Low Skeletal Muscle Index and Myosteatosis as Predictors of Mortality in Critically Ill Surgical Patients

Low muscle mass and other specic body composition indexes, assessed by computed tomography (CT), are associated with adverse outcomes after elective surgery, such as an increased risk of postoperative complications and higher mortality. However, limited information is available about the role of these indexes on short- and long-term outcomes in surgical patients admitted to the intensive care unit (ICU). The aim of the study was to assess the association of body composition indexes with 90-days mortality in this specic patient cohort. We performed a retrospective study including adult surgical patients admitted to the ICU between 2014 and 2018 who underwent a CT scan at the time of admission. Total Muscle Area (TMA), Total Fat Area (TFA), Visceral fat area (VFA) and Intramuscular fat area (IMFA) were measured. Skeletal Muscle Index (TMA/m2), MyoSteatosis (IMFA/TMA), Sarcopenic Obesity (VFA/TMA) were then calculated. We analyzed the impact of these indexes on mortality. 204 patients were included. Overall 90-day mortality was 28%. Log rank test and cox multivariate analysis on 90-day mortality showed a signicant association of low SMI and myosteatosis with 90-days mortality. Myosteatosis was also signicantly associated with prolonged mechanical ventilation and increased ICU length of stay. (SAPS) II, Sequential Organ Failure Assessment (SOFA) score on ICU admission, clinical data (use of vasopressor, use of mechanical ventilation, diagnosis of abdominal urgency or type of complication after elective surgery), length of ICU and hospital stay, duration of mechanical ventilation, outcome (hospital discharge or death).


Introduction
In recent years, there has been a growing interest on the association between body composition and surgical outcomes. Speci c indexes assessed by computed tomography (CT) accurately identify subgroups of patients at risk of complications after major elective surgery [1][2][3][4][5].
Most of the prognostic scoring systems adopted in ICU [6] focus on disease severity at presentation, organ failures and comorbidities, whereas none of them include body composition parameters.
Sarcopenia -de ned as loss of skeletal muscle mass and function [7] -is a surrogate index of advanced age, frailty, and protein catabolism [7]. These conditions have shown to be valuable predictors of poor prognosis in critically ill patients [8,9]. A strong association between CT-assessed body composition and increased mortality in ICU trauma [10,11] and septic patients [12][13][14] has been also established.
Recent studies [15,16] reported a correlation between a single parameter of body composition (low skeletal muscle index) and decreased survival in surgical critically ill patients. Moreover, the results of a large multicenter trial [17] demonstrated that a low baseline phase angle (re ecting fat-free mass loss), measured by bioelectrical impedance analysis, was associated with higher 28-day mortality in a mixed population of ICU patients.
However, sparse literature exists on the association of other speci c body composition indexes (i.e. myosteatosis and sarcopenic obesity) and outcomes in this subset of ICU patients.
The aim of the present study was to investigate the association of body composition parameters, speci cally skeletal muscle index, myosteatosis and sarcopenic obesity, with 90-days mortality of patients admitted to the ICU after complicated abdominal surgery.

Patients and study design
We evaluated surgical patients admitted to a tertiary-level ICU between June 2014 and December 2018.
Inclusion criteria were the following: age ≥ 18 years; ICU admission after urgent abdominal surgery or reoperation for complicated elective major abdominal surgery (gastrointestinal, gynecologic or urologic procedures); patients who underwent an abdominal CT within 30 days before and 48 hours after the admission in intensive care. We excluded patients admitted to ICU following trauma, intraoperative medical complications (e.g. cardiac arrhythmia) or patients with planned ICU admission for monitoring after elective surgery.

Ethics statement
The study was reviewed and approved by the Institutional Review Board (Comitato Etico ASST Monza). Written informed consent was waived. Results are reported according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.

CT scan and Body Composition measurement
Body composition indexes were measured and calculated from the CT scan closest in time to the admission (from 72 hours before to 24h after the admission to the ICU). A multidetector CT scan was performed with 256-slice CT scanners (Brilliance iCT or iCT-elite, Philips Medical Systems, Eindhoven, Netherlands) and an unenhanced scan was acquired in every study protocol. The raw data were reconstructed with Hybrid-Iterative Reconstruction algorithm (iDose4), in order to obtain the same image quality between the two different CT scanners; subsequently, all the scans were transferred to an image workstation (Intellispace portal 8.0; Philips Medical Systems) to evaluate, select, anonymize and save the image for the analysis in DICOM format . The analysis was performed on the axial CT 5mm-image  through L3 with the open-source image analysis software ImageJ (developed by the National Institutes of Health; available from http://rsbweb.nih.gov/ij/download.html), which produces comparable results to other software for body composition analysis [18].
Two different radiologists, blinded to patient information and using the selected CT image, drew multiple regions of interests (ROI) in the outer and inner perimeter of abdominal muscles, and analyzed pixels with densities between -20 Houns eld units (HU) to +150 HU for muscles and with densities in the -190 HU to -30 HU range for fat-tissue. The radiologists then calculated total muscle area (TMA, which estimates the total muscle mass) [19], total fat area (TFA), visceral fat area (VFA) and intramuscular fat area (IMFA). Subcutaneous fat area (SFA) was obtained by subtracting VFA from TFA and intramuscular fat area (IMFA) was obtained subtracting VFA from the ROI of the outer abdominal muscle perimeter.
Body composition indexes were normalized for height in meters squared [1,18], and expressed as cm2/m2. We used TMA and VFA to calculate Skeletal Muscle Index (SMI=TMA/m2) and Sarcopenic Obesity (SO=VFA/TMA). We also determined the grade of MyoSteatosis through the intramuscular adipose tissue content (MS=IMFA/TMA) [20]. Tertiles were estimated for each index according to sex [21,22].

Data collection
The following parameters were retrieved from the medical records: demographics (age, sex, height, weight, and body mass index [BMI]), Charlson Comorbidity Index (CCI), Simpli ed Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score on ICU admission, clinical data (use of vasopressor, use of mechanical ventilation, diagnosis of abdominal urgency or type of complication after elective surgery), length of ICU and hospital stay, duration of mechanical ventilation, outcome (hospital discharge or death).

Study endpoints
The primary aim of the present study was to investigate the association of body composition parameters, speci cally skeletal muscle index, myosteatosis and sarcopenic obesity, with 90-day mortality.
Secondary aims included exploring the association of the same parameters with ICU, in-hospital and 1year mortality, mechanical ventilation days and ICU length of stay Statistical analysis Continuous variables were described as mean ± standard deviation or median [interquartile range] depending on their distribution, categorical variables as absolute (relative) frequency. The normality of distribution was assessed using the Shapiro-Wilk test.
Differences in 90-day mortality were tested using a non-parametric test for trend across tertiles of body composition indexes. If the trend was statistically signi cant, multiple pairwise comparisons among tertiles of indexes were explored using the Chi-square test.
The Kaplan Meier approach was applied to assess the unadjusted probability of survival at 90-days and 1-year follow up. Log-rank test was used to compare curves between 3 groups de ned by tertiles of body composition indexes. Mortality at 90-day follow up was then tested into a multivariate Cox-regression model using a stepwise selection approach (cut-off p <0.20 for selection at the univariate analysis).
The association of patient characteristics with outcomes was assessed with univariate logistic regression (for ICU, in-hospital and 1-year mortality) and linear regression (duration of mechanical ventilation and ICU length of stay) analyses. Variables with a p<0.20 were included into a multivariable logistic and linear regression model, respectively, using a stepwise selection approach.
To further explore the interaction of low skeletal muscle index and myosteatosis -we explored the role of combination of low/high levels of SMI with low/high levels of myosteatosis on 90-day hospital mortality. Patients with low or high SMI were de ned as the groups of patients with SMI level below or above the 50th percentile, respectively. Equally, patients with low or high myosteatosis were de ned as the groups of patients below or above the 50th percentile of myosteatosis, respectively. Furthermore, to evaluate the improvement in the discrimination performance of the multivariate Cox model on the primary end-point (i.e. 90 days mortality) when myosteatosis and skeletal muscle index are combined, we compared its Harrel's C-index to alternate Cox models where only one of the 2 indexes is included.

Results
During the study period 275 consecutive patients were admitted to ICU after urgent abdominal surgery or reoperation for complicated elective major abdominal surgery. Among them, 204 patients met the inclusion criteria and were included in the analysis. Table 1 shows the parameters of the study population at baseline and during the ICU stay. Median time from CT exam to ICU admission was 1 day (interquartile range 0-2 days), ranging from 30 days before to ICU admission to 2 days after ICU admission. Mean values for SMI, SO and MS were 37 ± 8 cm2/m2, 1.6 ± 0.9 and 0.25 ± 0.16 for females and 41 ± 10 cm2/m2, 1.9 ± 1.1 and 0.20 ± 0.11 for males, respectively.
Outcomes for the study population are shown in Table 2. One hundred and seventy-two patients (84%) were discharged alive from the ICU, whereas in-hospital and 90-day survival was 73% and 72%, respectively. 131 patients (64%) were alive at 1-year follow up. 1-year mortality, n (%) 73 (36) Figure 1 shows the association of single body composition indexes (strati ed by tertiles) and 90-day mortality. A lower total muscular area (panel A) was associated with a higher 90-day mortality. Figure 2 shows the association of composite body composition indexes and 90-day mortality. A low skeletal muscle index (SMI, Panel A) and a higher degree of myosteatosis (MS, Panel C) were associated with a higher 90-day mortality. Figure 3 displays the impact of skeletal muscle index (panel A) and myosteatosis (panel B) strati ed by tertiles over 90-day follow-up with a Kaplan-Meier survival curve. Log-rank test on population tertiles was signi cant for both parameters (p = 0.019 and p < 0.001, respectively). This nding was con rmed at the 1-year follow-up for both skeletal muscle index and myosteatosis (Log-rank p-value = 0.045 and < 0.001, respectively, see eFigure 1, Supplementary Material).
Besides the signi cant and independent predictive ability of some well-recognized risk factors (SAPS II and CCI) on 90-day mortality, the association of low skeletal muscle index and myosteatosis remained signi cant after adjusting for covariates (  The independent association of low SMI and high myosteatosis with the primary outcome was further con rmed by the analysis of combination of high or low SMI with high or low myosteatosis (i.e. 4 groups) with 90-day mortality and survival. The group with low SMI and high myosteatosis showed the highest rate of mortality (eFigure 2, Supplementary Material). This nding was con rmed by the Kaplan-Meier survival curves over 90-day follow-up (eFigure 3, Supplementary Material).
An overall description of the role of composite body composition indexes on ICU, in-hospital and 1-year outcome was adjusted for confounders and described in Table 4. Myosteatosis was independently associated with prolonged mechanical ventilation (Table 5) and ICU length of stay (Table 6).

Discussion
In the present study, we assessed the impact of body composition indexes on outcome of critically ill surgical patients admitted to ICU after urgent procedures. We found that low skeletal muscle index and high myosteatosis were independently associated with 90-day mortality. The prognostic value of these parameters was independent from other well-known risk indicators such as SAPS II score, SOFA score and pre-existing comorbid burden [23]. Moreover, myosteatosis was signi cantly associated with prolonged mechanical ventilation and increased ICU length of stay Improving the prognostic performance of predictors in critically ill surgical patients may help to enhance the value of care, as the above scores can help the clinicians to choose the right treatment for the right patient. Several outcome scoring systems [8] have been developed in critical care medicine. Most of the current outcome predictors (such as SAPS) rely on age, comorbidities, derangement of clinical parameters and laboratory tests. Other scores focus on the severity of the disease by assessing the number and degree of sequential organ failure (e.g. SOFA). None of these scores evaluate patient physical status and/or performance, as these can hardly be standardized. However, when evaluating a critical patient for possible ICU care, clinicians routinely assess patient frailty and resilience and include these variables into prognostication.
Unfavorable outcomes often occur in patients lacking the physiological reserve to survive major emergency procedures or postoperative complications, even when treated with best available care [24,25].
In surgical oncology, the assessment of preoperative body composition obtained by the morphologic analysis of CT scans has shown that low skeletal muscle index and other speci c indexes (i.e. SO and MS) are associated with unfavorable short-and long-term outcomes [1,2,20,26,27]. CT imaging is easily available because it is performed routinely before any scheduled major abdominal operation and before most urgent cases. Furthermore, due to its accuracy and reproducibility, CT is the reference technique [18] to appraise quantity and quality of body compartments.
Data showing a relationship between radiologically determined low skeletal muscle mass and short-and long-term mortality [28][29][30] in mixed ICU populations are not new. Several authors reported that low muscle mass may predict adverse outcomes in critically ill patients with blunt trauma [10,11], septic shock [12][13][14] or severe injury [31]. Less evidence is available for more speci c ICU cohorts, namely critically ill surgical patients. Rangel et al. [15] described an association between low skeletal muscle mass and mortality in elderly patients undergoing emergency abdominal surgery. Recently, reports from Eastern countries con rmed the association of low skeletal muscle mass with ICU mortality [18], di cult weaning from mechanical ventilation [32], and extubation failure in surgical patients with long-term mechanical ventilation [33]. Our ndings are consistent with the above results, and con rm low SMI as a key determinant for ICU, in-hospital, and 1-year survival, even though they are collected in a Western population, with documented differences in body architecture and component distribution, The originality of the present study lies in reporting the different impact of speci c body composition indexes on outcomes. Indeed, our data suggest that muscle degenerative morphologic features, such as myosteatosis, are signi cant determinants of 90-day mortality. We did not collect any parameter of physical performance or functional capacity tests, but the association of fat in ltration of the muscle and need for prolonged ventilation support suggests that CT-assessed muscle quality is a reliable surrogate of muscle function. The presence of adipose tissue in the muscle may induce the release of proin ammatory cytokines driving decreased protein synthesis, increased proteolysis, oxidative stress and other mitochondrial dysfunction eventually leading to impaired respiratory muscle performance [34].
Notably, while low SMI performed as an independent predictor of mortality at all time points, myosteatosis turned out to be a predictor of increased ICU length of stay and extended need for mechanical ventilation. Based on this nding, we might speculate that while the overall degree of muscle depletion (i.e. a low SMI) implies a reduction of muscle strength with an impact on patient outcome, the proportion of intramuscular fat (myosteatosis) drives an impairment of muscle endurance, as re ected by a prolonged duration of mechanical ventilation.
Our ndings do not support recent results of Ji et al. [14] who reported that sarcopenic obesity was the only determinant of short-term mortality in patients with abdominal sepsis. The relative proportion of muscle mass and visceral fat may represent a different risk factor according to ethnicity.
Another peculiarity of this study is that ICU, in-hospital, and 1-year mortality were associated with different risk variables. Speci cally, while low skeletal muscle index had a signi cant impact across all time-related mortality, age and SOFA were risk factors for ICU mortality, whereas SAPS and comorbidity burden for in-hospital and 1-year mortality. This implies that a multiparametric assessment of the risk is required to intercept different time-related outcome measures.
Last, our analysis showed that the including both skeletal muscle index and myosteatosis in the of the multivariate Cox model improved its discrimination performance on the primary end-point (i.e. 90 days mortality), highlighting the importance of these two indexes as predictors.
This study has some limitations. First, it is a single-center retrospective study, and the observed associations will need to be validated in prospective observational trials. Second, in some patients the preoperative CT scan was used for elective patients who experienced a complication, preceding ICU admission up to 30 days. We assumed that body composition in elective patients went through nonsigni cant changes during that period of time. However, this assumption cannot be con rmed, and thus represent a limitation of the present study. Third, being a retrospective data collection, some relevant risk factors could have been missed. Due to the retrospective nature of our study and on the smaller sample size -in comparison with the Phase Angle Project Study [17] we could not propose a score that integrated body composition indexes with already validated scores (such as SAPS and SOFA score). This would be an analysis of potential clinical relevance to further optimize the prediction of long-term outcomes in critically ill surgical patients. Fourth, no formal sample size calculation was performed. Fifth, as we measured body composition indexes with CT-scan, longitudinal changes in body parameters during the clinical course were not described. Currently, novel, alternative, non-invasive, and repeatable methods are emerging to estimate muscle mass easily, allowing to evaluate the extent of changes of muscle breakdown and turnover over time. Among those, muscle ultrasound [35], bioelectric impedance analysis [36] and urinary creatinine extraction [37] have been shown to be reliable tools to estimate skeletal muscle mass. These techniques may also allow to measure the effect of interventions on the management and prevention of sarcopenia in critically ill patients [38]. Last, our study was not designed to assess superiority of any body composition index over another.
In conclusion, the present results support the inclusion of speci c body composition indexes in the evaluation of surgical critically ill patients. The routine measurement of these parameters whenever a CT is performed before or after ICU admission may help to predict the risk of unfavorable outcome at ICU admission. Future prospective observational studies may help to better de ne the exact predictive value of the different body composition indexes on outcomes.

Declarations
Ethics approval and consent to participate The study protocol was reviewed by the institutional review board (Comitato Etico ASST Monza) and informed consent was waived. Figure 1 shows the association of single body composition indexes (strati ed by tertiles) and 90-day mortality. A lower total muscular area (panel A) was associated with a higher 90-day mortality. Figure 2 shows the association of composite body composition indexes and 90-day mortality. A low skeletal muscle index (SMI, Panel A) and a higher degree of myosteatosis (MS, Panel C) were associated with a higher 90-day mortality. Figure 3