Early detection and assessment of intensive care unit-acquired weakness: a comprehensive review

Hanan Elkalawy; Pavan Sekhar; Wael Abosena

doi:10.4266/acc.2023.00703

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Review Article Surgery Early detection and assessment of intensive care unit-acquired weakness: a comprehensive review: Hanan Elkalawy¹, Pavan Sekhar¹, Wael Abosena²; Acute and Critical Care 2023;38(4):409-424.
DOI: https://doi.org/10.4266/acc.2023.00703
Published online: November 30, 2023

¹Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Boston, MA, USA

²Department of Surgery, Faculty of Medicine, Tanta University, Gharbeya, Egypt

Corresponding author: Hanan Elkalawy Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA Tel: +1-832-375-0853, Fax: +1-617-636-8384, Email: hananelsaied33@gmail.com

• Received: May 14, 2023 • Revised: October 4, 2023 • Accepted: October 17, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
METHODS
EPIDEMIOLOGY
CLASSIFICATION
RISK FACTORS
PATHOPHYSIOLOGY
SHORT AND LONG‐TERM CONSEQUENCES
DETECTION OF ICU-AW
IMAGING
CONCLUSIONS
KEY MESSAGES
NOTES
Acknowledgments
References

Abstract

Intensive care unit-acquired weakness (ICU-AW) is a serious complication in critically ill patients. Therefore, timely and accurate diagnosis and monitoring of ICU-AW are crucial for effectively preventing its associated morbidity and mortality. This article provides a comprehensive review of ICU-AW, focusing on the different methods used for its diagnosis and monitoring. Additionally, it highlights the role of bedside ultrasound in muscle assessment and early detection of ICU-AW. Furthermore, the article explores potential strategies for preventing ICU-AW. Healthcare providers who manage critically ill patients utilize diagnostic approaches such as physical exams, imaging, and assessment tools to identify ICU-AW. However, each method has its own limitations. The diagnosis of ICU-AW needs improvement due to the lack of a consensus on the appropriate approach for its detection. Nevertheless, bedside ultrasound has proven to be the most reliable and cost-effective tool for muscle assessment in the ICU. Combining the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE) II score assessment, and ultrasound can be a convenient approach for the early detection of ICU-AW. This approach can facilitate timely intervention and prevent catastrophic consequences. However, further studies are needed to strengthen the evidence.
Keywords: computed tomography; critical illness; diagnosis; intensive care units; muscle weakness; ultrasound

INTRODUCTION

Skeletal muscle dysfunction is a common issue in intensive care units (ICUs), which can result from ICU admission or be the underlying cause. Muscle weakness and loss of function are common manifestations of this condition [1]. The history of this condition dates to Hippocrates, who described “spontaneous lassitude" and muscle atrophy in patients dying from infection and cancer [2]. Osler also observed weakness in critical illness early [3]. In 1977, a status asthmaticus patient who received greater doses of hydrocortisone and concurrent neuromuscular inhibition was reported to have developed myopathy [4]. Since then, Bolton and his colleagues have conducted significant research on ICU patients with polyneuropathy [5]. In the past 20 years, advances in post-ICU survival have led to a deeper understanding of frailty acquired in the ICU. Healthcare professionals, patients, and families are all aware of the severity of neuromuscular damage in the growing number of patients receiving post-ICU rehabilitation [6]. ICU-Acquired Weakness (ICU-AW) is defined as the weakness and inability to move against resistance in critically ill patients, manifesting as widespread and symmetrical weakness affecting both the extremities and the respiratory muscles following the onset of a severe medical condition, with no discernible underlying cause other than the critical illness itself along with Medical Research Council (MRC) sum score of less than 48/60 or Dominant-hand grip dynamometry scores of less than 11 kg (interquartile range [IQR], 10–40 kg) in males and less than 7 kg (IQR, 0–7.3 kg) in females [2,7]. Healthcare professionals need to know when to suspect ICU-AW, what risk factors to identify, how to diagnose it, what the prognosis is, and how to improve recovery to lower the prevalence of the disorder. [6].

METHODS

To ensure a thorough and reliable literature review, various steps were taken. Initially, an extensive search was conducted on peer-reviewed journals using a diverse set of keywords such as "bioimpedance," "computed tomography," "dual-energy X-ray absorptiometry," "intensive care unit-acquired weakness," "muscle assessment," and "ultrasound." The search was limited to peer-reviewed journals and excluded conference papers or reports. Two databases, namely PubMed and Google Scholar were used for the search. Additionally, the reference section of each identified article was examined to find more relevant articles. The search included articles published between 2000 and 2022.

EPIDEMIOLOGY

ICUs globally care for 13-20 million patients annually [8], with ICU-AW occurring in 25%–31% of medical and 57%–74% of surgical ICUs [9]. The Incidence varies by patient characteristics [10], and can develop rapidly, even within hours of admission or mechanical ventilation [11-13], ICU-AW can persist for years, especially in patients ventilated for over 4–7 days, and is common in elderly patients (up to 70%) [1,14].

CLASSIFICATION

ICU-AW can impact the entire neuromuscular system, causing critical illness polyneuropathy (CIP) in the peripheral nerves, critical illness myopathy (CIM) in the muscle, or critical illness neuromyopathy (CINMB), which is a combination of both. These conditions can result in symmetrical weakness and atrophy of the muscles, with CIP primarily affecting lower limbs. In contrast, CIM acts the proximal areas and can lead to respiratory muscle weakness, and descriptions of CINMB have been observed to be transient with flaccid areflexic weakness affecting all four limbs, facial and ocular muscles without sensory impairment, occurring 2 to 10 days after discontinuing non-depolarizing neuromuscular blocking agents [6,7,15]. However, muscle weakness, called ICU-AW, more frequently appears as a secondary problem while patients receive treatment for more serious illnesses. ICU-AW is clinically detectable in critically ill patients without a plausible explanation. These conditions could significantly impact long-term patient outcomes if not addressed [6].

RISK FACTORS

There are many risk factors (Figure 1), including that ICU-AW is strongly linked with continuous APACHE II scores ≥15. Additionally, corticosteroids, aminoglycosides, and neuromuscular blocking agents have been demonstrated to be significantly associated with ICU-AW [16]. Although there is no significant association between Sequential Organ Failure Assessment (SOFA) and ICU-AW, the SOFA score is >7, the first-week total SOFA score is >45, the duration of dysfunction in two organs, and neurologic failure appeared to be independent risk variables for ICU-AW in every single research [17]. Individuals with sepsis were more vulnerable to muscle weakness caused by sepsis-induced myopathy or axonal neuropathy [18]. Pro-inflammatory cytokines have been identified to control muscle mass, so it is important to control sepsis early [19]. It was concluded that no significant association existed between days of norepinephrine administration and ICU-AW [20]. But treatment with norepinephrine was found to be a substantial risk for developing ICU-AW in the single study on multivariable analysis [21]. Several other risk factors were presented, including the female sex, as women were more vulnerable than men, possibly because of their less muscle mass. In every study, hyperosmolarity, hyperglycemia, high lactate, and duration of mechanical ventilation and parenteral nutrition were associated with an increased risk of developing ICU-AW [16].

PATHOPHYSIOLOGY

ICU-AW pathogenesis still needs to be better understood. Two main factors contribute to this condition: decreased muscle mass and reduced muscle function. In critical illness, muscle mass loss occurs due to a reduction in protein production and an increase in protein degradation by the ubiquitin-proteasome system. This catabolic state is characterized by decreased anabolic hormone effect, increased catabolic hormones, and immobilization, all contributing to muscle wasting [17]. Structural muscle changes, such as inflammation or necrosis, substantial infiltration of muscle with adipose tissue, and fibrosis, are commonly observed in severely ill individuals [22]. Microcirculatory disturbances can also jeopardize oxygen supply and perfusion, leading to chronic membrane depolarization of terminal motor axons, neuronal damage, and axonal degeneration [23,24].

Bioenergetic failure caused by cellular damage worsened by inflammation, hyperglycemia, and free radical damage can compromise mitochondrial energy synthesis. Dysfunctional mitochondria generate reactive oxygen species and free radicals, leading to a macromolecular and organelle damage cycle [24]. Impaired autophagy activation during acute disease allows damage to accumulate to mitochondria and other cellular components, leading to degenerative alterations that impair muscle function [22,24-26]. The inactivation of sodium channels in neuronal and muscle cell membranes leads to reversible hypo- or inexcitability. Altered excitation-contraction coupling and intracellular calcium homeostasis contribute to reduced muscle contractility [24].

Recent research suggests that failure of coordinated repeated firing within motor neurons may occur early, involving the central nervous system. This failure may occur before the electrical breakdown of axons and nerve-muscle coupling [27]. Muscle inactivity during ICU stays leads to a rapid decline in protein synthesis and proteolysis in respiratory and limb muscles, indicating early disturbances in proteostasis (Figure 1). These effects are independent of muscle function or type, emphasizing the need for therapeutic interventions to prevent skeletal muscle wasting in critical care patients. Studies show that anabolic signaling and protein synthesis decrease rapidly while key proteolytic systems activate during ICU care [28].

SHORT AND LONG‐TERM CONSEQUENCES

ICU-AW can cause a variety of short- and long-term negative effects (Figure 1).

Short‐Term Consequences

A higher risk of ICU death has been independently linked to the onset and severity of ICU-AW, which has been linked to limb muscle loss. Although not conclusive, it has also been seen in diaphragm malfunction [29]. Additionally, it has been discovered that respiratory muscle and limb weakness are separate predictors of a protracted need for artificial ventilation [30]. Elevated extubation failure rates in medical patients were independently correlated with limb muscular weakness [31]. Reintubation was required in 50% of them after extubation failed; of them, 50% died in the ICU. Additionally, muscle weakness is linked to longer ICU and hospital stays and costs [29]. Furthermore, neuromuscular weakening has been cited as a major factor causing ICU-acquired swallowing difficulties, such as post-extubation dysphagia [32]. Effective coughing may be hampered by abdominal muscular weakness [15]. More patients were sent to rehabilitation facilities, and worse short-term results were linked to ICU-acquired frailty.

Long‐Term Consequences

The survivors of critical illnesses have a higher chance of dying later in life [26,33], which is exacerbated in patients suffering from ICU-acquired frailty. A lower compound muscle action potential on ICU day 8, regardless of clinical weakness identified by the MRC total score [34], and respiratory muscle weakness demonstrated by a low maximal inspiratory pressure field [35] was also independently associated with greater 1-year mortality. A 5-year survival rate is also linked to a low (MRC sum score of 48) at hospital discharge [36]. Five years following ICU admission, a diverse sample of patients with critical illness demonstrated decreased physical quality of life, significantly shortened 6-minute walking distance (6-MWD), and lower handgrip force [33]. A significant independent predictor for long-term weakness, various illnesses, and poor quality of life after ICU discharge appeared to be the development of weakness [37]. A myogenic origin of ICU-AW seemed to have a more favorable outcome in nearly full recovery than a neurogenic origin, which left 50 to 75% of patients with persisting weakness or even tetraparesis [29,38].

DETECTION OF ICU-AW

The consensus across various studies is that early identification of ICU-AW is important in its prevention. However, there is no precise designated day for such assessments. Based on consensus, patients who remain in the ICU beyond the 8th day from admission, referred to as "long-stay patients," undergo a systematic evaluation to assess awakening and cooperation. So, it is preferred that as soon as admission to ICU, we start with SOFA and APACHE screening accompanied by an ultrasound assessment in the first week is the most beneficial approach [11,39]. Early detection, diagnosis, and successful prevention are crucial measures to reduce ICU-AW incidence, given the absence of an effective treatment for this condition. The importance of timely identification and management of ICU-AW must be considered [40]. A cross-sectional survey study conducted in 2021 focused on assessing ICU-AW in some low-income countries; insufficient diagnosis and early identification of ICU-AW are common due to staff-related, patient-related, and management-related factors. Staff obstacles include limited understanding, lack of guidelines for high-risk patients, and low priority for ICU-AW. Patient-related barriers involve cognitive decline, inability to participate, unconsciousness, and excessive sedation. Management-related challenges are perceived as low priority and inadequate staffing for ICU-AW assessment. However, achieving a clinical diagnosis, performing appropriate testing, and maintaining clear communication with patients and ICU colleagues is crucial [14]. This study also found that the MRC scores (79%), Manual Muscle Tests scale (73%), and electrophysiological assessments (70%) were the top three preferred tools for assessing ICU-AW [14]. The most used voluntary methodology for evaluating ICU-AW is the 6-grade MRC sum score [2,15,41,42]. A score below 48 on the 6-grade MRC sum score indicates clinically evident muscle weakness. In contrast, a score below 36 suggests severe muscle weakness. However, it can be challenging to differentiate between higher scores [43]. Compared to the conventional 6-grade assessment, a modified 4-grade score demonstrated improved reliability in identifying ICU-AW. However, this approach still needs to undergo validation [44]. Hand-held dynamometry is commonly utilized to assess handgrip and quadriceps strength. However, concerns have been raised regarding its ability to provide a continuous quantitative measure [15,42,45]. Less commonly employed tools for assessing ICU-AW include the Scored Physical Function in Intensive Care Test, Functional Status Score for the ICU, and Chelsea critical care physical assessment tool. However, their use is less widespread [46]. The 6-MWD test is another assessment tool that measures patients' functional capacity and is utilized to evaluate their motor function [47]. Electrophysiological assessments are possible even when patients are unconscious and can distinguish between CIP and CIM. However, this approach is time-consuming, and expertise in this area may be limited.

Additionally, the significant co-occurrence of CIP and CIM can further complicate the differential diagnosis [41,48]. Direct muscle stimulation helps distinguish between CIP and CIM. Imaging techniques can measure muscle mass and quality, but the 4-compartment model is not practical in clinical settings. Clinicians must rely on accessible methods for assessing muscle mass and quality [49]. Numerous methods have been developed for identifying ICU-AW. However, in practical terms, the diagnosis relies primarily on clinical tests and electrophysiological studies after excluding underlying causes of neuromuscular disorders [29].

Dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), computed tomography (CT), and bioelectrical impedance analysis (BIA) are all methods to measure and quantify muscle size and quality [50]. MRIs and CTs are gold standards for evaluating muscle quality and quantity [50]. However, they are expensive, require extensive measurements, are not portable, and cannot assess larger individuals, along with radiation exposure [50]. DXA is a fast and simple method for measuring lean mass, which comprises both skeletal muscle mass and non-skeletal elements such as skin, connective tissue, and the fat-free portion of adipose tissue cells. However, DXA has some limitations, including high costs, exposure to radiation, limited equipment availability, and immobility of the patient [51,52]. BIA is an indirect method that uses electrical impedance to estimate muscle, lean, or fat-free mass. It involves running a low-level electrical current through the body and measuring the resistance, which is then used to calculate the amount of muscle present in the body. However, several variables, including the instrument itself, the electrodes, the operator, the participant, and the surrounding environment, can affect the precision and reliability of the measurements. Therefore, BIA measurements must be interpreted cautiously and in conjunction with other assessment methods to obtain more accurate muscle mass estimation [52-54].

IMAGING

Computed Tomography

CT analysis offers precise body composition data divided into lean and fat tissue depots. Unlike other techniques that only measure overall lean body mass, CT can provide more detailed information [55]. Single-slice scans can predict whole-body muscular and fat mass in healthy and cancer-bearing populations. Still, this association needs to be better understood in ICU patients and can vary from image to image [55]. An important bone landmark is the third lumbar vertebra for measuring skeletal muscle mass [56]. Skeletal muscle boundaries are identified based on Hounsfield units (HUs) and specialized software, including ImageJ and Slice-O-Matic, can be utilized to determine the muscle cross-sectional area (CSA) [57]. CSA indicates how much the tissue attenuates the X-ray beam during the scan. Attenuation of muscle, a measure of muscle density, is associated with lipid deposition in skeletal muscle. It acts as a proxy for muscle quality [55,58]. Both CSA and muscle attenuation have a strong prognostic value, with lower values linked to poorer outcomes. Analysts' variability is generally less than 2% [59].

CT scans can provide valuable information on body composition but have limitations. One of the main drawbacks is the high radiation exposure during prospective CT scans. Consequently, CT can only be used to measure body composition if a CT scan has been performed for a medical condition [60]. Additionally, the thickness of slices and patient placement are crucial variables to consider. A patient's position during the scan and the relaxation state of muscles in the L3 region can influence the number of slices in the L3 and CSAs during the scan [60]. Another concern is that HUs can be altered by various factors, even though they primarily represent tissue attenuation. While some researchers have used average CT HUs to assess muscle quality, the validity of this method is still being determined and requires further research with muscle biopsies [61].

Dual-Energy X-Ray Absorptiometry

DXA is an advanced method for assessing body fat, lean muscle mass, and bone mineral mass that relies on X-ray attenuation principles like those used in CT but with considerably lower radiation exposure [62-65]. A DXA scan is preferred over a CT scan because of its safety and ease of access [66]. However, DXA scans only pass the energy beam down one side of the body, resulting in a planar image. DXA imaging uses two separate energy spectra—a "high" and a "low" energy level—to detect attenuation [67]. By calculating the R_ST in which R value represents the ratio of photon attenuation of soft tissue which is defined as the ratio of soft tissue attenuation at two photon energies (e.g., 40 keV and 70 keV), it can be predicted what the percentage of body mass is composed of the percentage of body fat (%fat) [67].

Common technological limitations in DXA include issues related to patient location, as well as differences between devices and software [68]. Physical limitations include the patient's height and weight, their level of hydration, and the timing of the scan about daily activities such as meal timing, bathroom habits, and exercise [69-71]. While slight variations in hydration are generally not thought to affect body composition measurements, disease-related fluid accumulation such as ascites or oedema can impact the results [70-72]. Additionally, this procedure is highly costly [49].

Bioimpedance

Bioimpedance is a technique for estimating body composition involving devices that fall into three categories: single-frequency, multiple-frequency, and spectroscopy. All these devices work by applying a low-intensity alternating electric current via surface electrodes at one or more radio frequencies. This current helps to determine the body's conductive and non-conductive tissue and fluid components [52,73]. The rate of the applied current varies based on the body's composition, including total body water, fat-free mass, or fat mass. Tissues rich in water and electrolytes, such as blood and muscle, conduct the current well, while tissues with more fat, bone, and air-filled spaces conduct the current poorly [49].

Bioimpedance involves measuring the body's resistance and reactance to a weak electrical current at different radio frequencies, which depends on the body's composition. Reactance refers to how the current interacts with membrane surfaces, while resistance generally refers to the current's ability to travel through fluid and tissues like cell membranes [73]. Equations based on impedance measurements estimate fluid and other body composition compartments [52]. Bioimpedance measurements are useful for estimating metabolic activity and can be used therapeutically [74].

Bioimpedance, like DXA, is a reliable and convenient method for accumulating normative body composition data using single-frequency measurements. It can also measure nutrition-related markers beyond body composition, such as the 50-kHz phase angle, 200/5-kHz impedance ratio, and bioimpedance vector analysis [75]. Bioimpedance-generated estimates of body composition are subject to several assumptions that may not hold in a clinical setting, including fluid status, tissue hydration, and body geometry [76]. Obesity and fluid overload further complicate these methods' accuracy. Although BIS algorithms use different constants customized for each patient, they may still introduce errors. While improved algorithms can be applied in a research setting, applying them at the bedside presents significant challenges [49]. Currently, bioimpedance is the most convenient and precise tool for measuring body composition at the patient's bedside. However, notable variations between the different techniques need to be considered. Irrespective of the approach, standardized procedures are imperative when performing bioimpedance measurements. For investigations, it is recommended that only one technician use the same device and equation/algorithm [76].

Magnetic Resonance Imaging

MRI is a method for determining muscle CSA and volume that is non-invasive and free of radioactivity, and it provides excellent tissue differentiation capabilities. As a result, MRI is regarded as the standard for evaluating changes in muscle size. However, MRI imaging requires highly trained personnel and is limited by the cost of operations, availability and time-consuming post-acquisition processing [77].

Ultrasound

Clinical assessment is supplemented with volition and neurophysiology testing to diagnose ICU-AW. However, when patients receive mechanical ventilation, many are administered strong sedatives during the initial stages of critical illness. As a consequence, diagnosing ICU-AW may be delayed [78]. Ultrasound is a promising diagnostic tool for identifying individuals at risk of ICU-AW. It is a low-cost, non-invasive, widely available, and efficient imaging technique that can assess skeletal and respiratory muscles. The five main parameters used for ultrasound muscle assessment include muscle thickness, CSA, pennation angle, fascicle length, and echo intensity. Furthermore, researchers have identified four new potential parameters for ultrasound muscle assessment. These parameters include muscle volume, measuring muscle stiffness through elastography, evaluating the ability of a muscle to contract by comparing its CSA at rest and during maximal contraction, and assessing the microcirculation of a muscle [79].

Assessment of peripheral skeletal muscle

Research has shown that sarcopenia, which refers to the deterioration of muscle mass and strength with age, is more prominent in the lower limb muscles than in the upper limb muscles. Furthermore, there is a strong correlation between muscle strength and the CSA of the rectus femoris (RF) muscle. Studies conducted in ICU have shown that muscle mass can decrease rapidly, with a 10% decline in the RF' CSA within 7 days [80].

Assessment of respiratory muscles by ultrasound

Ultrasound technology has been used to assess respiratory muscles since Kai Haber et al., first utilized it to evaluate diaphragmatic motion in patients with intra-abdominal illnesses [81]. The diaphragm is the most significant respiratory muscle, accounting for almost 70% of total lung capacity [82]. Diaphragm excursion (DE) and diaphragm thickening fraction (TFdi) are the two most used ultrasonography markers for assessing diaphragm function. DE represents the distance the diaphragm extends from the end of expiration to the end of inspiration. TFdi represents the percentage by which the diaphragm thickens during inspiration. A healthy individual breathing deeply typically has a DE of 4.7–7.6 cm and a TFdi of 42%–78%. Although DE and TFdi are commonly considered indicators of extubation outcomes, their accuracy has been debated [83].

For successful extubation, compensatory action from the intercostal, sternocleidomastoid, abdominal muscles, and other accessory respiratory muscles is necessary when the diaphragm is not functioning properly. Thus, muscle ultrasonography to assess respiratory muscle weakness should include these additional muscles, particularly the parasternal intercostal muscles, which play an important role as supplementary inspiratory muscles. TFic, the thickening fraction of the parasternal intercostal muscle during inspiration, indicates respiratory muscle function when the diaphragm is ineffective [83].

The parasternal intercostal muscle's thickness at end-expiration is 3.3 mm in healthy males and 2.2 mm in healthy females, with a typical TFic of 3% [84]. In Dres et al.'s study [84], which examined the relationship between TFic and respiratory stress, diaphragm function, and spontaneous breathing trial (SBT) outcomes, patients with lower levels of pressure support, diaphragm dysfunction, or SBT failure exhibited greater TFic than healthy individuals. Mechanically ventilated patients' TFic decreased with increasing pressure support, indicating a dose-response relationship between TFic and respiratory load. The predictive ability of TFdi >28.7% for extubation outcomes was comparable to that of TFic >9.5% in sensitivity and accuracy. While TFic and TFic/TFdi may not have significantly improved DE and TFdi as predictors of extubation outcomes, they provide healthcare providers with an alternative method and contribute to understanding the patient's balance between respiratory volume and capacity [83]. Evaluating the severity of respiratory problems can help determine when tracheostomies will be necessary and when mechanical ventilation will be weaned. If mechanical ventilation is prolonged or extubation fails, a tracheostomy may be required, while noninvasive mechanical ventilation and mechanically assisted coughing can help safely extubate patients with difficulty extubating [85]. Although ICU-AW complications are associated with higher mortality rates [86], longer ICU and hospital stays [87,88], and increased costs, it is often reversible within three weeks [89], though recovery may be incomplete [90,91], and prognosis may vary depending on the electrophysiological subtype, with CIP having a worse recovery prognosis compared to CIM [38,92]. The abdominal expiratory and lower limb muscles can also be evaluated by ultrasound to predict extubation outcomes in addition to the diaphragm and intercostals, especially for patients with suboptimal diaphragm or parasternal intercostal muscle function [93]. Muscle ultrasonography has yet to be extensively studied in diagnosing and predicting the prognosis of ICU-AW. Still, one study found that using ultrasound to measure the CSA of the RF and comparing it with frailty can effectively forecast the outcome of critically ill patients [94]. Another study observed that a larger CSA of the RF muscle on admission was associated with less muscle atrophy and fibre necrosis [95]. Additionally, the size of the quadriceps muscle as determined by ultrasound, has been linked with an increased risk of unplanned readmissions or mortality. Nevertheless, research has indicated that using ultrasound to measure muscle thickness (TH) for multiple muscles is not an accurate diagnostic tool [96]. According to a study in 2021 by Zhang et al. [39], changes in muscle ultrasound measurements using MRC criteria can effectively diagnose ICU-AW. The most effective cutoff ratios were a reduction of over 15% for muscle thickness (ΔTH day 10) and over 12% for CSA (ΔCSA day 10) in the lower extremity on the right side. As a result, muscle ultrasound can be considered a useful supplementary diagnostic tool for ICU-AW [39]. Although certain muscle parameter changes within 10 days effectively predict ICU-AW, SOFA and APACHE II scores during ICU admission are more advantageous in predicting ICU-AW occurrence. The latter scores are more time-efficient and easier to implement, with similar receiver operating characteristic-area under curve (ROC-AUC) scores compared to the changes in muscle parameters [97,98], even though muscle parameter changes over 10 days effectively predict ICU-AW, relying exclusively on them may not be necessary. At the same time, there are many validated predictors of ICU-AW; the SOFA and APACHE II scores can serve as indicators of multiple high-risk factors combined, making them more time-efficient and easier to implement. However, previous studies have shown that the SOFA and APACHE II scores alone are inadequate diagnostic tools [11,99]. Therefore, it is necessary to validate these findings further, considering the small sample size of the current study [39]. Table 1 shows the criteria for diagnosing ICU-AW from various imaging tests [100-107].

Preventive and Therapeutic Measures of ICU-AW

Unfortunately, there is still no cure for ICU-AW, while prevention has been successful when focusing on particular risk factors.

Avoiding Hyperglycemia

In two large trials, intensive insulin therapy with blood glucose levels below 110 mg/dl has been shown to reduce the risk of CIP and CIM, resulting in shorter periods of mechanical ventilation, shorter stays in the ICU, and a lower mortality rate over 180 days [20,108,109]. A study on Guillain-Barre syndrome also found blood glucose control to improve functional outcomes [6].

Avoiding Early Parenteral Nutrition

The optimal approach to nutritional management in the ICU, particularly in relation to early parenteral nutrition, is not fully comprehended. There is a recognized concern that using parenteral nutrition might have unfavorable consequences on ICU-AW risk, making enteral nutrition a more favorable choice [110]. Notably, it's intriguing to note that obesity offers some protection against ICU-AW risk. This safeguarding effect could likely be attributed to the presence of ketone bodies [111].

Amount of Calories

Even after adjusting for the severity of the illness, obtaining 80% of the recommended calories was related to lower mortality. However, significance needed to be recovered when accounting for the amount of proteins. This study shows that delivery of ≥80% of prescribed protein is associated with substantially reduced mortality, independently of energy intake. Furthermore, in the more severely injured or ill patients who stay in the ICU for 12 or more days, achieving ≥80% of prescribed protein also predicted a shorter time to discharge alive, an outcome that was independent of energy intake. The converse, that greater energy intake affected outcomes positively when adjusting for protein intake, could not be demonstrated. they could not see any beneficial association between greater energy intake and outcomes. Efforts to achieve >80% of the prescribed protein intake are warranted. However, further studies are needed to determine the optimal amount of protein that critically ill patients require to maximize their chances of survival and recovery [112]. Muscle atrophy and weakness have been linked to the caloric deficit caused by critical illness-related anorexia and gastrointestinal dysfunction [113].

Number of Proteins and Route of Nutrition

Early and complete enteral feeding is recommended to prevent muscle atrophy in critically ill patients, with parenteral supplementation as an option if necessary. Increasing protein supply in nutritional support is important to counter muscle protein depletion. Delaying the administration of parenteral nutrition beyond the first week may protect against ICU- AW, but the optimal timing for its introduction is uncertain [114-116].

Quality of Protein

It is advisable to consider the specific types of proteins or amino acids proven particularly advantageous in preserving muscle mass. A third or more of the proteins that make up muscle mass are branched-chain amino acids. Despite this, administering branched-chain amino acids has not improved the prognosis. The most extensively researched branched-chain amino acid is leucine. Research has linked its metabolites, alpha-isocaproate and beta-hydroxy-beta-methyl butyrate (HMB), to reduced protein catabolism under acute stress conditions and to ergogenic effects in muscle [117]. HMB has been demonstrated to minimize proteolysis and muscle damage, enhance lean mass and strength in young and older adults when accompanied by a physical exercise program [118-120], and prevent muscle loss associated with bed confinement in healthy participants [121]. Obesity is found to have a protective effect on the risk of ICU-AW, which may be due to the presence of ketone bodies [111].

Minimizing Sedation and Early Mobilization

Early movement and physical therapy can lower the risk of ICU-AW. At the same time, daily sedative infusion stoppage can shorten mechanical ventilation and ICU stay, indirectly reducing the risk of ICU-AW [122]. High-frequency physiotherapy in the ICU has been suggested to improve quality of life at 6 months. Early rehabilitation has been found to strengthen only short-term physical-related outcomes. There is low-quality evidence for a reduced likelihood of ICU-AW compared to standard treatment or no early rehabilitation [123]. The current ICU approach emphasizes early mobilization through exercises, but more clinical trials are needed while considering patient pain. One-third of ICU-AW patients die in the acute phase, another third regain mobility within 4 months, and many experience long-term sensory loss, atrophy, or focal weakness [124].

Neuromuscular Electrical Stimulation

The use of Neuromuscular electrical stimulation (NMES) as a substitute for mobilization has been suggested. Despite a few small randomized controlled trials (RCTs) being carried out on critically ill patients with NMES of varying frequency, intensity, and duration, with some encouraging results, a recent systematic review and meta-analysis concluded that there was no significant difference between standard care and NMES in terms of muscular strength or reliance on mechanical ventilation and intensive care [125].

Drugs

(1) Anabolic hormones: although anabolic hormones such as growth hormone, insulin like growth factor -1, and nandrolone can increase muscle mass, they do not qualify as first-line therapy due to complications. Their use may be restricted to chronic critically ill patients [126]. (2) Beta-blockers: these are effective but only for oral use (propranolol). Inotropic medications which emphasize muscular dysfunction rather than atrophy by boosting intracellular calcium flux, beta-adrenergic agonists (fenoterol, not albuterol) have beneficial inotropic effects. Additionally, individuals with chronic bronchitis (chronic obstructive pulmonary disease) who had mechanical ventilation with the infusion of dopamine reported positive outcomes (diaphragmatic perfusion and cardiac output). Levosimendan, a calcium sensitizer, increases neuromechanical effectiveness and reduces contraction fatigue. These treatments were all identified in a systematic assessment of initially promising pharmaceutical approaches as unsuitable for routine use [127].

(3) Inflammatory modulation: treatment with intravenous immunoglobulins (IVIg) was linked to a lower incidence of ICU-AW, according to a retrospective review [128]. A RCT was conducted to determine whether early treatment with IgM-enriched IVIg could reduce ICU-AW in patients with multi-organ failure. Still, the problem was prematurely stopped due to the interventions [129]. (4) Cytokines are produced less when NF-kB is inhibited. On the other hand, although toll-like receptor 4's proteolytic effects are known, using a blocker of these receptors (eritoran) did not help septic patients' prognoses. New perspectives have been opened with the identification of novel inflammatory mediators such as GFD-15 [130].

(5) Contradictory effects of corticosteroids include the fact that. In contrast, low dosages of methylprednisolone (5 mg/kg) increase diaphragmatic dysfunction. In comparison, large doses of the drug (30 mg/kg) seem to shield the diaphragm from the negative effects of mechanical ventilation [131]. (6) Mesenchymal stem cell therapy has been shown to restore mitochondrial function in satellite cells in a mouse model of sepsis [132].

CONCLUSIONS

ICU-AW is a common and potentially life-threatening complication in ICU patients which can be prevented through reducing sedation, insulin therapy, and early mobilization. Although multiple methods have been developed for the detection of ICU-AW, each method has its own advantages and limitations. The bedside ultrasound has proven to be the most reliable, safe, and cost-effective tool for muscle assessment and detection of ICU-AW. The combination of the SOFA score, Acute Physiology and Chronic Health Evaluation (APACHE) II score assessment, and Ultrasound can be a convenient approach for the early detection of ICU-AW. This approach can facilitate timely intervention and prevent the catastrophic consequences associated with ICU-AW. However, further studies are necessary to reinforce the evidence supporting this approach.

KEY MESSAGES

▪ Intensive care unit-acquired weakness (ICU-AW) is a common and potentially life-threatening complication in critically ill patients, and early detection is crucial for timely intervention.

▪ Bedside ultrasound is the most reliable and cost-effective tool for muscle assessment and detection of ICU-AW, and a combination of Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation II scores with ultrasound can be a convenient approach for early detection and monitoring of ICU-AW.

▪ As there is no treatment, prevention of ICU-AW is so important and can be achieved through early mobility, avoiding hyperglycemia, optimizing nutrition, and minimizing sedation.

NOTES

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

None.

AUTHOR CONTRIBUTIONS

Conceptualization: HE, WA. Methodology: HE, WA. Formal analysis: HE, WA. Data curation: HE, WA.

Visualization: HE, WA. Project administration: HE, WA. Writing–original draft: HE, WA. Writing–review & editing: all authors.

Acknowledgments

None.

Figure 1.

Pathophysiology, risk factors, and consequences of intensive care unit-acquired weakness (ICU-AW). ADLS: activity of daily livings; TNF: tumor necrosis factor; IL: interleukin.

a) Drugs: like vasoactive medication as B-Blockers (+), corticosteroids (±), neuromuscular blocking agents (–) combined with corticosteroids infused for more than 48 hours (+), certain antibiotics as clindamycin, erythromycin, quinolones, polymyxin, tetracycline and vancomycin which act on neuromuscular junction but not proven to be the sole cause for ICU-AW (±).

Table 1.

Criteria for diagnosing ICU-AW from various imaging tests

Different types of imaging	Diagnostic criteria
Computed tomography	Through measured Fat volume: the total volume ratio to provide the overall fat percentage as a surrogate for muscle atrophy. Fat volume was defined as the summated volume of pixels with attenuation coefficients between –50 and –250 Hounsfield units, the known attenuation range for fat [100].
Dual-energy X-ray absorptiometry	Percent fat mass increased, whereas the lean mass decreased for the whole body, trunk, and legs [101].
Bioimpedance	Bioimpedance equation was developed for fat-free mass and may produce substantial scaling errors when compared against total body water measures. Studies that focus on evaluating a bioimpedance method’s ability to measure changes in muscle volume or mass [102].
Magnetic resonance imaging	Extensive muscle atrophy, fatty infiltration (replacement of muscle with fat), and edema (fluid accumulation) within muscles show hyperintensity, which was more florid in the lower limbs and pelvic muscles. There is a lesser extent of involvement in the upper limbs, possibly due to a smaller volume of muscles in the upper extremity [103].
Ultrasound	• Decrease of muscle strength relates to muscle volume, the latter may be inferred from its CSA. Some authors tried to predict CSA directly from muscle thickness [104].
	• Change in muscle composition can be gathered by quantification of muscle echogenicity [105].
	• The angle of insertion of muscle fibers into the aponeurosis. This angle provides information about muscle strength, as the greater the pennation angle, the more the contractile material packed within a given volume and by inference, the higher is the muscle’s capacity to generate force. The loss of pennation angle seemed to have high diagnostic accuracy for ICU-AW and could be assessed before patients became able to perform volitional tests, allowing for earlier diagnosis. Even if these results are considered as an exploratory background for more focused studies, the monitoring of changes to muscle architecture may lead to timely detection and better quantification of muscle loss [106,107].

ICU-AW: intensive care unit-acquired weakness; CSA: cross-sectional area.

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