Clinical review: peripheral muscular ultrasound in the ICU

The cross-sectional area (CSA) is determined by the number and size of individual fibers within a muscle. It is comprised of two areas: anatomical (cross section of a muscle perpendicular to its longitudinal axis) and physiological (cross section of a muscle perpendicular to its fibers, generally at its largest diameter). The term ‘muscle architecture’ (parallel or pennate) refers to the physical arrangement of muscle fibers at the macroscopic level and determines the muscle’s mechanical function. In a parallel muscle, the two CSAs coincide, as the fibers are parallel to the longitudinal axis. In pennate muscles, both areas may be used to describe the contraction properties (Fig. 2). In fact, since muscle strength relates to muscle volume, the latter may be inferred from its CSA [30]. Because these measurements do not need muscle tension, they are often assessed instead of muscle strength tests [45], especially in non-cooperative patients. Muscle atrophy mainly affects fast fibers (type II) rather than a relatively equal loss of slow and fast fibers. This loss potentially results in a drop in physical activity levels, in the denervation/re-innervation process, and in reduced synthetic rates of muscle proteins. Thus, muscle bulk can be measured by the CSA, whose variation is dependent on age, gender, and muscle group [46].

Muscle thickness, the distance between two fasciae, is easily identifiable with ultrasound (Fig. 3). Its reliability has been previously reported in comparison with other imaging modalities as well as direct measurements on dissected cadavers [25, 47, 48], while its reproducibility has been defined as the highest in various muscles [26, 49, 50]. Since CSA is directly related to the loss of strength, some authors tried to predict CSA directly from muscle thickness. Although the two parameters significantly correlate [51], the prediction of CSA from muscles thickness has not been proven [26]. Thus, even if it has been shown that muscle loss of ICU patients could be monitored by thickness measurements [52], we suggest that other indexes reflecting muscle strength should be added to muscle thickness in order to improve precision.

Information about muscle composition can be gathered by quantification of muscle echogenicity [53]. The measure of the image grayscale reflect the muscle’s composition: increased echogenicity indicates more homogenous muscle [54]. Echointensity is calculated by performing grayscale analysis of image pixels. Briefly, all the pixels in a selected area of the muscle are categorized on a grayscale configuration using a standard histogram function widely available in many commercially available types of software for image editing (Fig. 4). Quantitative grayscale analysis has proven to be better than visual assessment alone of ultrasound images [37], but it is slightly more time consuming and requires the establishment of normal reference values. Ultrasonic echogenicity can be graded according to a score that classifies ultrasonic echogenicity semiquantitatively into four levels, with higher grades corresponding to increased severity of muscle impairment [55]. Graded echogenicity has been shown to correlate with muscle pathologic findings on biopsy [53]. As with other measures, echogenicity measurements are highly influenced by observer-dependent factors, such as the adjustment of the ultrasound probe. Additional, factors, such as hydration balance, might also have an impact.

As mentioned above, muscle architecture can be described by the pennation angle, i.e., the angle of insertion of muscle fibers into the aponeurosis (Fig. 5). 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 [56]. Moreover, pennation angle has been shown to be significantly correlated with the CSA [57]. Therefore, the angle of pennation is critical for determining force dynamics of muscle. Because pennation angle measurements are strongly influenced by adjustment of the ultrasound probe, some authors have expressed concerns regarding the observer dependency of this technique [58]. In particular, its reproducibility in muscles other than the quadriceps has been reported low [38]. Eventually, the fascicle length (FL) can be derived from pennation angle and muscle thickness, as described elsewhere [51] using the following formula: FL = TH/(sin PA), where TH is muscle thickness and PA the pennation angle. Muscles with larger pennation angles are thicker, as they have greater numbers of sarcomeres in parallel with the direction of the fascicle. It is possible that these parallel sarcomeres are lost first, causing loss of pennation angle as an indication of reduced thickness.

Lower limbs muscles are more subject to early atrophy than those of the upper limbs [32]. The quadriceps, the largest muscle group of the lower limb, is the one generally explored with ultrasound. The image obtained allows assessments of muscle thickness, area, and ultrasound pattern, information, which can monitor contraction patterns that characterize muscular physiology and pathology. In the following section, we will describe the evidence on the use of this technique in critically ill patients (Table 1). Our comprehensive bibliographic search strategy accessed the following databases: PubMed, CINAHL, Cochrane Library, Scopus, Web of Science, from their inception to the cutoff date of July 31, 2018. The following keywords were used, alone or combined with appropriate Boolean operators, to search these databases: “muscular,” “peripheral muscular,” “ultrasound,” “intensive care unit,” “critical care,” “critical illness,” “weakness.”

Many studies examining the association between muscle weakness and clinical outcome have reported how muscle weakness was an independent predictor of mortality [59], increased ventilator-dependent time [60] and prolonged ICU length of stay (LOS) [61]. In particular, a negative correlation has been shown between muscular thickness (in both upper and lower limbs) and ICU LOS [52, 62, 63]. Several studies that investigated alterations in anabolic and catabolic signaling have introduced the use of ultrasound for the detection of muscular characteristics with the aims to improve pathophysiological knowledge of strength and to aid early diagnosis. However, interpretation of such reports is difficult because of significant methodological variability (such as small sample sizes and the lack of standardization of imaging assessment). Moreover, we are currently unaware of how sex, age and presenting illness affect loss of muscle mass in the critically ill. In most studies reliability of the ultrasonic technique was not the primary targeted outcome, which helps explain the lack of methodological consistency and precision. Some studies reported assessments of quantitative ultrasound reliability for measures of muscle linear depth, only two for CSA, and only one for echogenicity. Puthucheary et al. [16] showed a correlation coefficient (R²) of 0.97 for measuring rectus femoris CSA between two blinded independent raters. Baldwin published two observational methodological studies evaluating the reliability of muscle linear depth of mid-upper arm, mid-forearm, and mid-thigh and reported intra-rater intra-class correlation coefficients ranging from 0.998-1.0 [64] and ≥ 0.976 [65]. Regarding the muscle thickness, Gruther et al. [52] reported a coefficient of variation on repeated anterior thigh mean linear depth measures of 0.25%, without assessing the intra- or inter-rater reliability. More recently, Hadda [31] showed an excellent intra-observer (> 0.997) and inter-observer (0.963) agreement among five evaluators measuring arm muscle thickness. Finally, Grimm [66] also assessed muscle echogenicity, showing good inter-rater (0.915) and intra-rater (0.972) coefficients.

Another issue that should be taken into account is that most of the studies of ICUAW have been performed under the assumption that abnormalities found by the authors are ICU-acquired; no study attempted to control for prehospital muscle function or overall functional status as a predictor of ICUAW [67]. In fact, the so-called age-related frailty syndrome is characterized by a the loss of muscle mass that seems to be encountered in up to 80% of elderly ICU patients even in the absence of ICUAW diagnosis [68]. This condition constitutes an important predictor of long-term mortality [69] and morbidity [68], but the impact of pre-existing frailty on ICUAW is still unknown.

Most published studies investigated the lower limb muscles for the reasons explained above. Relatively few studies have selected the upper arm as their principal zone of interest, and when doing so sometimes compared it with other regions. Among these, Reid [66] performed serial measurements of mid-upper arm thickness within the first 72 h of ICU stay, showing how it decreased in almost every one of the 50 patients enrolled, independently of positive or negative energy balance. With a similar purpose, Baldwing et al. [65] more recently performed serial measurements of the thickness of the anterior mid-upper arm, mid-forearm in 16 septic ICU patients compared with healthy subjects. As expected, septic patients were significantly weaker than control participants, with significant differences recorded in the thickness and thickness/free fatty mass (FFM) of all peripheral muscles. Such data suggest that by 2 weeks of ICU admission, muscles of different functionality may not be equally affected by a combination of insults that occur during critical illness. Finally, Turton et al. [32] investigated the elbow flexor compartment, the medial head of gastrocnemius and the vastus lateralis muscle at admission and after 10 days in 22 ICU mechanically ventilated patients. Interestingly, this study showed no changes to the size of the elbow flexor compartment, and loss of muscle mass occurred preferentially in the lower limb. These data help justify interrogating the lower limb, as it appears to be the peripheral muscle group predisposed to develop early disuse atrophy among in critically ill patients. Moreover, the Turton study was the first to investigate the role of pennation angle. Patients who had a larger pennation angle at the day of admission had greater percentage reductions of pennation angle as well as of muscle thickness.

Focusing largely on lower limb ultrasound investigations, most published studies considered the muscle layer thickness and the CSA parameters, whereas only a few papers assessed ultrasonic muscle echogenicity as the key parameter of interest. In this regard, Grimm et al. [66] found significant alterations in muscle echostructure in the early stage of sepsis compared with healthy controls. Since those patients were septic and had a positive fluid balance, it is difficult to clarify to what extent the observed change in muscle echogenicity was caused by edema rather than muscle wasting. However, as the authors pointed out, the significance of tissue edema in the assessment of muscle echogenicity may be overestimated, since tissue edema cannot alter the bone signal that is part of the echogenicity score. Moreover, since the muscle echostructure score increased during the first 2 weeks of care despite a concomitant decrease in fluid balance, a specific structural damage in muscle architecture has been assumed. Cartwright and colleagues [70] found similar observations in echostructure changes over 2 weeks in both the tibialis anterior and rectus femoris muscles. Interestingly, these changes were similar to those seen in other myopathic conditions and included a significant increase in mean grayscale value, indicating an increased muscle echogenicity, and a decrease in grayscale standard deviation, indicating that the muscle became more homogeneous [71]. The use of grayscale standard deviation to define muscle homogeneity is justified, considering that the standard deviation decreases as the pixels in the region of interest become more uniform. However, once again, it is difficult to define whether this pattern of change occurred because of muscle breakdown and loss of the normally well-organized muscle architecture or due to inflammation or fluid retention in the subcutaneous tissue and muscle. Since it is not clear if the ultrasonographic muscle changes correlate with strength, Parry et al. [72] addressed this topic and reported that muscle echogenicity scores increased in quadriceps muscle (both rectus femoris and intermedious vastus) by 12% and 25%. Such observations suggest deterioration in muscle quality and establish a strong association between function and echogenicity. Eventually, in a recent prospective, two-center, observational study comparisons were made between sequential histological samples and ultrasound assessment of rectus femoris echogenicity [66]. This interesting paper showed how muscle echogenicity changes were greater in patients who developed muscle necrosis than in those who did not (8.2% vs. − 15.0%). In a previous study [16], rectus femoris CSA and protein/DNA ratio were assessed over time, suggesting that all decreased over the first week. Hence, lower limb muscle wasting has suggested to occur as a consequence of both depressed muscle protein synthesis and an elevation in protein breakdown relative to protein synthesis, resulting in a net catabolic state. Unfortunately, muscle ultrasound significantly underestimated protein loss (as measured by the protein/DNA ratio), perhaps in part because of the presence of interstitial edema. Moving forward on CSA studies, there is only one paper that integrated the ultrasound values into a sarcopenia and frailty prediction model, showing how the rectus femoris CSA, adjusted for sex and integrated with nutrition, comorbidities, depression, and patient demographics data, was able to predict adverse discharge disposition in surgical ICU patients [33]. With similar purpose, looking at the risk of unscheduled readmission or death, Greening et al. [73] demonstrated how smaller quadriceps muscle size described by CSA in the acute care setting was an independent risk factor for subsequent unscheduled readmission. CSA has been also evaluated in selected critically ill populations—such as trauma and obesity—confirming the previous observations. In particular, a 3-week follow-up analysis of CSA and muscle diameter followed in ICU trauma patients showed how 100% of them experienced severe muscle mass loss. Approximately 45% of rectus femoris muscle mass was lost by day 20, together with a progressive increase in echogenicity score [34]. The muscle depth as a measure of muscle wasting was compared among obese, overweight and normal-weight patients using a muscle ultrasound technique [74]. Compared with a previous study that used a similar methodology, the muscle depth loss was comparable and not statistically different between the groups at each of the interrogated time points. Lastly, muscle thickness of different muscle groups was investigated in many studies, and the main results in the majority indicated that it was significantly reduced. Among these, as already mentioned, a 0.2–5.7% decrease/day has been described for the upper arm [66], and a similar percentage in the lower limb [36]. Interestingly, the progression of this reduction was not uniform among the different quadriceps muscles, with a 30% reduction in rectus femoris and vastus intermedius thickness and 14% reduction in vastus lateralis [56]. Palakshappa [35] described the relationship between rectus femoris CSA and quadriceps muscle thickness, with volitional measures of strength and function at 7 days after the admission in ICU in 29 patients with sepsis. The authors observed an expected decrease in both rectus femoris CSA and thickness (23.2% and 17.9%, respectively) but established only a moderate correlation with strength on day 7. Similarly, Puthucheary showed that thickness measurements significantly underestimate ICU muscle wasting compared with rectus femoris CSA [75].

Based on the current knowledge on this topic, we developed a methodological flowchart with the aim to diagnose ICUAW at an early stage and to optimize different patient-dependent factors, such as pharmacological strategies, muscular overloading or inactivity, and metabolic derangements (Fig. 6). Ideally, within the first 48 h after the admission to ICU, we suggest that a first muscular ultrasound assessment should be performed to paint a “baseline picture.” We also suggest confining the evaluation to the quadriceps muscle, and in particular to the rectus femoris. At the same time, volitional strength evaluation, using validated tools such as the Medical Research Council (MRC) scale [27, 43], should be performed as soon as cognitive impairment allows. The degree of possible cooperation should also be evaluated with validated scales for sedation, agitation level and delirium, such as the Richmond agitation sedation scale (RASS) and the confusion assessment method for the ICU (CAM-ICU) [76, 77]. In patients able to follow commands, manual muscle testing should be performed, with a score in the normal range confirming the absence of ICUAW. However, the necessary level of cooperation can reasonably be achieved on average only 8–10 days after ICU admission [72]. Impaired mental status or a low MRC score dictates the need for additional examination for ICUAW, with the aim of optimizing muscle load; in this case, serial reevaluations by muscular ultrasound may represent valuable tools. In this regard, reductions of 20% in muscle thickness, 10% of CSA, 5% of pennation angle and an increment in echointensity of at least 8% [66] seem reasonable indicators of ICUAW, even if the latter technique has not been standardized and no clear cutoff has yet been determined [72].