Reliability of the Clinical Frailty Scale in very elderly ICU patients: a prospective European study

Abstract

Purpose
Frailty is a valuable predictor for outcome in elderly ICU patients, and has been suggested to be used in various decision-making processes prior to and during an ICU admission. There are many instruments developed to assess frailty, but few of them can be used in emergency situations. In this setting the clinical frailty scale (CFS) is frequently used. The present study is a sub-study within a larger outcome study of elderly ICU patients in Europe (the VIP-2 study) in order to document the reliability of the CFS.

Materials and methods
From the VIP-2 study, 129 ICUs in 20 countries participated in this sub-study. The patients were acute admissions ≥ 80 years of age and frailty was assessed at admission by two independent observers using the CFS. Information was obtained from the patient, if not feasible, from the family/caregivers or from hospital files. The profession of the rater and source of data were recorded along with the score. Interrater variability was calculated using linear weighted kappa analysis.

Results
1923 pairs of assessors were included and background data of patients were similar to the whole cohort ( n = 3920). We found a very high inter-rater agreement (weighted kappa 0.86), also in subgroup analyses. The agreement when comparing information from family or hospital records was better than using only direct patient information, and pairs of raters from same profession performed better than from different professions.

Conclusions
Overall, we documented a high reliability using CFS in this setting. This frailty score could be used more frequently in elderly ICU patients in order to create a more holistic and realistic impression of the patient´s condition prior to ICU admission.

Full text

Flaattenetal. Ann. Intensive Care (2021) 11:22
https://doi.org/10.1186/s13613-021-00815-7
RESEARCH
Reliability oftheClinical Frailty Scale invery
elderly ICU patients: aprospective European
study
Hans Flaatten1* , Bertrand Guidet2, Finn H. Andersen3,4, Antonio Artigas5, Maurizio Cecconi6,
Ariane Boumendil7, Muhammed Elhadi8, Jesper Fjølner9, Michael Joannidis10, Christian Jung11,
Susannah Leaver12, Brian Marsh13, Rui Moreno14, Sandra Oeyen15, Yuriy Nalapko16, Joerg C. Schefold17,
Wojciech Szczeklik18, Sten Walther19, Ximena Watson20, Tilemachos Zafeiridis21 and Dylan W. de Lange22 on
behalf of the VIP2 Study Group
Abstract
Purpose: Frailty is a valuable predictor for outcome in elderly ICU patients, and has been suggested to be used in
various decision-making processes prior to and during an ICU admission. There are many instruments developed
to assess frailty, but few of them can be used in emergency situations. In this setting the clinical frailty scale (CFS) is
frequently used. The present study is a sub-study within a larger outcome study of elderly ICU patients in Europe (the
VIP-2 study) in order to document the reliability of the CFS.
Materials and methods: From the VIP-2 study, 129 ICUs in 20 countries participated in this sub-study. The patients
were acute admissions ≥ 80 years of age and frailty was assessed at admission by two independent observers using
the CFS. Information was obtained from the patient, if not feasible, from the family/caregivers or from hospital files.
The profession of the rater and source of data were recorded along with the score. Interrater variability was calculated
using linear weighted kappa analysis.
Results: 1923 pairs of assessors were included and background data of patients were similar to the whole cohort
(n = 3920). We found a very high inter-rater agreement (weighted kappa 0.86), also in subgroup analyses. The agree-
ment when comparing information from family or hospital records was better than using only direct patient informa-
tion, and pairs of raters from same profession performed better than from different professions.
Conclusions: Overall, we documented a high reliability using CFS in this setting. This frailty score could be used more
frequently in elderly ICU patients in order to create a more holistic and realistic impression of the patient´s condition
prior to ICU admission.
Keywords: Clinical frailty scale, Inter-rater variability, Intensive care, Octogenarians
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Background
Frailty assessment is increasingly used in critically ill
elderly patients and has in many studies been shown
to correlate with outcomes [1–3]. Frailty assessment
has recently been suggested as one of several ele-
ments that could theoretically considered for decision
to admit patients to the ICU during the present pan-
demic [4], although firm evidence for its use is lacking.
Open Access
*Correspondence: Hans.flaatten@uib.no
1 Department of Anaesthesia and Intensive Care, Dep of Clinical Medicine,
Haukeland University Hospital Bergen Norway, University of Bergen,
5019 Bergen, Norway
Full list of author information is available at the end of the article

Page 2 of 7
Flaattenetal. Ann. Intensive Care (2021) 11:22
Traditionally, frailty assessments are performed within
the context of a comprehensive geriatric assessment and
require active participation from the patient [5].Under-
standably,this is not feasible in mostacutely admittedor
critical ill patients, and hence other methods have been
developed to overcome this problem. One of the most
frequently used tool for frailty assessments in this set-
ting is the Clinical Frailty Scale (CFS) [6] developed from
the large Canadian studies of frailty that established the
cumulative deficit approach to frailty. e CFS has since
increasingly been used in intensive care as well as in
other emergency settings and was found in a recent sys-
tematic review to be the most frequent instrument used
to assess frailty in ICU patients, but is only properly vali-
dated in patients ≥ 65years [7].
As in any assessment method, the psychometric prop-
erties of the test are important. Regarding the CFS, the
original publication [6] established construct validity by
comparing it with the frailty index [8]. Inter-rater reli-
ability of the CFS has been tested in a limited number
of patients in three studies [9–11] and the feasibility was
clinically demonstrated in the VIP1 study where CFS was
collected in 99.8% of the 5187 patients included [1]. As a
pre-defined sub-study nested within the VIP2 study [12]
we additionally planned to perform a large international
assessment of CFS reliability.
Interrater variability may vary for several reasons: indi-
vidual differences in how to use the CFS, the rater’s pro-
fession and experience, and the source of information
necessary to perform a frailty score. Our hypothesis is
that the CFS, being intuitive to perform, may vary little
with the rater’s profession and source of available infor-
mation to perform the score.
e main aim of this study was to document inter-rater
reliability within a large prospective observation study
and assess the results of the score being derived from dif-
ferent raters and dissimilar information source, and in
addition study potential variances between countries.
Methods
Study design andsetting
e observational VIP-2 study was performed in acute
ICU admissions of patients ≥ 80years, and its primary
aim was to describe the influence and interaction of sev-
eral geriatric syndromes: frailty, co-morbidity, the activity
of daily life, and cognition on many different outcomes.
e study was performed over 12months in 2018–2019
and included 3920 patients from 22 countries. More
details and results can be found in the original publica-
tion [12]. Units could voluntarily sign up additionally to
participate in a pre-defined sub-study of the inter-rater
variability of CFS. e English version of CFS was used
except for France and Switzerland using a validated ver-
sion in French [13].
Clinical Frailty Scale (CFS)
e CFS was used to assess frailty in all recruited patients
as it presented prior to the acute event and admission
to the ICU. e CFS is a pictographic scale from 1–9
describing nine different grades of frailty with a short text
attached [6]. Patients with scores from 1 to 3 are con-
sidered not frail, 4 is pre-frail or vulnerable, and 5 to 9
are considered to be frail. No specific training, except a
written explanation of the use of the CFS, was given to
the participating units where many, but not all units had
prior experience with using it.
Assessment performed bydierent raters
In this study, two different study personnel from the
ICU independently and blinded for each other results,
assessed the patient at admission (first 24h in the ICU)
using the CFS with input from patients if possible, if not
from care-givers or the medical and nursing hospital
notes. e second rater was free to use sources of input
and was not constrained to use the same as rater 1. e
CFS score was noted for assessor 1 and 2 with informa-
tion about the profession of the assessor: ICU nurse, ICU
physician, dedicated study person, or other. Furthermore,
they documented the kind of information that was used
to perform the score. ese data were then recorded in
the electronic case record form (CRF) for the VIP-2 study
by the local study investigator.
e assessors were named Rater 1 and Rater 2. In the
analysis of data, the CFS rating was considered as an
ordinal variable, and the occupation of the assessors
were grouped as ICU nurse; ICU physician; research
staff or other. e main source where the information
was obtained was classified into 4 groups: (a) from the
patient; (b) from family/care-givers; (c) from hospital
records; and (d); another source, and they could only
choose one option.
Registration andethics
is pre-defined sub-study was registered on Clinical
Trials.gov identifier NCT03370692 at the same time as
the main study. e main study was approved by ethical
committees in all participating countries by institutional
research boards, for details see the VIP-2 study main
paper [12]. Since this study involved health profession-
als (raters) in some countries, this sub-study had to go
through an independent review, and the rater then had to
give informed consent to participate.

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Flaattenetal. Ann. Intensive Care (2021) 11:22
Statistical analyses
A statistical analysis plan was discussed in the VIP2 study
group and was decided to adopt to the guidelines for
reporting of reliability and agreement studies (GRAAS)
[14], see Additional file1.
Data were analysed using SPSS version 25.0 (IBM,
Armonk, NY USA) and with MedCalc 19.0 (http://www.
medca lc.org Ostend, Belgium). e inter-rater reliabil-
ity was assessed using linear weighted kappa in order to
minimise outlier ratings and with intraclass correlation
coefficient where raters for each subject were selected at
random and with a one-way random effects model. We
first analysed the inter-rater variability using all pairs
then compared raters from different professions, infor-
mation sources and participating countries. In the manu-
script, we further use the accepted grouping of weighted
kappa: Poor: 0–0.2, Fair (0.21–0.4), Moderate (0.41–0.6),
good (0.61–0.8) and very good (0.81–1.0) [14, 15].
Results
20 countries and 129 ICUs contributed to the inter-rater
study that included 1923 pairs of raters, and hence two
independent CFS assessments. is represented 49.1% of
the whole VIP-2 study population, and patients’ details
compared to patients not studied are given in Table1.
Overall the number of completed CFS in the VIP-2
study was 99.6%, higher than activity of daily life score
(ADL): 88.6% or cognition (IQCODE): 76.0%, showing
very high compliance with this score. e profession of
rater 1 and rater 2 were most often ICU physicians fol-
lowed by ICU nurses, and the source of information for
the rating was most often the family/care-givers (Fig.1).
e mean CFS from rater 1 and 2 was 4.18 (± 1,764) and
4.25 (± 1.76), respectively. Since the “other” group of
raters and information sources were few and not speci-
fied, we have excluded these from further analysis.
e 9 different pairs of raters with regard to the profes-
sion are given in Table2. e weighted kappa for all pairs
was 0.86 (95% CI 0.84–0.87).
e intraclass correlation coefficient (absolute agree-
ment) was 0.93 for single measures and 0.96 for average
measures, and the weighted kappa for all measures was
0.86 (95% CI 0.84–0.87) (Table3). Worth noting is the
distribution of scores of 4 and 5 in Table3. A notewor-
thy number of rater one and two have scores above and
below these values. Among rater one, 30 of 402 (7.4%)
scored one or more CFS classes above 4 and by rater two
in 65 of 407 (16%) patients demonstrating some difficulty
of judging vulnerable from frail patients.
e results in Table 4 demonstrate the variability
between pairs from different professions and less vari-
ability when similar source for information was used for
both pairs. e best results were obtained when both
raters were either nurses or physicians, and mixed pairs
of assessors performed slightly worse. Likewise, there are
better results when information does not come from the
patients. ere is also a good performance of the CFS
across countries, but the three countries with the least
number of pairs included performed less well than the
others, although most countries were overall classified as
very good (weighted kappa ≥ 0.80).
We also performed a sensitivity analysis looking at two
subgroups according to rater 1: frail (CFS > 4) versus non-
frail (CFS < 5). In the frail the kappa was 0.70 (95% CI
0.66–0.74) compared to 0.76 (95% CI 0.74–0.79).
Discussion
In this large prospective study on frailty assessment in
the ICU using the CFS, we found the overall agreement
of inter-rater variability in patients > 80years to be very
good. We revealed, however, distinct variations between
groups of raters and between countries. e agreement
between obtaining CFS from hospital records or family
Table 1 Details of VIP-2 patients studied compared
tothose notstudied
The CFS is the value from Rater 1, and the % relates to the column (within the
subgroup)
SOFA sequential organ failure assessment, CFS clinical frailty scale, IQCODE
informant questionnaire on cognitive decline in the elderly, ADL activity of daily
living, CPS Co-morbidity and Polypharmacy score
Included Not included
Number 1923 1997
Age (median IQR) year 84 (81–87) 84 (81–87)
Male sex (%) 53.8% 53.3%
ICU LOS (median IQR) days 4 (1.96–8.89) 4 (1.71–7.12)
SOFA score (median IQR) 6 (4–9) 6 (4–9)
CFS fit (1–3) 789 (41%) 754 (38.1%)
CFS vulnerable (CFS 4) 407 (21.1%) 384 (19.4%)
CFS frail (CFS 5–9) 732 (37.8%) 840 (42.5%)
IQCODE (median, IQR) 3.25 (3–3.75) 3.19 (3–3.56)
Katz ADL score (mean) 4.8
Co-morbidity/polypharmacy
score (mean and 95% CI 10.6 (10.4–10.9)
Admission groups (%)
Acute respiratory failure 22.8 25.3
Emergency surgery 15.4 12.3
Sepsis 14.5 13.0
Acute circulatory failure 13.8 13.8
Respiratory and circulatory 10.7 12.2
Trauma 6.1 4.6
Cerebral failure 5.8 4.0
Other 10.4 13.0

Page 4 of 7
Flaattenetal. Ann. Intensive Care (2021) 11:22
was nearly identical but was lower when the patients were
used as the primary source of information.
Frailty is important in order to understand critical ill
patients, particularly in advanced age [16], and most
studies have demonstrated a close link between frailty
and survival. Hence, knowledge of frailty status could be
important when issues such as ICU triage and limitation
of life-sustaining therapy are discussed. Recent guidelines
0,0%
10,0 %
20,0 %
30,0 %
40,0 %
50,0 %
60,0 %
70,0 %
Profession ICU
pysician
ICUnurse Research
staff
Source Patients Care-giver Hospital
record s
Raters profession andsourceofinformation
Rater1 Rater2
Fig. 1 Raters profession and source of information in the two groups
Table 2 Distribution ofpairs ofRater 1 versusRater 2
a Missing pairs in 4 patients
Profession ofraters Rater 1
Rater 2aICU nurse ICU physician Research sta
ICU nurse 57 309 126
ICU physician 162 785 120
Research staff 46 96 138
Table 3 Intraclass variance Rater 1 (CFS1) andRater 2(CFS2); weighted kappa (linear) 0.86 (0.84–0.87)
CFS 2 CFS 1
1 2 3 4 5 6 7 8 9 Sum %
176 3 0 1 1 0 0 0 0 81 (3.5%)
2 0 71 0 0 0 0 0 0 196 (14.0%)
3 2 40 403 25 7 2 0 1 0 480 (25.0%)
4 1 4 54 313 22 7 1 0 0 402 (20.9%)
5 0 0 10 58 163 28 2 0 1 262 (13.6%)
6 0 0 5 5 43 177 17 2 0 249 (12.9%)
7 0 0 0 1 2 44 126 8 0 181 (9.4%)
80001031346 2 65 (3.4%)
90000000077 (0.4%)
Sum % 94 (4.9%) 202 (10.5%) 493 (25.6%) 407 (21.2%) 240 (12.5%) 261 (13.6%) 159 (8.3%) 57 (3.0%) 10 (0.5%) 1923

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Flaattenetal. Ann. Intensive Care (2021) 11:22
propose the use of frailty assessment as a part of the tri-
age process to be used with COVID-19 [17]. However,
use of frailty in triage setting has its limitations, and is
at present not confirmed in prospective studies. How-
ever, use of CFS would be effective in analysing the clini-
cal decision-making process of an ICU team. ere are
several methods to assess frailty, and CFS is frequently
used in clinical studies with ICU patients [2] as well as
in emergency admission [18] and is also used in routine
clinical use in intensive care units outside study settings
[19].
Using an instrument such as a frailty score requires
knowledge about its performance and with special atten-
tion to reliability and construct validity [20]. Of interest
is also its ability to predict risk for death, where CFS have
been found to perform well. is was recently confirmed
in the VIP-2 study, where CFS alone had similar predic-
tive value for 30-day mortality as a model incorporating
cognition and functional disability [12], again providing
good criterion validity.
e aim of the present study was to document several
unanswered questions using CFS. What is the inter-rater
variability when analysing more heterogeneous groups
of raters using a various source of data for the score?
Both aspects are important properties of a clinical test
or score. e variation of a score in the same patient
between two raters is the inter-rater variability. Overall,
our data proves a very high degree of agreement between
raters with a weighted kappa of 0.86. Since we had a large
number of pairs to study, we could study results in sub-
groups, both between raters from different professions,
the source of information as well as performance across
countries. ere seems to be better agreement when the
raters are from the same profession; physicians or nurses.
When the raters are from different professions the agree-
ment is slightly less. We also provide data showing that
obtaining information from family members and care-
givers or from written records in order to classify CFS
is in fact, better compared to the information obtained
from the patient. is may have a simple explanation that
many elderly patients, although seemingly awake and
co-operable, may not perform at their best at the time
of ICU admission. Hence important information may
not be revealed for the rater. We have found that it can
be a problem to differentiate between CFS 4 and 5. is
could be important since 5 is the first stage on the frail
part of the CFS and 4 is borderline. Recently the CFS was
upgraded to version 2.0 and a more detailed guideline
in how to understand and use the different levels in the
scale have been published [21].
Our study is in line with three recent studies of the
inter-rater variability of the CFS. All studies are from
single countries with a smaller number of pairs included,
and only the overall inter-rater variability was reported.
In a study from Canada involving two ICUs [8], different
assessors from a research coordinator, an occupational
therapist, and a geriatric resident, performed CFS scores
in 150 newly admitted ICU patients. ey reported no
significant differences between the three raters using
Spearman’s rank correlation coefficient. In a more recent
study from six ICUs in Wales and Scotland, 101 patients
were studied with two independent CFS assessments of
frailty by assessors from medical or nursing backgrounds
[7]. ey found a good agreement with a weighted kappa
of 0.74 between raters, and also that agreement differed
slightly depending on the assessor’s background.
A more recent study comparing CFS scored in 158
adult ICU patients scored by geriatricians and intensiv-
ists reported however a poor agreement between raters
[9]. e authors suggest that these two groups have a
different conception of how frailty presents in critical ill
patients as an explanation for this result.
Our study has its limitation: this was not a controlled
trial with regard to the choice of profession and source
of data used and may have been at the centres’ discre-
tion. We also have no information about the clinical
experience of the raters nor their age. e study has also
strengths. It has a very large sample size of nearly 2000
pairs of raters, with at least three important sources of
variation: the profession of raters, source of information,
and country.
Table 4 Weighted kappa in subgroups (physicians
andnurses) and8 countries (≥ 100 pairs)
Group profession NWeighted
kappa 95% CI
ICU physician/ICU physician 785 0.87 0.85 to 0.89
ICU nurse/ICU nurse 57 0.92 0.87 to 0.97
Research staff/research staff 276 0.84 0.80 to 0.87
ICU nurse/ICU physician 162 0.77 0.71 to 0.83
ICU physician/ICU nurse 309 0.80 0.77 to 0.84
Group: information source
Patient/patient 394 0.85 0.82–0.88
Family/family 818 0.89 0.87–0.90
Hospital records/hospital records 187 0.89 0.85–0.92
Group: countries
England 397 0.90 0.87 to 0.97
France 257 0.81 0.78 to 0.85
Spain 186 0.89 0.85 to 0.93
Poland 163 0.89 0.85 to 0.92
Greece 133 0.89 0.85 to 0.94
Germany 125 0.81 0.75 to 0.86
Norway 110 0.71 0.63 to 0.78
Portugal 106 0.82 0.76 to 0.89

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Flaattenetal. Ann. Intensive Care (2021) 11:22
Conclusion
In very elderly ICU patients, the CFS has a high compli-
ance rate and exhibits high overall inter-rater agreement
with a weighted kappa analysis of 0.86. Furthermore,
there are minor variations in performance across dif-
ferent health care professionals, countries and source of
data. We found the best agreement using raters from the
same health care professionals, but with no difference
between pair of nurses or physicians. To determine CFS,
caution should be used to rely on the elderly ICU patients
as the sole source of information.
Frailty assessment should be routine in the critical ill
elderly patients, and the CFS is a good instrument in this
respect, and will give a more holistic impression of the
patient´s condition prior to admission.
Supplementary Information
The online version contains supplementary material available at https ://doi.
org/10.1186/s1361 3-021-00815 -7.
Additional le1. Guideline for reporting of reliability and agreement
studies (GRAAS).
Additional le2. List of local investigators.
Abbreviations
CFS: Clinical frailty scale; VIP: Very old intensive care patients; ADL: Activity of
daily life; IQCODE: Informant questionnaire on cognitive decline in the elderly;
GRAAS: Guidelines for reporting of reliability and agreement studies.
Acknowledgements
The study was endorsed by the European Society of Intensive Care Medicine
(ESICM).
Authors’ contributions
HF, BG, DDL designed the study and wrote the study protocol. AM provided
geriatric expertise in designing the protocol. HF and AB performed the
statistical analysis. JF was responsible for data management and the electronic
CRF; HF drafted the first manuscript, and the writing group (BG, DDL, CJ and
HF) discussed and finalised the manuscript. The rest of the authors were
country coordinators and hence were responsible for data retrieval and have
participated reading and commenting the final draft of the manuscript. The
VIP-2-study collaborators from all individual ICUs are listed in Additional file 2.
Funding
Free support for running the electronic database and was granted from
University of Aarhus, Denmark. Financial support for creation of the e-CRF
and maintenance of the database was possible from a grant (open project
support) by Western Health region in Norway 2018 who also funded the par-
ticipating Norwegian ICUs. DRC Ile de France and URC Est helped conducting
VIP-2 in France.
Availability of data and materials
Data are embedded in the main database, and as such cannot be opened for
general inspection. The main author can at request give an extract from the
database for each pair of raters with necessary information about the inter-
rater agreement.
Ethics approval and consent to participate
The VIP2 study that includes this cohort of patients received ethical approval
from all participating countries, as revealed in the original publication [12].
Briefly this included informed consent at admission in some countries, and
this was not necessary in others because of the observational nature of the
study. Some countries did require informed consent from raters, since they
were in fact considered as “test persons” and this was approved when neces-
sary. Ethical approval from Norway (the country of the PI) had the number
2018/87/REK sør-øst D.
Consent for publication
Not applicable.
Competeing interests
JCS declares that the Dept. of Intensive Care Medicine Bern has/had research
and/or development/consulting contracts with (full disclosure): Orion Corpo-
ration, Abbott Nutrition International, B. Braun Medical AG, CSEM SA, Edwards
Lifesciences Services GmbH/SA, Kenta Biotech Ltd, Maquet Critical Care AB,
Omnicare Clinical Research AG, and Nestlé. Educational grants were received
from Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; AstraZeneca; B. Braun
Medical AG, CSL Behring, Maquet, Novartis, Covidien, Nycomed, Pierre Fabre
Pharma (Roba Pharma); Pfizer, Orion Pharma. The money went into depart-
mental funds. No personal financial gain applies. All other authors do not have
any conflict of interest to declare related to this manuscript.
Author details
1 Department of Anaesthesia and Intensive Care, Dep of Clinical Medi-
cine, Haukeland University Hospital Bergen Norway, University of Bergen,
5019 Bergen, Norway. 2 Sorbonne Université, INSERM, Institut Pierre Louis
D’Epidémiologie Et de Santé Publique, Saint Antoine Hospital, AP-HP, Hôpital
Saint-Antoine, Service de Réanimation, 75012 Paris, France. 3 Department
of Anaesthesia and Intensive Care, Ålesund Hospital, Ålesund, Norway. 4 Dep
of Circulation and Medical Imaging, NTNU, Trondheim, Norway. 5 Deparment
of Intensive Care Medicine, CIBER Enfermedades Respiratorias, Corpora-
cion Sanitaria Universitaria Parc Tauli, Autonomous University of Barcelona,
Sabadell, Spain. 6 Department of Anesthesia and Intensive Care Medicine,
Humanitas Clinical and Research Center–IRCCS, Via Alessandro Manzoni 56,
20089 Rozzano, MI, Italy. 7 AP-HP, Hôpital Saint-Antoine, Service de Réanima-
tion, 75012 Paris, France. 8 Faculty of Medicine, University of Tripoli, Tripoli,
Libya. 9 Department of Intensive Care, Aarhus University Hospital, Aarhus,
Denmark. 10 Division of Intensive Care and Emergency Medicine, Department
of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria. 11 Divi-
sion of Cardiology, Pulmonology and Vascular Medicine, University Hospital
Düsseldorf, Heinrich-Heine- University, Düsseldorf, Germany. 12 Research Lead
Critical Care Directorate St George’s Hospital, London, UK. 13 Mater Misericor-
diae University Hospital, Dublin, Ireland. 14 Faculdade de Ciências Médicas de
Lisboa (Nova Médical School), Unidade de Cuidados Intensivos Neurocríticos
E Trauma. Hospital de São José, Centro Hospitalar Universitário de Lisboa Cen-
tral, Lisbon, Portugal. 15 Department of Intensive Care 1K12IC, Ghent University
Hospital, Ghent, Belgium. 16 European Wellness International, ICU, Luhansk,
Ukraine. 17 Department of Intensive Care Medicine, Inselspital, Universitätsspi-
tal, University of Bern, Bern, Switzerland. 18 Intensive Care and Perioperative
Medicine Division, Jagiellonian University Medical College, Kraków, Poland.
19 Heart Center, Linkoping University Hospital, Linkoping, Sweden. 20 ICU,
St George’s University Hospital, London, UK. 21 Intensive Care Unit General
Hospital of Larissa, Larissa, Greece. 22 Department of Intensive Care Medicine,
Dutch Poisons Information Center (DPIC), University Medical Center, University
Utrecht, Utrecht, The Netherlands.
Received: 10 November 2020 Accepted: 27 January 2021
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