Pilot Study: Validation of Operators and Inter-Evaluator Variability in Diagnostic Strategies for ICU-Acquired Weakness (NMusICU-R)
Conditions: Critical Illness
Sponsor: University of Chile

 
 
PILOT STUDY: 
"Operator Validation and Inter-Rater Variability in Diagnostic Strategies for 
ICU-Acquired Weakness" 
 
 
October 8, 2024 
Version number 2 
 
 
 
 
Óscar Arellano-Pérez  
Benito Arévalo Pereda  
Nicole Peña León  
Paola Llanos Vidal  
 
 
 
 

 
 
Abstract 
Background: 
Intensive Care Unit-Acquired Weakness (ICU-AW) is characterized by muscle weakness that 
may result from critical illness polyneuropathy (CIP), critical illness myopathy (CIM), or a 
combination of both. This condition is a frequent complication that increases mortality and 
hospital length of stay, and contributes to post-intensive care syndrome, leading to long-term 
cognitive and physical dysfunction. Early diagnosis is crucial, as muscle mass loss and 
electrophysiological alterations can occur within the first 10 days of hospitalization. Muscle 
ultrasound has been used to support early detection, since electrophysiological tests are costly 
and not always available. Peripheral nerve ultrasound emerges as an effective alternative for 
differentiating between CIM and neuropathy. This study aims to evaluate the feasibility of 
quadriceps muscle and peripheral nerve ultrasound as assessment tools for physical 
therapists in the critical care setting, as well as their inter-rater reliability, with the goal of 
facilitating early diagnosis and timely therapeutic strategies in hospitalized patients. 
Methods: 
This study will be conducted in patients admitted to the critical care unit at Clínica INDISA. 
Inter-rater reliability will be assessed using the intraclass correlation coefficient (ICC) across 
several quadriceps muscle and peripheral nerve ultrasound variables, as measured by three 
experienced physical therapists. Variables will include anterior quadriceps complex thickness, 
cross-sectional area (CSA) of the rectus femoris and vastus intermedius (transverse view), 
and pennation angle of the vastus lateralis (longitudinal view). For peripheral nerve ultrasound, 
CSA and echogenicity will be evaluated. Echogenicity will be analysed using ImageJ software. 
Inter-rater agreement of the MRC Sum Score (MRC-SS) and the Functional Status Score for 
the ICU (FSS-ICU) will also be assessed using Kendall’s W coefficient. Finally, ultrasound 
findings will be correlated with clinical scale scores using Pearson or Spearman correlation 
coefficients, as appropriate. All procedures will comply with bioethical standards and be 
approved by the Research Ethics Committee of Clínica INDISA. 
Expected Results: 
We expect to find sufficient inter-rater agreement in quadriceps and peripheral nerve 
ultrasound measurements performed by physical therapists in the ICU setting. Additionally, 
MRC-SS and FSS-ICU scale results are expected to demonstrate reliable agreement and 
correlate with the ultrasound findings. 
 
 
 
 
 
 

 
 
Introduction 
ICU-AW is a neuropathy and/or myopathy characterized by symmetrical proximal-predominant 
muscle weakness1,2, without involvement of facial or ocular muscles2,3, and may affect 
respiratory muscles3,4, leading to diaphragmatic dysfunction associated with mechanical 
ventilation (VIDD) and difficulty weaning from ventilatory support5. CU-AW may be triggered 
by a) a neurogenic disorder known as critical illness polyneuropathy (CIP); b) a muscular 
disorder known as critical illness myopathy (CIM); and/or c) the coexistence of both3,6–9.  CIP 
is an acute, acquired sensory-axonal neuropathy caused by peripheral nerve inflammation5,10. 
CIM is characterized by alterations in muscle mass and contractility6,12, and presents 
pathognomonic features such as preserved sensation, elevated creatine kinase levels10, and 
most notably, preferential loss of myosin relative to actin in muscle biopsy samples5,11,12. Since 
muscle atrophy and impaired contractility are the main features associated with increased 
mortality13–17 and physical disability18,19, most studies have focused on CIM and skeletal 
muscle degradation pathways20
Importance of ICU-AW 
ICU-AW is a common complication in critically ill patients16,21,22 and is associated with 
increased mortality8,10,21,23–25, prolonged hospital stays8,9,23,25, longer duration of mechanical 
ventilation9,24, higher healthcare-related costs, and reduced long-term physical function and 
quality of life8,9,21,24,26. Moreover, this condition can progress into post-intensive care syndrome 
(PICS), which may result in persistent cognitive, mental, and physical dysfunction3,25,27. A 
multicentre study conducted in Chile evaluated the functional and cognitive sequelae of PICS 
in patients who experienced critical illness due to COVID-19, determining that a high 
percentage of survivors will present some degree of disability after hospital discharge28. 
Therefore, early identification of ICU-AW is crucial to designing both pharmacological 
and non-pharmacological therapeutic strategies.
Diagnosis of ICU-AW 

 
 
Regarding the diagnosis of critical illness myopathy (CIM), there are strategies available for 
both cooperative and non-cooperative patients2.
Medical Research Council Sum Score (MRC SS) 
Clinical quantification of muscle strength in awake and cooperative patients is commonly 
performed using the Medical Research Council Sum Score (MRC-SS)2,8,29.  his score assigns 
a value from 0 (no muscle contraction) to 5 (normal strength) to each of 12 muscle groups. 
These include muscles responsible for shoulder abduction, elbow flexion, wrist extension, hip 
flexion, knee extension, and ankle dorsiflexion, all evaluated bilaterally30. A score of ≤48 
indicates the presence of muscle weakness, while a score below 36 indicates severe 
weakness 3,29,31. However, this scale has several limitations. First, it does not identify the 
underlying cause of weakness and cannot distinguish between CIP and CIM. Moreover, 
it requires patients to be fully awake and cooperative—criteria that many ICU patients do not 
meet30. Although most studies have reported good reproducibility in critically ill patients32–35, 
further research is still needed to support this assertion.
Electrophysiology 
Another important aspect is the differential diagnosis between CIM and CIP. 
Electrophysiological evaluation is also used to diagnose ICU-AW and can be applied in 
unconscious or uncooperative patients, as well as to differentiate between CIP and CIM31,36. 
Nerve conduction studies assess the reduction of the compound muscle action potential 
(CMAP). In cases where CIP and CIM coexist, sensory nerve action potentials (SNAPs) may 
also be reduced, while nerve conduction velocity is typically normal or only slightly 
decreased37. Both CIP and CIM may show spontaneous electrical activity on 
electromyography (EMG). Voluntary muscle contraction—requiring patient cooperation—or 
more complex electrophysiological methods such as direct muscle stimulation can be used to 
differentiate between CIP and CIM38. However, these techniques do not allow for early 
diagnosis during the initial phase of ICU-AW development. Full electrophysiological testing 

 
 
is often unavailable in many ICUs, is time-consuming, and costly 30. Furthermore, the 
clinical significance of electrophysiological abnormalities in the absence of muscle weakness 
remains unclear37.
Biopsies 
Nerve and muscle biopsies can provide valuable mechanistic insights and allow for differential 
diagnosis between CIP and CIM. However, biopsy is an invasive procedure and is not 
recommended for routine clinical use; it is therefore advised only within the context of scientific 
research29,31. 
Imaging-Based Diagnosis of ICU-Acquired Weakness 
In non-cooperative patients, various imaging techniques have been used to assess muscle 
mass as a surrogate for muscle strength in the diagnosis of ICU-AW. Computed tomography 
(CT) and magnetic resonance imaging (MRI) allow for visualization of muscle quality, detection 
of fatty infiltration, and quantification of lean muscle mass 15; However, these are high-cost 
techniques that require specialized personnel and software15,31. Quadriceps muscle 
ultrasound is considered the most promising approach, as it enables rapid and 
repeatable bedside assessments, allowing the evaluation of both muscle quantity 
(muscle thickness, anatomical and physiological cross-sectional area) and quality 
(echogenicity and muscle architecture)17,31,39.
Muscle Ultrasound 
Diagnosis of CIM through muscle ultrasound is based on changes in ultrasound-derived 
variables within 7 to 10 days of critical illness onset. These changes include a 20% decrease 
in muscle thickness, a 10% reduction in cross-sectional area, a 5% decrease in pennation 
angle, and an 8–10% increase in echogenicity16,17,39. Regarding percent changes in ultrasound 
parameters over time, a study by Formenti et al. reported a significant decrease in pennation 
angle within the first 7 days of critical illness among patients who developed ICU-acquired 

 
 
weakness 40. Additionally, increased echogenicity of the rectus femoris during the first 7 days 
of ICU stay has been shown to be a predictor of ICU-AW17. 
Early diagnosis is crucial, as protein degradation, muscle mass loss41,42, y and 
electrophysiological alterations43 occur within the first 10 days in the ICU. Given the 
importance of early detection, some critical illness severity scores have been used alongside 
ultrasound evaluation to raise suspicion and consider the presence of this clinical condition44–
47. However, further research is needed to support this strategy. 
Differential Diagnosis Between CIM and CIP Using Ultrasound 
As previously mentioned, the differential diagnosis between CIM and CIP has traditionally 
been made using electrophysiological evaluation2. However, this method is not available in 
all centres and is rarely feasible at the bedside. 
D Since various neuropathies have been assessed using ultrasound48 this technique has been 
proposed as an alternative approach to address this challenge49. In a study by Gruber et al.49, 
the Ultrasonic Pattern Sum Score (UPSS)50 was used to demonstrate that peripheral nerve 
ultrasound can differentiate between pure CIM and neuropathy in ICU-AW patients, with a 
sensitivity of approximately 84%49. Although the authors noted that this method does not 
distinguish between sensory and motor neuropathy, peripheral nerve ultrasound emerges as 
a reliable tool for identifying neuropathy in these patients49. This strategy could facilitate the 
detection of neuropathy in ICU-AW and aid in identifying its coexistence with CIM. However, 
further studies are needed to validate and strengthen this approach. 
Based on the aforementioned evidence, although several strategies exist for diagnosing ICU-
acquired weakness (ICU-AW), there remains a pressing need to promote early detection, as 
muscular alterations41,42 occur within the first days of critical illness. One promising solution is 
the validation of muscle and peripheral nerve ultrasound to detect ICU-AW at an early stage. 
This would allow for a more accurate differential diagnosis and facilitate the selection 
of the most appropriate therapeutic strategy. 

 
 
This pilot study aims to assess the usefulness and inter-rater reliability of ultrasound 
in the early diagnosis of ICU-acquired weakness, as well as the consistency of 
standardized clinical assessment scales. The results will support the validation of 
physical therapists as qualified operators for future research projects and contribute 
to strengthening physiotherapy interventions for hospitalized patients in critical care 
settings. 

 
 
Hypothesis 
Considering the aforementioned background, the hypothesis of this research project is: 
Quadriceps muscle and peripheral nerve ultrasound is a feasible technique for 
physical therapists in the critical care unit and demonstrates good inter-rater 
reliability. 
General Objective 
To assess the feasibility of quadriceps muscle and peripheral nerve ultrasound as a technique 
for physical therapists in the critical care unit, as well as to determine its inter-rater 
reliability. 
Specific Objectives 
• 
SO1: To evaluate the inter-rater variability of quadriceps muscle ultrasound 
measurements performed by physical therapists in the critical care unit. 
• 
SO2: To assess the feasibility and inter-rater variability of peripheral nerve ultrasound 
in the same clinical setting. 
• 
SO3: To evaluate the inter-rater variability of the MRC-SS and FSS-ICU clinical scales 
and correlate their results with findings from quadriceps muscle and peripheral nerve 
ultrasound. 

 
 
Study Design 
SO1: To evaluate the inter-rater variability of quadriceps muscle ultrasound 
measurements performed by physical therapists in the critical care unit. 
Rationale: ICU-AW is a frequent complication in critically ill patients16,21,22, associated with 
prolonged hospital stays8,9,23,25, increased mortality8,10,21,23–25, higher healthcare costs, and 
long-term functional impairments8,9,21,24,26. Protein degradation and muscle mass loss can 
begin within the first 10 days of critical illness41,42 , highlighting the importance of early 
diagnosis. In non-cooperative patients, quadriceps muscle ultrasound has been proposed as 
an effective tool for early detection of ICU-AW44–47.  Although ultrasound has shown good 
inter-rater reliability 51–54, these findings mostly reflect the consistency of the method itself, not 
of the individual operators—underscoring the need to validate operator reliability. 
Experimental Approach: To address this objective, inter-rater variability will be assessed 
using the intraclass correlation coefficient (ICC) for various quadriceps muscle ultrasound 
variables, measured by three physical therapists experienced in the technique. In the 
transverse view, the following variables will be assessed: anterior quadriceps complex 
thickness, rectus femoris thickness, vastus intermedius thickness, and their respective cross-
sectional areas (CSA). In the longitudinal view, the pennation angle of the vastus lateralis 
fibers relative to the superficial aponeurosis of the vastus intermedius will be evaluated. In 
addition, echogenicity will be assessed using histogram analysis via ImageJ software. 
Expected Results: We anticipate sufficient inter-rater agreement in quadriceps muscle 
ultrasound measurements performed by physical therapists in the critical care unit. 
SO2: To assess the feasibility and inter-rater variability of peripheral nerve ultrasound 
in the same clinical setting. 
Rationale: Although the differential diagnosis between CIM and CIP is commonly performed 
using electrophysiological assessment31,36, this tool is not widely available in all healthcare 
centres and is even less accessible at the patient’s bedside. To address this limitation, 

 
 
peripheral nerve ultrasound has been proposed as a strategy to evaluate changes in cross-
sectional area (CSA) and echogenicity in specific peripheral nerve segments49. 
Experimental Approach: To address this objective, inter-rater variability will be assessed 
using the intraclass correlation coefficient (ICC) for various peripheral nerve ultrasound 
variables evaluated by three physical therapists who have received recent training in the 
technique. The variables to be analysed will include the cross-sectional area (CSA) and 
echogenicity of peripheral nerves, the latter of which will be evaluated using histogram 
analysis in ImageJ software. 
Expected Results: We expect to observe sufficient inter-rater agreement in the peripheral 
nerve ultrasound measurements performed by physical therapists in the critical care unit.
SO3: To assess the inter-rater variability of the MRC-SS and FSS-ICU scales, and to 
correlate their results with findings from muscle and peripheral nerve ultrasound. 
Rationale: The Medical Research Council Sum Score (MRC-SS) is the most commonly used 
tool to assess muscle strength in cooperative critically ill patients and is employed to diagnose 
both critical illness myopathy and ICU-acquired weakness (ICU-AW)2. The Functional Status 
Score for the ICU (FSS-ICU) evaluates patients' physical functionality during ICU stay2. 
Although both scales have demonstrated good inter-rater reliability32,55,56, this reliability 
primarily refers to the measurement method and not to the evaluators themselves, 
underscoring the need to validate this aspect. Given that muscle mass loss begins within the 
first 10 days of critical illness and that severely ill patients are often unable to participate in 
scale-based evaluations due to impaired consciousness, quadriceps muscle ultrasound has 
been proposed as an early detection strategy for ICU-AW. Additionally, ultrasound findings 
indicative of muscle alterations—such as increased echogenicity—may correlate with poorer 
functional outcomes on the MRC-SS and FSS-ICU scales. 
Experimental Approach: To address this objective, inter-rater variability for the MRC-SS and 
FSS-ICU scales will be assessed using Kendall’s coefficient of concordance (W) among three 
physical therapists. The findings from these clinical scales will be correlated with muscle and 

 
 
nerve ultrasound parameters using Pearson or Spearman correlation coefficients, depending 
on the distribution of the variables. 
Expected Results: We expect to find sufficient inter-rater agreement in the MRC-SS and 
FSS-ICU scores evaluated by physical therapists in the critical care unit. Additionally, we 
anticipate that these clinical scores will correlate with ultrasound findings. 
General Methodology 
Study Design 
This is a quantitative, analytical, non-experimental, and cross-sectional study. 
Patients 
Inclusion criteria: Adult patients admitted to the Critical Care Unit who are able to provide 
informed consent and sign the corresponding consent form will be selected. 
Exclusion criteria: For ultrasound assessments, patients with a known allergy to ultrasound 
gel or a body mass index (BMI) ≥ 30 will be excluded. For the MRC-SS and FSS-ICU scale 
assessments, exclusion criteria include a history of malnutrition or cachexia, pre-existing 
neuromuscular disorders, coagulopathies (such as severe liver disease or continuous 
dialysis), thrombocytopenia <20,000/μL, lower limb amputations, lower limb fractures, ongoing 
chemotherapy, pregnancy, uncontrolled epileptic status, or prolonged corticosteroid use. 
All enrolled patients will undergo quadriceps and peripheral nerve ultrasound assessments, 
as well as evaluation using the MRC-SS and FSS-ICU scales. While the timing of these 
evaluations may vary, all assessments will be performed on the same day. Safety criteria will 
follow the expert consensus guidelines established by Hodgson et al. 57,  and include 
continuous monitoring of clinical parameters such as hemodynamic and respiratory variables.
Clinical Recruitment Site 
All patients will be recruited from the Adult ICU of Clínica INDISA. Each enrolled participant 
will have a clinical file in which all relevant clinical data will be recorded. All patient information 
will be kept strictly confidential. 

 
 
 
Sample Size Calculation 
The sample size was determined based on the intraclass correlation coefficient (ICC), which 
evaluates agreement between continuous quantitative variables and requires a larger sample 
size than Kendall’s W coefficient. These continuous variables include measurements obtained 
from quadriceps muscle ultrasound (cross-sectional area [CSA], muscle thickness, pennation 
angle) and peripheral nerve ultrasound (CSA and echogenicity). Assuming 80% power, a two-
sided alpha of 0.05, a 10% attrition rate, three raters, a minimum acceptable ICC of 0.6, and 
an expected ICC of 0.8—as reported in previous studies51,53, the required sample size is 37 
patients.
Evaluators 
The methodology involves the assessment of quadriceps muscle ultrasound and the MRC-SS 
and FSS-ICU scales by physical therapists working in the Critical Care Unit at Clínica INDISA. 
All evaluators either have experience or are currently undergoing training in these methods. 
Statistical Analysis 
To assess inter-rater reliability among physical therapists, ICC and Kendall’s W coefficient will 
be applied. Results will be visualized using Bland–Altman plots. A p-value <0.05 will be 
considered statistically significant. Correlation between the results of Objectives 1 and 2 with 
those of Objective 3 will also be assessed. Depending on the distribution of variables 
(analysed using the Shapiro–Wilk test), Pearson or Spearman correlation coefficients will be 
used. All statistical analyses and graphics will be conducted using R Studio and Stata 
software. 
Ultrasound Procedures 
Quadriceps Muscle Ultrasound 
For the transverse measurement, patients will be placed in the supine position with the knee 
joint in a neutral resting position. A line will be drawn from the anterior superior iliac spine 
(ASIS) to the superior border of the patella, and the measurement site will be located at the 

 
 
junction between the middle and lower thirds of this line. At this site, the thickness of the 
anterior quadriceps compartment, rectus femoris (RF), and vastus intermedius (VI), as well as 
their cross-sectional areas (CSA), will be measured. Images will also be acquired for 
echogenicity analysis using ImageJ software. For longitudinal measurements, the probe will 
be positioned 5 cm lateral to the transverse measurement point to evaluate the pennation 
angle of the vastus lateralis fibers on the superficial aponeurosis of the vastus intermedius. All 
ultrasound examinations will be performed using a linear transducer (4–12 MHz) on a 
Sonosite™ system. 
Peripheral Nerve Ultrasound 
Peripheral nerve segments will be assessed using a standardized protocol at predefined 
anatomical sites. The ultrasound probe will be positioned perpendicular to the nerve path to 
minimize measurement error of CSA. Cross-sectional areas will be determined by manually 
tracing the nerve’s contour, including the epineurium. Echogenicity changes—indicative of 
neuropathy—will also be evaluated. Based on literature evidence regarding accessibility and 
changes seen in critical illness polyneuropathy (CIP), the following nerves will be evaluated: 
a) Median nerve: upper arm, cubital fossa (medial to the brachial artery), and mid-forearm 
b) Ulnar nerve: mid-arm (medial) and mid-forearm 
c) Fibular nerve: proximal popliteal fossa 
d) Tibial nerve: proximal popliteal fossa and ankle (near the flexor tendons at the medial 
malleolus) 
Ultrasound will be performed using a linear transducer (4–12 MHz) on a Sonosite™ system. 
 
 
Ethical Considerations 
Social Value 
ICU-acquired weakness (ICU-AW) is characterized by muscle atrophy and impaired 
contractility, conditions that contribute to increased mortality13–17, prolonged hospital stays 
8,9,23,25, longer durations of mechanical ventilation 9,24, higher healthcare-related costs 8,9,21,24,26 

 
 
and greater long-term physical disability 18,19. Given that muscle protein degradation and 
electrophysiological abnormalities occur within the first 10 days of ICU stay 42,43, early and 
timely rehabilitation is critical in critically ill patients. Therefore, the identification of diagnostic 
strategies is essential to enable early detection and the development of targeted 
pharmacological and non-pharmacological therapeutic interventions. Research into critical 
illness myopathy and neuropathy could ultimately benefit the broader population by informing 
public policies that support expanded physical therapy and rehabilitation programs in intensive 
care units across the country.  
Protection of Vulnerable Populations  
This study focuses on validating evaluations conducted by physical therapists and, as a pilot 
project, will include only patients who are cognitively able to provide informed consent. 
Therefore, it does not involve any inherently vulnerable populations. Moreover, the study is 
free from biases related to sex, race, or age. 
Adverse Events  
Ultrasound evaluation, which is a routine procedure in ICU settings 58, will be used in this study. 
Although rare, cases of contact dermatitis due to ultrasound gel have been reported 59–64. 
Accordingly, the skin at the site of ultrasound evaluation will be monitored after each session. 
Additionally, the exclusion criteria proposed in this study aim to minimize the likelihood of 
adverse events.  
Risk/Benefit Ratio  
The potential for significant risks is minimized by the defined exclusion criteria. Physical 
therapy assessments performed by kinesiologists in the ICU at Clínica INDISA are routine 
procedures carried out under strict safety criteria in accordance with current literature57.  
Obtaining additional neuromusculoskeletal assessment data on hospitalized ICU patients may 
enhance early detection of ICU-AW, allowing attending physicians to address this condition 
with an integrated and multidisciplinary approach. 
 
 

 
 
Privacy Protection  
All information collected will be securely stored by the principal investigator. Participant data 
will be recorded in an Excel spreadsheet, and results will be presented anonymously. No 
identifying information will be disclosed or shared with third parties. 
Ethical Oversight  
Any issues that arise during the study or any amendments to the protocol will be reported to 
the ethics committee. In accordance with Article 10 of Chilean Law No. 20.120, “Any serious 
adverse event that occurs during the study must be reported by the investigator to the Ethics 
Committee and the Director of the institution where the study is being conducted.” Feasibility 
This study has the full support of the Adult Critical Care Unit at Clínica INDISA, which will serve 
as the recruitment site from the second semester of 2024 through the end of 2025. No external 
funding is required for its implementation. 
 

 
 
References  
1. 
De Jonghe, B. Paresis Acquired in the Intensive Care Unit. A Prospective Multicenter 
Study. JAMA 288, 2859 (2002). 
2. 
Vanhorebeek, I., Latronico, N. & Van den Berghe, G. ICU-acquired weakness. Intensive 
Care Med 46, 637–653 (2020). 
3. 
Chen, J. & Huang, M. Intensive care unit-acquired weakness: Recent insights. Journal 
of Intensive Medicine 4, 73–80 (2024). 
4. 
Kress, J. P. & Hall, J. B. ICU-Acquired Weakness and Recovery from Critical Illness. 
New England Journal of Medicine 370, 1626–1635 (2014). 
5. 
Schefold, J. C. et al. Muscular weakness and muscle wasting in the critically ill. J 
Cachexia Sarcopenia Muscle 11, 1399–1412 (2020). 
6. 
Wang, W., Xu, C., Ma, X., Zhang, X. & Xie, P. Intensive Care Unit-Acquired Weakness: 
A Review of Recent Progress With a Look Toward the Future. Front Med (Lausanne) 7, 
(2020). 
7. 
Barreiro, E. Models of disuse muscle atrophy: therapeutic implications in critically ill 
patients. Ann Transl Med 6, 29–29 (2018). 
8. 
Fan, E. et al. An Official American Thoracic Society Clinical Practice Guideline: The 
Diagnosis of Intensive Care Unit–acquired Weakness in Adults. Am J Respir Crit Care 
Med 190, 1437–1446 (2014). 
9. 
Stevens, R. D. et al. A framework for diagnosing and classifying intensive care unit-
acquired weakness. Crit Care Med 37, S299–S308 (2009). 
10. 
Wilcox, S. R. Corticosteroids and neuromuscular blockers in development of critical 
illness neuromuscular abnormalities: A historical review. J Crit Care 37, 149–155 
(2017). 
11. 
Derde, S. et al. Muscle atrophy and preferential loss of myosin in prolonged critically ill 
patients*. Crit Care Med 40, 79–89 (2012). 
12. 
Stibler, H., Edström, L., Ahlbeck, K., Remahl, S. & Ansved, T. Electrophoretic 
determination of the myosin/actin ratio in the diagnosis of critical illness myopathy. 
Intensive Care Med 29, 1515–1527 (2003). 
13. 
Zhang, X.-M. et al. Sarcopenia as a predictor of mortality among the critically ill in an 
intensive care unit: a systematic review and meta-analysis. BMC Geriatr 21, 339 (2021). 
14. 
Yanagi, N. et al. Assessment of Sarcopenia in the Intensive Care Unit and 1-Year 
Mortality in Survivors of Critical Illness. Nutrients 13, 2726 (2021). 
15. 
Giani, M. et al. Low skeletal muscle index and myosteatosis as predictors of mortality 
in critically ill surgical patients. Nutrition 101, 111687 (2022). 
16. 
Hrdy, O. et al. Incidence of muscle wasting in the critically ill: a prospective 
observational cohort study. Sci Rep 13, 742 (2023). 
17. 
Mayer, K. P. et al. Acute skeletal muscle wasting and dysfunction predict physical 
disability at hospital discharge in patients with critical illness. Crit Care 24, 637 (2020). 
18. 
Rodriguez, B., Larsson, L. & Z’Graggen, W. J. Critical Illness Myopathy: Diagnostic 
Approach and Resulting Therapeutic Implications. Curr Treat Options Neurol 24, 173–
182 (2022). 

 
 
19. 
Vongchaiudomchoke, W., Sathitkarnmanee, B., Thanakiattiwibun, C., Jarungjitaree, S. 
& Chaiwat, O. The association between sarcopenia and functional outcomes after 
hospital discharge among critically ill surgical patients. Asian J Surg 45, 1408–1413 
(2022). 
20. 
Friedrich, O., Diermeier, S. & Larsson, L. Weak by the machines: muscle motor protein 
dysfunction - a side effect of intensive care unit treatment. Acta Physiologica 222, 
e12885 (2018). 
21. 
Kanova, M. & Kohout, P. Molecular Mechanisms Underlying Intensive Care Unit-
Acquired Weakness and Sarcopenia. Int J Mol Sci 23, 8396 (2022). 
22. 
Appleton, R. T., Kinsella, J. & Quasim, T. The incidence of intensive care unit-acquired 
weakness syndromes: A systematic review. J Intensive Care Soc 16, 126–136 (2015). 
23. 
Tortuyaux, R., Davion, J.-B. & Jourdain, M. Intensive care unit-acquired weakness: 
Questions the clinician should ask. Rev Neurol (Paris) 178, 84–92 (2022). 
24. 
Latronico, N. et al. The ICM research agenda on intensive care unit-acquired weakness. 
Intensive Care Med 43, 1270–1281 (2017). 
25. 
Nakanishi, N., Takashima, T. & Oto, J. Muscle atrophy in critically ill patients : a review 
of its cause, evaluation, and prevention. The Journal of Medical Investigation 67, 1–10 
(2020). 
26. 
Batt, J., Mathur, S. & Katzberg, H. D. Mechanism of ICU-acquired weakness: muscle 
contractility in critical illness. Intensive Care Med 43, 584–586 (2017). 
27. 
Sidiras, G. et al. Long term follow-up of quality of life and functional ability in patients 
with ICU acquired Weakness – A post hoc analysis. J Crit Care 53, 223–230 (2019). 
28. 
Castro-Ávila, A. C., Merino-Osorio, C., González-Seguel, F., Camus-Molina, A. & 
Leppe, J. Impact on Mental, Physical and Cognitive functioning of a Critical care sTay 
during the COVID-19 pandemic (IMPACCT COVID-19): protocol for a prospective, 
multicentre, mixed-methods cohort study. BMJ Open 11, e053610 (2021). 
29. 
Friedrich, O. et al. The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill. 
Physiol Rev 95, 1025–1109 (2015). 
30. 
Hermans, G. & Van den Berghe, G. Clinical review: intensive care unit acquired 
weakness. Crit Care 19, 274 (2015). 
31. 
Vanhorebeek, I., Latronico, N. & Van den Berghe, G. ICU-acquired weakness. Intensive 
Care Med 46, 637–653 (2020). 
32. 
Hough, C. L., Lieu, B. K. & Caldwell, E. S. Manual muscle strength testing of critically 
ill patients: feasibility and interobserver agreement. Crit Care 15, R43 (2011). 
33. 
Hermans, G. et al. Interobserver agreement of medical research council sum-score and 
handgrip strength in the intensive care unit. Muscle Nerve 45, 18–25 (2012). 
34. 
Connolly, B. A. et al. Clinical predictive value of manual muscle strength testing during 
critical illness: an observational cohort study. Crit Care 17, R229 (2013). 
35. 
Connolly, B. A. et al. Clinical predictive value of manual muscle strength testing during 
critical illness: an observational cohort study. Crit Care 17, R229 (2013). 
36. 
Stevens, R. D. et al. A framework for diagnosing and classifying intensive care unit-
acquired weakness. Crit Care Med 37, S299–S308 (2009). 

 
 
37. 
Latronico, N. & Bolton, C. F. Critical illness polyneuropathy and myopathy: a major 
cause of muscle weakness and paralysis. Lancet Neurol 10, 931–941 (2011). 
38. 
Lefaucheur, J.-P. Origin of ICU acquired paresis determined by direct muscle 
stimulation. J Neurol Neurosurg Psychiatry 77, 500–506 (2006). 
39. 
Formenti, P., Umbrello, M., Coppola, S., Froio, S. & Chiumello, D. Clinical review: 
peripheral muscular ultrasound in the ICU. Ann Intensive Care 9, 57 (2019). 
40. 
Paolo, F. et al. The possible predictive value of muscle ultrasound in the diagnosis of 
ICUAW in long-term critically ill patients. J Crit Care 71, 154104 (2022). 
41. 
Lad, H. et al. Intensive Care Unit-Acquired Weakness: Not Just Another Muscle 
Atrophying Condition. Int J Mol Sci 21, 7840 (2020). 
42. 
Puthucheary, Z. A. et al. Acute Skeletal Muscle Wasting in Critical Illness. JAMA 310, 
1591 (2013). 
43. 
Hickmann, C. E. et al. Impact of Very Early Physical Therapy During Septic Shock on 
Skeletal Muscle: A Randomized Controlled Trial. Crit Care Med 46, 1436–1443 (2018). 
44. 
Elkalawy, H., Sekhar, P. & Abosena, W. Early detection and assessment of intensive 
care unit-acquired weakness: a comprehensive review. Acute and Critical Care 38, 
409–424 (2023). 
45. 
Weber-Carstens, S. et al. Risk factors in critical illness myopathy during the early course 
of critical illness: a prospective observational study. Crit Care 14, R119 (2010). 
46. 
Weber-Carstens, S. et al. Critical Illness Myopathy and GLUT4. Am J Respir Crit Care 
Med 187, 387–396 (2013). 
47. 
Vijayan, D., Thomas, S. M. & Rajagopal, K. Association of SOFA Score with Severity of 
Muscle Wasting in Critically Ill Patients: A Prospective Observational Study. Indian 
Journal of Critical Care Medicine 27, 743–747 (2023). 
48. 
Beekman, R. & Visser, L. H. High-resolution sonography of the peripheral nervous 
system – a review of the literature. Eur J Neurol 11, 305–314 (2004). 
49. 
Gruber, L. et al. Differentiation of Critical Illness Myopathy and Critical Illness 
Neuropathy Using Nerve Ultrasonography. Journal of Clinical Neurophysiology 40, 
600–607 (2023). 
50. 
Grimm, A., Décard, B. F., Axer, H. & Fuhr, P. The Ultrasound pattern sum score – UPSS. 
A new method to differentiate acute and subacute neuropathies using ultrasound of the 
peripheral nerves. Clinical Neurophysiology 126, 2216–2225 (2015). 
51. 
Mittal, S., Hadda, V., Khilnani, G. C., Dhunguna, A. & Khan, M. A. Intra- and Inter-
Observer Reliability of Quadriceps Muscle Thickness Measured with Bedside 
Ultrasonography by Critical Care Physicians. Indian Journal of Critical Care Medicine 
21, 448–452 (2017). 
52. 
Di Matteo, A. et al. Reliability assessment of ultrasound muscle echogenicity in patients 
with rheumatic diseases: Results of a multicenter international web-based study. Front 
Med (Lausanne) 9, (2023). 
53. 
Pardo, E. et al. Reliability of ultrasound measurements of quadriceps muscle thickness 
in critically ill patients. BMC Anesthesiol 18, 205 (2018). 
54. 
Karapınar, M., Atilla Ayyıldız, V., Ünal, M. & Fırat, T. Ultrasound imaging of quadriceps 
muscle in patients with knee osteoarthritis: The test-retest and inter-rater reliability and 

 
 
concurrent validity of echo intensity measurement. Musculoskelet Sci Pract 56, 102453 
(2021). 
55. 
Turan, Z., Topaloglu, M. & Ozyemisci Taskiran, O. Medical Research Council-sumscore: 
a tool for evaluating muscle weakness in patients with post-intensive care syndrome. 
Crit Care 24, 562 (2020). 
56. 
González-Seguel, F. et al. Inter-observer reliability of trained physiotherapists on the 
Functional Status Score for the Intensive Care Unit Chilean-Spanish version. 
Physiother Theory Pract 38, 365–371 (2022). 
57. 
Hodgson, C. L. et al. Expert consensus and recommendations on safety criteria for 
active mobilization of mechanically ventilated critically ill adults. Crit Care 18, 658 
(2014). 
58. 
Messina, A. et al. Head to toe ultrasound: a narrative review of experts’ 
recommendations of methodological approaches. Journal of Anesthesia, Analgesia and 
Critical Care 2, 44 (2022). 
59. 
Chasset, F. et al. Contact dermatitis due to ultrasound gel: A case report and published 
work review. J Dermatol 43, 318–320 (2016). 
60. 
Cacciapuoti, S., Masarà, A., Fabbrocini, G. & Patruno, C. Contact Urticaria to 
Ultrasound Gel: A Case Report. Dermatitis 29, 93–93 (2018). 
61. 
Martínez Antón, M. D. et al. Two cases of allergic contact dermatitis to different 
elements in identical ultrasound gels. Contact Dermatitis 85, 477–478 (2021). 
62. 
Villa, A., Venegoni, M. & Tiso, B. Cases of contact dermatitis caused by 
ultrasonographic gel. Journal of Ultrasound in Medicine 17, 530–530 (1998). 
63. 
KESSLER, J., SCHAFHALTERZOPPOTH, I. & GRAY, A. Allergic Contact Dermatitis 
Caused by Ultrasonic Gel. Reg Anesth Pain Med 31, 480–481 (2006). 
64. 
Chasset, F. et al. Contact dermatitis due to ultrasound gel: A case report and published 
work review. J Dermatol 43, 318–320 (2016).