Female - ICU-AW

Journal of
Clinical Medicine
Article
Sex-Specific Aspects of Skeletal Muscle Metabolism in the
Clinical Context of Intensive Care Unit-Acquired Weakness
Lilian Jo Engelhardt 1,2 , Julius J. Grunow 1 , Tobias Wollersheim 1 , Niklas M. Carbon 1 , Felix Balzer 2 ,
Joachim Spranger 3 and Steffen Weber-Carstens 1, *
1
Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK),
Med. 2022, 11, x FOR PEER REVIEW 4 of 14
Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu
J. Clin. Med. 2022, 11, x FOR PEER REVIEW Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; [email protected] (L.J.E.); 4 of 14
2022, 11, x FOR PEER REVIEW J. Clin. Med. 2022, 11,
[email protected] x FOR
(J.J.G.); PEER REVIEW
[email protected] 4 of 14
(T.W.); [email protected] (N.M.C.)
in. Med. 2022, 11, x FOR PEER REVIEW 2
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4 of 14
Institute of Medical Informatics, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität
3.1. Clinical Baseline Characteristics
Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany; [email protected]
3.1. Clinical
3 Baseline Characteristics
Department of Endocrinology and Metabolic Diseases, Charité–Universitätsmedizin Berlin, Corporate
Baseline
3.1. Clinical Baselinedata, caloric intake, and quantity of physiotherapy
Characteristics 3.1. Clinical zu are shown
Baseline in Table 1.
Characteristics
3.1. Baseline
Clinical Member
Baselinedata, ofcaloric
Freie Universität
Characteristicsintake, Berlin,quantity
and Humboldt-Universität
of physiotherapy
3.1. Berlin,
Clinical Charitéplatz
are shown
Baseline 1,in
10117 Berlin,
Table
Characteristics 1. Germany;
Body height
Baseline (p
data, < 0.001)
caloric and
intake,weight
and
[email protected](p = 0.001)
quantity were
of lower
physiotherapyin female
Baseline
are patients,
data,
shown while
caloric
in Table median
intake,
1. and quantity of physiot
BMI Body
was height
Baseline
27 kg/m (p2 <incaloric
data, 0.001)
both and
groupsweight
intake, and
(p = (p0.833).
= 0.001)
quantity were
of
Mean lower in
physiotherapy
caloric female
Baseline
intake are
perpatients,
data,
shown while
caloric
predicted in Tablemedian
intake,
body 1. and quantity ofin
p
* Correspondence: [email protected]
Body height (p < 0.001) and weight (p = 0.001) were lower in Body
female
height
patients,
(p < 0.001)
while and
median
weight (p = 0.001) were lower
Body BMI was
height 27< kg/m 2 in both groups (p = 0.833). Mean caloric intake per predicted body
BMIweight
was 27 was
kg/m 2(pin
higher 0.001)
both and weight
in females
groups during (p
(p =during= 0.001)
ICU
0.833). stay were
Mean lower
(p =caloric
0.001)
BMI in
Body
and
was female
intakein
27 height
the
kg/m
per patients,
2(pin
first < 0.001)
seven
predicted while
both and
days
body median
weight
after
groups = (p
(pafter = 0.001)
0.833). were
Mean lo
calo
ICUBMI weight
was
admissionwas
27 kg/m
(phigher
Abstract:= 2 in in
0.008).
(1)
females
both groups
Females
Background: (p =
received
Female
ICU a
sex
stay
0.833). Mean
higher
is
(p = insulin
considered
0.001)
BMI
caloric a
and
was
dose
risk
in27
intake the
until
factor
first
kg/m
per
forthe 2 seven
predicted
in
day
Intensive
days
both
of body
groups
the
Care (p =
Unit-Acquired 0.833). Mea
weight was ICU higher in females
admission during Females
(p (ICUAW).
= 0.008). ICU stayreceived
(p = 0.001) weight
and in was
the first
higher
seven in until
females
daysthe after
during ICU stay (p = 0.001) a
ICU muscleweight
admission was
biopsy
(p higher
(p0.008).
Weakness
= in
= 0.048). females
No sexduring
Females ICU
differences
The aim
received stay
isa towere =ainsulin
(pfound
investigate
higher
higher
0.001)
ICU in insulin
weight
and
the
admission
dose inuntil
was
thedose
frequency
sex-specific first
higher
aspects
(p the
= seven
and
0.008).
day in day
females
days
duration
of skeletal
of ofof
after
muscle
Females
the
the
during ICU
metabolism
received stay (p =ins
a higher 0.
ICU muscle
physiotherapy. biopsy
admissionin the(p (p= =0.008).
context
0.048).
of
No sex(2)
Females
ICUAW.
differences
received
Methods: a were
higher
This
found
is a insulin
ICU inadmission
the
sex-specific
frequency
dose until (p
sub-analysisthe
= and duration
0.008).
day
from ofFemales
the
two
of received
prospectively a high
muscle biopsy (p = 0.048). No sex differences were found muscle
physiotherapy. in the frequency
biopsy (pand = 0.048).
durationNo sex
of differences were found in
muscle
physiotherapy. biopsy (p = 0.048).
conducted trialsNo sex differences
examining were found
skeletal muscle muscle
in
metabolism
physiotherapy.the frequency
andbiopsy
advanced (p and
= 0.048).
duration
muscle No sex
of differences
activating measures were fou
Table 1. Baseline
physiotherapy. characteristics.
in critical illness. Muscle strength was assessed by physiotherapy.
Medical Research Council Score. The insulin
Citation: Engelhardt, L.J.; Grunow,
Table 1. Baseline characteristics.
J.J.; Wollersheim,Table 1. Baseline
T.; Carbon, N.M.; sensitivity index was analyzed by hyperinsulinemic-euglycemic
characteristics. (HE) clamp. Muscular metabolites
Table 1. Baseline
Male ICU Patients
characteristics. Table 1. Baseline characteristics.
Balzer, F.; Spranger, J.; were studiedMale
by ICU Patients
microdialysis. M. vastus lateralis biopsies were taken. The molecular analysis included
Weber-Carstens, S. Sex-Specific
Male ICU
protein Male Patients
degradation Female ICU Patients
pathways. Morphology was assessed by myocyte Male Male ICU Patients area (MCSA).
cross-sectional
ICU Patients Female ICU Patients ICU Patients
Aspects of Skeletal Muscle Multivariable linear regression models for the effect
Female ICU Patients of sex on outcome p-Value
parameters were performed.Female I
Metabolism in the Clinical Context of
♂ FemalenICU Patients p-Value Fem
(3) Results: n = 83 (♂n = 57, 68.7%; ♀n =♀ = 26ICU
26, 31.3%) (31.3%) p-Value
Intensive Care Unit-Acquired ♂ n = 26patients
(31.3%)were included. ICUAW was ♂
p-Value
present in n =81.1% ♂ and in 82.4% ♀ at first awakening
57 (68.7%) n = 26 (31.3%) 0.911) and in 59.5%♂ and in 70.6% ♀
Weakness. J. Clin. Med. 2022, 11, 846.
n = 57 (68.7%) ♀ n = (p
26=(31.3%) ♀
Age (years)
https://doi.org/10.3390/ at ICU 49.0
n = discharge
57 (37.0/63.0)
(68.7%) (p = 0.432). Insulin sensitivity 60.5 (44.0/68.0)
index was reduced 570.082
n =more in women than in men
(68.7%)
Age (years)
jcm11030846 (p = 0.026). nSex 49.0
was (37.0/63.0)
=(23.4/29.8)
57 (68.7%)
significantly associated with 60.5 (44.0/68.0)
insulin sensitivity index and n =MCSA
570.082
(68.7%)
of Type IIa fibers
AgeBMI (kg/m2)
(years)BMI (kg/m 2) 49.0 27.1
(37.0/63.0)
27.1 (23.4/29.8)Age (years)60.5 27.0 (23.1/31.2)
(44.0/68.0)
27.0 (23.1/31.2) 49.0
0.082 0.833
(37.0/63.0)0.833 60.5 (4
Age
Height (years)
(cm) in the 178.049.0
adjusted (37.0/63.0)
regression
(175.0/185.0) models. Age
(4) (years)
Conclusion:
165.0 60.5 (44.0/68.0)
This hypothesis-generating
(163.0/170.0) 49.00.082
<0.001 (37.0/63.0)
analysis suggests that
BMIAcademic
(kg/m )
2Editors: Joel T. Cramer and 27.1 (23.4/29.8) BMI (kg/m 2)27.0 (23.1/31.2) 27.1
0.833
(23.4/29.8) 27.0 (2
BMIHeight
Weight
Toshiaki (kg/m
(kg)
Nakajima
(cm)
2) more pronounced
85.0
178.0
27.1 (175.0/185.0)
(23.4/29.8)
impairments in
(80.0/96.0) BMI (kg/m
insulin 165.0
2)27.0
sensitivity
71.0
(163.0/170.0)
(23.1/31.2)
and
(65.0/85.0) lower MCSA of 0.001 27.1
Type <0.001
0.833
(23.4/29.8)
IIa fibers in critically
Height (cm) Weight (kg) 178.0 (175.0/185.0)
85.0 (80.0/96.0)Height (cm) 165.0 (163.0/170.0)71.0 (65.0/85.0)178.0 <0.001
(175.0/185.0)
0.001 165.0 (1
SOFA score Height
at ICU(cm) admission ill women 178.0
may
12.0 (175.0/185.0)
be relevant
(10.0/14.0) for sexHeight (cm)
differences 165.0 (163.0/170.0)
in ICUAW.
14.0 (11.0/16.0) 178.0
<0.001
0.167 (175.0/185.0) 1
Weight
SOFA (kg)
score14 at
Received: ICU admission
December 2021 85.0 (80.0/96.0)
12.0 Weight (kg) 71.0
(10.0/14.0) Weight (kg)71.014.0 (65.0/85.0) (11.0/16.0) 85.0
0.001
(80.0/96.0)0.167 71.0 (6
Weight (kg) 85.0 (80.0/96.0) (65.0/85.0) 85.00.001
(80.0/96.0)
AAPACHE
score at at ICU
ICU
Accepted:
APACHE
admission
admission
3 February 2022
at ICU admission 12.0 21.0 (17.0/27.0)
(10.0/14.0)
21.0SOFA score at ICU admission
(17.0/27.0) 14.0 23.5 (17.0/30.0)
(11.0/16.0)
23.5 (17.0/30.0) 12.0
0.167 0.170
(10.0/14.0)0.170 (CIM); gender; 14.0 (1
SOFA score at ICU admission Keywords:12.0 intensive
(10.0/14.0)care
SOFA unit-acquired
score at weakness
ICU admission
14.0 (ICUAW);
(11.0/16.0) critical illness12.0
myopathy
0.167
(10.0/14.0)
SAPS
ACHE at 2 at ICU
ICU2admission
Published: admission
5 February 2022 52 (38.0/62.0)
21.0 (17.0/27.0) APACHE at ICU admission 54.5 (44.0/69.0)
23.5 (17.0/30.0) 21.0
0.170 0.107
(17.0/27.0) 23.5 (1
APACHESAPS atat ICU ICU admission
admission sex; muscle; 21.0 52
atrophy; (38.0/62.0)
(17.0/27.0)metabolism;
APACHEmetabolites;
at ICU admission 54.5
insulin
23.5 (44.0/69.0)
sensitivity; glucose21.0
(17.0/30.0) 0.1700.107
(17.0/27.0)
APS Length
2 atLength
ICU of ICU
Corrected: 20stay
admission (days)
September 2022 52 29 (20.0/41.0)
(38.0/62.0) SAPS 2 at ICU admission
54.5 27 (17.0/49.0)
(44.0/69.0) 52
0.107 0.933
(38.0/62.0) 54.5 (4
SAPS 2 ICU of ICU
at ICU stay (days)
admission 52 29 (20.0/41.0) 27 (17.0/49.0) 0.933
rvival
ngth ofuntil
ICU stay discharge
(days) (n, %) 29 45(38.0/62.0)
(20.0/41.0) (78.9)Length
SAPS 2 at ICU admission
of ICU stay 27
(days)
54.5
(17.0/49.0)
(44.0/69.0)
24 (92.3) 29
0.933
520.107
0.132 (38.0/62.0)
(20.0/41.0) 27 (1
Survival
Lengthfor until
Publisher’s
ofICU
ICU ICU stay discharge
Note: MDPI
(days) (n, %)
stays neutral 45 (78.9)
29 (20.0/41.0) Length of ICU stay 27 (days) 24 (92.3)
(17.0/49.0) 290.9330.132
(20.0/41.0)
alReasons
untilReasons
ICU discharge
with regard
for
admission
(n,
to jurisdictional
ICU %)
admission claims in 45 (78.9) Survival until ICU discharge 24 (92.3)
(n, %) 0.132 0.289
45 (78.9) 0.289 24
urvival untilARDS ICU (n, discharge
%) (n, %) 1945 (78.9)
(33.3) Survival until ICU discharge 9 24 (92.3)
(n, %)
(34.6) 0.132
45 (78.9)
asons forpublished
ICUARDS admission
maps and institutional affil-
(n, %) 1. Introduction Reasons
19 (33.3) for ICU admission 9 (34.6) 0.289
Reasons for ICU
Sepsis
iations. (n,%)admission 13 (22.8) Reasons for ICU admission 7 (26.9) 0.289
ARDS (n, Sepsis
%) 19 (33.3)
Intensive Care ARDS
Unit-Acquired (n, %) 9
Weakness(34.6) (ICUAW) is a 19 (33.3)
serious long-term 9(
ARDS (n,
Polytrauma
(n,%)
%)
(n,%) 1619
13
(33.3)
(28.1)
(22.8) ARDS (n, %) 3 (11.5) 7
9 (34.6)(26.9) 19 (33.3)consequence
Sepsis (n,%)
Polytrauma (n,%) of 13
critical (22.8)
illness associated
16 (28.1) Sepsis
with(n,%)increased7 (26.9)
morbidity 3 (11.5) and 13
mortality (22.8)
[1]. It is characterized 7(
Sepsis
Neurological (n,%)
(n,%) 9 13
(15.8)(22.8) Sepsis (n,%) 6 (23.1) 7 (26.9) 13 (22.8)
Polytrauma (n,%)
Neurological (n,%) 16 (28.1)
by loss of muscle9mass Polytrauma
(15.8)and Polytrauma (n,%) 3 (11.5)
functionality [2,3]. ICU-related 16 (28.1)
6 (23.1) physical impairments contribute 3 (
Polytrauma
Other (n,%) (n,%) 16- (28.1) (n,%)1 3(3.8) (11.5) 16 (28.1)
Neurological
Copyright:
(n,%)
Other © 2022(n,%) by the authors.
to reduced9 (15.8)
quality of -Neurological (n,%)6in
life and disabilities (23.1)
survivors’ 1 (3.8)activities of9daily
(15.8)living [4,5]. ICUAW 6(
nsulin Neurological
dose and caloric (n,%) intake is a risk factor 9 (15.8)
for the Neurological
post-intensive care(n,%) 6 (23.1)
syndrome (PICS), which is 9 (15.8) by physical
defined
Other
Insulin (n,%)
dose
Licensee MDPI,andBasel,caloric intake
Switzerland. - Other (n,%) 1 (3.8) - 1
nsulin
in dosedose and per
Other
caloric body
(n,%)
intake surface and cognitive -
impairments
Insulin dose as
and
Other
well (n,%)
as
caloric mental
intake
1health
(3.8) problems [5]. Recently, - attention has
area Insulin
during
Insulin dose dose
ICUandstay per body
This article is an open access article
caloric (IE/m surface
2
intake 18.5 (10.5/26.7)
) and2 been drawn 18.5 Insulin dose and 20.1 (15.6/30.9)
caloric intake 0.289
in dose
area per body
distributed
during surface
under
ICU
the terms
stay (IE/m )
toInsulin
PICS asdose
(10.5/26.7) per
a relevant body
burdensurface
in the 20.1 COVID-19
(15.6/30.9)pandemic [5]. 0.289
Insulin
Insulin dose
during dose
ICU perper
stayofbody
conditions body
(IE/m 2surface
surface
the Creative ) surface
Commons
18.5
Risk(10.5/26.7)
factors Insulin
for ICUAW dose
area during ICU stay (IE/m per
include body
20.1 severe surface
(15.6/30.9)
2 sepsis
) (15.6/30.9) with 18.5
0.289
multiple(10.5/26.7)
organ failure, immo- 20.1 (1
Insulin dose per body 2 18.5(9.2/27.8)
18.6 (10.5/26.7) 20.1
30.0 (17.7/37.0)
2 18.50.289
0.048 (10.5/26.7)
area
until
lin dose
during
muscle
permuscle
ICU
biopsy
Attribution
body
stay
(CC BY) (IE/m
surface
(IE/m )
license)(https://
2 bilization, use
18.6 of area
(9.2/27.8)
Insulin
during
neuromuscular ICU stay
blockers (IE/m
or
dose per body surface30.0 (17.7/37.0)
)
corticosteroids as well as
0.048stress-induced
until
Insulin doseper perPBW biopsy
body
creativecommons.org/licenses/by/ (IE/m2)
surface 18.6 (9.2/27.8)
hyperglycemia [6]. Furthermore,
Insulin dose per a30.0 (17.7/37.0)
multivariable
body surfaceanalysis by 18.6
0.048
De(9.2/27.8)
Jonghe et al. identified 30.0 (1
Caloric
til muscle intake
biopsy (IE/m 2 during
) 18.6 until muscle biopsy (IE/m
(9.2/27.8) 2 ) (17.5/28.2)
30.0 (17.7/37.0) 18.6
0.048(9.2/27.8)
Caloric
until
ICU stay4.0/).intake
muscle biopsy
(kcal/kgPBW)
per PBW (IE/mduring2) female 18.5sex as (14.0/20.7)
18.5an (14.0/20.7)
independent
until musclepredictor
biopsy 21.6
of(IE/m
ICU-acquired
21.6 )(17.5/28.2)
2 0.001
paresis [2]. The reasons for this
0.001
ric intake ICU per PBW
stay during
(kcal/kgPBW) Caloric intake per PBW during
Caloric
Caloric intake per
intake per PBW ICU PBW during 18.5 (14.0/20.7) Caloric intake 21.6
per (17.5/28.2)
PBW during 18.5
0.001
(14.0/20.7) 21.6 (1
CU stay (kcal/kgPBW)
Caloric intake per PBW ICU 18.5
13.7 (10.5/19.1) ICU stay (kcal/kgPBW)
(14.0/20.7) 21.6
17.7 (17.5/28.2)
(13.5/24.9) 18.50.001
0.008 (14.0/20.7)
ICU1–7 stay (kcal/kgPBW) ICU stay (kcal/kgPBW)
oric day
intake day
(kcal/kgPBW)
per 1–7PBW ICU
(kcal/kgPBW)
13.7Caloric
(10.5/19.1)
intake per PBW ICU 17.7 (13.5/24.9) 0.008
Caloric
hysiotherapy intake during per PBWICU ICU
stay 13.7 (10.5/19.1) Caloric intake17.7 per (13.5/24.9)
PBW ICU 13.7
0.008
(10.5/19.1) 17.7 (1
day Physiotherapy
1–7 (kcal/kgPBW)
J. Clin. Med. 2022, 11, 846. https://doi.org/10.3390/jcm11030846
during ICU stay 13.7 (10.5/19.1) day 1–7 (kcal/kgPBW) 17.7 (13.5/24.9) https://www.mdpi.com/journal/jcm 13.70.008
(10.5/19.1)
alotherapyday 1–7
duration (kcal/kgPBW) (min)
of physiotherapy 445 (267.5/662.5) day 1–7 (kcal/kgPBW)397.5 (265.0/740.0) 0.673
Total duration during of ICU stay
physiotherapy Physiotherapy during ICU stay
Physiotherapy during ICU stay (min) 445 (267.5/662.5)
Physiotherapy during ICU 397.5stay (265.0/740.0) 0.673
J. Clin. Med. 2022, 11, 846 2 of 14
remain unclear. Physiological differences in body composition, muscle strength, and energy
metabolism may contribute [7].
Some pathomechanisms of ICUAW have already been investigated by our research
group. Characteristic findings included Type II fiber atrophy, increase in atrophic genes,
loss of myosin heavy chains, and inexitability of muscle membrane [3,6,8]. In addition, we
found impairments in skeletal muscle glucose metabolism, such as reduced insulin sensi-
tivity, disturbed GLUT4 translocation, and decreased stimulation of muscular glycolysis
metabolites [9].
Skeletal muscle metabolism associated with ICUAW has not been studied from a
sex-specific perspective. In this hypothesis-generating analysis, we will examine the
pathomechanisms contributing to ICUAW in sex-specific groups, with a focus on skeletal
muscle metabolism. To our knowledge, this is the first sex-specific study involving analysis
of insulin sensitivity by hyperinsulinemic-euglycemic (HE) clamp, metabolites of muscular
microdialysis, and molecular analysis of muscle biopsies in critically ill patients at high
risk for ICUAW.
2. Materials and Methods

2.1. Study Design, Inclusion Criteria, and Setting
This is a sex-specific sub-analysis of two prospectively conducted observational and in-
tervention ICU studies. First, the observational study examined skeletal muscle metabolism
and Critical Illness Myopathy in the early phase of critical illness (ISRCTN77569430) [3,9].
Patients in the observational study received standard physiotherapy. This was followed by
an intervention study to examine skeletal muscle metabolism and atrophy in ICU patients
who received advanced early muscle-activating measures compared with protocol-based
physiotherapy (ISRCTN19392591) [10,11]. The clinical investigations were approved by
the Ethics Committee, Ethikkommission Charité. The setting was two ICUs of the tertiary
care center Charité–Universitätsmedizin Berlin. Inclusion criteria were mechanically venti-
lated ICU patients ≥18 years with a SOFA Score ≥9 in the first 72 h after ICU admission.
Exclusion criteria were patients with known diabetes mellitus, BMI > 35 kg/m2 , known
neuromuscular disorder, and infaust prognosis.
In our previous publications, the results were not reported in a sex-specific manner.
This sub-analysis summarizes the results of both trials in groups of female and male ICU
patients to identify differences in skeletal muscle metabolism during critical illness and to
account for potential sex bias. In this sub-analysis, sex is defined according to the classifi-
cation in the patient data management system. At the time point of data collection, this
classification was binary. Non-binary gender identities were not assessed. The proportion
of males and females and the measurements obtained per trial are shown in Figure S1.
The following measurements examined during the two trials were included in this
sub-analysis.
2.2. Clinical Parameters

Routine clinical parameters from the local patient data management system: patient
demographics (sex, age, BMI, weight, height, and severity of illness scores), diagnosis
leading to ICU admission, mortality, medications, and nutrition. Muscle strength was
assessed by Medical Research Council (MRC) Score at first awakening and at ICU discharge.
ICUAW was defined by median MRC Score <4. Frequency and time of physiothera-
peutic sessions were investigated.
2.3. Glucose and Lipid Metabolism

2.3.1. Insulin Sensitivity by Hyperinsulinemic-Euglycemic Clamp
Insulin sensitivity index (ISI) was determined by the gold standard technique of
hyperinsulinemic-euglycemic (HE) clamp. Since endogen gluconeogenesis and glycogenol-
ysis are suppressed by supraphysiological blood insulin concentrations during HE clamp,
ISI is an indicator for peripheral insulin sensitivity. ISI is determined by the steady-state
J. Clin. Med. 2022, 11, 846 3 of 14
glucose infusion rate (mg/kg/min) divided by steady-state serum insulin concentration

(mU/L) [12].
2.3.2. Muscular Metabolites by Microdialysis in the M. vastus lateralis

Insulin-dependent stimulation of glucose metabolism was assessed by skeletal muscle
microdialysis during HE clamp based on diffusion of metabolites across a semipermeable
membrane. CMA 600 Microdialysis AB (Solna, Sweden) was used. The Type 70 catheter was
inserted into M. vastus lateralis. It contained an inlet tubing (perfusion fluid) connected to a
pump and an outlet tubing (dialysate) leading to a microvial where the metabolites were
collected. Metabolite analysis was based on enzymatic reactions. The metabolites glucose,
pyruvate, lactate, and glycerol were measured in the M. vastus lateralis during HE clamp
baseline and HE clamp steady-state.
2.4. Protein Degradation, Content, and Muscle Morphology

Molecular and Histological Analyses in Surgical Biopsies of M. vastus lateralis
Surgical muscle biopsies were obtained from M. vastus lateralis of ICU patients and
healthy controls. Molecular and histological analysis has been described in detail previ-
ously [10]. The molecular analysis included real-time PCR and Western plot to determine
mRNA expression of protein synthesis and degradation pathways and myosin heavy
chains as well as myosin protein content. Muscle morphology was assessed by histological
analysis of myocyte cross-sectional area (MCSA) analysis for Type I, IIa, and IIb fibers.
Med. 2022, 11, x FOR PEER REVIEW 4 of 14
Med. 2022, 11, x FOR PEER REVIEW 2.5. Statistical Analysis 4 of 14
Statistical analysis was performed using IBM Corp. Released 2020. IBM® SPSS®
J. Clin. Med. 2022, 11, x FOR PEER REVIEWStatistics, Version 27. Armonk, NY. The Results were categorized into groups of4 the of 14male
J. Clin. Med. 2022, 11,3.1.
x FOR PEER REVIEW
Clinical Baseline Characteristics 4 of 14
3.1. Clinical Baseline and female sex. Results are reported as median with interquartile range or as absolute
Characteristics
J. Clin. Med. 2022, 11, x FOR PEER
Baseline
REVIEW
data,
numbers caloric
with intake, and quantity
percentages. of physiotherapy
Non-parametric tests were areused shown in Tablevariables
to compare 1. 4 between
of 14
J. Clin. Med. 2022, 11,Body Baseline
x FORheight
PEER REVIEW(pdata,
< caloric
0.001) and intake,
weight and
(p = quantity
0.001) were oflower
physiotherapy
in female are shown
patients, while in Table
median 1. 4 ofand
14
Bodywas height 3.1. independent
Clinical Baseline groups.
CharacteristicsThe Mann–Whitney test was used for numerical variables
BMI 27 (p < 0.001)
3.1.
kg/m
the Clinicaland
2 in both weight
Baseline
groups (p(p= 0.001)
Characteristics
= were
0.833). Meanlower in female
caloric intake patients,
per while median
predicted body
BMI was 27higher
kg/m 2Pearson–Chi2
Baseline data,
infemales
both groups for(pcategorical
caloric intake,
= 0.833). variables.
andMean quantitycaloricMultivariable
of physiotherapy
intake linear
per seven
predictedareregression
shown
body in models
Table 1.were
weight was in
Baseline
conducted data,
for during
the caloric
effectICU ofstay
intake,
sex (p
on = 0.001)
and the and in
quantity
outcome of the first
physiotherapy
parameters days
are
insulin after
shown in Table
sensitivity, muscle 1.
J. Clin. Med. 2022, 11, xweight was Body
higherheight (p < 0.001) and ICU weight stay(pa(p= 0.001) wereandlower theinfirstfemale patients, while median
J. Clin. Med. 2022,
FOR PEER
ICU 11, xadmission
FOR PEER
3.1.
REVIEW
=in
Clinical
atrophy
3.1.
REVIEW
females
(pClinical
Body
Baseline
0.008).
height
gene (p
during
Characteristics
Females
< 0.001)
expression
Baseline received
and weight
Characteristics (p
= 0.001)
higher
= insulin
0.001)
Atrogin-1) were
indose
and lower
2 in both groups (p = 0.833). Mean caloric intake per predicted body IIb
(Calpain-1, MCSA until
in
seven
the
female
analysis
daysofafter
daypatients,
for the
Type while
I, IIa,
4 of 14
median
and 4 of 14
ICU admission BMI Baseline
was 27
(p= =0.048).kg/m
0.008).
data, Females
caloric received
intake, a higher
and quantity insulin dose untiland theare dayshownof the
muscle biopsyBMI (p
fibers.was 27 Nokg/m
Regarding sex differences
in
2the both were
groups
categorical found
(p
variable = in of
0.833).
sex, the physiotherapy
frequency
Mean
male caloric
patients duration
intake
were per
defined of in the
Table
predicted
as 1.
body
reference
muscle biopsy weight
Body Baseline
=was
(pheight higher
0.048).
(p <No data,
sex
0.001) caloric
in females
differences
and intake,
during
weight were and
(p =ICU found
0.001) quantity
stay in
were(pthe of
=lower
0.001) physiotherapy
frequencyinand inand
female the areseven
first
duration
patients, shown
of days
while in Table
after 1.
median
physiotherapy. in the
weight multivariable
was higher in linear
females regression
during analyses.
ICU stay The
(p = models
0.001) andwere in adjusted
the first for
seven the covariates
days after
physiotherapy. ICU
BMI Body
was height
admission
27 kg/m (p <2=0.001)
0.008).
in both and weight
Females
groups (p= =0.833).
(preceived 0.001) were lower
a Mean
higher insulin
caloric in intake
female
dose until patients,
per the day
predictedwhile median
ofbody
the
3.1.
ICUClinical
BMI, age, Baseline
admission and mean
(p Characteristics
= caloric
0.008). intake
Females per predicted
received a body
higher weight
insulin during
dose ICU
until stay.
the dayp-values
of the<
Table 1. Baseline
BMI
muscle
weight was
3.1.
biopsy
was 27(pkg/m
Clinical
higher
characteristics.
2
=Baseline
0.048). in No
in=caloric
females both groups
Characteristics
sex (p =stay
differences
during ICU 0.833).
were Meaninand
=found
(pwere 0.001) caloric
thein intake
frequency
the first per
andpredicted
seven duration
days afterbody
of
0.05
muscle
weight were
Baseline considered
biopsy
was data,(p
higher 0.048). statistically
in females intake,
No sex andsignificant.
quantity
differences
during ICU of physiotherapy
found in the are
frequency shown and in Table
duration 1.of
Table 1. Baseline
ICU
Body
characteristics.
physiotherapy.
admission
height Baseline
(p (p
< = data,
0.008).
0.001) and caloric
Females
weight intake,
received
(p = and stay
0.001) quantity
awere (p = 0.001)
higher lower of
insulin
in
and
physiotherapy
femaledosein the first
until
patients,are seven
the day days
shown
while ofinthe
median
after
Table 1.
physiotherapy.
ICU Male ICU Patients
admission (p <=0.001)
0.008). Females received afound
higher insulin dose until the day of the
muscle
BMI 3. Body
biopsy
Results
Male height
27ICU(p = (p
0.048).
Patients No and
sex weight
differences (p = 0.001)
were were lower
in the in female
frequency patients,
and durationwhile median
of
1.was kg/m 2 in both groups (p = 0.833). Mean caloric intake per predicted body
TablemuscleBaseline
biopsy characteristics.
(pkg/m
= 0.048).2 in No sex differences were found incaloric
the frequency andpredicted
duration of
weight BMI
physiotherapy.
Table 1.
was was
Baseline
Overall 27
highern characteristics.
=in83females both
critically groups
ill
during Female
patients
ICU (pstay
=were
0.833).
ICU
(p = Mean
Patients
included
0.001) and in in this the intake
pooled,
first per
sex-specific
seven days after body
sub-
physiotherapy.
weightofwas higher in females Female
during ICU
ICUastay Patients
(p = insulin
0.001) and inuntil
the first
ICU analysis
admission the (pMale ICU
observational
= 0.008). Patients
Femalesand interventional
received higher study. Fewer dose p-Value
women the seven
were day ofdays
included the after
in
Table 1.ICU Baseline ♂ Male
admission (p
characteristics. = ICU Patients
0.008). Females received a higher insulin p-Value
dose until the day of the
muscle
Table biopsy
1. Baseline
the studies, (p =ncharacteristics.
♂ 0.048).
= 57, (68.7%) No sexvs. ♀n = 26, were
differences n = 26
(31.3%).found(31.3%) in the
Non-binary frequency and duration
gender identities wereofnot
muscle biopsy (p = 0.048). No sex♀ differences n Female
= were
26 (31.3%) ICU
found Patients
in the frequency and duration of
physiotherapy.
assessed. Male ICU Patients Female ICUand Patients
n = The sex
57 (68.7%)
physiotherapy.
distribution
Male♂
in groups in the observational
ICU Patients
intervention p-Value study was:
n = 57 (68.7%) p-Value
Age (years) 49.0 (37.0/63.0)
• 1. Observation:
Table Baseline n = 33, ♂n = 24 (72.7%),
characteristics.
♀Female
60.5 (44.0/68.0)
n♀ n = 26
ICU
= 9 (24.3%). (31.3%)
Patients
Standard 0.082 physiotherapy was
Age (years)2 Table 49.0 (37.0/63.0)
1. Baseline characteristics. 60.5 (44.0/68.0) n
Female ICU Patients = 26 (31.3%)
0.082
BMI (kg/m ) 27.1 (23.4/29.8)
performed. 27.0 (23.1/31.2) 0.833 p-Value
BMI (kg/m2) 27.1 (23.4/29.8) n = 57ICU
Male ♂(68.7%)
Patients 27.0 (23.1/31.2) 0.833 p-Value
Height (cm) 178.0 (175.0/185.0) nMale
= 57♂ (68.7%) 165.0 (163.0/170.0)
♀ n = 26 (31.3%)<0.001
Height (cm) Age (years) • 178.0 Intervention: 49.0
(175.0/185.0) 33, ICU
n =(37.0/63.0) n =Patients
24 (72.7%), n♀
165.0 (163.0/170.0) =60.5
9 (24.3%).
(44.0/68.0)
n = Advanced
26 <0.001
(31.3%) muscle-activating
0.082
Weight (kg) Age (years) 85.0 (80.0/96.0)
measures (e.g., 49.0 (37.0/63.0)
electrical 71.0 (65.0/85.0)
Female 60.5ICU (44.0/68.0)
Patients 0.001 were used 0.082
Weight (kg) BMI (kg/m2) 85.0 (80.0/96.0) 27.1
n = 57 (68.7%)muscle 71.0
(23.4/29.8) stimulation, 27.0
(65.0/85.0) vibration
(23.1/31.2)
Female
therapy)
ICU 0.001 Patients
0.833 in addi-
OFA score at ICU admission BMI (kg/m2) 12.0
tion (10.0/14.0) 27.1
n = (23.4/29.8)
57 (68.7%) 14.0 (11.0/16.0) 27.0 (23.1/31.2) 0.167 0.833
p-Value study
OFA score at ICU Height admission
Age (years) (cm) 12.0to(10.0/14.0)
protocol-based
178.0
49.0(175.0/185.0)
(37.0/63.0)
♂
physiotherapy. The control arm of the
165.0
14.0 (11.0/16.0) 60.5(163.0/170.0)
(44.0/68.0) 0.167
interventional
<0.001
0.082p-Value
APACHE at ICU admission Height
Age (cm)
(years) 21.0 (17.0/27.0) 178.0
49.0 (175.0/185.0)
(37.0/63.0)
♂ 23.5 (17.0/30.0)
♀ 165.0
60.5 (163.0/170.0)
n(44.0/68.0)
= 26 0.170
(31.3%) <0.001
0.082
APACHE at ICU admission Weight
BMI (kg/m (kg) 2) included n =85.0
21.0 (17.0/27.0) 27.1 (80.0/96.0)
(23.4/29.8) n = 9 (52.9%),
17 patients, 23.5 (17.0/30.0)n71.0
=♀
27.0 (65.0/85.0)
8 (47.1%),
(23.1/31.2) who received
0.170 0.001
protocol-based
0.833
SAPS 2 at ICU admission Weight (kg) 52 (38.0/62.0)85.0 (80.0/96.0) 54.5 (44.0/69.0)71.0 n
(65.0/85.0) = 26 (31.3%)
0.107 0.001
SOFA BMI (kg/m 2) 27.1 (23.4/29.8) 27.0 (23.1/31.2) 0.833
SAPS 2 at ICU score at ICU
admission
Height (cm) admission physiotherapy.
52 (38.0/62.0) 12.0
178.0 (10.0/14.0)
See 57Figure
=(175.0/185.0)
n12.0 (68.7%) S1 for details.
54.5 (44.0/69.0) 14.0 (163.0/170.0)
165.0 (11.0/16.0) 0.107 0.167
<0.001
Length of ICU SOFAstayscore
(days)
Heightat ICU (cm) admission 29 (20.0/41.0) 178.0 (10.0/14.0)
(175.0/185.0)
n = 57 (68.7%) 27 (17.0/49.0) 14.0(163.0/170.0)
165.0 (11.0/16.0) 0.933 0.167
<0.001
APACHE
Length of ICU stay at
Weight
Age ICU
(days) admission
(kg)
(years) The29 pooled
(20.0/41.0) 21.0
results
85.0
49.0 (17.0/27.0)
of the observational
(80.0/96.0)
(37.0/63.0) and 71.0
27 (17.0/49.0) 23.5 (17.0/30.0)
intervention
60.5 (65.0/85.0)
(44.0/68.0) studies
0.933in groups 0.170
0.001
0.082of sex are
vival until ICUAPACHE discharge at
Weight (n,
ICU
Age %) admission
(kg)
(years) 45 (78.9) 21.0
85.0 (17.0/27.0)
(80.0/96.0)
49.0 24
(37.0/63.0) 24 (92.3)54.5 (92.3) 23.5
71.0 (17.0/30.0)
(65.0/85.0)
60.5 0.132
(44.0/68.0) 0.170
0.001 0.082
vival untilSOFA SAPS
ICU 2 at
discharge
scoreBMIICU
at admission
(n,
ICU %)
admission presented 45in the
(78.9) 52
12.0 (38.0/62.0)
following results.
(10.0/14.0) 14.0 (44.0/69.0)
(11.0/16.0) 0.132 0.107
0.167
2 at (kg/m ) 27.1 (23.4/29.8) 27.0 (23.1/31.2) 0.833
2
Reasons for ICU SOFA admission
SAPS score ICU
at
BMI ICU admission
(kg/m admission 52
12.0 (38.0/62.0)
(10.0/14.0) 54.5
14.0 (44.0/69.0)
(11.0/16.0) 0.289 0.107
0.167
Reasons for Length ofatICU
ICU admission
APACHE ICU stay (days))
admission
2
21.0 27.1 (23.4/29.8)
29 (20.0/41.0)
(17.0/27.0) 23.5 27.0 (23.1/31.2)
27 (17.0/49.0)
(17.0/30.0) 0.289 0.933
0.170 0.833
ARDS APACHE
(n, %)Height
Length ofatICU (cm)
ICU
Height stay (days)
admission
(cm) 19 (33.3)178.0 29
21.0
(175.0/185.0)
(20.0/41.0)
178.0(17.0/27.0)
(175.0/185.0) 9 (34.6)165.0 27
23.5
(163.0/170.0)
(17.0/49.0)
165.0(17.0/30.0)
(163.0/170.0)
<0.001
0.933
0.170
<0.001
Survival
ARDS (n,until
SAPS %)
2 atICU
ICUdischarge
Weight admission
(kg) (n, %) 19 (33.3)5245 (78.9)
(38.0/62.0) 9 (34.6)54.5 24(44.0/69.0)
(92.3) 0.132
0.107
Sepsis (n,%)
Survival
SAPS until
2 at ICU
ICU
Weight discharge
admission
(kg) (n, %) 13 (22.8) 85.0 5245
(80.0/96.0)
(78.9)
(38.0/62.0)
85.0 (80.0/96.0) 7 (26.9) 71.0 54.524
(65.0/85.0)
(92.3)
(44.0/69.0)
71.0 (65.0/85.0)
0.001
0.132
0.107 0.001
Reasons
Sepsis
SOFA (n,%)
Lengthscorefor ICU
of ICUat ICUadmission
stayadmission
(days) 13 (22.8) 2912.0(20.0/41.0)
(10.0/14.0) 7 (26.9) 2714.0(17.0/49.0)
(11.0/16.0) 0.289
0.933
0.167
Polytrauma (n,%)
Reasons
Length
SOFA for
of
score ICU
ICU at admission
stay
ICU (days)
admission 16 (28.1) 29(33.3)
(20.0/41.0)
12.0 (10.0/14.0) 3 (11.5) 27(34.6)
(17.0/49.0)
14.0 (11.0/16.0) 0.289
0.933 0.167
Polytrauma
Survival APACHE ARDS
(n,%)
until ICU (n,
at ICU %)
discharge
admission (n, %) 16 (28.1) 21.0 19
45 (78.9)
(17.0/27.0) 3 (11.5) 23.5 9
24 (92.3)
(17.0/30.0) 0.132
0.170
Neurological
Survival (n,%)
ARDS
until
APACHE ICU (n,
at ICU%) admission
discharge (n, %) 9 (15.8) 19
45
21.0 (33.3)
(78.9)
(17.0/27.0) 6 (23.1) 9 (34.6)
24
23.5 (92.3)
(17.0/30.0) 0.132 0.170
Neurological Sepsis
Reasons(n,%) for ICU(n,%) admission 9 (15.8) 52 13(38.0/62.0)
(22.8) 6 (23.1) 54.5 7 (26.9) 0.289
OtherSAPS (n,%)
Reasons
2 at
SAPS
ICU
Sepsis
for2 ICU
at
admission
(n,%)
ICU admission
admission - 1352 (22.8)
(38.0/62.0) 1 (3.8) (44.0/69.0)
7 (26.9)
54.5 (44.0/69.0)
0.107
0.289 0.107
OtherLength Polytrauma
(n,%)ARDSof ICU (n,%)
(n, stay
%) (days) - 16 (28.1)
19(20.0/41.0)
29 (33.3) 3 (11.5)
1 (3.8) 279 (17.0/49.0)
(34.6) 0.933
sulin dose and caloric Length intake
Polytrauma
ARDS of (n,
ICU (n,%)
%)stay (days) 16
1929 (28.1)
(33.3)
(20.0/41.0) 3 (11.5)
927(34.6)
(17.0/49.0) 0.933
Neurological
sulin dose and caloric intake (n,%) 9 (15.8) 6 (23.1)
lin. Med. 2022, 11, x FOR PEER REVIEW 4 of 14
J. Clin. Med. 2022, 11, 846 4 of 14

Baseline data, caloric intake, and quantity of physiotherapy are shown in Table 1.
Body height (p < 0.001) and weight (p = 0.001) were lower in female patients, while median
Body height3.1. (p <Clinical
0.001) and Baseline
weight Characteristics
(p = 0.001) were lower in female patients, while median
BMI was 227 kg/m2 in both groups (p = 0.833). Mean caloric intake per predicted body
BMI was 27 kg/m in both groups (p intake,
= 0.833).and Mean caloricofintake per predicted body in Table 1.
weight Baseline
was higher data, caloric
in females during ICU quantity
stay (p = 0.001) physiotherapy
and in the first areseven
shown days after
weight wasBody higher in females
height during
(p(p<=0.001) and ICU stay(p
weight (p== 0.001)
0.001)were and in lowerthe first sevenpatients,
in female days after while
ICU admission 0.008).
2 in both
Females received a higher insulin dose until the day ofmedian
the
ICU admission BMI (p was= 0.008).
27 kg/m Females received
groupsa (p higher insulin
= 0.833). Mean dose until intake
caloric the day per ofpredicted
the body
muscle biopsy (p = 0.048). No sex differences were found in the frequency and duration of
muscle biopsy weight(p = was
0.048). No sex
higher differences
in females duringwereICU found stayin(pthe frequency
= 0.001) and and in the duration
first sevenof days after
physiotherapy.
physiotherapy. ICU admission (p = 0.008). Females received a higher insulin dose until the day of the
Tablemuscle biopsycharacteristics.
1. Baseline (p = 0.048). No sex differences were found in the frequency and duration of
physiotherapy.
Male ICU Patients
Male ICU Patients
Female ICU Patients
Female ICU Patients
Male ICU Patients Female ICU Patients p-Value
♂ p-Value p-Value
♂n = 57 (68.7%) ♀n = 26 (31.3%) n = 26 (31.3%)
♀ n = 26 (31.3%)
Age (years) 49.0n (37.0/63.0)
= 57 (68.7%) 60.5 (44.0/68.0) 0.082
BMI (kg/m 2) n = 57 (68.7%)
27.1 (23.4/29.8) 27.0 (23.1/31.2) 0.833
Age (years) 49.0 (37.0/63.0) 60.5 (44.0/68.0) 0.082
Age (years)Height (cm) 49.0 (37.0/63.0)
178.0 (175.0/185.0) 60.5165.0
(44.0/68.0)
(163.0/170.0) 0.082 <0.001
BMI (kg/m 2) 27.1 (23.4/29.8) 27.0 (23.1/31.2) 0.833
BMI (kg/m2Weight ) (kg) 85.0 (80.0/96.0)
27.1 (23.4/29.8) 27.0 71.0 (65.0/85.0)
(23.1/31.2) 0.833 0.001
SOFA Height
score at ICU (cm)admission 178.0
12.0 (175.0/185.0)
(10.0/14.0) 14.0165.0 (163.0/170.0)
(11.0/16.0) <0.001
Height (cm) 178.0 (175.0/185.0) 165.0 (163.0/170.0) <0.001 0.167
APACHE Weight at ICU (kg) admission 21.085.0 (80.0/96.0)
(17.0/27.0) 71.0 (65.0/85.0)
23.5 (17.0/30.0) 0.001
0.170
Weight (kg) 85.0 (80.0/96.0) 71.0 54.5
(65.0/85.0) 0.001 0.107
SOFASAPS score 2 atatICUICUadmission
admission 5212.0
(38.0/62.0)
(10.0/14.0) (44.0/69.0)
14.0 (11.0/16.0) 0.167
SOFA score atLength ICU admission
of ICU stay (days) 12.0 (10.0/14.0)
29 (20.0/41.0) 14.0 (11.0/16.0)
27 (17.0/49.0) 0.167 0.933
APACHE at ICU admission 21.0 (17.0/27.0) 23.5 (17.0/30.0) 0.170
APACHE Survival
at ICUuntil ICU discharge (n, %)
admission 21.0 (17.0/27.0) 45 (78.9) 24 (92.3)
23.5 (17.0/30.0) 0.170 0.132
SAPS 2 atforICU admission 52 (38.0/62.0) 54.5 (44.0/69.0) 0.107
Reasons
SAPS 2 at ICU admission ICU admission 52 (38.0/62.0) 54.5 (44.0/69.0) 0.107 0.289
Length ofARDS ICU (n, stay %)(days) 29
19 (20.0/41.0)
(33.3) 27 (17.0/49.0)
9 (34.6) 0.933
Length of ICU stay (days)
Sepsis (n,%) 29 (20.0/41.0) 13 (22.8) 27 (17.0/49.0)
7 (26.9) 0.933
Survival until ICU discharge (n, %) 45 (78.9) 24 (92.3) 0.132
Survival until ICU discharge (n,(n,%)
%) 45 (78.9) 24 (92.3) 0.132
ReasonsPolytrauma
for ICU admission 16 (28.1) 3 (11.5) 0.289
Reasons for ICUNeurological admission(n,%) 9 (15.8) 6 (23.1) 0.289
ARDSOther (n,(n,%)
%) 19 (33.3) 9 (34.6)
ARDS (n, %) 19 (33.3) - 9 (34.6) 1 (3.8)
InsulinSepsis
dose and (n,%)caloric intake 13 (22.8) 7 (26.9)
Sepsis (n,%) 13 (22.8) 7 (26.9)
InsulinPolytrauma
dose per body (n,%)surface area 16 (28.1) 3 (11.5)
Polytrauma (n,%) 18.5 (10.5/26.7)
16 (28.1) 320.1
(11.5)(15.6/30.9) 0.289
during ICU stay(n,%)
Neurological (IE/m2 ) 9 (15.8) 6 (23.1)
Neurological
Insulin dose (n,%)
per body surface until 9 (15.8) 6 (23.1)
Other
muscle
(n,%)
biopsy (IE/m 2) 18.6 (9.2/27.8) - 30.0 (17.7/37.0)1 (3.8) 0.048
Other (n,%) - 1 (3.8)
Insulin dose
Caloric 11, and caloric intake
J. Clin. dose
Insulin andintake
Med. 2022, caloric per PBW
x FOR PEER intake during ICU
REVIEW 18.5 (14.0/20.7) 21.6 (17.5/28.2) 4 of 14
0.001
Insulin
J. Clin. dose
Med. 2022,stay xper
FORbody
11,(kcal/kgPBW) surface
PEER REVIEW 4 of 14
Insulin
OR dose
PEER REVIEW perintake
bodyper surface day21–7 18.5 (10.5/26.7) 20.1 (15.6/30.9)
4 of 14 0.289
area
Caloricduring ICU stay
PBW (IE/m
ICU ) 18.5 (10.5/26.7)
13.7 (10.5/19.1) 20.1 (15.6/30.9)
17.7 (13.5/24.9) 0.289 0.008
x FOR
areaPEER REVIEW
during ICU stay (IE/m2)
(kcal/kgPBW)
Insulin dose per body surface
4 of 14
Insulin dose Physiotherapy

per body surface during 3.1. ICUClinical
stay 18.6 (9.2/27.8)
Baseline Characteristics 30.0 (17.7/37.0) 0.048
until
Total muscleofbiopsy
duration physiotherapy(IE/m 2)
3.1. 18.6 (9.2/27.8)
Clinical Baseline
(min) 445Characteristics
(267.5/662.5) 30.0397.5
(17.7/37.0)
(265.0/740.0) 0.048 0.673
until muscle biopsyBaseline
(IE/m )Characteristics
2
Baseline data, caloric intake, and quantity of29.0 physiotherapy
3.1.
TimeClinical
Caloric perintake per PBW
physiotherapy during
session (min)
Baseline data, 27.8 (24.8/29.9)
caloric intake, and quantity of (24.0/30.3) areare
physiotherapy
shown in 0.488
shown
Table 1.
in Table 1.
Caloric intake 3.1. Clinical
per PBW Baseline
during Characteristics
Body heightand (p18.5
< quantity
0.001) 18.5
and (14.0/20.7)
weight (p = 0.001)are were lower 21.6 (17.5/28.2)
inTable
female 0.001
NumberICU of physiotherapeutic
stay
Baseline (kcal/kgPBW)
data, caloric sessions
intake,
Body height (p <
16 (11/23.5)
(14.0/20.7)
0.001) of
and physiotherapy
weight (p = 0.001) shown
21.6
were
17 in (11/24)
(17.5/28.2)
lower in 1. patients,
female
while0.701
0.001
patients, while
median
median
ICU stay (kcal/kgPBW)
Baseline (p <data, caloric intake, and quantity
BMI was 27arekg/m 2 in bothof physiotherapy
groups (p = 0.833). are shown
Mean inmedian
Table 1. withpredicted
Body height
Caloric intake 0.001)
per PBW and ICU weight
Results (p = 0.001)
reported were
as median lower withininterquartile
female patients,
range as caloric
orwhile absolute intake
numbersper percentages.bodyBMI: Body
CaloricBMI Body
intake height
per (p <ICU 0.001) andBMIweightwas higher
27 ==kg/m
(pSOFA: 0.001)
2 in
13.7both
were groups
(10.5/19.1)
lower in (p =stay
female 0.833).
patients, Mean 17.7
while caloric intake
(13.5/24.9)
median per predicted 0.008 body
was
day 27PBW
1–7 kg/m 2 in both
(kcal/kgPBW)
weight Mass
weight
was
groups Index,
was (p
13.7
higher
inSequential
0.833).females
(10.5/19.1)
in Mean
females
during
Organ
caloric
during
ICU
Failure
intake
ICU
(p =predicted
Assessment,
per
17.7
stay (p
0.001)
ICU:
(13.5/24.9)
= 0.001)
and
Intensive in Care
body
and
the
in
first
Unit, seven
the 0.008
first seven
days
ARDS: Acute after
Respiratory
days
2 Test. Missing after
BMI was Distress Syndrome, PBW: Predicted Body Weight. Mann–Whitney Test and Pearson–Chi values:
was 27 kg/min in bothadmission
groups (p(p= =stay
0.833).(p =Mean caloric intake a per predicted body
2
day weight
1–7 (kcal/kgPBW)higher ICU 0.008). Females received higher insulin dose until the day of the
Physiotherapy duringfemales ICU ICUstay
Timeduring
admission ICU (p
per physiotherapeutic= 0.008). 0.001)
session and
Females
was notin the first
received
available foraseven
nhigher
= 2 males.days after
insulin
No other dose until
missing the
values day
were of
found.the
Data
Physiotherapy ICUweight was higher
during
admission ICU (p stay in muscle
= 0.008). femalesFemales
on during
biopsy
insulin (pICU
received
dose per stay
= 0.048).
body (pNo= sex
a surface
higher 0.001) andmuscle
differences
insulin
area before in the
dose werefirstfound
until
biopsy seven
the
are397.5dayindays
reported the
ofin after
frequency
the
n = 42 male and andn durationfemaleof
= 170.673 patients
Total duration of physiotherapy muscle(min) biopsy (p = 445
0.048). (267.5/662.5)
No sex differences were found (265.0/740.0)
in the frequency and duration of
otal duration ICU admission
biopsy (p =(p0.048).
of physiotherapy
muscle = 0.008).
(min) No Females
physiotherapy.
who
sex 445received
received
differencesbiopsy.
(267.5/662.5)
were a higher
found insulin
in dose
the frequency 397.5untilandthe
(265.0/740.0) day of of
duration the 0.673
Time per
musclephysiotherapy
biopsy (p = session
0.048). No(min)
physiotherapy.
sex differences 27.8
were (24.8/29.9)
found in the frequency and 29.0 (24.0/30.3)
duration of 0.488
me per physiotherapy
physiotherapy. session (min) 27.8 (24.8/29.9) 29.0 (24.0/30.3) 0.488
Number of physiotherapeutic sessions
3.2. Clinical16 Diagnosis 16 (11/23.5) 17 (11/24) 0.701
physiotherapy.
umber of physiotherapeutic sessions Table 1. Baseline
Table 1.are Baseline (11/23.5)of ICUAW by MRC at First
characteristics.
characteristics.
Awakening
17 (11/24) and ICU Discharge
0.701
Results reported as median with interquartile range or as absolute numbers with percentages.
Results are reported MRCmedian at first awakening andrangeat ICU discharge was assessed in n = 37 male and
Table 1. BaselineBMI: BMI:
characteristics. Body as Mass Index, Male with
ICU
SOFA:interquartile
Patients
Sequential Organor asFailure
absolute numbers
Assessment, with
ICU:percentages.
Intensive Care Unit,
Body n
Mass = 17 female
Index, SOFA: Male
patients. ICU
Sequential ICUAW Patients
Organ by median
Failure MRC
Assessment, < 4 was
ICU: present
Intensive in n = 30
Care (81.1%)Test
Unit, males
MaleAcute ARDS:
ICU Acute Respiratory Distress Syndrome, PBW: Predicted Body Weight. Mann–Whitney
Patients
ARDS: Maleand and
ICU n =
Respiratory
Patients
Pearson–Chi 14 (82.4%)
Distress
2 females
Syndrome, at first
PBW: awakening
Predicted
Test. Missing values: Time per physiotherapeutic
Female
(p
Body= ICU
0.911)
Weight. Patients
and in
session n was not available for and
=
Mann–Whitney 22 (59.5%)
Test males n
and Pearson–Chi 2 Test. Missing values: Time per physiotherapeutic Female
session ICU
was Patients
not available for area
nobserved
n = 12 (70.6%) females
= 2 males. No other missingFemale at ICU
values discharge
were
ICU found.
Patients (p =
Data 0.432).
on insulin No sex
dose differences
per body p-Value
were
surface before in
= 2 males.muscle No other missing values were ♂ found.
Female Data
ICU onninsulin
Patients dose patients
pern body surface area biopsy.p-Value
before
biopsy are reported in n
MRC at first awakening (♂3.3 (2.9/3.8) vs. 3.0 = 42 male and = ♀
17 female p-Value = 26 (31.3%)
who received
muscle biopsy ♂ are reported in n = 42 male and n = 17 female patients ♀ (2.4/3.6),
whop-Value n =p 26
received= 0.460)
(31.3%)
biopsy. and at ICU discharge
♂ 3.9 (3.1/4.3) n ♀ (68.7%)
vs.=of57 n = 26p(31.3%)
3.2.( Clinical Diagnosis n by ♀ 3.6 (3.3/4.0),
=ICUAW
57 (68.7%) n = 26=
by MRC 0.661).
at(31.3%) A separate
First Awakening and sex-specific
ICU Discharge analysis of ICU by
3.2. Clinical
Age (years) n = 57 (68.7%) Diagnosis of
MRC in groups 49.0 ICUAW MRC
of observational at First
(37.0/63.0) and intervention Awakening and
60.5 ICU
trials Discharge
identified no differences.
(44.0/68.0) 0.082 Details
Age (years) n = 57are (68.7%)
presented in27.1 49.0S1.
Table (37.0/63.0) 60.5 (44.0/68.0) 0.082
(years) BMI (kg/m 2)
49.0 (37.0/63.0) (23.4/29.8)
60.5 (44.0/68.0) 27.0 (23.1/31.2)
0.082 0.833
e (years) BMI (kg/m 2)
49.0 (37.0/63.0) 27.1 (23.4/29.8)
60.5 (44.0/68.0) 27.0 (23.1/31.2)
0.082 0.833
kg/m2) Height (cm) 27.1 (23.4/29.8) 178.0 (175.0/185.0)27.0 (23.1/31.2) 165.00.833 (163.0/170.0) <0.001
I (kg/m2) Height (cm) 27.1 (23.4/29.8) 178.0 (175.0/185.0)
27.0 (23.1/31.2) 165.00.833 (163.0/170.0) <0.001
ht (cm) Weight (kg) 178.0 (175.0/185.0) 85.0 (80.0/96.0)
165.0 (163.0/170.0) 71.0 (65.0/85.0)
<0.001 0.001
Weight
ght (cm) SOFA score at ICU admission (kg) 178.0 (175.0/185.0) 85.0 (80.0/96.0)
165.0 (163.0/170.0) 71.0 (65.0/85.0)
<0.001 0.001
ht (kg) 85.0 (80.0/96.0) 12.0 (10.0/14.0) 71.0 (65.0/85.0) 14.00.001 (11.0/16.0) 0.167
SOFA score
ight (kg) APACHE at ICU admission at ICU admission
85.0 (80.0/96.0) 12.0 (10.0/14.0)
71.0 (65.0/85.0) 14.0 (11.0/16.0)
0.001 0.167
ICU admission 12.0 (10.0/14.0) 21.0 (17.0/27.0) 14.0 (11.0/16.0) 23.50.167 (17.0/30.0) 0.170
at ICU admission APACHE at ICU admission 12.0 (10.0/14.0) 21.0 (17.0/27.0)
14.0 (11.0/16.0) 23.5 (17.0/30.0)
0.167 0.170
SAPS 2 at ICU admission 52 (38.0/62.0) 54.5 (44.0/69.0) 0.107
BMI was 27 Body
kg/m2height
in both(p <groups
0.001) and
(p =weight
0.833).(pMean
= 0.001) wereintake
caloric lower per
in female patients,
predicted bodywhile median
BMI was 27 kg/m 2 in both groups (p = 0.833). Mean caloric intake per predicted body
weight was higher in females during ICU stay (p = 0.001) and in the first seven days after
CU admissionweight
(p = was higher
0.008). in females
Females during
received ICU stay
a higher (p = dose
insulin 0.001)until
and the
in the
dayfirst
of seven
the days after
ICU admission (p = 0.008). Females received a higher insulin
muscle biopsy (p = 0.048). No sex differences were found in the frequency and duration ofdose until the day of the
muscle
J. Clin.
physiotherapy. biopsy
Med. 2022, (p
11, 846 = 0.048). No sex differences were found in the frequency and duration of 5 of 14
physiotherapy.
3.3. Glucose and Lipid Metabolism
Male ICU Patients
Male ICU 3.3.1. Insulin Sensitivity Index (ISI) by Hyperinsulinemic-Euglycemic Clamp
Patients
Female
HE clamp wasICU Patientsin n = 36 male and n = 14 female ICU patients (Figure 1a).
performed
Female ICU Patients
The procedure was conducted on ICU p-Value Day 17 (15/21). Compared with healthy controls
♂ p-Value
♀ n
(♂n = 2, n = 2), insulin = 26 (31.3%)
♀ sensitivity was(31.3%)
n = 26 impaired in male and female ICU patients. Insulin
n = 57 (68.7%) sensitivity at steady state of the HE clamp was reduced more in women, with a value of 0.024
n = 57(0.021/0.030)
(68.7%) than in men, who had a value of 0.032 (0.023/0.052) (mg/kg/min)/(mU/L),
49.0 (37.0/63.0) 60.5 (44.0/68.0) 0.082
e (years) p = 0.026). Steady-state plasma
49.0 (37.0/63.0) insulin levels were 174.7
60.5 (44.0/68.0) (138.4/202.4) in males and 234.0
0.082
27.1 (23.4/29.8) 27.0 (23.1/31.2) 0.833
I (kg/m2) (191.8/265.5) in females (p =
27.1 (23.4/29.8) 0.010).
27.0 Sex, age and mean0.833
(23.1/31.2) caloric intake were all significantly
178.0 (175.0/185.0) 165.0 (163.0/170.0) <0.001
ght (cm) associated with insulin sensitivity
178.0 (175.0/185.0) index in the multivariable
165.0 (163.0/170.0) <0.001 model with the adjusted effect
85.011,
J. Clin. Med. 2022, (80.0/96.0)
x FOR PEER REVIEW
estimate for 71.0
sex (65.0/85.0)
being β = − 0.014 95% 0.001
CI ( − 0.026 to −0.003). With R2 = 0.439 the model6 of 14
ight (kg) 85.0 (80.0/96.0) 71.0 (65.0/85.0) 0.001
ssion 12.0 (10.0/14.0) explained 43.9% 14.0 (11.0/16.0)
of the overall 0.167
at ICU admission 12.0 (10.0/14.0) 14.0variance of insulin sensitivity.
(11.0/16.0) 0.167 Details are shown in Table 2.
sion 21.0 (17.0/27.0) 23.5 (17.0/30.0) 0.170
t ICU admission 21.0 (17.0/27.0) 23.5 (17.0/30.0) 0.170
on 52 (38.0/62.0) 54.5 (44.0/69.0) 0.107
ICU admission 52 (38.0/62.0) 54.5 (44.0/69.0) 0.107
ys) 29 (20.0/41.0) 27 (17.0/49.0) 0.933
ICU stay (days) 29 (20.0/41.0) 27 (17.0/49.0) 0.933
e (n, %) 45 (78.9) 24 (92.3) 0.132
CU discharge (n, %) 45 (78.9) 24 (92.3) 0.132
sion 0.289
r ICU admission 0.289
19 (33.3) 9 (34.6)
DS (n, %) 19 (33.3) 9 (34.6)
13 (22.8) 7 (26.9)
sis (n,%) 13 (22.8) 7 (26.9)
16 (28.1) 3 (11.5)
auma (n,%) 16 (28.1) 3 (11.5)
9 (15.8) 6 (23.1)
ogical (n,%) 9 (15.8) 6 (23.1)
- 1 (3.8)
her (n,%) - 1 (3.8)
ntake
and caloric intake
rface
E/m2body
per surface 18.5 (10.5/26.7) 20.1 (15.6/30.9) 0.289
) 2 18.5 (10.5/26.7) 20.1 (15.6/30.9) 0.289
ICU
rface
stay (IE/m )
per body surface 18.6 (9.2/27.8) 30.0 (17.7/37.0) 0.048
m2) 18.6 (9.2/27.8) 30.0 (17.7/37.0) 0.048
e biopsy (IE/m2)
uring
e per PBW during 18.5 (14.0/20.7) 21.6 (17.5/28.2) 0.001
W) 18.5 (14.0/20.7) 21.6 (17.5/28.2) 0.001
(kcal/kgPBW)
ICU
ke per PBW ICU 13.7 (10.5/19.1) 17.7 (13.5/24.9) 0.008
) 13.7 (10.5/19.1) 17.7 (13.5/24.9) 0.008
(kcal/kgPBW)
U stay
y during ICU stay
py (min) 445 (267.5/662.5) 397.5 (265.0/740.0) 0.673
physiotherapy (min) 445 (267.5/662.5) 397.5 (265.0/740.0) 0.673
on (min) 27.8 (24.8/29.9) 29.0 (24.0/30.3) 0.488
therapy session (min) 27.8 (24.8/29.9) 29.0 (24.0/30.3) 0.488
sessions 16 (11/23.5) 17 (11/24) 0.701
otherapeutic sessions 16 (11/23.5) 17 (11/24) 0.701
Results are reported as median with interquartile range or as absolute numbers with percentages.
BMI: Body MassResults areSOFA:
Index, reported as median
Sequential with Failure
Organ interquartile range orICU:
Assessment, as absolute numbers
Intensive with percentages.
Care Unit,
ARDS: Acute Respiratory Distress Syndrome, PBW: Predicted Body Weight. Mann–Whitney Test Care Unit,
BMI: Body Mass Index, SOFA: Sequential Organ Failure Assessment, ICU: Intensive
ARDS:
nd Pearson–Chi Acute
2 Test. Respiratory
Missing Distress
values: Time per Syndrome, PBW: Predicted
physiotherapeutic Body
session was notWeight. Mann–Whitney
available for n Test
and Pearson–Chi 2 Test. Missing values: Time per physiotherapeutic session was not available for n
2 males. No other missing values were found. Data on insulin dose per body surface area before
muscle biopsy=are
2 males. No in
reported other missing
n = 42 values
male and n = were found.
17 female Data on
patients insulin
who dosebiopsy.
received per body surface area before
muscle biopsy are reported in n = 42 male and n = 17 female patients who received biopsy.
3.2. Clinical Diagnosis of ICUAW by MRC at First Awakening and ICU Discharge
Figure1.1.(a)
Figure (a)Sex-specific
Sex-specificinsulin
insulin sensitivity
sensitivity index
index by by
HEHE clamp
clamp andand metabolites
metabolites of (b–d)
of (b–d) glycolysis
glycolysis and
and (e) lipid metabolism by microdialysis in M. vastus lateralis during HE clamp. Missing
(e) lipid metabolism by microdialysis in M. vastus lateralis during HE clamp. Missing measurements measure-
ments
of of metabolites
metabolites occurredoccurred
duringduring microdialysis
microdialysis in n = in n = 5 patients.
5 male male patients. The number
The number of patients
of patients for
for each measurement are given in the figure. The results are given as median with interquartile
each measurement are given in the figure. The results are given as median with interquartile range.
range. Mann–Whitney Test.
Mann–Whitney Test.
3.4.1. Molecular Analysis of Protein Degradation Pathways, Myosin Heavy Chains, and
Myosin Protein Content in M. vastus lateralis Biopsies
Surgical muscle biopsies were extracted at median Day 15. The relative mRNA ex-
J. Clin. Med. 2022, 11, 846 6 of 14
Table 2. Multivariable linear regression for insulin sensitivity index.
Model 1 (Unadjusted) Model 2

Variable n B 95% CI B p-Value Variables n B 95% CI B p-Value
(−0.033 (−0.026
Sex 50 −0.017 0.014 Sex 50 −0.014 0.016
0.047) −0.003)
(−0.030 (−0.002
Constant 0.040 <0.001 BMI 50 −0.001 0.231
−0.003) 0.000)
(−0.001
Age 50 −0.001 <0.001
0.000)
Caloric (0.000
50 0.001 0.009
intake 0.002)
(0.034
Constant 0.067 <0.001
0.100)
n = 50, R = 0.345, R2 = 0.119 n = 50, R = 0.662, R2 = 0.439
(adjusted R2 = 0.101), p = 0.014 (adjusted R2 = 0.389), p < 0.001
3.3.2. Muscular Metabolites of Glycolysis by Microdialysis in M. vastus lateralis

No sex differences were observed in muscular glucose levels and concentrations
of metabolites of glycolysis (Figure 1b–d). In both groups, glucose decreased during the
steady state of HE clamp compared to baseline (Figure 1b). The aerobe glycolysis metabolite
pyruvate increased in male patients during the HE clamp, whereas it decreased in females
(Figure 1c).
3.3.3. Muscular Glycerol Concentrations by Microdialysis in M. vastus lateralis

The metabolite of fatty acid metabolism glycerol was significantly higher in female
ICU patients during HE clamp at the steady state (p = 0.026) (Figure 1e).
Spearman’s correlation of circulating triglycerides and muscular glycerol by micro-
dialysis in M.vastus lateralis as well as sex-specific analysis of circulating triglycerides is
shown in Figure S2.

3.4.1. Molecular Analysis of Protein Degradation Pathways, Myosin Heavy Chains, and
Myosin Protein Content in M. vastus lateralis Biopsies
Surgical muscle biopsies were extracted at median Day 15. The relative mRNA
expression of protein degradation atrogenes compared to healthy controls is shown in
Figure 2. Relative gene expression of the protein degradation atrogenes Atrogin-1 (p = 0.031)
(Figure 2b) and Calpain-1 (p = 0.020) (Figure 2c) was higher in female ICU patients. Gene
expression for atrogenes MuRF-1 (Figure 2a), CASP-3 (Figure 2d), TRIM62 (Figure 2e),
and PSMB2 (Figure 2f) was probable in male and female patients. No differences were
found in healthy control subjects. Sex was not significantly associated with muscle atrophy
gene expression of Calpain-1 and Atrogin-1 in the unadjusted linear regression model and
adjusted for age. Details are shown in Table S2.
J. Clin. Med. 2022, 11, 846

No sex differences were observed in the relative mRNA expression of myosin heavy7 of 14
chains (Figure 3a–c) and relative myosin protein content (Figure 3d–f) in ICU patients or
healthy control patients.
Figure 2.
Figure 2. (a–f)
(a–f) Sex-specific
Sex-specific relative
relative mRNA
mRNA expression
expressionofofprotein
proteindegradation
degradationatrogenes
atrogenesininbiopsies
biopsies
of M.
of M. vastus
vastus lateralis
lateralis in
in ICU
ICU patients
patients and
and healthy
healthy control
controlsubjects.
subjects.Results
Resultsare
aregiven
givenasasmedian
medianwith
with
interquartile range. Mann–Whitney Test.
interquartile range. Mann–Whitney Test.
No sex differences were observed in the relative mRNA expression of myosin heavy
chains (Figure 3a–c) and relative myosin protein content (Figure 3d–f) in ICU patients or
healthy control patients.
3.4.2. Histological Analysis of Surgical Biopsies of M. vastus lateralis—Myocyte

Cross-Sectional Area (MCSA)
MCSA of all fiber types was significantly lower in female patients (Table 3). The
differences were comparable to sex differences in MCSA of healthy persons published by
Staron et al. [13]. Sex (β = −1345.6 95% CI (−2411.4 to −279.8)) and BMI (β = 161.7 95% CI
(58.3 to 265.1)) were significantly associated with MCSA of Type IIa in the multivariable
model. With R2 = 0.325 the model explained 32.5% of the overall variance of MCSA of Type
IIa fibers. Sex was not significantly associated with MCSA of Type I and IIb fibers after
adjusting for BMI, age, and caloric intake. Details are shown in Table 4.
J. Clin. Med. 2022, 11, 846 8 of 14


Body height (p < 0.001) and 2weight (p = 0.001) were lower in female patients, while median
BMI was 27 kg/m in both groups (p = 0.833). Mean caloric intake per predicted body
BMI was 27 kg/m2 in both groups (p = 0.833). Mean caloric intake per predicted body
J. Clin. Med. 2022, 11, x FOR ICU PEERadmission
REVIEW (p = 0.008). Females received a higher insulin dose until the day of the 4
J. Clin. Med. 2022, 11, x FOR PEER REVIEW ICU admission (p = 0.008). Females received a higher insulin dose until the day of 4 ofthe
14
physiotherapy.
Figure
Figure
physiotherapy. 3.3. (a–c)
(a–c) Sex-specific
Sex-specific relative
relative mRNAmRNA expression
expression of of myosin
myosin heavyheavy chains
chains (MYH)
(MYH) and and (d–f)
(d–f)
relative myosin protein content in biopsies of M. vastus lateralis in ICU patients and healthy control
relative myosin protein
3.1. content
Clinical in biopsies
Baseline of M. vastus lateralis in ICU patients and healthy control
Characteristics
3.1. Table
subjects.
Clinical 1. Baseline
Results
Baseline arecharacteristics.
given as median with interquartile range. Mann–Whitney Test.
Characteristics
Table 1. BaselineResults
subjects. characteristics.
areBaseline
given as data,median with interquartile
caloric intake, andrange. Mann–Whitney
quantity Test.
of physiotherapy are shown in Tab
Baseline data, caloric intake, Male andPatients
ICU quantity of physiotherapy are shown in Table 1.
3.4.2. Histological Body
Maleand height
Analysis
ICU (p
Patients< 0.001)
of Surgicaland weight
Biopsies (p =
of 0.001)
M. were
vastus lower in female
lateralis—Myocyte patients,
Cross- while med
Body height
Table 3.(pMyocyte
< 0.001) weight
cross-sectional (parea.
=2 0.001) were lower in female patients, while median
BMI
sectional Area (MCSA) was 27 kg/m in both groups (p = 0.833).
Female Mean
ICU caloric
Patients intake per predicted b
BMI was 27 kg/m2 in both groups (p = 0.833). Mean Female caloric intake
ICUstayPatients per predicted body
weight was higher in females during ICU (p = 0.001) and in the first
Theseven
3).p-Value dif- days a
Myocyte Cross-Sectional weight was MCSA
Area (MCSA) higher of in all fiber
females
Male ICU types
during was
Patients
♂ ICU significantly lower
stay (p = Female
0.001) andin in
ICU female
Patients patients
the first (Table
sevenp-Value
days after
ferences were ICU admission to
comparable (p = 0.008). Females received
♀n = 17 ahealthy
higher
n until insulin p-Value
= 26 (31.3%) dose until the by day of
M. vastus lateralisICU admission (p = 0.008). ♂ n = 37 sex
Females differences
received a♀higherin MCSA
insulin of
dose
n = 26were
(31.3%)
persons
the day published
of the
Staron2 et(pal. muscle
[13]. Sex biopsy
(β (p = 0.048).
= −1345.6 95%were No sex differences
CI (−2411.4 found in the
(β = 161.7of95% CI duratio
frequency and
Mean MCSA Type I muscle musclefiberbiopsy
(µm ) = 0.048).
3844.4No sex
n = differences
57 (68.7%)
(2999.7/4929.6) found intothe
−279.8))
frequency
2740.0 (2471.8/3591.1)
and BMI
and duration 0.031
(58.3 physiotherapy.
to2 )265.1))4006.2
Mean MCSA Type IIa physiotherapy.
muscle fiber (µm nwere significantly associated2036.3
= 57(2240.7/5002.2)
(68.7%) with (1675.4/3245.1)
MCSA of Type IIa in the multivariable 0.003 0.082
Age (years) model.2 With R2 = 0.32549.0 the(37.0/63.0)
model explained 32.5% of60.5
the (44.0/68.0)
overall variance of MCSA of
Mean MCSA Age (years)
Type IIb muscle2 fiber (µm ) 49.0
3229.7(37.0/63.0)
(2080.6/4390.5)
Table 1. Baseline characteristics. 60.5
2309.5 (44.0/68.0)
(1708.8/2958.8) 0.082 0.020
BMI (kg/m ) Type IIa fibers. Sex was 27.1not(23.4/29.8)
significantly associated 27.0
with (23.1/31.2)
MCSA of Type I and 0.833
IIb fibers
BMI (kg/m
Results are
2)
givenTable
as 1. Baseline
median with characteristics.
27.1 (23.4/29.8)
interquartile range. MCSA myocyte 27.0 (23.1/31.2)
cross-sectional area. Mann–Whitney 0.833
Test.
Height (cm) after adjusting for BMI, 178.0 (175.0/185.0)
age, and Malecaloric
ICUintake.
Patients Details 165.0 (163.0/170.0)
are shown in Table 4. <0.001
Myocyte Height (cm) area (MCSA) reference
cross-sectional 178.0
Malevalues(175.0/185.0)
ICU fromPatients vastus lateralis in n 165.0
M.(80.0/96.0) (163.0/170.0)
= 95 healthy, untrained men, and<0.001
n = 55 healthy,
Weight (kg) 85.0 71.0 (65.0/85.0) 0.001
Weight (kg) untrained women. 85.0 (80.0/96.0)
Staron et al., Table 3. J Histochem 71.0 (65.0/85.0)
Cytochem, 2000 [13]Female ICU 0.001
Patients
SOFA score at ICU admission Table 3. Myocyte cross-sectional 12.0 (10.0/14.0)
area. Female ICU14.0 (11.0/16.0)
Patients 0.167
SOFA score at ICU admission 12.0Healthy
(10.0/14.0) 14.0 (11.0/16.0) Healthy female 0.167 p-Valu
APACHE at ICU admission 21.0male
(17.0/27.0) ♂ 23.5 (17.0/30.0) p-Value 0.170
APACHE at ICU Myocyte
admission Cross-Sectional Area21.0 (MCSA)
(17.0/27.0) Male ICU Patients
23.5 (17.0/30.0)Female ICU Patients
0.170
♀n = 55 n = 26 (31.3%) p-
SAPS 2 at ICU admission ♂n52 (38.0/62.0)
SAPS 2 at ICU admission M. vastus lateralis 52 (38.0/62.0)
= 95 ♀ = 54.5
♂n n = 54.5
37 (44.0/69.0)
(44.0/69.0)
26 (31.3%) ♀n = 170.107
0.107
Value
Mean Length
MCSA TypeofIICU stay
muscle (days)
fiber (µm 2) 4844 ±291286
(20.0/41.0)n = 57 (68.7%) 27 (17.0/49.0)
4084 ± 895 0.933
Length of ICU stay MCSA
Mean (days) Type I muscle n29=(µ
fiber (20.0/41.0)
57 m(68.7%)
2 ) 27 (17.0/49.0)
3844.4 (2999.7/4929.6) 0.933
2740.0 (2471.8/3591.1) 0.031
Mean Survival
MCSA Type untilIIa ICU discharge
muscle (n,2 )%)
fiber(years)
Age (µm 6174 45 (78.9)
± 1587 49.0 (37.0/63.0) 24 (92.3)
3879 867 (44.0/68.0) 0.132
±60.5
Survival until
Mean MCSA AgeICU discharge
Mean
(years)
Typefor
MCSA
IIb ICU
(n,
muscle
Type%) IIa
fiber (µm 2)
muscle
2 fiber 45(µ (78.9)
m 2)
49.0 (37.0/63.0)
5160 ± 1324 4006.2 24
(2240.7/5002.2) (92.3)
60.5 (44.0/68.0) 2036.3 0.132
(1675.4/3245.1)
3116 ± 792 0.082 0.003 0.082
Reasons admission
BMI (kg/m ) 27.1 (23.4/29.8) 0.289
ReasonsBMI for ICU
Mean
(kg/m admission
2)MCSA Type IIb muscle fiber (µ m2) 3229.7 (2080.6/4390.5) 2309.5 27.0 (23.1/31.2)
0.289
(1708.8/2958.8) 0.020 0.833
ARDS (n, %)
Height Values
(cm) reported27.1 (23.4/29.8)
by Staron et 19
al. (33.3)
are178.0
means ± standard
(175.0/185.0)
27.0deviation.
(23.1/31.2) 9 (34.6)
165.0
0.833
(163.0/170.0) <0.001
ARDS
Results
Height (n,
are %) as median with interquartile
given
(cm) 178.019 (33.3)
range. MCSA myocyte165.0
(175.0/185.0) 9(163.0/170.0)
(34.6)
cross-sectional area. Mann–Whitney
<0.001 Test.
Sepsis (n,%) Weight (kg) 13 (22.8) 85.0 (80.0/96.0) 7 (26.9)71.0 (65.0/85.0) 0.001
Sepsis
Weight (n,%)
(kg) 85.013(80.0/96.0)
(22.8) 71.07(65.0/85.0)
(26.9) 0.001
Polytrauma (n,%)
SOFA score at ICU admission16 (28.1) 16 (28.1)12.0 (10.0/14.0) 3 (11.5) 3 (11.5)14.0 (11.0/16.0) 0.167
SOFAPolytrauma ICU(n,%)
score atNeurologicaladmission (n,%) 12.0 (10.0/14.0) 9 (15.8)21.0 (17.0/27.0) 14.0 (11.0/16.0) 0.167
6 (23.1)23.5 (17.0/30.0)
Neurological APACHE
(n,%) at ICU admission 0.170
APACHE at ICUOther
admission (n,%) 21.09(17.0/27.0)
(15.8) 6 (23.1)
- 52 (38.0/62.0)23.5 (17.0/30.0) 0.170
1 (3.8)54.5 (44.0/69.0)
Other (n,%) SAPS 2 at ICU admission - 1(44.0/69.0)
(3.8) 0.107
SAPSInsulin
2 at ICUdose admission
and caloric intake 52 (38.0/62.0) 54.5 0.107
Length of ICU stay (days) 29 (20.0/41.0) 27 (17.0/49.0) 0.933
J. Clin. Med. 2022, 11, 846 9 of 14
Table 4. Multivariable linear regression model for myocyte cross-sectional area (MCSA).
Model 1 (Unadjusted) Model 2

MCSA Type I Fibers
(−1756.6 (−1677.2
Sex 54 −904.4 0.038 Sex 54 −793.1 0.078
−52.3) 91.0)
(3592.2 (17.6
Constant 4070.4 <0.001 BMI 54 103.4 0.019
4548.5) 189.2)
(−24.0
Age 54 1.0 0.938
26.0)
Caloric (−97.2
54 −37.2 0.219
intake 22.8)
(−808.7
Constant 1865.6 0.167
4539.8)
n = 54 ICU patients, R = 0.283, R2 = 0.08 n = 54 ICU patients, R = 0.437, R2 = 0.191
(adjusted R2 = 0.063), p = 0.038 (adjusted R2 =.125), p = 0.032
MCSA Type IIa Fibers
(−2730.9 (−2411.4
Sex 54 −1651.8 0.003 Sex 54 −1345.6 0.014
−572.7) −279.8)
(3421.8 (58.3
Constant 4027.2 <0.001 BMI 54 161.7 0.003
4632.7) 265.1)
(−50.4
Age 54 −20.2 0.183
9.9)
Caloric (−121.7
54 −49.3 0.177
intake 23.0)
(−1694.7
Constant 1529.1 0.345
4753.0)
(adjusted R2 = 0.137), p = 0.003 (adjusted R2 = 0.270), p < 0.001
MCSA Type IIb Fibers
(−2166.4 (−1945.8
Sex 54 −1161.7 0.024 Sex 54 −960.1 0.067
−157.1) 64.6)
(2840.1 (23.1
Constant 3403.8 <0.001 BMI 54 123.1 0.017
3967.5) 219.9)
(−50.3
Age 54 −20.7 0.159
7.3)
Caloric (−89.2
54 −21.6 0.538
intake 29.2)
(−1467.8
Constant 1485.7 0.343
4733.3)
(adjusted R2 = 0.076), p = 0.024 (adjusted R2 = 0.158), p = 0.014
4. Discussion
In this pooled sub-analysis, we examined sex differences in potential pathomechanisms
of skeletal muscle metabolism in the clinical context of ICUAW. In this cohort of critically
ill patients, sex-specific variations were observed in insulin sensitivity, muscular lipid
J. Clin. Med. 2022, 11, 846 10 of 14
metabolism, and muscle morphology. The adjusted regression model estimated a significant
association of female sex with lower insulin sensitivity index and MCSA of Type IIa fibers.
4.1. Insulin Sensitivity

The insulin sensitivity index was most impaired in critically ill women. Sex was
still associated with insulin sensitivity index when adjusted for age, caloric intake, and
BMI in the multivariable linear regression analysis. With R2 = 0.439 the model explained
43.9% of the total variance in insulin sensitivity, roughly 30% more than in the unadjusted
model. Previous data from our research group have shown that insulin sensitivity is
impaired in ICU patients, which was particularly pronounced in patients with Critical
Illness Myopathy [9]. This sex-specific analysis adds to the field that critically ill women
were more severely affected by decreased insulin sensitivity. Severely impaired insulin
sensitivity may be a contributing factor to the increased risk of ICUAW in women reported
by De Jonghe [2]. The strength of our data is the measurements by the gold standard
technique of the HE clamp, which is an elaborate procedure to perform in the ICU setting.
In line with our finding, model-based calculations have shown lower insulin sensitivity in
female ICU patients [14].
In particular, postmenopausal women, who make up the majority of women in the ICU
due to their age, may be at higher risk for impaired insulin sensitivity. In healthy women,
impaired insulin sensitivity has been noted after menopause, suggesting an influence of
sex hormones [15–17]. Sharshar et al. investigated the effect of hormonal status on ICUAW
and found a higher prevalence of hyperglycemia in postmenopausal females, which was
associated with ICUAW [18]. This could be an indicator of impaired insulin sensitivity
in older, critically ill women. However, there are no studies that have actually measured
insulin sensitivity and assessed sex hormones in pre- and postmenopausal critically ill
patients. Further studies are needed to investigate the effects of sex hormones on insulin
sensitivity and muscle weakness during critical illness in fertile and postmenopausal
patients. In clinical practice, elderly female patients could be an important target group
for advanced muscle-activating measures to improve insulin sensitivity through exercise-
induced glucose uptake. In addition, special attention should be paid to glycemic control
in this cohort.
4.2. Muscular Substrate Metabolism

Impaired glucose metabolization in skeletal muscle cells could contribute to decreased
insulin sensitivity in women. The aerobe glycolysis metabolite pyruvate in M. vastus
lateralis increased only in men during HE clamp. Energetic failure at the enzymatic level
due to decreased activity of glycolysis key enzymes may play a role. This has not been
studied as a contributing factor in ICUAW, but it has been observed in nerve damage-
induced muscle atrophy in rodents [19]. Interestingly, although neither pyruvate (aerobe
glycolysis) nor lactate (anaerobe glycolysis) increased in the women, a decrease in muscular
glucose was observed, suggesting insulin-dependent metabolization of glucose. Alternative
pathways of glucose metabolization, such as glycogen synthesis, may have been stimulated
in women.
Higher muscle glycerol concentrations by microdialysis during HE clamp suggest
increased energy utilization of lipolysis substrates and decreased suppression of lipolysis
by insulin in this cohort of critically ill women. Exogenous administration and endogenous
release of catecholamines may contribute to an increase in glycerol utilization in critically
ill women. Consistent with this, studies in healthy subjects have found increased glycerol
turnover in women during infusion of ß- and alpha-adrenergic stimulation [20,21] and
during exercise [22]. In addition, the muscular phenotype in females is described with
a higher percentage of Type I muscle fibers utilizing primary mitochondrial oxidative
phosphorylation, whereas males have more glycolytic fibers [23]. Circulating triglyceride
concentrations measured during routine clinical practice did not correlate with glycerol
J. Clin. Med. 2022, 11, 846 11 of 14
measured in the skeletal muscle. However, interpretation is limited as triglycerides were

not measured simultaneously to glycerol levels during microdialysis.
Knowledge on sex-specific preferential muscle substrate metabolization may be rele-
vant for diet composition to meet energetic requirements during critical illness. Concerning
nutrition, sex-specific differences in resting energy expenditure must also be taken into
account. Using indirect calorimetry, adipose (BMI ≥ 25 kg/m2 ), mechanically ventilated
women were found to have significantly lower energy expenditure, adjusted for actual
and ideal body weight, compared with men [24,25]. As per their BMI, the ICU patients in
our cohort had a BMI of 27 kg/m2 . However, men received a significantly lower caloric
intake per predicted body weight, indicating a higher risk for undernutrition in critically
ill male patients. In critically ill women, in addition to impaired insulin sensitivity, the
higher caloric intake per predicted body weight in females may result in higher insulin
requirements to achieve normoglycemia. Accordingly, in this cohort women received a
higher insulin dose during the first two weeks of ICU stay (until muscle biopsy). In patients
who do not receive indirect calorimetry, sex differences in energy expenditure, body height,
and weight should be taken into account in the nutrition during critical illness to avoid a
discrepancy between energy requirements and caloric intake.
4.3. Muscular Phenotype and Atrophy

Differences in muscular phenotype are discussed in a recent review of sex-specific
muscle metabolism and atrophy by Rosa–Caldwell et al. [23]. Sex hormones may play a
role in counteracting the upregulation of atrophy genes [23,26]. Interestingly, a prospective
observational study of critically ill patients found an association between hypogonadism
and ICUAW in men [18]. In our cohort, muscle atrophy gene expressions of Atrogin-1 and
Calpain-1 were more severely upregulated in female patients only in the group comparison
by non-parametric tests. A potential effect of sex on muscle atrophy gene expression was
not observed in either the unadjusted regression model or when adjusted for age.
It is discussed that women are more prone to atrophy from disuse due to a higher
proportion of Type I oxidative fibers [23]. Glycolytic fibers, which are found at a higher
percentage in male muscle, tend to be more prone to inflammatory atrophy in cancer
cachexia [23]. Our research group has found predominant atrophy of Type IIa myofibers
in consecutive muscle biopsies in patients with ICUAW [3]. Interestingly, in this analysis
a potential influence of sex on MCSA was exclusively observed for Type IIa fibers in the
adjusted multivariable regression analysis. Females may be clinically more affected by
ICUAW due to more pronounced atrophy of Type IIa myofibers and pre-existing lower
MCSA of all fiber types [13].
Consecutive muscle biopsies in patients with risk for ICUAW may provide insight
into whether the dynamics of fiber atrophy are more pronounced in females.
4.4. Limitations
This is a descriptive, hypothesis-generating analysis with single time point measure-
ments. It is unclear whether the sex differences were pre-existing or due to critical illness.
Although we excluded patients with diabetes mellitus, we cannot exclude the possibil-
ity of pre-existing impaired insulin sensitivity in women. Variable confounding factors
may influence the observed sex differences. For example, age could potentially bias the
observed sex differences for women, who tended to be slightly older. Though, sex seemed
to independently impact on insulin sensitivity index and MCSA of Type IIa fibers after
adjusting for age, BMI, and caloric intake. There are severe limitations due to the small
size of the patient cohort. The multivariable regression analysis was narrowed to sex and
three additional covariates to avoid overfitting of the model. In addition, more covariates
would have resulted in missing values. Importantly, further studies with larger data sets,
particularly of women, are, therefore, needed to conduct a more comprehensive and robust
analysis, including multiple regression models, to draw consistent conclusions.
J. Clin. Med. 2022, 11, x FOR PEER REVIEW
1. Clinical Baseline Characteristics 3.1. Clinical Baseline Characteristics
3.1. Clinical Baseline Characteristics 3.1. Clinical Baseline Characteristics
Baseline data, caloric intake, and quantity of physiotherapy Baseline data, are shown caloricin intake,
Table and 1. quantity of physiotherapy are shown in Table
dy height (p < 0.001) and 3.1.weight =Baseline
Clinical(pBaseline
data,
0.001)Characteristics
were lowercaloric
Body intake,
inheight
female <and
(ppatients,
0.001) quantity
and
while of physiotherapy
weight
median Baseline
(p = 0.001) were are
data, shown
lower caloric in intake,
in female Table 1.and quantity
patients, while med of
MI was 27 kg/m2 in both groups Body height
(p data,
= 0.833). (p <
Mean0.001)
BMI and 3.1.
was
caloric weight
Clinical
27 kg/m
intake (p = 0.001)
Baseline
per
2 inpredicted
both were lower
Characteristics
groups Body
body(p =arein female
height
0.833). (p
patients,
<
Mean 0.001) while
and
caloric weight
median (p = 0.001) were lo
Baseline
BMI was 27 caloric
kg/m 2intake,
in both and quantity
groups (p = of0.833).
physiotherapy
Mean BMIcaloricwas shown
27
intake kg/m in 2Table
per in
predicted
both 1. intake
groups
body
per predicted bo
(p = 0.833). Me
eight wasJ. higher in2022,
Clin. Med. females
Body during
11, 846
height ICU
(p < wasstay (p
0.001) and = 0.001)
weight
weight and was
(p Baseline
=in higher
the first
0.001) weredata,
in seven
females
lowercaloric
days intake,
induring
after
female ICU and stay
patients, quantity
(pwhile
= 0.001) of physiotherapy
median and in the first12are sevenshown
of 14 daysinaf
U admission (p = 0.008). Females weight received higher
a higher in
ICU females
Body
insulin
admission during
height
dose (p ICU
(p
until
= < stay
0.001)
0.008).
the day(p
and =
Females
of 0.001)
weight
weight
the and (p
received was
=in the
higher
0.001)
a first
were
higher in
sevenfemales
lower
insulin daysin during
after
female
dose ICU stay
patients,
until the day (pof
=0
while
BMI wasICU 27 kg/m 2
admission in both (pfoundgroups
=muscle
0.008). (p = 0.833).
Females Mean caloric intake perdose predicted body
uscle biopsy (p = 0.048).weight No sexwas differences
higher inwere
females in
during BMI the
biopsy was 27=received
frequency
ICU (p
stay kg/m
0.048).
(p and
=
2 inaboth
No higher
duration
0.001) sex
and
ICU
ofinsulin
groups
differences
in the
admission
(p =were
first seven
until
0.833).(p =Mean
found
days
0.008).
thein
after
day
the Females
caloricof the
intake
frequency received
and a hig
perduration
predict
muscle biopsy (p = 0.048). No
weight sex differences
was higher were
in females found musclein thebiopsy
frequency(p = 0.048).
and duration
No sex differences
of were fo
ysiotherapy. ICU admission Because
(p = 0.008). physiotherapy.
of the
Females small
receivednumber of patients
a higher insulin perduring
group,
dose ICU
thethe
until stayday (p =of0.001)
observational theand and in the first seven d
intervention
physiotherapy. physiotherapy.
muscle biopsy (pstudies = 0.048). were sex ICU
No pooled. Aadmission
differences possiblewere (pfound
= 0.008).
sex-specific in the Females
effect received
of advanced
frequency a higherofinsulin measures
and physiotherapeutic
duration dose until the da
ble 1. Baseline characteristics. Table 1. Baseline
muscle characteristics.
biopsy (p = 0.048). No sex differences were of the two studies was and du
found in the frequency
physiotherapy.Table 1. is therefore
Baseline neglected in this sub-analysis. A separate
characteristics. sex analysis
physiotherapy.during the review process. Sex differences in MRC scores
Male ICU Patients conducted by MRC for ICUAW Male ICU Patients
were
Table 1. Baseline characteristics. not Male
found ICU
in Patients
either pooled or separate analyses of observational Male ICU andPatients
intervention
trials. This Female
may be Table
ICU biased1. Baseline
Patients by thecharacteristics.
high incidence of ICUAW in Female
this cohortICU Patients
of critically ill
Male ICU Patients Female ICU Patients Fe
patients. While the underrepresentation p-Value
Male of females compared to males in the observational p-Value
♂ ♂ ICU Patients p-Value
study ( ♀27.3% vs. n♂ = 26 (31.3%)
72.7%) andFemale ICU Patients
the intervention ( ♀27.3% vs. n =♂ 2672.7%)
(31.3%)of the
♀ ngroup
= 26 (31.3%) Female ICU Patients ♀
n = 57 (68.7%) intervention study was equal, the n control
= 57 (68.7%)group of the intervention p-Valuestudy had a slightly
♂ n = 57 (68.7%) n = 57 (68.7%) p-V
49.0 (37.0/63.0) Agehigher (years)proportion of women ( ♀
60.5 (44.0/68.0) 52.9%
49.0 vs.
(37.0/63.0)
0.082 n♂ = 26 (31.3%)This may60.5
47.1%). have led nto= a26sex
(44.0/68.0) bias 0.082
Age (years) 49.0 (37.0/63.0) Age (years) 60.5 (44.0/68.0) ♀ 49.0publications.
(37.0/63.0)
0.082 (31.3%)
27.1 (23.4/29.8) BMIwhen (kg/m n results
2)
= 57 (68.7%) of (23.1/31.2)
27.0 female and male 27.1patients0.833 were mixed in previous
(23.4/29.8) 27.0 (23.1/31.2) The 0.833
BMI (kg/m ) 2
underrepresentation 27.1 (23.4/29.8)
of critically BMI (kg/m
ill womenn = 2 )
57 27.0
(68.7%) (23.1/31.2)
is most likely related 27.1 (23.4/29.8)
0.833
to lower ICU admission <0.001
Age (years) 178.0 (175.0/185.0)Height (cm) 165.0 (163.0/170.0)
49.0 (37.0/63.0) 178.0 (175.0/185.0)
<0.001
60.5 (44.0/68.0) 165.0
0.082 (163.0/170.0)
Height (cm) rates
Age among
(years) 178.0
women (175.0/185.0)
[27]. Height 49.0 (cm)(37.0/63.0)
165.0 (163.0/170.0) 178.060.5 (175.0/185.0)
<0.001
(44.0/68.0) 1
BMI (kg/m2)85.0 (80.0/96.0) Weight (kg) 27.1 (23.4/29.8)71.0 (65.0/85.0) 85.0 27.0
(80.0/96.0)
0.001
(23.1/31.2) 71.0 (65.0/85.0)
0.833 0.001 0
Weight (kg) 2)85.0 (80.0/96.0) Weight27.1 (kg)(23.4/29.8)
71.0 (65.0/85.0) 85.027.0 (80.0/96.0)
0.001
ion Height (cm)12.0 (10.0/14.0) SOFA score atBMI ICU178.0
(kg/m
admission 14.0 (11.0/16.0)
(175.0/185.0) 12.0 (10.0/14.0)
165.0 0.167
(163.0/170.0) 14.0 (11.0/16.0)
<0.001
(23.1/31.2) 0.167 0
SOFA score at ICU admission 5.Height Conclusions 12.0 (10.0/14.0)
(cm)23.5 (17.0/30.0) SOFA score at ICU admission14.0 (11.0/16.0) 12.0 (10.0/14.0)
0.167
on Weight (kg)21.0 (17.0/27.0) APACHE at ICU85.0 admission
(80.0/96.0) 21.0178.0 (175.0/185.0)
(17.0/27.0)
71.00.170(65.0/85.0) 23.5165.0 (163.0/170.0)
(17.0/30.0) 0.170<0
APACHE at ICU admission Weight In this (kg) cohort of non-diabetic
21.0 (17.0/27.0) APACHE atICU ICU 85.0patients
admission 23.5
(80.0/96.0)with a high risk0.001
(17.0/30.0) for21.0
ICUAW, relevant sex
(17.0/27.0)
71.00.170
(65.0/85.0)
n score at ICU admission
OFA 52 (38.0/62.0)
SAPS 2 at ICU admission 12.0 (10.0/14.0)54.5 (44.0/69.0) 52 (38.0/62.0)
14.00.107(11.0/16.0) 54.5 (44.0/69.0)
0.167 0.107 0
SAPS 2 at ICU admission SOFA differences
score at ICU inadmission
energy
52 (38.0/62.0)metabolism
SAPS 2 atwere ICU12.0found.
admission This analysis suggests
54.5 (44.0/69.0)
(10.0/14.0) that
5214.0 more
(38.0/62.0)
0.107 pronounced
(11.0/16.0)
)PACHE at ICU admission 29 (20.0/41.0)
Length of ICU stay 21.0(days) 27 (17.0/49.0)
(17.0/27.0) 29 (20.0/41.0)
23.50.933(17.0/30.0) 27 (17.0/49.0)
0.170 0.933 0
Length of ICU stay (days) impairments in29insulin
(20.0/41.0) sensitivity
Length of and
ICU lower
stay MCSA
(days)27 of Type IIa muscle
(17.0/49.0) 29 fibers in critically ill
(20.0/41.0)
0.933
(n, %) 2 at ICU admission 45Survival
(78.9) untilAPACHE at ICU admission
ICU discharge (n,24 %) (92.3) for sex differences 21.0
4554.5(78.9)
0.132 (17.0/27.0) 23.5 (17.0/30.0) 0
SAPS 52 may(38.0/62.0) (44.0/69.0) 0.10724 (92.3) limitations, 0.132
Survival until ICU discharge (n, SAPS %)women
2 at ICU
be
admission
relevant
45Survival
(78.9) until ICU discharge 52
in ICUAW.
(38.0/62.0) (n, %) Due to the mentioned
24 (92.3) 450.132
54.5 (78.9)
(44.0/69.0) 0
on
Length of ICU stay (days) Reasons forthe ICU admission
29 (20.0/41.0)
data need to be interpreted 270.289
(17.0/49.0)
and clearly regarded0.933 0.289
Reasons for ICU admission Length of ICU stay (days) Reasonswith for ICU caution
29admission
(20.0/41.0)
as hypothesis-generating.
270.289
(17.0/49.0) 0
19
val until ICU discharge (n, %) (33.3) ARDS (n, %)
It is important45 (78.9) 9 (34.6)
to consider gender/sex in24future 19 (33.3) (92.3)studies addressing 0.132 9 (34.6)
metabolic and muscle-
ARDS (n, %) Survival until ICU discharge 19 (n,(33.3) ARDS
%)ICU patients. (n, %)45 (78.9) 9 (34.6) 19 (33.3)
24 (92.3) 0
easons for ICU admission 13 (22.8) Sepsis (n,%)science issues
specific 7 (26.9)in 13 (22.8) 0.2897 (26.9)
Sepsis (n,%) Reasons for ICU admission 13 (22.8) Sepsis (n,%) 7 (26.9) 13 (22.8) 0
ARDS (n, %) 16 (28.1) Polytrauma (n,%) 19 (33.3)3 (11.5) 16 (28.1) 9 (34.6) 3 (11.5)
Polytrauma (n,%) ARDS
Supplementary (n, %) Materials: 16 (28.1)ThePolytrauma following are(n,%)
19 (33.3)3online
available (11.5) at https://www.mdpi.com/article/
16 (28.1)
9 (34.6)
Sepsis (n,%) 9 (15.8) Neurological (n,%)
13 (22.8) 6 (23.1) 9 (15.8)
7 (26.9) 6 (23.1)
Neurological (n,%) Sepsis (n,%)
10.3390/jcm11030846/s1, 9 (15.8) FigureNeurological
S1: Sex (n,%)
13
distribution (22.8) 6
in (23.1)
the observational and 9intervention
(15.8)
7 (26.9) study.;
Polytrauma (n,%) - Other (n,%)16 (28.1) 1 (3.8) - 3 (11.5) 1 (3.8)
Other (n,%) Table
Polytrauma S1: Sex-specific
(n,%) -
analysis of Other
ICU by (n,%)
MRC 16 in groups
(28.1) 1 (3.8)
of observational and - (11.5)
intervention
3 trial.;
akeNeurological (n,%) Insulin dose and caloric intake
9 (15.8) 6 (23.1)
Insulin dose and caloric intakeNeurological Table S2: Multivariable(n,%) Insulin
linear dose
regression andmodelcaloricfor intake
atrophy
9 (15.8) gene expression of Calpain-1 and
6 (23.1) Atrogin-
face Other (n,%) Insulin dose per bodyS2:surface -(a) 1 (3.8) triglycerides and muscular
2 Insulin dose 18.5 per body
(10.5/26.7)surface 1.;Other
Figure(n,%) 20.1Spearman’s Insulin
2 (15.6/30.9) dose
correlation per
18.5 of body
(10.5/26.7)
0.289
circulating surface
- 20.1 (15.6/30.9) 1 (3.8) by micro- 0.289
glycerol
m ) dose and caloric intake
ulin area during 2 ICU stay (IE/m 18.5) (10.5/26.7) 20.1 (15.6/30.9)
2triglycerides. 18.5 (10.5/26.7)
0.289
area during ICU stay (IE/m
Insulin ) per body
dose dose
dialysis in M.vastus
and caloric
surfaceintake
area during ICU stay (IE/m )
lateralis. (b) Sex-specific circulating
ulin dose
ace per dose
body18.6surfaceInsulin
(9.2/27.8) 30.0 (17.7/37.0)
Insulin dose18.6 (9.2/27.8)
0.048 30.0 (17.7/37.0)
L.J.E., J.J.G., T.W. 0.048
a2) during
Insulin
ICU stay
per body
(IE/m Insulin
2until
) muscledose
surface Author
biopsy per(IE/m
18.5 body18.6
Contributions:2)surface
(10.5/26.7) Conceptualization,
(9.2/27.8)
per body
20.1L.J.E., surface
(15.6/30.9)
T.W. and S.W.-C.; Data
30.02 (17.7/37.0)
0.289curation,
18.6 0.048
(9.2/27.8)
2 18.5 (10.5/26.7) 20.1 (15.6/30.9) 0
sulin
until muscle biopsy (IE/m
ing dose per body surface Caloric area 2 ) during ICU stay (IE/m )until muscle biopsy (IE/m )
intake
and
per
N.M.C.; Formal
PBWadministration,
during
analysis, L.J.E.; Funding acquisition, S.W.-C.; Investigation, T.W. and S.W.-
Caloric intake 18.5
per(14.0/20.7)
PBW during C.; Project 21.6 (17.5/28.2) S.W.-C.;
Caloric intake Resources,
18.5per (14.0/20.7)
0.001
PBW S.W.-C.;
during Supervision, S.W.-C.; Visualization,
21.6 (17.5/28.2) L.J.E.; 0.001
Insulin dose 18.6 per body (9.2/27.8) surface 30.0 (17.7/37.0) 0.048
ntil muscle biopsy (IE/m2) ICU stay (kcal/kgPBW) Writing—original 18.5 (14.0/20.7)
draft, L.J.E.; Writing—review 18.6 and 21.6
(9.2/27.8) (17.5/28.2)
editing, J.J.G., T.W., N.M.C., 18.530.0 (14.0/20.7)
0.001
F.B.,(17.7/37.0)
J.S. and S.W.-C. 0
ICU stay (kcal/kgPBW)until muscle biopsy (IE/m 2 ICU stay (kcal/kgPBW)
) agreed to the published version of the manuscript.
U intake per PBW during
oric Caloric intake Allper PBW
authors haveICU read and
Caloric intake 13.7per
(10.5/19.1)
PBWCaloric
ICU intake 18.5 17.7during
per(14.0/20.7)
PBW (13.5/24.9)Caloric intake 13.7 21.6
(10.5/19.1)
per 0.008
PBW
(17.5/28.2)ICU 17.7 (13.5/24.9)
0.001 0.008
ICU stay (kcal/kgPBW) day 1–7 (kcal/kgPBW) 13.7 (10.5/19.1) 18.5 17.7
(14.0/20.7) (13.5/24.9) 13.7 (10.5/19.1)
21.60.008
(17.5/28.2) 0
day 1–7 (kcal/kgPBW) ICU Funding: The partial projectday 3 (Critical illness myopathy and timely electrical muscle stimulation)
1–7 (kcal/kgPBW)
stay intake per PBW ICU Physiotherapyof stay
during (kcal/kgPBW)
ICU stay
aloric Klinische Forschergruppe KFO 192 (Regulation und Fehlregulation von Muskelwachstum) was
Physiotherapy during ICUCaloric stay intake 13.7per (10.5/19.1)
PBW ICU Physiotherapy during 17.7 ICU stay
(13.5/24.9) 0.008 (265.0/740.0)
y day
(min) 445Total
1–7 (kcal/kgPBW) (267.5/662.5)
duration of funded physiotherapy 397.5
by Deutsche (min)
(265.0/740.0)
Forschungsgemeinschaft 445 (267.5/662.5)
0.673
13.7 (WE4386
(10.5/19.1) 1-2, 34181657), 397.5 and Berlin Institute of Health 0.673 0
Total duration of physiotherapy day (min) 1–7 (kcal/kgPBW) 445 (267.5/662.5)
Total duration of physiotherapy 397.5 (265.0/740.0)
(min) 445 17.7 (13.5/24.9)
(267.5/662.5)
0.673 3
nsiotherapy
(min) 27.8
Time
during ICU stay(24.8/29.9)
per physiotherapyresearch session
twinning 29.0 (min)
(24.0/30.3)
grant 3 (S.W.C.). 27.8 (24.8/29.9)
0.488 29.0 (24.0/30.3) 0.488
Time per physiotherapy session (min)
Physiotherapy 27.8
duringsessions ICU Time
(24.8/29.9)
stay per physiotherapy session
29.0 (24.0/30.3)
(min) 27.8 (24.8/29.9)
0.488
essions of physiotherapy
duration 16
Number
(11/23.5)
(min) of physiotherapeutic 445 (267.5/662.5) 17 (11/24) 16 (11/23.5)
397.5
The 0.701
(265.0/740.0)
study was conducted according 0.673 17 (11/24) the guidelines of 0.701
Number of physiotherapeutic Total sessions
duration
Institutional
of physiotherapy
Review16Number Board Statement:
(11/23.5)
(min) of physiotherapeutic445 (267.5/662.5)sessions
17 (11/24) 16 to
397.5 (11/23.5)
0.701
(265.0/740.0) 0
sults are reported as median with
per physiotherapy session (min)Results are interquartile range or Results
27.8 (24.8/29.9)
the Declaration as absolute
are reported
numbers
of Helsinki. The clinical as with
median percentages.
29.0 with interquartile
(24.0/30.3)
investigations range
were approved or as
0.488 absolute
by the Ethics numbers with percentag
Commit-
MI: Body Mass Index, SOFA: Time per physiotherapy
Sequential Organ reported
FailureBMI: as median
sessionBody(min)
Assessment, with
Mass interquartile
ICU: Index,
Intensive
SOFA: range
27.8
Care or Results
as
(24.8/29.9)
Sequential
Unit, andabsolute are
Organ reported
numbers
Failure as
with
medianpercentages.
with
29.0 (24.0/30.3)
Assessment, interquartile
ICU: Intensive range 0o
er of physiotherapeutic sessionsBMI: Body tee,MassEthikkommission
16 Index,
(11/23.5) SOFA: Charité,
Sequential Charité
Organ EA2/061/06,
17 (11/24)
Failure Assessment,
BMI: Body EAMass 2/041/10.
ICU: 0.701 SOFA:
Index,
Intensive TrialCareregistration:
Sequential
Unit, IS- Care
Organ
U
Failur
RDS: Acute Respiratory Distress Syndrome,
Number PBW: Predicted
of physiotherapeutic
RCTN77569430 ARDS: and Body
Acute
sessionsWeight.
Respiratory
ISRCTN19392591. Mann–Whitney
Distress Syndrome,
Test
16 (11/23.5)
Retrospectively PBW: Predicted
registered 13/02/2008 Body Weight.
17and
(11/24) Mann–Whitney 0T
17/02/2011.
Results are reported
ARDS: as Respiratory
median withDistress
interquartile range PBW:
or as absolute numbers with percentages.
d Pearson–Chi2 Test. Missing values: TimeAcute
per physiotherapeutic
and Pearson–Chi
Results
Syndrome,
session 2 was
Test.not
are reported
https://www.isrctn.com/ISRCTN77569430 Missing Predicted
available
values:
asAssessment,
median
and
ARDS:
for n
Time
with
BodyAcute
per Weight.
Respiratory
Mann–Whitney
physiotherapeutic
interquartile range or
https://www.isrctn.com/ISRCTN19392591
Distress Test
Syndrome,
as session
absolutewas not
numbers
PBW: Pred
available
(Last with perfo
BMI: Body Mass Index,
and Pearson–Chi SOFA:
2 Test. Sequential
Missing Organ
values: Failure
Time per physiotherapeutic ICU:
andfound. Intensive
Pearson–Chi
session was
2 Care
Test. Unit,
notMissing
available
values:
for n Time per area
physiot
males. No other missing values were found. Data
accessed: on29 insulin
= 2 males.
dose
BMI:
November Noperother
Body
2021 body missing
Mass
15:35 surface
Index,
CET). values
area
SOFA:before
wereSequential Data
Organon insulin
Failure dose per body
Assessment, surface
ICU: Intensivebef
C
ARDS: Acute Respiratory Distress Syndrome, PBW: Predicted Body =Weight. Mann–Whitney Test
uscle biopsy are reported in n = 42 =male
2 males.
and nNo other
= 17 missing
female muscle values
patients
biopsy
ARDS: who were
are found.
received
Acute reported Data
biopsy.
Respiratory
on
42insulin
in n =Distress
male 2 males.
dose
and n =No
Syndrome,
per
17 other
body missing
female
PBW:
surface
patients
Predicted
area
values
who before
Body
were found.
received
Weight.
Data on
biopsy.
Mann–Whi
and Pearson–Chi 2 Test. Missing
muscle biopsy values:
are reported in Time
n = 42per
malephysiotherapeutic
and
Informed n = 17 femalesession
muscle
patientswas
biopsy
whonotfrom
available
received
are reportedforin
n n involved
biopsy. = 42 male inand n = 17 fema
Informed Consent Statement:
and Pearson–Chi 2 Test. consent
Missing was
values:obtained
Time all subjects
per physiotherapeutic the
session was not avail
= 2 males. No other missing values were found. Data on insulin dose per body surface area before
2. Clinical Diagnosis of ICUAW by MRC prospective studies
at First Awakening = (or
3.2. Clinical
and
2 from
ICU
males. his/her
Diagnosis
Discharge
No legal
of
other proxy).
ICUAW
missing byConsent
valuesMRC wereatfor publication:
First
found. Awakening
Data onAnonymous
and ICU
insulin dosepublication
Discharge
per body surface ar
muscle biopsy areofreported
3.2. Clinical noinidentifiable
Diagnosis
data, n = of
42ICUAW
maledata
andbyn MRC
= 17 female
published. patients
at Patients
First who
Awakening received
3.2. Clinical
and ICU biopsy.
Diagnosis
Discharge of ICUAW theby MRC at First Awa
muscle biopsy are reported inornlegal proxy
= 42 male were
and n =informed
17 femaleabout
patients publication
who received biopsy
of data before they gave their written consent.
3.2. Clinical
Data Availability Statement: ForDiagnosis of data
ethical and ICUAW by MRC
protection at First
reasons, Awakening
public and
disclosure of ICU Discharge
data is not
possible. Editors, reviewers, and interested researchers can contact the corresponding author or sent
a request to [email protected] to get access to the data.
Acknowledgments: J.J.G. is participant of the BIH-Charité Junior Clinician Scientist Program funded
by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. T.W. was supported
J. Clin. Med. 2022, 11, 846 13 of 14
by the BIH–Charité Clinician Scientist Program funded by the Charité–Universitätsmedizin Berlin

and the Berlin Institute of Health. Finally, we thank the involved ICU staff and all patients for their
participation in the two clinical trials.
Conflicts of Interest: The authors declare no conflict of interest. Outside of the submitted work F.B.
reports grants work from the German Federal Ministry of Education and Research, grants from the
German Federal Ministry of Health, grants from the Berlin Institute of Health, personal fees from
Elsevier Publishing, grants from the Hans Böckler Foundation, other from the Robert Koch Institute,
grants from the Einstein Foundation, and grants from the Berlin University Alliance.
References
1. Van Aerde, N.; Meersseman, P.; Debaveye, Y.; Wilmer, A.; Gunst, J.; Casaer, M.P.; Bruyninckx, F.; Wouters, P.J.; Gosselink, R.;
Van den Berghe, G.; et al. Five-year impact of ICU-acquired neuromuscular complications: A prospective, observational study.
Intensive Care Med. 2020, 46, 1184–1193. [CrossRef]
2. De Jonghe, B.; Sharshar, T.; Lefaucheur, J.-P.; Authier, F.-J.; Durand-Zaleski, I.; Boussarsar, M.; Cerf, C.; Renaud, E.; Mesrati,
F.; Carlet, J.; et al. Paresis Acquired in the Intensive Care Unit: A Prospective Multicenter Study. Available online: https:
//pubmed.ncbi.nlm.nih.gov/12472328/ (accessed on 11 January 2021).
3. Wollersheim, T.; Woehlecke, J.; Krebs, M.; Hamati, J.; Lodka, D.; Luther-Schroeder, A.; Langhans, C.; Haas, K.; Radtke, T.; Kleber,
C.; et al. Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness. Intensive Care
Med. 2014, 40, 528–538. [CrossRef]
4. Thomas, S.; Mehrholz, J. Health-related quality of life, participation, and physical and cognitive function of patients with intensive
care unit-acquired muscle weakness 1 year after rehabilitation in Germany: The GymNAST cohort study. BMJ Open Br. Med. J.
Publ. Group 2018, 8, e020163. [CrossRef] [PubMed]
5. Nakanishi, N.; Liu, K.; Kawakami, D.; Kawai, Y.; Morisawa, T.; Nishida, T.; Sumita, H.; Unoki, T.; Hifumi, T.; Iida, Y.; et al.
Post-Intensive Care Syndrome and Its New Challenges in Coronavirus Disease 2019 (COVID-19) Pandemic: A Review of Recent
Advances and Perspectives. J. Clin. Med. 2021, 10, 3870. [CrossRef] [PubMed]
6. Weber-Carstens, S.; Deja, M.; Koch, S.; Spranger, J.; Bubser, F.; Wernecke, K.D.; Spies, C.D.; Spuler, S.; Keh, D. Risk factors in
critical illness myopathy during the early course of critical illness: A prospective observational study. Crit. Care 2010, 14, R119.
[CrossRef] [PubMed]
7. Kautzky-Willer, A.; Harreiter, J.; Pacini, G. Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2
Diabetes Mellitus. Endocr. Rev. 2016, 37, 278–316. [CrossRef]
8. Weber-Carstens, S.; Koch, S.; Spuler, S.; Spies, C.D.; Bubser, F.; Wernecke, K.D.; Deja, M. Nonexcitable muscle membrane predicts
intensive care unit-acquired paresis in mechanically ventilated, sedated patients. Crit. Care Med. 2009, 37, 2632–2637. [CrossRef]
[PubMed]
9. Weber-Carstens, S.; Schneider, J.; Wollersheim, T.; Assmann, A.; Bierbrauer, J.; Marg, A.; Al Hasani, H.; Chadt, A.; Wenzel, K.;
Koch, S.; et al. Critical Illness Myopathy and GLUT4: Significance of Insulin and Muscle Contraction. Am. J. Respir. Crit. Care
Med. 2013, 187, 387–396. [CrossRef] [PubMed]
10. Wollersheim, T.; Grunow, J.J.; Carbon, N.M.; Haas, K.; Malleike, J.; Ramme, S.F.; Schneider, J.; Spies, C.D.; Märdian, S.; Mai,
K.; et al. Muscle wasting and function after muscle activation and early protocol-based physiotherapy: An explorative trial. J.
Cachexia Sarcopenia Muscle 2019, 10, 734–747. [CrossRef] [PubMed]
11. Grunow, J.J.; Goll, M.; Carbon, N.M.; Liebl, M.E.; Weber-Carstens, S.; Wollersheim, T. Differential contractile response of critically
ill patients to neuromuscular electrical stimulation. Crit. Care 2019, 23, 308. [CrossRef]
12. DeFronzo, R.A.; Tobin, J.D.; Andres, R. Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am.
J. Physiol. -Endocrinol. Metab. 1979, 237, E214. [CrossRef]
13. Staron, R.S.; Hagerman, F.C.; Hikida, R.S.; Murray, T.F.; Hostler, D.P.; Crill, M.T.; Ragg, K.E.; Toma, K. Fiber Type Composition of
the Vastus Lateralis Muscle of Young Men and Women. J. Histochem. Cytochem. 2000, 48, 623–629. [CrossRef]
14. Uyttendaele, V.; Chase, J.G.; Knopp, J.L.; Gottlieb, R.; Shaw, G.M.; Desaive, T. Insulin sensitivity in critically ill patients: Are
women more insulin resistant? Ann. Intensive Care 2021, 11, 12. [CrossRef]
15. Yan, H.; Yang, W.; Zhou, F.; Li, X.; Pan, Q.; Shen, Z.; Han, G.; Newell-Fugate, A.; Tian, Y.; Majeti, R.; et al. Estrogen Improves
Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1. Diabetes 2019, 68, 291–304. [CrossRef]
[PubMed]
16. Manson, J.E.; Chlebowski, R.T.; Stefanick, M.L.; Aragaki, A.K.; Rossouw, J.E.; Prentice, R.L.; Anderson, G.; Howard, B.V.;
Thomson, C.A.; LaCroix, A.Z.; et al. Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended
Poststopping Phases of the Women’s Health Initiative Randomized Trials. JAMA 2013, 310, 1353. [CrossRef] [PubMed]
17. Geer, E.B.; Shen, W. Gender differences in insulin resistance, body composition, and energy balance. Gend. Med. 2009, 6, 60–75.
[CrossRef] [PubMed]
18. Sharshar, T.; Bastuji-Garin, S.; De Jonghe, B.; Stevens, R.D.; Polito, A.; Maxime, V.; Rodriguez, P.; Cerf, C.; Outin, H.; Touraine,
P.; et al. Hormonal status and ICU-acquired paresis in critically ill patients. Intensive Care Med. 2010, 36, 1318–1326. [CrossRef]
[PubMed]
J. Clin. Med. 2022, 11, 846 14 of 14
19. Langer, H.T.; Afzal, S.; Kempa, S.; Spuler, S. Nerve damage induced skeletal muscle atrophy is associated with increased
accumulation of intramuscular glucose and polyol pathway intermediates. Sci. Rep. 2020, 10, 1908. Available online: http:
//www.nature.com/articles/s41598-020-58213-1 (accessed on 24 July 2020). [CrossRef]
20. Horton, T.J.; Dow, S.; Armstrong, M.; Donahoo, W.T. Greater systemic lipolysis in women compared with men during moderate-
dose infusion of epinephrine and/or norepinephrine. J. Appl. Physiol. 2009, 107, 200–210. [CrossRef]
21. Schmidt, S.L.; Bessesen, D.H.; Stotz, S.; Peelor, F.F.; Miller, B.F.; Horton, T.J. Adrenergic control of lipolysis in women compared
with men. J. Appl. Physiol. 2014, 117, 1008–1019. [CrossRef]
22. Horton, T.J.; Pagliassotti, M.J.; Hobbs, K.; Hill, J.O. Fuel metabolism in men and women during and after long-duration exercise.
J. Appl. Physiol. 1998, 85, 1823–1832. [CrossRef] [PubMed]
23. Rosa-Caldwell, M.E.; Greene, N.P. Muscle metabolism and atrophy: Let’s talk about sex. Biol. Sex Differ. BioMed Cent. 2019, 10, 43.
[CrossRef]
24. Drolz, A.; Wewalka, M.; Horvatits, T.; Fuhrmann, V.; Schneeweiss, B.; Trauner, M.; Zauner, C. Gender-specific differences in
energy metabolism during the initial phase of critical illness. Eur. J. Clin. Nutr. Nat. Publ. Group 2014, 68, 707–711. [CrossRef]
[PubMed]
25. Zauner, A.; Schneeweiss, B.; Kneidinger, N.; Lindner, G.; Zauner, C. Weight-adjusted resting energy expenditure is not constant in
critically ill patients. Intensive Care Med. 2006, 32, 428–434. [CrossRef] [PubMed]
26. Zhao, W.; Pan, J.; Zhao, Z.; Wu, Y.; Bauman, W.A.; Cardozo, C.P. Testosterone protects against dexamethasone-induced muscle
atrophy, protein degradation and MAFbx upregulation. J. Steroid Biochem. Mol. Biol. 2008, 110, 125–129. [CrossRef]
27. Hollinger, A.; Gayat, E.; Féliot, E.; Paugam-Burtz, C.; Fournier, M.-C.; Duranteau, J.; Lefrant, J.-Y.; Leone, M.; Jaber, S.; Mebazaa,
A.; et al. Gender and survival of critically ill patients: Results from the FROG-ICU study. Ann. Intensive Care 2019, 9, 43. Available
online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441070/ (accessed on 14 May 2021). [CrossRef] [PubMed]

Female - ICU-AW

Uploaded by

Copyright:

Available Formats

Female - ICU-AW

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Female - ICU-AW

Uploaded by

Copyright:

Available Formats

Journal of

2. Materials and Methods

2.2. Clinical Parameters

2.3. Glucose and Lipid Metabolism

glucose infusion rate (mg/kg/min) divided by steady-state serum insulin concentration

2.3.2. Muscular Metabolites by Microdialysis in the M. vastus lateralis

2.4. Protein Degradation, Content, and Muscle Morphology

J. Clin. Med. 2022, 11, 846 4 of 14

Insulin dose Physiotherapy

Table 2. Multivariable linear regression for insulin sensitivity index.

Model 1 (Unadjusted) Model 2

3.3.2. Muscular Metabolites of Glycolysis by Microdialysis in M. vastus lateralis

3.3.3. Muscular Glycerol Concentrations by Microdialysis in M. vastus lateralis

3.4. Protein Degradation, Content, and Muscle Morphology

J. Clin. Med. 2022, 11, 846

3.4.2. Histological Analysis of Surgical Biopsies of M. vastus lateralis—Myocyte

J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4 of 14

3.1. Clinical Baseline Characteristics

Model 1 (Unadjusted) Model 2

4.1. Insulin Sensitivity

4.2. Muscular Substrate Metabolism

measured in the skeletal muscle. However, interpretation is limited as triglycerides were

4.3. Muscular Phenotype and Atrophy

by the BIH–Charité Clinician Scientist Program funded by the Charité–Universitätsmedizin Berlin

You might also like