reported cognitive problems. To this end, we used the
following approach. From our study population 1,000
bootstrap samples were drawn with replacement. Within
each bootstrap sample two models were developed: a
model as described in the previous paragraph, including all
potential confounders (Model 1) and a model containing
the same variables plus the amount of inflammation during
ICU stay (expressed as the AUC of the daily CRP levels)
(Model 2). The effect estimates indicating the association
between delirium (single and multiple days) and CFQ
resulting from both models were compared by calculating
their ratio and their absolute difference. Subsequently,
these ratios were averaged over the bootstrap samples to
obtain an overall estimate; a 95% CI around these esti-
mates was obtained non-parametrically. The overall esti-
mate for the absolute difference with accompanying 95%
CI was calculated in a similar fashion. If the ratios were
statistically significant different from 1 or the absolute dif-
ferences were statistically significant different from 0, the
amount of acute systemic inflammation could be consid-
ered to contribute to the association between delirium and
CFQ.
27
In our cohort, subjects with at least one missing value
in the CFQ were different from those with complete CFQ
JAGS APRIL 2017–VOL. 65, NO. 4 ICU DELIRIUM, INFLAMMATION AND COGNITION 787
data with regard to age, gender, CCI and maximal SOFA
score (Supplementary Appendix S1). Missing data rarely
occurs entirely at random, and excluding these subjects
could potentially lead to biased results.
26,28
Therefore,
next to analyzing data restricted to subjects who com-
pleted the full CFQ (i.e. complete case analysis) we also
performed multiple imputation to assign values to missing
answers to the questions of the CFQ in the 1-year ICU
survivors, and analyzed the imputed dataset as a secondary
analysis.
28
For multiple imputation we conducted 10 itera-
tions and used subjects and ICU-specific variables (e.g.,
gender, age, comorbidity score, severity of illness mea-
sures, and length of ICU stay), as well as answers to other
questionnaires that were also included in the survey as pre-
dictors in the imputation model.
All data analyses were performed using IBM SPSS
Statistics 21.0 for Windows and R version 3.1.1 for Win-
dows (R Foundation for Statistical Computing Vienna,
Austria). A significance level of 0.05 was used for all sta-
tistical inferences and the null hypotheses were tested
against two-sided alternatives.
RESULTS
Between January 2011 and June 2013, 2,669 subjects were
screened for delirium of whom eventually 567 persons
were eligible for this study (i.e., the 1-year ICU survivors).
Application of the exclusion criteria is described in Fig-
ure 1. In total, 546 subjects received a survey, of whom
402 individuals answered to the CFQ questionnaire (re-
sponse rate 74%), and 363 (90% of the responders) com-
pleted the full CFQ (i.e. complete cases). These 363
subjects reported their CFQ scores after a median of
400 days (interquartile range [IQR] 380–415) following
ICU discharge. Their characteristics are described in
Table 1. Characteristics and differences between complete
cases, subjects who completed the CFQ partially (i.e. par-
tial responders), subjects who did not respond (i.e. nonre-
sponders), and nonreceivers are outlined in Supplementary
Appendix S1.
Intensive care unit delirium was present in 186 (51%) of
the 363 patients, and the median duration of delirium when
delirium was present was 3 days (IQR 1–5). The median
CFQ scores for subjects who never had delirium, those who
had a single day of delirium, and subjects with multiple days
of delirium were 23 (IQR 12–34), 20 (IQR 10–31) and 25
(IQR 16–35), respectively. Multivariable linear regression
with adjustment for potential confounders showed that a sin-
gle day of ICU delirium was not associated with worse CFQ
scores, as compared to subjects with no delirium (adjusted
B = 0.72, 95% CI 5.75–4.31, Table 2). In contrast, sub-
jects with multiple ICU delirium days had more self-reported
cognitive problems, than subjects with no delirium (adjusted
B = 5.10, 95% CI 1.01–9.20, Table 2).
Of the daily measured CRP levels, 6% was missing
and was therefore imputed using longitudinal imputation.
The median AUC of the CRP was 545 (IQR 259–
1,029 mg*days/L). The ratios of the effect estimates did
not differ from 1 and the absolute differences were not dif-
ferent from 0 (Table 2), indicating that the AUC of the
CRP levels were not contributing into the association
between delirium and CFQ scores.
Although the distribution of the CFQ scores was altered
after multiple imputation, as compared to the CFQ scores
of the complete cases (higher versus lower scores and bimo-
dal versus right skewed, respectively), multivariable linear
regression analysis after multiple imputation showed similar
results on both the association between delirium and CFQ,
and the absence of a contributing effect of acute systemic
inflammation (Supplementary Appendix S2).
DISCUSSION
In our study, we found that multiple days of ICU delirium
was associated with long-term self-reported cognitive prob-
lems, in contrast to a single day of delirium. In addition,
the association between delirium and long-term self-
reported cognitive problems was not influenced by sys-
temic inflammation during ICU stay. These findings sug-
gest that not merely in the context of inflammation, but in
the setting of other problems as well, delirium has worse
long-term self-reported cognitive outcomes.
The association between delirium and long-term cog-
nitive problems is consistent with previous research.
3–6
One earlier study investigated the association between
inflammation during delirium onset and long-term self-
reported cognitive problems measured with the CFQ.
29
In
this previous study, no association was found between
Figure 1. Study Flowchart.
a
Neurological patients and/or
other reasons for impaired delirium assessment e.g. mental
retardation or language barrier.
b
Partial responders sent the
questionnaire back, with a partially completed CFQ. Nonre-
sponders were subjects who did not sent the questionnaire
back. To the nonreceivers we did not send a questionnaire
because: they moved abroad (n = 10), they died more than
1 year after discharge, but before the questionnaire was sent
(n = 6) or they declined any follow-up, and announced this in
advance (n = 5). ICU = intensive care unit.
788 WOLTERS ET AL. APRIL 2017–VOL. 65, NO. 4 JAGS
“inflamed” delirium (i.e. acute systemic inflammation at
the onset of delirium) and long-term self-reported cognitive
problems. Nevertheless, the sample size of this study was
small (n = 52) and inflammation was less well defined
using systemic inflammatory response syndrome criteria at
delirium onset.
29,30
Using systemic inflammatory response
syndrome criteria to define acute systemic inflammation is
not advisable, as it has low sensitivity, and insufficient face
and construct validity.
30,31
We used a cumulative measure for inflammation dur-
ing ICU stay (i.e., the AUC of the daily CRP levels) since
we were interested in the effect of the total burden of
inflammation on the association between delirium and
long-term self-reported cognitive problems. We did not
take the temporal association between inflammation and
delirium into account, and therefore did not investigate the
causal influence of inflammation related to delirium, and
subsequently, self-reported cognitive outcome. It is plausi-
ble that the effect of acute systemic inflammation on long-
term self-reported cognitive problems is more pronounced
in patients with multiple days of delirium than in those
with only a single delirium day, as the absolute difference
is larger. Nevertheless, this difference was not statistically
significant and therefore this observation is merely
speculative.
Our large prospective cohort study has several
strengths. The study population consisted of mixed medi-
cal-surgical ICU patients, which contributes to the gener-
alizability of our results. The validated delirium
assessment conducted by research nurses reduced the risk
of misclassifying subjects.
13
The response rate was rela-
tively high thanks to careful follow-up of subjects using
Table 1. Characteristics of the Study Population
Characteristic
Delirium during ICU stay
P-value
a
No
(n = 177; 49%)
Single day
(n = 55; 15%)
Multiple days
(n = 131; 36%)
Age in years, mean (SD) 56 (16) 60 (14) 61 (15) 0.01
Male, n (%) 103 (58) 33 (60) 86 (66) 0.41
CCI, median (IQR) 4 (0–10) 6 (0–13) 6 (0–11) 0.07
APACHE IV score, mean (SD) 63 (25) 72 (26) 75 (23) < 0.001
Max SOFA score, median (IQR)
b
5(3–7) 7 (4–9) 8 (6–10) 0.002
ICU LOS in days, median (IQR) 3 (3–6) 6 (4–9) 9 (6–19) < 0.001
Type of admission, n (%)
Medical 72 (41) 23 (42) 51 (39) 0.99
Acute surgical 51 (29) 16 (29) 37 (18)
Elective surgical 54 (31) 16 (29) 43 (33)
AUC of CRP in mg*days/L, median (IQR) 348 (179–646) 493 (340–911) 986 (535–2,127) <0.001
APACHE IV score = Acute Physiology and Chronic Health Evaluation IV score; AUC = Area under the Curve; CCI = Charlson Comorbidity Index; Max
SOFA = maximal total Sequential Organ Failure Assessment; ICU = Intensive Care Unit; IQR = Interquartile Range; LOS = Length of stay; SD = Standard
Deviation; CRP = C-reactive Protein.
a
Group comparisons were made using the Chi Square Test for categorical variables, one-way ANOVA for normally distributed continuous variables, or
Kruskal-Wallis test for skewed distributed continuous variables.
b
Maximal total SOFA score without the neurological component.
Table 2. Association Between Delirium and Cognitive Failures Questionnaire (CFQ) and the Effect of Systemic
Inflammation
Analysis
Delirium during ICU stay
No A single day Multiple days
Association between delirium and the CFQ
a
Crude Reference 1.96 (6.95 to 3.03) 2.53 (1.20 to 6.26)
Adjusted
b
Reference 0.72 (5.75 to 4.31) 5.10 (1.01–9.20)*
The effect of acute systemic inflammation on the association between delirium and CFQ
c
Ratio (95% confidence interval) – 1.00 (0.59–1.44) 0.86 (0.47–1.16)
Difference (95% confidence interval) – 0.01 (0.20 to 0.24) 0.87 (2.26 to 0.54)
CFQ = Cognitive Failures Questionnaire.
*P-value = 0.02.
a
Unstandardized coefficient B with 95% confidence interval.
b
Adjusted for: age, gender, Charlson Comorbidity Index, Acute Physiology and Chronic Health Evaluation IV score, and maximal total Sequential Organ
Failure Assessment without the neurological component.
c
Ratio and absolute difference between the effect estimates indicating the association between delirium and CFQ adjusted for the aforementioned covari-
ables (Model 1), and the effect estimates adjusted for the same covariables and including the AUC of CRP (Model 2), calculated by averaging over 1,000
bootstrap samples and non-parametrically obtaining 95% confidence intervals.
JAGS APRIL 2017–VOL. 65, NO. 4 ICU DELIRIUM, INFLAMMATION AND COGNITION 789
a postal reminder and follow-up phone calls. Further-
more, similar results were found in secondary analyses
with multiple imputation, indicating that the results were
robust. Also, the multivariable analyses were adjusted
for important potential confounders, such as age, which
is associated with a higher risk of delirium and may be
associated with increased inflammation. Some potential
limitations of our study should also be addressed. Differ-
entiation between sedation-related and non-sedation
related delirium could not be made in our cohort. Nev-
ertheless, it is plausible that a single day of delirium
during ICU stay reflects, at least in part, the rapidly-
reversible sedation-related delirium. It could be that the
sample of subjects with a single day of ICU delirium
was too small to demonstrate any association. Further-
more, our results cannot directly be compared with stud-
ies that used a neuropsychological test battery, as the
CFQ estimates subjective self-reported cognitive prob-
lems. Also, we did not have a baseline assessment of
cognitive functioning and therefore cannot be sure that
1 year self-reported cognitive problems are solely due to
prolonged ICU delirium or that subjects experienced pro-
longed ICU delirium because they already had underly-
ing cognitive problems. In future studies, measuring
baseline cognitive functioning is recommended. We also
did not have information about events after ICU dis-
charge, which may have influenced cognitive outcome,
such as delirium after ICU discharge. As with all obser-
vational studies, residual confounding might have
occurred. Hence, we could not causally relate ICU delir-
ium to long-term self-reported cognitive problems. The
CRP is a well-acknowledged marker of inflammation.
However, it is nonspecific and not validated as a marker
for neuroinflammation. For future research it may be
interesting to focus on neuroinflammation-specific mark-
ers. It is also important to realize that, as the domain of
our study was subjects alive 1 year after ICU discharge,
no inference can be made to subjects who died earlier.
CONCLUSION
In conclusion, multiple days of ICU delirium was associ-
ated with long-term self-reported cognitive problems. The
cumulative exposure to systemic inflammation did not
alter this association, which suggests that delirium in the
context of little inflammation is also detrimental.
ACKNOWLEDGEMENTS
Funding Source: none.
Conflict of Interest: The editor in chief has reviewed
the conflict of interest checklist provided by the authors
and has determined that the authors have no financial or
any other kind of personal conflicts with this paper.
Author Contributions: AEW contributed to the design
of the study, carried out the main analyses, interpreted the
data and wrote the manuscript. LMP, DSV, and AJCS
assisted substantially in the design of the study, the analy-
sis, and critically revised the manuscript for important
intellectual content. IJZ, DWL, DD, and OLC also partici-
pated substantially in the conception and design, partici-
pated considerably in its design and coordination, and
reviewed the manuscript critically. WP made a substantial
contribution to the acquisition of the data by constructing
the dataset, performed part of the analyses, and reviewed
the manuscript critically as well. All authors read and
approved the final manuscript.
Sponsor’s Role: No sponsor had any role in the
design, methods, subject recruitment, data collections,
analysis or preparation of the paper.
REFERENCES
1. Ehlenbach WJ, Hough CL, Crane PK et al. Association between acute care
and critical illness hospitalization and cognitive function in older adults.
JAMA 2010;303 :763–770.
2. Iwashyna TJ, Ely EW, Smith DM et al. Long-term cognitive impairment
and functional disability among survivors of severe sepsis. JAMA
2010;304:1787–1794.
3. Pandharipande PP, Girard TD, Jackson JC et al. Long-term cognitive
impairment after critical illness. N Engl J Med 2013;369:1306–1316.
4. Van den Boogaard M, Schoonhoven L, Evers AW et al. Delirium in criti-
cally ill patients: Impact on long-term health-related quality of life and cog-
nitive functioning. Crit Care Med 2012;40:112–118.
5. Girard TD, Jackson JC, Pandharipande PP et al. Delirium as a predictor of
long-term cognitive impairment in survivors of critical illness. Crit Care
Med 2010;38:1513–1520.
6. Wolters AE, van Dijk D, Pasma W 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:R125.
7. Cerejeira J, Firmino H, Vaz-Serra A et al. The neuroinflammatory hypothe-
sis of delirium. Acta Neuropathol 2010;119:737–754.
8. Cunningham C. Systemic inflammation and delirium: Important co-factors
in the progression of dementia. Biochem Soc Trans 2011;39:945–953.
9. Van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and
delirium: When cytokines and acetylcholine collide. Lancet 2010;375:773–
775.
10. MacLullich AMJ, Beaglehole A, Hall RJ et al. Delirium and long-term cog-
nitive impairment. Int Rev Psychiatry 2009;21:30–42.
11. Qin L, Wu X, Block ML et al. Systemic LPS causes chronic neuroinflam-
mation and progressive neurodegeneration. Glia 2007;55:453–462.
12. Patel SB, Poston JT, Pohlman A et al. Rapidly reversible, sedation-related
delirium versus persistent delirium in the intensive care unit. Am J Respir
Crit Care Med 2014;189:658–665.
13. Zaal IJ, Tekatli H, van der Kooi AW et al. Classification of daily mental
status in critically ill patients for research purposes. J Crit Care
2015;30:375–380.
14. Sessler CN, Gosnell MS, Grap MJ et al. The Richmond agitation sedation
scale: Validity and reliability in adult intensive care unit patients. Am J
Respir Crit Care Med 2002;166:1338–1344.
15. Ely EW, Margolin R, Francis J et al. Evaluation of delirium in critically ill
patients: Validation of the confusion assessment method for the intensive
care unit (CAM-ICU). Crit Care Med 2001;29:1370–1379.
16. Merckelbach H, Muris P, Nijman H et al. Self-reported cognitive failures
and neurotic symptomatology. Pers Individ Diff 1996;20:715–724.
17. Broadbent DE, Cooper PF, Fibgerald P et al. The Cognitive Failures Ques-
tionnaire (CFQ) and its correlates. Br J Clin Psychol 1982;21:1–16.
18. Kastaun S, Gerriets T, Schwarz NP et al. The relevance of postoperative
cognitive decline in daily living: Results of a 1-year follow-up. J Cardiotho-
rac Vasc Anesth 2016;30:297–303.
19. van Vliet M, van den Boogaard M, Donnelly P et al. Long-term health
related quality of life following intensive care during treatment for haema-
tological malignancies. PLoS ONE 2014;9:e87779.
20. Standage SW, Wong HR. Biomarkers for pediatric sepsis and septic shock.
Expert Rev Anti Infect Ther 2011;9:71–79.
21. Matthews JNS, Altman DG, Campbell MJ et al. Analysis of serial measure-
ments in medical research. BMJ 1990;300:230–235.
22. Quan H, Li B, Couris CM et al. Updating and validating the Charlson
comorbidity index and score for risk adjustment in hospital discharge
abstracts using data from 6 countries. Am J Epidemiol 2011;173:676–
682.
23. Zimmerman JE, Kramer A, McNair DS et al. Acute physiology and chronic
health evaluation (APACHE) IV: Hospital mortality assessment for today’s
critically ill patients. Crit Care Med 2006;34:1297–1310.
24. Vincent J, de Mendonca A, Cantraine F et al. Use of the SOFA score to
assess the incidence of organ dysfunction/failure in intensive care units:
790 WOLTERS ET AL. APRIL 2017–VOL. 65, NO. 4 JAGS
