Anxiety and depression among out-of-hospital cardiac arrest survivors

Abstract

Aim:
Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA-survivors.

Methods:
OHCA-survivors randomized to targeted temperature of 33°C or 36°C within the Target Temperature Management trial (TTM-trial) attended a follow-up after 6 months that included the questionnaire Hospital Anxiety and Depression Scale (HADS). A control group with ST-elevation myocardial infarction (STEMI) completed the same follow-up. Correlations to variables assumed to be associated with anxiety and depression in OHCA-survivors were tested.

Results:
At follow-up 278 OHCA-survivors and 119 STEMI-controls completed the HADS where 24% of OHCA-survivors (28% in the 33°C group/22% in the 36°C group, p=0.83) and 19% of the STEMI-controls reported symptoms of anxiety (OR 1.32; 95% CI (0.78-2.25), p=0.30). Depressive symptoms were reported by 13% of OHCA-survivors (equal in both intervention groups, p=0.96) and 8% of STEMI-controls (OR 1.76, 95% CI (0.82-3.79), p=0.15). Anxiety and depression among OHCA-survivors correlated to Health-Related Quality-of-Life, and subjectively reported cognitive deterioration by patient or observer. In addition, depression was associated with a poor neurological outcome.

Conclusion:
One fourth of OHCA-survivors reported symptoms of anxiety and/or depression at six months which was similar to STEMI-controls and previous normative data. Subjective cognitive problems were associated with an increased risk for psychological distress. Since psychological distress affect long-term prognosis of cardiac patients in general it should be addressed during follow-up of survivors with OHCA due to a cardiac cause. ClinicalTrials.gov NCT01020916/NCT01946932.

Full text

Resuscitation
97
(2015)
68–75
Contents
lists
available
at
ScienceDirect
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jou
rn
al
hom
epage
:
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ww.elsevie
r.com/locate/resuscitation
Clinical
paper
Anxiety
and
depression
among
out-of-hospital
cardiac
arrest
survivors夽
G.
Liljaa,b,∗,1,
G.
Nilssonb,1,
N.
Nielsenc,d,
H.
Fribergd,e,
C.
Hassagerf,
M.
Koopmansg,
M.
Kuiperg,h,
A.
Martinii,
J.
Mellinghoffj,
P.
Pelosik,
M.
Wanscherl,
M.P.
Wisem,
I.
Östmann,
T.
Cronberga,b
aDepartment
of
Neurology
and
Rehabilitation
Medicine,
Skåne
University
Hospital,
221
85
Lund,
Sweden
bDepartment
of
Clinical
Sciences,
Neurology,
Lund
University,
221
85
Lund,
Sweden
cDepartment
of
Intensive
care
and
Anesthesiology,
Helsingborg
Hospital,
Södra
Vallgatan
5,
251
87
Helsingborg,
Sweden
dDepartment
of
Clinical
Sciences,
Anesthesiology
and
Intensive
Care,
Lund
University,
221
85
Lund,
Sweden
eDepartment
of
Intensive
and
Perioperative
Care,
Skåne
University
Hospital,
221
85
Lund,
Sweden
fDepartment
of
Cardiology,
The
Heart
Centre,
Copenhagen
University,
Hospital,
Rigshospitalet,
Blegdamsvej
9,
2100
Copenhagen,
Denmark
gDepartment
of
Intensive
Care,
Medisch
Centrum
Leeuwarden,
PO
Box
888,
8901
BR
Leeuwarden,
The
Netherlands
hDepartment
of
Intensive
Care,
Academic
Medical
Center,
Meibergdreef
9,
1105,
Amsterdam,
AZ,
The
Netherlands
iDepartment
of
Anaesthesia,
Intensive
Care
and
Emergency
Medical
Service,
Santa
Maria
degli
Angeli
Hospital,
Via
Montereale
24,
33170
Pordenone
(PN),
Italy
jDepartment
of
Intensive
and
Perioperative
Care,
St.
George’s
University
Hospitals
NHS
Foundation
Trust,
1st
floor
St.
James
Wing,
Blackshaw
Road,
London
SW17
0QT,
United
Kingdom
kDepartment
of
Surgical
Sciences
and
Integrated
Diagnostics,
IRCCS
AOU
San
Martino
IST,
University-Hospital
Genoa,
Genoa
16132,
Italy
lDepartment
of
Cardiothoracic
Anaesthesia
4142,
The
Heart
Center,
Copenhagen
University
Hospital,
Rigshospitalet,
9
Blegdamsvej,
2100
Copenhagen,
Denmark
mAdult
Critical
Care,
University
Hospital
of
Wales,
Heath
Park,
Cardiff
CF14
4XW,
United
Kingdom
nDepartment
of
Cardiology,
Örebro
University
Hospital,
Södra
Grevrosengatan,
701
85
Örebro,
Sweden
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
30
June
2015
Received
in
revised
form
14
September
2015
Accepted
18
September
2015
Keywords:
Out-of-hospital
cardiac
arrest
Resuscitation
Anxiety
Depression
Patient
outcome
assessment
Target
temperature
management
a
b
s
t
r
a
c
t
Aim:
Survivors
of
out-of-hospital
cardiac
arrest
(OHCA)
may
experience
psychological
distress
but
the
actual
prevalence
is
unknown.
The
aim
of
this
study
was
to
investigate
anxiety
and
depression
within
a
large
cohort
of
OHCA-survivors.
Methods:
OHCA-survivors
randomized
to
targeted
temperature
of
33 ◦C
or
36 ◦C
within
the
Target
Temper-
ature
Management
trial
(TTM-trial)
attended
a
follow-up
after
6
months
that
included
the
questionnaire
Hospital
Anxiety
and
Depression
Scale
(HADS).
A
control
group
with
ST-elevation
myocardial
infarction
(STEMI)
completed
the
same
follow-up.
Correlations
to
variables
assumed
to
be
associated
with
anxiety
and
depression
in
OHCA-survivors
were
tested.
Results:
At
follow-up
278
OHCA-survivors
and
119
STEMI-controls
completed
the
HADS
where
24%
of
OHCA-survivors
(28%
in
33 ◦C
group/22%
in
36 ◦C
group,
p
=
0.83)
and
19%
of
the
STEMI-controls
reported
symptoms
of
anxiety
(OR
1.32;
95%
CI
(0.78–2.25),
p
=
0.30).
Depressive
symptoms
were
reported
by
13%
of
OHCA-survivors
(equal
in
both
intervention
groups,
p
=
0.96)
and
8%
of
STEMI-controls
(OR
1.76;
95%
CI
(0.82–3.79),
p
=
0.15).
Anxiety
and
depression
among
OHCA-survivors
correlated
to
Health-Related
Quality-of-Life,
and
subjectively
reported
cognitive
deterioration
by
patient
or
observer.
In
addition,
depression
was
associated
with
a
poor
neurological
outcome.
夽A
Spanish
translated
version
of
the
summary
of
this
article
appears
as
Appendix
in
the
final
online
version
at
http://dx.doi.org/10.1016/j.resuscitation.2015.09.389.
∗Corresponding
author
at:
Department
of
Neurology
and
Rehabilitation
Medicine,
Skåne
University
Hospital,
221
85
Lund,
Sweden.
E-mail
addresses:
gisela.lilja@med.lu.se
(G.
Lilja),
gabriella.nilsson@hotmail.com
(G.
Nilsson),
niklas.nielsen@telia.com
(N.
Nielsen),
hans.a.friberg@gmail.com
(H.
Friberg),
hassager@dadlnet.dk
(C.
Hassager),
matty.koopmans@znb.nl
(M.
Koopmans),
mi.kuiper@wxs.nl
(M.
Kuiper),
alice.martini.2@gmail.com
(A.
Martini),
j.mellinghoff@nhs.net
(J.
Mellinghoff),
ppelosi@hotmail.com
(P.
Pelosi),
michael.jaeger.wanscher@regionh.dk,
wanscher@dadlnet.dk
(M.
Wanscher),
mattwise@doctors.org.uk
(M.P.
Wise),
ingela.ostman@orebroll.se
(I.
Östman),
tobias.cronberg@skane.se
(T.
Cronberg).
1These
authors
contributed
equally
to
this
work.
http://dx.doi.org/10.1016/j.resuscitation.2015.09.389
0300-9572/©
2015
Elsevier
Ireland
Ltd.
All
rights
reserved.

G.
Lilja
et
al.
/
Resuscitation
97
(2015)
68–75
69
Conclusion:
One
fourth
of
OHCA-survivors
reported
symptoms
of
anxiety
and/or
depression
at
6
months
which
was
similar
to
STEMI-controls
and
previous
normative
data.
Subjective
cognitive
problems
were
associated
with
an
increased
risk
for
psychological
distress.
Since
psychological
distress
affects
long-term
prognosis
of
cardiac
patients
in
general
it
should
be
addressed
during
follow-up
of
survivors
with
OHCA
due
to
a
cardiac
cause.
ClinicalTrials.gov
NCT01020916/NCT01946932.
©
2015
Elsevier
Ireland
Ltd.
All
rights
reserved.
Introduction
The
ultimate
goal
of
cardio-pulmonary
resuscitation
of
patients
with
out-of-hospital
cardiac
arrest
(OHCA)
is
survival
with
good
health,1but
survival
may
be
complicated
by
neurolog-
ical
sequelae,2increased
psychological
distress,3and
reduced
quality-of-life.4Although
the
predominant
cause
of
death
for
OHCA-patients
treated
in
an
intensive
care
unit
(ICU)
is
related
to
brain
injury,5severe
neurological
impairment
is
rare
at
follow-
up.
On
the
contrary
mild
to
moderate
cognitive
impairment
is
found
among
half
of
the
survivors2,6 with
most
previous
studies
reporting
a
relationship
between
neurological
and
psychological
outcome.7–10
Psychological
distress
has
been
reported
as
an
important
determinant
of
health-related
quality-of-life
(HRQoL)
in
OHCA-
survivors.11 For
cardiac
patients
in
general
(i.e.
myocardial
infarction)
psychological
distress,
especially
depression
is
asso-
ciated
with
an
increased
risk
of
a
new
cardiac
event
and
mortality.12,13 Few
OHCA-studies
have
focused
primarily
on
the
aspect
of
psychological
distress
and
a
recent
review
concluded
that
psychological
distress
in
OHCA-survivors
was
unsatisfactorily
reported
due
to
small
study
samples
and
heterogeneous
method-
ologies,
but
expected
in
approximately
25%.3
To
evaluate
potential
neuro-protective
effects
of
two
target
temperatures,
the
Target
Temperature
Management
(TTM)
trial
randomized
950
unconscious
OHCA-patients
to
either
33 ◦C
or
36 ◦C.
The
TTM-trial
found
no
significant
difference
between
the
two
intervention
groups
in
overall
mortality,14 neurological
function,14 HRQoL15 or
cognitive
function.6,15
The
aim
of
this
study
was
to
describe
anxiety
and
depres-
sion
in
a
large
cohort
of
OHCA-survivors
within
the
TTM-trial
and
relate
their
outcome
to
a
non-cardiac
arrest
control
group
with
ST-elevation
myocardial
infarction
(STEMI)
matched
for
age,
gen-
der
and
time
for
hospitalization.
Additionally,
we
investigated
the
correlation
to
selected
variables
assumed
associated
with
psycho-
logical
distress
in
OHCA-survivors.
Methods
Study
design
The
multicenter
randomized
clinical
TTM-trial
recruited
patients
from
November
2010
to
January
2013.14 Unconscious
adult
patients
after
OHCA
of
a
presumed
cardiac
cause
were
ran-
domized
to
a
target
temperature
of
33 ◦C
or
36 ◦C
for
a
total
intervention
period
of
36
h.
Survivors
and
their
relatives
attended
a
face-to-face
follow-up
at
6
months
after
their
OHCA,
evalu-
ating
neurological
function
and
HRQoL,
with
the
last
follow-up
performed
in
July
2013.
At
the
time
of
the
follow-up,
20/36
TTM-sites
in
Sweden,
Denmark,
Italy,
the
Netherlands
and
the
United
Kingdom
performed
an
extended
follow-up
including
a
questionnaire
of
depression
and
anxiety.16 The
TTM-trial
and
the
extended
follow-up
are
registered
at
ClinicalTrials.gov
(Identi-
fier:
NCT01020916/NCT01946932).
A
control
group
completed
the
same
follow-up
as
the
OHCA-patients
with
the
last
control
par-
ticipating
in
a
follow-up
visit
in
September
2013.
All
assessors
were
blind
for
temperature
assignment
but
not
as
to
whether
the
patients
were
controls.
Study
population
Patients
included
in
the
TTM-trial
had
OHCA
of
a
presumed
cardiac
origin,
≥18
years
old
and
unconscious
after
sustained
return-of-spontaneous-circulation
(ROSC).
The
exclusion
criteria
have
been
reported
previously.14,16 A
control
group
of
patients
with
STEMI
and
emergency
percutaneous
coronary
intervention
that
never
had
sustained
a
cardiac
arrest
was
recruited
with
the
primary
intention
to
include
100
patients
in
each
group
(33 ◦C/36 ◦C/STEMI-
controls).
Controls
were
matched
for
country,
age,
gender,
and
time
for
hospitalization.
Ethical
applications
for
the
TTM-trial
and
this
extended
study
were
approved
in
participating
countries.
Written
informed
con-
sent
was
obtained
from
patients
before
the
testing.
Outcome
assessments
Anxiety
and
depression
were
assessed
with
the
Hospital
Anxi-
ety
and
Depression
Scale
(HADS)
which
has
been
widely
used
in
OHCA-studies
and
found
to
perform
psychometrically
well.17 It
consists
of
the
HADS-anxiety
and
HADS-depression
subscales,
with
seven
items
each
(scores
0–3)
having
a
maximum
sum
score
of
21.
A
cut-off
≥8
is
used
as
a
case
finder
for
anxiety
or
depression17
where
8–10
represents
a
milder
state,
and
11–21
definite
cases.18
The
additional
assessments
performed
at
the
180
days
follow-up
have
been
described
in
detail
previously.6,15,16 For
this
study
the
following
instruments
were
used;
examiner
rating
of
the
patients
neurological
function
(the
Cerebral
Performance
Category
Scale,
CPC),
a
cognitive
screening
test
(Mini-Mental
Status
Examina-
tion,
MMSE),
patient
reported
mental
recovery
and
dependency
in
daily
life
(Two
Simple
Questions,
TSQ),
informant
reported
changes
in
cognitive
performance
(Informant
Questionnaire
on
Cognitive
Decline
in
the
Elderly,
IQCODE),
Health-Related
Quality-
of-Life
(SF-36v2®Health
Survey,
SF-36v2®)
and
objective
tests
for
memory
(Rivermead
Behavioural
Memory
Test,
RBMT),
executive
functions
(Frontal
Assessment
Battery,
FAB)
and
attention/mental
speed
(Symbol
Digit
Modalities
Test,
SDMT).
Socio-demographical
and
medical
variables
were
obtained
at
the
follow-up
or
from
the
TTM-database.
Statistical
analysis
This
study
describes
a
sample
of
the
original
cohort
included
in
the
TTM-trial
(i.e.
excluding
deceased)
where
the
effects
of
the
original
randomization
may
be
broken.
Therefore
potential
differ-
ences
in
socio-demographical
and
pre-hospital
variables
between
the
groups
are
presented,
including
data
for
the
matched
STEMI-
controls.
The
two
subscales
HADS-anxiety
and
HADS-depression
were
used
as
outcome
variables.
To
obtain
complete
data
HADS-
questionnaires
with
one
item
missing
were
included
by
using
mean-half-rule
imputation
where
the
missing
value
was
substi-
tuted
by
the
average
score
of
the
completed
items.
For
all
between
groups
comparisons
descriptive
statistics
is
presented
and
analyzes

70
G.
Lilja
et
al.
/
Resuscitation
97
(2015)
68–75
performed
with
Fisher
test
or
a
univariate
binary
logistic
regres-
sion
for
categorical/binary
data,
and
the
Mann–Whitney–Wilcoxon
test
or
Kruskal–Wallis
test
for
continuous
data.
Pre-specified
cut-off
values
for
HADS
were
used
to
categorize
the
amount
of
cases
into
levels
of
psychological
distress
(normal,
mild
or
moderate/severe).
A
further
dichotomization
of
HADS-scores
separated
cases
within
the
normal
range
of
scores
(<8)
and
cases
with
scores
that
indicated
any
level
(mild/moderate/severe)
of
anxiety
or
depression
(≥8).
These
dichotomized
HADS-scores
were
used
as
binary
outcomes
in
a
multivariate
logistic
regression
including
covariate
adjust-
ment
for
age,
gender,
education
(</≥12
years)
and
comorbidities
(≤2/>2).
Since
this
is
a
post
hoc
study,
no
a
priori
power
calcu-
lation
was
performed
and
all
results
are
considered
hypothesis
generating
with
a
p-value
<0.05
indicating
statistically
significant
signals.
The
correlation
between
HADS-anxiety/HADS-depression
to
pre-specified
variables
theoretically
assumed
to
be
associated
with
psychological
distress
in
OHCA-survivors
(age,
sex,
educa-
tion,
comorbidities,
temperature
assignment,
time
to
ROSC,
days
at
hospital,
time
to
follow-up,
CPC,
MMSE,
TSQ,
IQCODE,
Mental
Component
Summary-MCS
and
Physical
Component
Summary-
PCS
scores
from
the
SF-36v2®,
RBMT,
FAB
and
SDMT)
were
analyzed
using
Spearman’s.
Analyses
were
performed
using
SPSS
22.0.
Results
Participating
sites
included
652
OHCA
patients
to
the
original
TTM-trial
with
a
balanced
randomization
to
the
two
tempera-
ture
groups
and
310
being
dead
at
6
months.
Of
the
survivors,
320
patients
were
eligible
for
a
follow-up
visit
(Fig.
1)
and
287
(90%
of
eligible
patients)
participated
(33 ◦C,
n
=
148/36 ◦C,
n
=
139).
Nine
(33 ◦C,
n
=
5
and
36 ◦C,
n
=
4)
participants
did
not
complete
the
HADS-questionnaire,
leaving
278
OHCA-survivors
to
analyze.
Three
of
the
participants
had
one
item
missing
at
the
HADS-questionnaire
and
complete
data
was
obtained
by
simple
imputation.
Follow-up
participants
not
completing
HADS
were
in
78%
(7/9)
classified
as
a
CPC
3
or
4.
Also
among
missing
patients
not
participating
in
the
follow-up
a
poor
neurological
function
were
more
likely
with
42%
(14/33)
having
a
CPC
3
or
4.
This
caused
a
slight
imbalance
in
neu-
rological
function
among
the
patients
completing
HADS
with
4%
(12/278)
having
CPC
3
or
4
compared
to
10%
(33/320)
of
eligible
patients.
Additionally
119
STEMI-control
patients
were
included
to
a
similar
follow-up
(72%
of
eligible
STEMI-patients).16
OHCA-survivors
had
a
median
time
to
ROSC
of
20
min
and
94%
had
a
shockable
initial
rhythm.
The
majority
of
participants
were
male
(86%
for
both
OHCA-survivors
and
STEMI-controls,
p
=
0.86)
with
a
mean
age
of
61
for
OHCA-survivors
and
63
for
STEMI-controls
(p
=
0.04).
According
to
the
CPC
scale,
93%
of
OHCA-survivors
and
99%
of
STEMI-controls
had
a
good
outcome
(CPC
1–2).
At
the
6
months
follow-up
<10%
received
medications
for
anxiety
or
depression
with
no
statistically
significant
differ-
ences
between
OHCA-survivors
and
STEMI-controls
(anti-anxiety
medication,
p
=
0.38/anti-depressive
medication,
p
=
1.00).
Further
baseline
characteristics
are
presented
in
Table
1.
The
individual
results
from
the
HADS
for
the
three
groups
(OHCA-survivors
33 ◦C,
OHCA-survivors
36 ◦C
and
STEMI-controls)
are
descriptively
presented
in
Fig.
2
(HADS-anxiety)
and
Fig.
3
(HADS-depression).
The
majority
of
OHCA-survivors
and
STEMI-
controls
had
scores
indicating
a
low
probability
of
anxiety
and/or
depression.
Further
descriptive
information
from
HADS
is
presented
in
Table
2.
Since
the
psychological
outcomes
were
similar
between
the
two
temperature
groups
(HADS-anxiety,
p
=
0.83/HADS-depression,
p
=
0.96)
all
OHCA-survivors
were
con-
sidered
as
one
group
in
further
analyses.
OHCA-survivors
in
the
five
participating
countries
did
not
differ
in
their
psychological
outcome
(HADS-anxiety,
p
=
0.11,
HADS-depression,
p
=
0.39).
Continuous
values
(Table
2)
were
similar
between
the
OHCA-survivors
and
STEMI-controls,
(HADS-anxiety,
p
=
0.66/HADS-depression,
p
=
0.87).
Anxiety
(mild/moderate/
severe)
was
reported
for
24%
of
the
OHCA-survivors
and
19%
of
the
STEMI-controls
(OR
1.32,
95%
CI
0.78–2.25,
p
=
0.30).
Depression
was
present
in
13%
of
OHCA-survivors
and
8%
of
STEMI-controls
(OR
1.76,
95%
CI
0.82–3.79,
p
=
0.15).
By
combining
the
two
sub-
scales
27%
of
the
OHCA-patients
reported
symptoms
of
anxiety
and/or
depression
compared
to
22%
of
the
STEMI-controls
(OR
1.30,
95%
0.78–2.16,
p
=
0.32).
The
covariate-adjusted
analyses
(age,
gender,
education
and
comorbidities)
were
consistent
with
the
unadjusted
analyses
with
no
statistically
significant
differences
between
OHCA-survivors
and
STEMI-controls
for
HADS-anxiety
(OR
1.12,
95%
CI
0.69–1.96,
p
=
0.68)
or
HADS-depression
(OR
1.55,
95%
CI
0.71–3.39,
p
=
0.27).
The
adjusted
analysis
revealed
that
reported
symptoms
of
anxiety
were
significantly
influenced
by
age
and
gender
with
a
decrease
of
the
odds
by
3.2%
for
every
year
of
age
(OR
0.97,
95%
CI
.95–.99,
p
=
0.004)
and
anxiety
being
three
times
more
likely
among
females
(OR
3.12,
95%
CI
1.71–5.71,
p
=
0.0001).
These
gender
and
age
effects
were
not
found
for
HADS-depression,
however
the
individuals
that
contributed
to
HADS-depression
were
few.
Similar
gender
effects
were
found
for
the
continuous
HADS-
values
with
increased
anxiety
among
female
OHCA-survivors
(HADS-anxiety,
p
=
0.02)
where
HADS-depression
scores
did
not
differ
between
the
genders
(p
=
0.90).
To
investigate
potential
influ-
ence
of
gender
on
the
main
comparison,
analyses
of
the
continuous
values
were
repeated
stratified
for
gender
that
confirmed
no
differ-
ences
between
the
three
groups
(33 ◦C,
36 ◦C
and
STEMI-controls)
for
males:
(HADS-anxiety,
p
=
0.74/HADS-depression,
p
=
0.98)
or
females
(HADS-anxiety,
p
=
0.63/HADS-depression,
p
=
0.72).
To
identify
cases
in
the
borderline
zone
of
symptoms
a
sensitiv-
ity
analysis
was
performed
by
adjusting
the
cut-off
of
HADS-anxiety
and
HADS-depression
from
8
to
7.
This
analysis
identified
that
for
HADS-anxiety
3–5%
of
the
OHCA-survivors
and
10%
of
STEMI-
controls
had
just
one
score
below
the
cut-off
value,
and
for
HADS-depression
this
amount
was
5–6%
of
OHCA-survivors
and
10%
of
STEMI-controls
(Table
2).
A
sensitivity
analysis
inves-
tigating
potential
influence
of
missing
eligible
OHCA-survivors
identified
that
in
a
best-case
scenario
where
all
missing
patients
were
assumed
to
have
no
psychological
distress
(<8)
the
number
of
cases
decreased
with
3%
for
HADS-anxiety
and
2%
for
HADS-
depression.
Conversely,
in
a
worst-case
scenario
with
all
missing
eligible
patients
having
psychological
distress
(≥8)
the
amount
of
cases
increased
with
10%
for
HADS-anxiety
and
11%
for
HADS-
depression.
The
strongest
correlation
between
HADS-scores
and
pre-
specified
variables
(Table
3)
was
found
for
the
SF-36v2®MCS-score
(HADS-anxiety
rs=
0.76/HADS-depression
rs=
0.67)
while
moder-
ate
correlations
were
found
for
self-reported
mental
recovery
by
TSQ
2
(HADS-anxiety
rs=
0.41/HADS-depression
rs=
0.47)
and
proxy
reported
cognitive
performance
in
everyday
activities
by
IQCODE
(HADS-anxiety
rs=
0.31/HADS-depression
rs=
0.38).
The
objective
cognitive
assessments
(MMSE,
FAB,
SDMT,
RBMT)
were
less
correlated
to
psychological
outcome
(rs<
0.30).
In
addi-
tion,
HADS-depression
was
moderately
associated
to
SF-36v2®
PCS-score
(rs=
0.40),
the
assessor-reported
CPC-score
(rs=
0.33)
and
self-reported
dependency
in
everyday
life
(TSQ
1:
rs=
0.34),
whereas
these
variables
had
a
lower
correlation
to
HADS-anxiety
(rs<
0.30).
Discussion
In
this
study
of
OHCA-survivors
we
found
clinically
relevant
symptoms
of
psychological
distress
in
27%
at
6
months
after
the

G.
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97
(2015)
68–75
71
Patients included at
stud
y sites, n=652
(67% of the
TTM
coh
ort)
36°C intervention
n= 324 (50%)
33°C intervention
n= 328 (50%)
Dead at 1
80 days
33°C n=150 (46%)/
36°C n=1
60 (49%)
Delayed ethical approval(UK)
:33°C n=5/36°C n=4
Completely
lost:33°C n= 3/ 36°C n=1
Other language:33°C
n=5 / 36°C n=2
Lives
too
far away:33°C n=1
/ 36°C n=1
Patients eligible to follow-up
n= 16
4 (50
%)
Pati
ents eligible to
follow-u
p
n= 156 (48%)
Missing
n= 17
CPC 1+
2= 8 +2(59%)
CPC 3+
4= 6+
1 (41%)
Missing n= 16
CPC 1+2= 9 (56%)
CPC 3+4 = 6+1
(44%)
Included to follow-up
n=
148
(91%)
CPC 1+2= 130+8 (93%)
CPC 3+4= 8+2 (7%)
Includ
ed
to follow-up
n= 139
(89%)
CPC 1+2= 114
+16
(93.5%)
CPC 3+4=
8+1(
6.5%)
STEMI-cont
rols n=
119
CPC 1+2= 116+2
(99%) CPC 3+4=
1 (1
%)
HADS n= 14
3
(87% of
eligible)
HADS n=
13
5
(87% of eligible)
HADS n= 119
Fig.
1.
Flow-chart
of
study
inclusion.
TTM,
the
Target
Temperature
Management
trial;
UK,
United
Kingdom;
CPC,
Cerebral
Performance
Category
Scale;
STEMI-controls,
ST-elevation
myocardial
infarction-controls;
HADS,
Hospital
Anxiety
and
Depression
Scale.
Table
1
Anxiety
and
depression
among
out-of-hospital
cardiac
arrest
survivors.
33 ◦C
36 ◦C
STEMI
p-Values
(n
=
148) (n
=
139)
(n
=
119)
Age,
mean
SD
±
(median)
62
SD
±
12
(63)
60
SD
±
12
(60)
63
SD
±
10
(64)
0.04*
Male
gender,
no.
(%)
129
(87)
118
(85)
102
(86)
0.86
Education
>12
years,
no.
(%)
53
(36)
74
(53)
59
(50)
0.01*
Comorbidity,
(>2)
27
(18)
26
(19)
16
(13)
0.47
Anti-anxiety
medication
at
time
for
follow-up,
no.
(%)
11
(8)
14
(11)
7
(6)
0.38
Anti-depressive
medication
at
time
for
follow-up,
no.
(%)
10
(7)
9
(7)
9
(8)
1.00
Good
outcome
(CPC
1–2),
no.
(%) 138
(93) 130
(94)
118
(99)
0.03*
Good
outcome
(mRS
0–2),
no.
(%)
133
(90)
121
(87)
117
(98)
0.002*
Previous
ischaemic
heart
disease,
no.
(%)
41
(28)
26
(19)
16
(13)
0.01*
Previous
AMI,
no.
(%)
32
(22)
19
(14)
17
(14)
0.16
Bystander
witnessed
cardiac
arrest,
no.
(%)
140
(95)
130
(94)
n/a
0.80
Bystander
performed
CPR,
no.
(%)
109
(74)
117
(84)
n/a
0.03*
Number
of
defibrillations,
median
(IQR)
3
(1–4)
3
(2–4)
n/a
0.93
Initial
rhythm
shockable,
no.
(%)
137
(93)
133
(96)
n/a
0.32
Minutes
to
return-of-spontaneous
circulation,
median
(IQR)
20
(15–30)
21
(13–30)
n/a
0.87
Hospital
length
of
stay,
(IQR)
14
(7–22)
13
(7–22)
4
(3–5)
<0.001*
Days
to
follow
up,
median
(IQR) 183
(177–196) 185
(177–195)
226
(195–261)
<0.001*
Baseline
characteristics:
Presented
as
mean
(SD
=
standard
deviation),
median
(IQR
=
interquartile
range)
or
number
(no.)
and
percentage
of
cases
(%).
Statistical
analyses
performed
with
Kruskal–Wallis
test
or
Mann–Whitney–Wilcoxon
test
for
continuous
data,
and
Fisher
test
with
exact
or
99%
Monte–Carlo
values
for
categorical
or
binary
data.
STEMI,
ST-elevation
myocardial
infarction
controls;
SD,
standard
deviation;
CPC,
cerebral
Performance
Category
(good
=
CPC
1–2,
poor
=
CPC
3–5);
mRS,
modified
Rankin
Scale
(good
=
mRS
0–2,
poor
=
mRS
3–5);
AMI,
acute
myocardial
infarction;
CPR,
cardiopulmonary
resuscitation;
IQR,
interquartile
range.
*p
<
0.05
indicating
statistical
significant
differences.
arrest,
with
anxiety
being
most
common.
Similar
levels
of
psy-
chological
distress
were
found
in
STEMI-controls.
Both
anxiety
and
depression
in
OHCA-survivors
were
associated
with
reduced
HRQoL
and
reports
of
cognitive
deterioration
by
the
patient
or
a
proxy.
There
were
no
significant
differences
in
symptoms
of
anxiety
or
depression
among
OHCA-survivors
receiving
tar-
get
temperature
of
33 ◦C
or
36 ◦C,
consistent
with
the
neutral
result
of
the
primary,
secondary
and
tertiary
outcomes
of
the
TTM-trial.14,15
The
observation
that
mental
HRQoL
(SF-36v2®MCS-score)
had
a
strong
association
to
both
HADS-anxiety
and
HADS-depression
was
expected.
The
definition
of
HRQoL
as
physical,
mental
and
social
well-being19 reflects
the
importance
of
psychological
outcome
for
a
good
HRQoL.
Physical
HRQoL
(SF-36v2®PCS-score)
was
related
to
depression
but
not
with
the
same
extent
to
anxiety,
similar
to
previously
reported.20 This
suggests
that
poor
functional
out-
come,
often
encompassing
physical
impairment
and
dependency,
may
have
a
specific
effect
on
the
patient’s
mood.
In
agreement,
the

72
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Resuscitation
97
(2015)
68–75
Fig.
2.
Distribution
of
individual
HADS-anxiety
scores
separated
for
OHCA
33 ◦C,
OHCA
36 ◦C
and
STEMI-controls,
range
0–21.
A
cut
off
≥8
indicates
anxiety
symptoms.HADS,
Hospital
Anxiety
and
Depression
Scale;
OHCA,
out-of-hospital
cardiac
arrest;
STEMI,
ST-elevation
myocardial
infarction
controls.
Fig.
3.
Distribution
of
individual
HADS-depression
scores
separated
for
OHCA
33 ◦C,
OHCA
36 ◦C
and
STEMI-controls,
range
0–21.
A
cut
off
≥8
indicates
depressive
symp-
toms.HADS,
Hospital
Anxiety
and
Depression
Scale;
OHCA,
out-of-hospital
cardiac
arrest;
STEMI,
ST-elevation
myocardial
infarction
controls.
CPC-score
was
more
associated
with
depression
than
anxiety.
In
our
study
patients
with
a
poor
outcome
were
few
and
more
likely
to
be
missing
or
excluded
from
the
analysis.
This
is
a
limitation
with
the
potential
risk
that
the
outcome
we
describe
is
being
too
optimistic.
In
our
study,
both
anxiety
and
depression
were
associated
with
cognitive
impairment,
especially
when
reported
by
the
patient
or
proxy
through
the
TSQ
or
IQCODE.
Importantly,
cognitive
impair-
ment
and
depression
share
many
symptoms
and
may
be
difficult
to
separate.
It
may
be
particularly
hard
for
patients
and
proxies

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68–75
73
Table
2
Anxiety
and
depression
among
out-of-hospital
cardiac
arrest
survivors.
OHCA-33 ◦C
OHCA-36 ◦C
33 ◦C/36 ◦C
OHCA-total
STEMI
OHCA/STEMI
(n
=
143)
(n
=
135)
p-Values
(n
=
278)
(n
=
119)
p-Values
HADS
anxiety
Mean
SD±
4.7
SD
±
4.4
4.3
SD
±
3.7
SD
±
4.1
SD
±
4.2
Median
(IQR)
3
(1–8)
4
(1–7)
0.83
4
(1–7)
3
(1–7)
0.66
Anxiety
normal,
no.
(%)
105
(73)
106
(78)
211
(76)
96
(81)
Anxiety
mild,
no.
(%)
18
(13)
19
(14)
37
(13)
13
(11)
Anxiety
moderate–severe,
no.
(%)
20
(14)
10
(7)
30
(11)
10
(8)
HADS
depression
Mean
SD±SD
±
3.7 SD
±
3.6 SD
±
3.7 SD
±
3.4
Median
(IQR)
2
(1–6)
2
(1–4)
0.96
2
(1–5)
2(1–5)
0.87
Depression
normal,
no.
(%)
125
(87)
118
(87)
243
(87)
110
(92)
Depression
mild,
no.
(%)
8
(6)
9
(7)
17
(6)
6
(5)
Depression
moderate–severe,
no.
(%)
10
(7)
8
(6)
18
(7)
3
(3)
HADS
anxiety
Sensitivity
analysis
≥7,
no.
(%)
43
(30)
36
(27)
79
(28)
34
(29)
HADS
depression
Sensitivity
analysis
≥7,
no.
(%)
25
(18)
26
(19)
51
(18)
21
(18)
HADS
depression
and/or
anxiety
(≥8),
no.
(%)
41
(29)
33
(24)
0.50
74
(27)
26
(22)
0.26
Results
from
the
Hospital
Anxiety
and
Depression
Scale
(HADS).
Normal
(0–7)/mild
(8–10)/moderate–severe
(≥11)
symptoms.
Presented
as
mean
(SD
=
standard
deviation),
medians
(IQR
=
interquartile
range)
or
number
(no.)
and
percentage
of
cases.
Statistical
analyses
performed
with
Mann–Whitney–Wilcoxon
test
for
continuous
data,
and
Fisher
test
with
exact
or
99%
Monte–Carlo
values
for
binary
data.
OHCA,
out-of-
hospital
cardiac
arrest;
STEMI,
ST
elevation
myocardial
infarction
controls.
Table
3
Anxiety
and
depression
among
out-of-hospital
cardiac
arrest
survivors.
Variables
HADS-anxiety
HADS-depression
Age
−0.14
(0.02*)
0.01
(0.87)
Gender
0.14
(0.02*)
0.01
(0.90)
Years
at
school
(>12
years/≤12
years)
−0.02
(0.74)
−0.10
(0.11)
Comorbidities
(>2/≤2)
0.06
(0.29)
0.10
(0.09)
Time-to-ROSC
0.05
(0.41)
0.10
(0.11)
Temperature
management
(33 ◦C/36 ◦C)
−0.01
(0.83)
−0.003
(0.96)
Days-at-hospital
0.14
(0.02*)
0.14
(0.02*)
Time-to-follow-up
0.06
(0.31)
0.05
(0.45)
MiniMental
Status
Examination
(MMSE)
−0.26
(<0.001*)
−0.29
(<0.001*)
Cerebral
Performance
Category
(CPC) 0.20
(<0.001*) 0.33
(<0.001*)
Informant
Questionnaire
on
Cognitive
Decline
(IQCODE)
0.31
(<0.001*)
0.38
(<0.001*)
Two
simple
questions
1,
dependency
in
daily
activities
0.23
(<0.001*)
0.34
(<0.001*)
Two
simple
questions
2,
mental
recovery
−0.42
(<0.001*)
−0.47
(<0.001*)
SF-36v2®,
Physical
Component
Summary
(PCS)
−0.29
(<0.001*)
−0.40
(<0.001*)
SF-36v2®,
Mental
Component
Summary
(MCS)
−0.76
(<0.001*)
−0.67
(<0.001*)
Rivermead
Behavioural
Memory
Test
(RBMT)
−0.18
(0.03*)
−0.19
(0.001)
Frontal
Assessment
Battery
(FAB)
−0.11
(0.06)
−0.22
(<0.001*)
Symbol
Digit
Modalities
Test
(SDMT)
−0.19
(<0.001)
−0.23
(<0.001*)
HADS-anxiety
n/a
0.67
(<0.001*)
HADS-depression
0.67
(<0.001*)
n/a
Pre-defined
variables
association
to
the
Hospital
Anxiety
and
Depression
Scale
(HADS)
anxiety
and
depression
sub-scales.
Statistical
analyses
performed
with
Spearman’s
(rs)
*p
<
0.05
indicates
statistical
significance.
to
differentiate
symptoms
of
cognitive
impairment
from
those
of
emotional
distress,21 and
subjective
reports
of
cognitive
dysfunc-
tion
have
been
reported
as
more
associated
to
depression
than
to
objectively
measured
cognitive
impairment.22 Depressive
symp-
toms
on
the
other
hand
may
indicate
a
mild
cognitive
decline23
sometimes
only
obvious
for
the
survivor’s
or
their
family,9and
in
cardiac
heart
failure
patients
depression
and
anxiety
were
found
associated
to
objective
changes
in
the
brain.24 This
potential
causal-
ity
in
both
directions
is
important
to
consider.23
A
few
earlier
small
studies
compared
psychological
distress
in
OHCA-survivors
to
disease-matched
controls
with
the
major-
ity
reporting
the
groups
as
similar25–27 or
with
a
tendency
for
more
anxiety/depression
among
OHCA-survivors.28 We
add
impor-
tant
information
to
these
previous
results
by
assessing
a
much
larger
cohort.
Our
findings
suggest
that
the
type
of
cardiac
event,
the
ICU
stay
or
the
hospital
length
of
stay
were
not
critical
for
the
psychological
outcome
of
the
OHCA-survivors
since
the
STEMI-controls
had
similar
levels
of
psychological
distress
despite
mostly
not
admitted
to
an
ICU
and
with
a
shorter
in-hospital
stay.
Both
OHCA-survivors
and
STEMI-controls
in
our
study
had
scores
comparable
to
the
general
population
where
i.e.
the
mean
scores
of
males
in
the
age
of
60–65
is
4.85
for
HADS-anxiety
and
3.93
for
HADS-depression.29 The
fact
that
we
found
more
symptoms
of
anxiety
among
female
OHCA-survivors
is
also
in
agreement
with
normative
data29 but
comparisons
are
complicated
by
differences
in
sample
selection.
Differences
in
age
are
partic-
ularly
relevant
to
consider
since
psychological
distress
decrease
with
age.29,30 Younger
OHCA-survivors
have
reported
more
psy-
chological
distress
(61%)31 compared
to
OHCA-survivors
of
all
ages
(34%).32 In
addition,
categorical/binary
values
of
HADS,
albeit
important
to
make
results
interpretable,
are
sensitive
to
the
cho-
sen
cut-off
as
indicated
by
the
sensitivity
analyses
we
performed.
These
factors
may
explain
some
of
the
variation
between
previ-
ous
studies3and
highlights
the
importance
of
using
continuous

74
G.
Lilja
et
al.
/
Resuscitation
97
(2015)
68–75
values
in
statistical
comparisons,
and
clinical
judgement
in
daily
practice.
Although
our
findings
indicate
that
the
majority
of
OHCA-
survivors
had
recovered
to
a
baseline
level
of
psychological
functioning
at
6
months
after
their
arrest,
we
recognize
as
a
limi-
tation
that
we
did
not
investigate
the
psychological
outcome
Post
Traumatic
Stress
Disorder
(PTSD)
as
such.
An
increased
risk
for
PTSD
has
been
reported
in
general
ICU-patients33 and
OHCA-survivors3
but
we
consider
it
unlikely
that
a
large
fraction
of
the
OHCA-
survivors
in
our
study
would
suffer
from
PTSD
considering
their
HADS-scores.
OHCA-survivors
with
PTSD
were
reported
to
have
increased
levels
of
depression
and
anxiety
measured
by
HADS
with
>5
points
higher
mean
scores
for
both
subscales.26
Further
limitations
of
our
study
are
that
STEMI-controls
that
declined
participation
may
have
a
different
psychological
outcome
than
those
included.
In
addition,
our
examiners
were
only
blinded
for
the
intervention
group
and
not
for
controls
which
may
have
affected
the
result.
The
data
could
be
interpreted
both
with
and
without
the
controls.
That
psychological
distress
has
a
negative
effect
on
progno-
sis
and
survival
after
myocardial
infarction
may
be
related
to
a
poorer
adherence
to
secondary
prevention
such
as
physical
activity
and
lifestyle
changes
among
those
who
are
affected.12
This
association
stresses
the
specific
importance
to
identify
car-
diac
patients
with
psychological
problems.
The
American
Heart
Association
(AHA)
recently
recommended
that
depression,
as
a
risk
factor
for
adverse
outcome
in
patients
with
acute
coronary
outcome,
deserves
attention,
identification
and
treatment.13 To
prevent
and
mitigate
symptoms
of
psychological
distress
a
follow-
up
2–3
months
after
the
ICU-stay/OHCA
is
recommended.34–36
There
are
local
and
national
variations
in
follow-up
routines34 and
we
cannot
exclude
potential
influence
of
follow-up
procedures
that
may
have
been
provided
outside
the
TTM-trial
protocol
on
the
rel-
atively
low
level
of
psychological
distress
that
we
discovered.
We
also
recognize
that
follow-up
and
attention
within
any
clinical
trial
may
have
a
positive
effect
by
itself.
Although
we
lack
information
on
other
therapies,
the
fraction
of
patients
receiving
medication
for
psychological
distress
was
low
in
our
cohort,
which
may
indicate
that
most
psychological
distress
was
unrecognized.
The
general
perspective
on
psychological
distress
after
OHCA
needs
to
be
extend
to
include
members
of
the
patient’s
family.37
Several
investigators
of
OHCA-
and
ICU-populations
reported
that
family
members
might
be
at
even
higher
risk
for
anxiety,
depression
and
PTSD
than
the
patients
themselves.35,38,39 All
OHCA-survivors
in
the
present
study
were
initially
unconscious
and
their
memo-
ries
of
the
ICU-stay
may
be
sparse.
Although
absent
or
delusional
memories
may
increase
the
risk
for
PTSD,
the
ones
who
actually
experienced
the
stressful
ICU-environment
were
their
closest
rela-
tives,
present
at
the
bedside.
In
addition,
cognitive
impairment
in
patients
was
found
to
increase
the
risk
of
psychological
dis-
tress
among
caregivers.40 Family
stress
and
interactions
between
patients
and
their
relatives
are
areas
that
need
to
be
addressed
in
forthcoming
studies.
Conclusions
One
quarter
of
the
OHCA-survivors
reported
anxiety
and/or
depression
6
months
after
their
arrest
and
these
symptoms
were
associated
with
decreased
HRQoL,
poor
neurologic
outcome
and
subjective
cognitive
problems.
Similar
levels
of
psychological
dis-
tress
were
found
for
the
STEMI-controls
and
comparable
with
previous
normative
data.
Although
the
majority
of
OHCA-survivors
reported
no
psychological
distress
patients
with
these
symptoms
deserve
further
attention
since
it
may
affect
long-term
prognosis
and
be
amendable
to
therapeutic
intervention.
Conflict
of
interest
Friberg,
Nielsen,
Pellis
and
Wise
report
lecture
fees
from
Bard
Medical.
Wise
is
on
the
advisory
board
for
Bard.
Östman
reports
a
single
fee
from
the
HeartNet
for
co-authorship
of
a
patient
infor-
mation
booklet.
The
authors:
Lilja,
Nilsson,
Hassager,
Koopmans,
Kuiper,
Martini,
Mellinghoff,
Pelosi,
Wanscher
and
Cronberg
report
no
conflicts
of
interest.
Acknowledgements
The
European
Union
Interreg
IVA
programme,
The
Swedish
Heart
and
Lung
Association,
the
Skåne
University
Hospital
Founda-
tions,
the
Gyllenstierna-Krapperup
Foundation,
Academy
of
Caring
Sciences
at
Skåne
University
Hospital,
the
Swedish
National
Health
System
(ALF),
the
County
Council
of
Skåne,
the
Swedish
Soci-
ety
of
Medicine,
the
Koch
Foundation,
the
Swedish
Heart–Lung
Foundation,
AFA
Insurance
Foundation,
the
Hans-Gabriel
and
Alice
Trolle-Wachtmeister
Foundation
for
Medical
Research,
the
Segerfalk
Foundation
and
the
Tryg
Foundation.
The
study
sponsors
have
no
involvement
in
the
study
design,
in
the
collection,
analysis
and
interpretation
of
the
data,
in
the
writing
of
the
manuscript
or
in
the
decision
to
submit
the
manuscript
for
publication.
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