The risk factors identified were scattered across various systematic reviews, none of which comprehensively covered all the risk factors or employed a definitive categorization. In this context, categorizing the risk factors as modifiable and nonmodifiable is based on established definitions in the literature, as highlighted in a narrative review by experts in ICUAW [3]. This categorization not only enhances the analysis but also amplifies the clinical utility of the findings. Distinguishing between factors that clinicians can modify and those that are immutable allows for more targeted and effective patient management in the ICU.

Of the nonmodifiable factors, age, female biological sex, and MOF, which were included in most of the reviews, were consistently associated with a higher risk of developing ICUAW. Advanced age may be related to decreased physiological reserve and increased vulnerability to complications [40, 41]. However, the review by Rooij et al. concluded that the risk of loss of functionality during an ICU stay is not solely dependent on advanced age but is also influenced by the patient's prior state, both cognitively and functionally [37]. One study focused on skeletal muscle metabolism in the context of ICUAW detected sex-specific differences in muscle strength, insulin sensitivity, muscle metabolites, protein degradation pathways, and the cross-sectional area of myocytes. These findings complement the analysis showing that females may be at a disadvantage in the context of ICUAW [42]. MOF, indicating more severe and prolonged illness, was identified as a risk factor for ICUAW in others reviews too [2, 3, 43]. Although MV, disease severity upon ICU admission, and sepsis were the most studied factors, they showed greater heterogeneity in the meta-analyses. This may be due to the diverse pathologies and the severity and type of illness, each with different recovery times, in patients admitted to the ICU [44].

The ICU length of stay, infectious diseases, and the presence of comorbidities may be associated with ICUAW, but these associations cannot be confirmed due to the high heterogeneity between primary studies in reviews, despite the meta-analysis showing an association. No meta-analyses were available for SIRS, neurological failure, shock, high lactate levels, hyperosmolarity, severe burns, or respiratory muscle dysfunction. Conclusions could not be drawn based on primary study descriptions only. However, the potential risk of high lactate levels cannot be overlooked. Lactate is the main metabolite of anaerobic glycolysis induced by hypoperfusion and tissue hypoxia. Hypoperfusion and hypoxia can cause muscle damage and mitochondrial dysfunction, contributing to the onset of ICUAW. Lactate can also act as an inflammatory and oxidative mediator that can contribute to ICUAW [45]. However, more specific studies are needed.

We identified a significant gap concerning the relationship between intrinsic and pre-existing characteristics of critically ill patients and ICUAW. Among these factors, high BMIs or obesity [46,47,48,49,50], prior frailty [40, 41, 51], comorbidities concurrent with the baseline condition or specific pathologies that triggered admission to the ICU including previous strokes, kidney dysfunction, decreased cardiac function, chronic pulmonary disease [44], cardiac surgery [52, 53], severe COVID-19 [54, 55], may play an important role as additional risk factors for ICUAW.

Of note, we did not find systematic reviews that specifically analyze the relationship between obesity and ICUAW. Whether obesity is a risk or protective factor is still under debate. An “obesity paradigm” has been proposed, hypothesizing that obese patients might be able to metabolize their excessive adipose reserves as a predominant energy source and preserve muscle mass during critical illness [56]. However, a study in critically ill patients suggests that obese and nonobese individuals experience muscle mass loss in a similar fashion [46]. Additionally, “sarcopenic obesity” has been proposed, in which fat accumulation and muscle mass loss mutually influence each other, resulting in muscles with excess fat [47]. Obesity also affects calcium signaling and proteins like adiponectin and actinin, influencing muscle contraction [48]. Furthermore, obesity may cause low-grade chronic inflammation, characterized by elevated levels of proinflammatory cytokines and adipokines during critical illness (i.e., an exacerbated inflammatory response in obese patients), which could increase the risk of muscular complications, including ICUAW. Zhao et al. [49] and Hogue et al. [50] investigated the relationship between mortality, MV, and hospital stay in critically ill obese patients but did not address functional outcomes. Both investigations showed that obesity did not increase mortality but did prolong MV, which may impact the incidence of ICUAW. Both reviews highlight the need for further research.

Frailty is a multidimensional syndrome characterized by a decrease in physiological and adaptive reserves, increasing vulnerability to adverse events. Frailty may be an important risk factor for the development of ICUAW. Preliminary epidemiological data suggest a high prevalence of frailty among critically ill patients, which may increase due to the demographic transition of the population [51]. In a systematic review and meta-analysis, Muscedere et al. [41] showed that frailty at the time of ICU admission impacts in hospital and long-term mortality. Additionally, frail patients are less likely to be discharged to return to their homes. Although Muscedere et al. did not address outcomes associated with physical function, this review highlights the potential use of frailty as an independent prognostic predictor in critically ill patients. However, a current systematic review aimed at assessing the impact of age, frailty, and comorbidities on ICU outcomes concluded that these variables were not evaluated in RCTs [57].

Results concerning the association between modifiable factors and ICUAW were inconsistent, reflecting the complex interplay of various therapeutic interventions. Critical factors, including drug dosage, timing of administration, duration of drug usage, and specific pathology being treated, underscore the nuanced impact of these variables on patient outcomes [2, 58, 59].

All reviews concerning the use of aminoglycosides showed significant associations between ICUAW and aminoglycoside use, but half of the meta-analysis exhibited high heterogeneity. Aminoglycosides affect neuromuscular transmission and neurotoxicity and may be involved in the development of ICUAW. Despite the lack of evidence, experts recommend careful monitoring of aminoglycoside levels in the blood and appropriate dosing [2, 60].

Although the results for hyperglycemia were contradictory, glucose variability should be considered in the prevention and treatment of myopathies in critically ill patients [2, 61, 62]. Establishing standards for glycemic control (between 90 and 144 mg/dl) [60] and using intensive insulin therapy may reduce ICUAW [62].

Meta-analyses have produced conflicting results regarding the association between NMBAs and neuromuscular complications. Some studies suggest that NMBAs are not significantly associated with muscle weakness when used alone. However, concurrent use of NMBAs and corticosteroids may elevate the risk of muscle weakness [59]. It is noteworthy that the administration of neuromuscular blockers may affect muscle nerve excitability, potentially leading to muscle weakness in critically ill patients. This interaction with neuromuscular function could pose a risk factor for the development of ICUAW, particularly when combined with other factors such as the duration of mechanical ventilation and illness severity. It is critical to acknowledge that factors like the duration of NMBA infusion, specific patient demographics (e.g., septic patients with multiorgan dysfunction), and simultaneous corticosteroid use might modify the risk associated with NMBAs. Furthermore, some NMBA compounds may share structural similarities with steroids, possibly intensifying the risk of developing myopathies. In summary, while NMBAs may not independently constitute a risk factor for ICUAW in most cases, their use in conjunction with factors such as corticosteroids and extended infusion periods might contribute to neuromuscular complications in critically ill patients [58, 59, 63].

Corticosteroids are commonly used in intensive care units and have been linked to ICUAW, despite the lack of consistent results in meta-analyses [22, 23, 29, 39]. However, excessive administration of corticosteroids can cause muscle dysfunction and nerve damage, promote the breakdown of muscle proteins, and increase protein loss. They can also have side effects such as lipodystrophy, and their use may increase the absorption and turnover of fatty acids in adipose tissue, which is closely related to the onset of ICUAW [59, 60, 63,64,65].

In relation to RRT and acute kidney injury (AKI), a recent literature review highlights the pathophysiological mechanisms, such as protein degradation, inflammation, and metabolic pathway alterations, through which AKI and its treatment with RRT–AKI may contribute to muscle loss, suggesting a relationship with ICU-AW. Preclinical and clinical data indicate that both AKI and RRT–AKI could influence the development of ICU-AW [66].

Norepinephrine is used in the ICU as a vasoconstrictor and positive inotropic agent to manage shock and sepsis, thereby improving arterial perfusion and pressure. Only one systematic review addressed its use as a potential factor in the development of ICUAW. Primary studies indicate that norepinephrine is significantly associated with an increased risk of ICUAW, with a dose-dependent effect that increases risk with each cumulative dose. Therefore, it is recommended to limit norepinephrine exposure and shorten its administration in clinical practice to reduce the incidence of ICUAW [45, 67].

A single review has demonstrated an association between nutritional intake and ICUAW [35]. Malnutrition and nutritional imbalance may increase the risk of ICUAW. Interestingly, the timing of total parenteral nutrition (TPN) administration appears to influence risk; early TPN may increase the likelihood, while early caloric restriction and delayed TPN administration may mitigate it [3]. It is important to mention that recent research findings indicate that early mobilization combined with timely nutrition support significantly reduced the incidence of ICUAW compared to early mobilization alone or standard care [68].

The impact of other medical treatments, such as the use of Propofol [69] or prolonged use of extracorporeal membrane oxygenation ECMO [70], also may contribute to ICUAW and should be more investigated.

Strategic interventions and proactive monitoring for modifiable risk factors: effective management of modifiable risk factors such as hyperglycemia, neuromuscular blockade, corticosteroids, aminoglycosides, and nutritional support is crucial for minimizing ICUAW risks. Implementing systematic glycemic control strategies tailored to individual patient conditions and refining guidelines for neuromuscular blocking agents are essential to balance benefits against the risks of prolonged use. Additionally, precise protocols for the timing and dosage of aminoglycosides require frequent monitoring to prevent ICUAW while effectively treating underlying conditions. Early detection and consistent monitoring enable clinicians to tailor interventions that mitigate risks and improve outcomes, necessitating regular evaluation of drug dosages, treatment timing, and ongoing patient conditions to adjust treatment protocols effectively.

The early detection and consistent monitoring of modifiable risk factors are critical for preventing and managing ICUAW. This proactive approach enables clinicians to tailor interventions that mitigate risk and improve patient outcomes. Regular evaluation of variables such as drug dosages, treatment timing, and ongoing patient conditions is essential for adjusting treatment protocols and ensuring effective management of ICUAW.

In an effort to identify patients at risk of developing ICUAW, various predictive models have been developed [52, 60, 64, 65] A recent systematic review by Zhang et al. [63], identified 11 risk models for ICUAW. These models incorporate a variety of predictors based on the type of diseases of the participants, conceptual definitions, and diagnostic tools used. Additionally, some studies have incorporated more specific variables, such as electrodiagnostic tests and ultrasound of the quadriceps rectus femoris muscle (QRF).

The evaluation of these models shows that their values in the area under the receiver operating characteristic curve (ROC) range from 0.7 to 0.923, indicating a moderate to high discriminatory capacity between patients with and without ICUAW. However, it is noted that most of the models analyzed exhibit certain biases, such as lack of blinding, incomplete reporting, insufficient sample sizes, lack of external validation, and inadequate calibration of the models. Therefore, it is concluded that although some models prove effective in predicting ICUAW, it is crucial to address these deficiencies and conduct additional studies to validate and refine the accuracy of these predictive models before their widespread implementation in clinical settings.

Our findings suggest that predictive models for ICUAW should be flexible and incorporate both modifiable and nonmodifiable factors associated with the condition. It is vital to consider factors that have demonstrated a consistent association, such as age, female gender, and organ failure. Additionally, it is essential to account for factors that may not have a conclusive association due to heterogeneity found in systematic reviews or their absence, yet have a significant pathophysiological basis in the development of ICUAW as discussed in this text. Prominent among these factors are comorbidities such as obesity, frailty, high lactate levels, hyperglycemia, the use of NMBAs, corticosteroids, aminoglycosides, renal replacement therapy, norepinephrine, and nutritional intake.

The findings of this review are primarily based on individual reviews. Any biases, methodological errors, or limitations present in the original reviews could impact the conclusions. The associations identified in this study may be affected by the heterogeneity highlighted in the meta-analyses and the lack of meta-analyses for some factors. We only reported the extent of overlap among the meta-analyses and did not devise a strategy to resolve this aspect. Nevertheless, we generated the overlap analysis matrices and a map delineating the primary studies incorporated in each systematic review (Supplementary Material), which can be utilized for subsequent in-depth analyses.

It is important to note that this review highlighted factors described in selected systematic reviews, leading to limited discussion of other potential factors not addressed in those reviews. Many of these unaddressed factors are related to therapies performed in the ICU, whose causal relationships remain unclear. However, the discussion briefly mentions conclusions from primary studies and narrative reviews which emphasize their possible implications with ICUAW.

A comprehensive literature search was conducted using a sensitive approach to identify all relevant reviews related to ICUAW. Nevertheless, the search may be limited by the omission of other databases or publications in nonconventional languages (primarily Asian languages), which could result in the absence of relevant reviews.