Attenuating Muscle Mass Loss in Critical Illness: the Role of Nutrition and Exercise

Purpose of Review Impaired recovery following an intensive care unit (ICU) admission is thought related to muscle wasting. Nutrition and physical activity are considered potential avenues to attenuate muscle wasting. The aim of this review was to present evidence for these interventions in attenuating muscle loss or improving strength and function. Recent Findings Randomised controlled trials on the impact of nutrition or physical activity interventions in critically ill adult patients on muscle mass, strength or function are presented. No nutrition intervention has shown an effect on strength or function, and the effect on muscle mass is conflicting. RCTs on the effect of physical activity demonstrate conflicting results; yet, there is a signal for improved strength and function with higher levels of physical activity, particularly when commenced early. Summary Further research is needed to elucidate the impact of nutrition and physical activity on muscle mass, strength and function, particularly in combination.


Recovery from Critical Illness
Critically ill patients are the sickest in the hospital, requiring substantial medical intervention for organ support. It has been reported that 20-70% of critically ill patients have low muscle mass at baseline [1], and ICU survivorship is affected by acute and extensive muscle wasting, with up to 30% lost within the first week of an ICU admission [2••]. This muscle wasting has consequences for patient recovery, with functional disability observed in ICU survivors even five years after ICU discharge [3], leading to an increase in healthcare utilisation, delayed capacity to engage in the workforce and ultimately a loss of independence [4•, 5•]. The ability to prevent or reverse skeletal muscle loss in critically ill patients is considered paramount to recovery.

Reasons for Muscle Loss in ICU
The mechanisms behind the observed loss in muscle mass, strength and physical functioning are complex, likely This article is part of the Topical Collection on Nutrition, Exercise and Lifestyle multifactorial and still being elucidated [6]. Maintaining muscle mass is dependent on a tightly regulated equilibrium between muscle protein synthesis and muscle protein breakdown, an equilibrium that is impaired in critical illness [7]. Whilst studies of whole-body protein turnover in critical illness have shown an increase in whole-body protein synthesis when compared to healthy volunteers, this does not compensate for the higher rate of protein breakdown also observed [8•]. This catabolic state is the result of significant systemic changes, which occur at muscle, nerve, immune, metabolic and mitochondrial levels exacerbated by periods of immobility and nutrient deficits [6,9]. In addition, critically ill patients have been shown to experience anabolic resistance, with a blunted capacity to utilise dietary protein for muscle protein synthesis [10••], and extended periods of inactivity impact on the bioenergetic level, affecting the force production capability of muscles to recover [6,9].

Measuring Muscle Mass, Strength and Function in Critical Illness
The measurement of skeletal muscle mass, strength and function in critical illness is met with a number of logistical challenges. Assessment of strength and function within ICU is limited by the large proportion of critically ill patients that are unable to follow commands required for active participation as a result of being intubated and ventilated or factors like delirium or fatigue in awake patients. These measures are therefore more often conducted at a later stage of the ICU/hospital admission. Given lower muscle mass and poorer muscle quality (echogenicity) have been shown to correlate with reduced strength and function [6,11], muscle mass is frequently used as a surrogate measure that can be conducted at the bedside to measure the acute response to an intervention. Gold standard methodologies for measuring muscle mass such as dual-energy x-ray absorptiometry (DXA) or magnetic resonance imaging (MRI) are rarely feasible as patients are often too unstable to be transferred out of the ICU to undergo such measurements alongside the additional considerations of costs and radiation exposure [12]. Historically, measures of nutritional statuses, such as mid-arm muscle circumference and proved popular, though they are affected by fluid shifts in ICU [13]. More recently, the assessment of muscularity using measures of psoas muscle from computed tomography (CT) scans of the third lumbar region collected for clinical purposes have been used [14]. This technique is equally limited in application due to radiation, preventing its implementation into clinical practice. Furthermore, a range of bedside noninvasive clinical methods has been introduced into ICU to quantify muscle size including ultrasonography [15,16] and bio-electrical impedance [17].

Strategies to Attenuate Muscle Loss or Improve Strength or Function
Skeletal muscle is highly responsive to external stimuli such as nutrition and physical activity interventions [7]. In health, a number of nutritional strategies have been shown effective in stimulating muscle protein synthesis, including essential amino acids or their metabolites (such as leucine and HMB) [18] and higher protein doses [19]. Physical activity and dietary intake are modifiable factors associated with the risk of chronic morbidity and mortality in the general population and can positively impact on muscle mass [20,21]. Further gains in muscle mass and strength can be induced through structured exercise such as resistance training which is needed to 'load' the muscle and induce a training effect [9,22]. Accordingly, general physical activity guidelines recommend a minimum of 30 min moderate-intensity aerobic exercise on five days per week combined with at least two sessions of moderateintensity resistance training, particularly in the older and comorbid population [23]. Nutrition and physical activity in combination may also confer greater benefits for muscle mass, strength and function than either intervention in isolation. Participation in exercise without the availability of amino acids results in rates of muscle protein breakdown that exceed rates of muscle protein synthesis leading to muscle loss [24]. Furthermore, muscle protein synthesis following amino acid provision is greater when combined with exercise than in the rested state due to an increase in both the magnitude and duration of muscle protein synthesis [25].
As ICU survivorship has improved, attention has shifted to potential strategies to improve recovery for critically ill patients. These often focus on attenuating muscle mass loss in the acute phase of illness with the aim of improving strength and function at a later time point. Given this, there has been a paradigm shift towards prioritising both nutrition and exercise interventions as part of usual ICU care practices, as reflected within recent clinical guidelines [26••, 27-29, 30••]. Consequently, there has been an exponential increase in the number of studies conducted in this important area. In this review, we discuss how nutrition and physical activity interventions may be employed in critical illness to attenuate muscle mass loss and improve strength and physical function. For the purpose of this review, we have focused on interventions commencing within the ICU setting.

Nutrition and Physical Activity in Critical Illness
Defining Nutrition in the ICU Setting Critically ill patients are frequently unable to consume nutrients orally due to the need for tracheal intubation. Therefore, critical care nutrition guidelines recommend the provision of liquid nutrition via a feeding tube into the stomachtermed enteral nutrition (EN) [28,29]. Critical care nutrition is a relatively new field of research, with a shift over the last 10 years from small physiological studies to robust large clinical trials [31]. The delivery of adequate nutrition to critically ill patients is challenging, frequently limited by extended periods of fasting and barriers to delivery caused by insulin resistance and gastrointestinal dysfunction [32•, 33]. Given this, the evidence base for nutrition recommendations, particularly those on outcomes of muscle mass, strength and function, is limited.

Defining and Measuring Physical Activity and Exercise in the ICU Setting
Physical activity is defined as 'any bodily movement produced by skeletal muscles that results in energy expenditure' [34]. This encompasses all movement which may occur as part of leisure time, work or daily activities. Exercise is often used interchangeably with physical activity; however, it is important to note that exercise is a subset of physical activity [34]. Exercise is defined as 'planned, structured, a repetitive bodily movement where the purpose is to improve or maintain physical fitness' [34]. Physical activity and exercise can be quantified in terms of the FITT principles: frequency (i.e. how often), intensity (i.e. how hard), time (i.e. duration of individual session and overall programme length) and type of modality (i.e. cycle ergometry, functional mobility). The health benefits of regular participation in physical activity are well documented within the literature with guidelines existing for the general, older and chronic disease populations [35,36].
Metabolic equivalent of tasks (METs) is a simple way of expressing the energy cost or intensity of physical activity [35]. The resting metabolic state is defined as one MET and refers to the amount of oxygen consumed at rest. The intensity of physical activity can be defined as low (<3.0 METs), moderate (3-5.9 METs) and vigorous (>6 METs) [35]. Within the ICU setting, patients are profoundly inactive which is in part due to the impact of their severity of illness, physiological instability, sedation, delirium and concomitant ICU lifesaving treatments received [37]. External factors include ICU and hospital room designs that do not encourage awake patients to be mobile and a lack of physical therapists or nurses to perform mobilisation [38]. There is significant heterogeneity in the energy costs associated with physical activity in the ICU setting. Beach et al. demonstrated that some participants recorded high physical activity levels in terms of MET levels (measured using the Sensewear armband mini-fly motor sensor) even whilst sedated and not participating in rehabilitation activities. Most of these patients were septic, which can result in a hypermetabolic state and thus altered MET levels [39]. Black et al. assessed the oxygen costs associated with exercise interventions in mechanically ventilated ICU patients. There was significant variability in the oxygen costs of exercise between participants, which may have been influenced by factors such as the ability to actively contribute to exercise, and found that the recovery time for 25% of sessions was longer than the total exercise duration [40•]. Dysfunctional mitochondrial functioning and regeneration capacity/production of ATP which is necessary for muscle contraction has been recognised within the ICU population [9]. More work needs to be undertaken to understand the bioenergetic costs of different types of physical activity (both in bed and out of bed) and the interplay with altered/ dysfunctional mitochondrial functioning.

Nutrition for Attenuation of Muscle Mass, Strength and Function in Critical Illness
A total of 12 RCTs of nutrition interventions in critical illness, of which two were pilot RCTs, were identified that included an outcome of muscle mass, strength or function (Table 1). Of these, the majority were conducted in Australia (n = 5) or Europe (n = 4). The interventions tested were primarily a strategy to increase nutrition overall (including calorie and protein delivery) (n = 7), protein delivery alone (n = 3) or the addition of a nutritional compound (e.g. HMB; n = 2). Six of the identified studies used a parenteral component to achieve greater nutrition delivery, either parenteral nutrition or intravenous amino acids alone [42-44, 46, 50, 52]. Seven studies reported an outcome related to muscle mass (including CT or ultrasound-derived muscle thickness or cross-sectional area (CSA)) [45•, 46, 47, 48•, 49•, 50, 51•], three relating to strength (handgrip strength) [46,50,52] and six studies relating to function (including Barthel Index, 6-min walk test and SF-36 physical component summary score) [41-44, 50, 52].
In 119 patients, Ferrie et al. delivered augmented protein intravenously compared to standard care and reported an attenuation of ultrasound-derived muscle layer thickness at day 7 with the greater protein dose (control: 2.8±0.4 vs intervention: 3.2±0.4 cm; p < 0.0001). This difference, however, was not sustained to ICU discharge [46]. Similarly, Fetterplace et al. compared augmented calorie and protein delivery to standard care in 60 patients, reporting greater amelioration of ultrasound-derived quadriceps muscle layer thickness (QMLT) loss with the intervention (mean difference (95% CI) 0.22 (0.06-0.38) cm, p = 0.01) [47]. These results are conflicting with more recent investigations. In 2021, Dresen et al. reported no difference in ultrasound-derived QMLT from study inclusion to week 2 or 4 with a higher protein dose (1.8 vs 1.2 g/kg/day [45•]); however, this study recruited patients after an extended duration of ICU stay (day 13±2 of ICU admission), and hence, the window of intervention success may have passed by this point (given muscle loss occurs early) Reasons for these discrepancies in results are unclear but may be related to the timing of intervention (early versus late protein delivery) or the type of protein delivered (specific versus mixed amino acids).
No study of a nutrition intervention has been shown to be effective in improving any outcome of strength or function in critically ill patients.

Physical Activity for Attenuation of Muscle Mass, Strength and Function in Critical Illness
Exercise interventions have been shown to be safe and feasible within the ICU setting and fall into three main modalities: neuromuscular electrical stimulation (which involves artificial stimulation of the underling muscles with surface electrodes), assistive technology such as cycle ergometry (with/without additional muscle stimulation) and functional-based strengthening and mobility training. For the purposes of this review, we have focused our reporting on cycle ergometry and functional-based mobility interventions. Recent systematic reviews have demonstrated exercise commencing in the ICU (such as mobilisation functional-based exercises) improves physical functioning at hospital discharge and reduces ICU and hospital length of stay and may improve mobility status and reduce the incidence of ICU-related weakness, muscle strength and days alive [54••, 55, 56].
A total of 28 RCTs of cycling/functional mobility in critical illness, of which three were pilot RCTs, were identified that included an outcome of muscle mass, strength or function (Tables 2 and 3). Of these, 79% of the studies were from Europe (n = 8), Australia (n = 6) or North/South America (n = 8). There is significant heterogeneity in terms of the modalities, frequency, timing and intensity of programmes which make it challenging to compare. This is in addition to varying trial endpoints and many lacking follow-ups beyond hospital discharge.
Exercise can be considered a drug as it causes a range of beneficial effects for health, as do pharmacological interventions [85]. Drug trials adhere to rigorous testing processes to determine the minimum effective dose, with titration up to a maximum dose level beyond which the adverse effects of the drug outweigh the benefits. Exercise trials have traditionally not undergone the same scrutiny as drug trials. Currently, the exercise dose that a patient receives is poorly described and articulated within ICU trials. This is in part due to the lack of consistency in defining the 'dosage' of interventions and reporting of the actual versus planned intervention delivery. Recently within the stroke literature, a dose articulation framework has been developed to improve the rigour in exercise dosage reporting which is also applicable to the ICU setting

Timing and Duration of Intervention
It appears that the greatest benefit may be observed in trials commencing within the first 72 hours of ICU admission with trials demonstrating higher muscle strength, functional independence, higher level of mobility including distance able to be walked and earlier attainment of mobility milestones at hospital discharge (Table 3). It also appears that rehabilitation delivered less than 5 days per week may be less effective [55, 79••, 88]. The length of the ICU-based exercise programmes may be another confounder. Numerous trials have had a median of 3-7 sessions delivered (often over 7-10 days) which may be too short an intervention period to induce changes in muscle mass, strength and function.

Frequency/Intensity
Achievement of higher levels of mobility has been related to better physical recovery outcomes for ICU survivors [70, 79••, 87•, 89•]. Conflicting evidence exists with regards to the increasing frequency of sessions, with several studies demonstrating 2× sessions per day resulted in earlier attainment of mobility milestones and improved strength [66,68,69,73,84]. This contrasts with a recently published secondary analysis of a prospective study of 186 ICU patients which found that increasing the number of mobility sessions did not independently influence health status 6 months post-ICU admission. It is important to note that there was variability in the amount of active mobilisation sessions performed in ICU, with 19% of the cohort performing less than one session per week and just under half completing a mobility session every 1-3 days with less than 5% completing more than one session per day. More research is required to elucidate the prescription    %, percentage parameters in terms of intensity, frequency and duration which may result in the greatest long-term benefits for ICU patients [61, 89•]. Several trials have attempted to provide higher programme intensities but failed to implement these targets [59, 83•]. The discrepancy between planned and actual therapy delivery in these trials has occurred due to patient-and setting-related barriers (e.g. participant fatigue, sedation) [59, 83•] as well as logistic challenges with missed physiotherapy visits due to weekends, medical procedures and/or physiological instability [59, 83•]. It may be that the field has overestimated how much patients may be able to achieve in the early ICU period, as it is likely that the muscle fatigue threshold required for a training response is lower in critical illness, particularly in the context of impaired muscle/nerve functioning [54••]. More work needs to be undertaken to understand the impact of fatigue and to develop personalised approaches to prescribing exercise doses within the ICU population.

Exercise Mode
Functional-based movement is the most used exercise intervention within the ICU setting and often involves sitting, standing, walking and resistance-based exercises ( Table 3). The importance of goal-directed early mobility has been emphasised in recent trials in terms of interprofessional communication and optimising patient status (in terms of sedation, pain, delirium) to achieve a target mobility level [70, 79••].
Several studies have proven that mobility can improve strength and physical functioning and impact on other important outcomes such as delirium and length of stay. There has been growing interest in the last 10 years in non-volitional exercise interventions which may enable earlier targeted optimisation of muscle mass and strength due to the awareness of muscle wasting occurring early and rapidly and the delay until patients are alert and able to engage in functional-based exercises [90]. Electrical muscle stimulation which involves artificial stimulation of the muscle using transcutaneous electrodes placed over the skin is one promising modality [56]. There is conflicting evidence; however, some studies have demonstrated the preservation of muscle mass and strength within the ICU setting [91•, 92]. The optimal stimulation parameters and impact on long-term outcomes need to be determined as well as the patient subgroups who may be of most benefit. Cycle ergometry is another attractive intervention which can be utilised passively (without patient effort whilst in a coma) and actively with increasing resistance. Nutrition and Physical Activitya Combined Intervention?
As we understand that the combination of amino acid administration and exercise has a synergistic effect on stimulating muscle protein synthesis in health [24,25], we also need to understand the mutual benefit of combined interventions of nutrition and exercise which may augment gains in muscle mass, strength and physical functioning in critical illness.
Only two RCTs in critical illness have been published that explore the combination of nutrition and physical activity interventions on outcomes of muscle mass, strength or function (

Future Directions
As this research field advances, we will continue to see a greater focus on combined exercise and nutrition therapies, with a number of clinical trials registered on this topic [95]. The ICU population is a highly heterogeneous population in terms of admission diagnoses and comorbid health statuses. Pre-ICU health factors such as comorbidities, age, sex and baseline nutritional status are likely to impact the response to exercise and nutrition, as well as the post-ICU recovery trajectory [96]. Therefore, a personalised approach to nutrition and exercise delivery may be needed with the identification of subgroups who may respond to different therapies and dosage levels. Greater articulation of the planned intervention delivery and actual delivery against intervention reporting frameworks are required. The separation between intervention and usual care also needs to be clearly documented, particularly as usual care nutrition delivery and mobility practices continue to evolve. A wide range of outcome measures relating to muscle mass, strength and function are currently reported in RCTs of nutrition and physical activity interventions, restricting synthesis and interpretation of results. Core outcome sets have been published for long-term ICU recovery follow-up [97•, 98] and are being developed for physical rehabilitation [99] and nutrition fields [100], which need to be adopted in order to improve comparability across future trials.
Further work is also likely to focus on the post-ICU phase, on the premise that nutrition and physical activity interventions of a sustained duration, throughout the hospital admission, are likely to be required. Whilst observational data report suboptimal nutrition intake [101,102] and reduced physical activity [37,39,103] in ICU survivors, studies conducted throughout the hospital admission are lacking.

Conclusions
Overall, few studies have quantified the effect of a nutrition intervention on muscle mass, strength or function in critical illness, and both the intervention and the outcome technique used vary greatly, limiting interpretation. Few studies have quantified the role of nutrition on muscle mass, strength or function, with conflicting results, particularly in relation to the role of augmented protein dose on attenuation of muscle mass loss. The time at which physical activity interventions are commenced appears to be important, with the greatest benefit seen when intervening within the first 72 hours and ensuring a sufficient intensity of exercise. However, more work needs to be undertaken to articulate the exercise dose considerations and identify the responders who may benefit from different types of personalised approaches to optimising physical activity levels to preserve muscle mass and strength and optimising physical functioning.
Author Contribution All authors contributed to the study's conception and design; formal analysis and investigation were performed by Leeanne S Chapple and Selina M Parry; the original draft preparation was conducted by Lee-anne S Chapple and Selina M Parry; and review and editing of the manuscript was performed by Stefan J Schaller.
Funding Open Access funding enabled and organized by CAUL and its Member Institutions

Declarations
Conflict of Interest The authors declare no competing interests.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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