Impact of sarcopenic obesity on 30-day mortality in critically ill patients with intra-abdominal sepsis

Accepted Manuscript Impact of sarcopenic obesity on 30-day mortality in critically ill patients with intra-abdominal sepsis

Yun Ji, Baoli Cheng, Zhipeng Xu, Hui Ye, Weina Lu, Xiaoqian Luo, Shuiqiao Fu, Xiangming Fang PII: DOI: Reference:

S0883-9441(17)31982-2 doi:10.1016/j.jcrc.2018.03.019 YJCRC 52888

To appear in: Please cite this article as: Yun Ji, Baoli Cheng, Zhipeng Xu, Hui Ye, Weina Lu, Xiaoqian Luo, Shuiqiao Fu, Xiangming Fang , Impact of sarcopenic obesity on 30-day mortality in critically ill patients with intra-abdominal sepsis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yjcrc(2017), doi:10.1016/j.jcrc.2018.03.019

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Title: Impact of sarcopenic obesity on 30-day mortality in critically ill patients with intra-abdominal sepsis Authors: a, b, 1

, Baoli Cheng

b, 1

, Zhipeng Xu b, Hui Ye b, Weina Lu a, Xiaoqian Luo a, Shuiqiao Fu a,

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Yun Ji

Surgical Intensive Care Unit, Department of General Surgery, the Second Affiliated Hospital, School

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a

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Xiangming Fang b

of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, China, 310009. Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University,

1

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79 QingChun Road, Hangzhou, China, 310003.

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b

Equal contributors.

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Corresponding Author:

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Xiangming Fang, Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, China, 310003. Tel: +8613857161019, E-mail:

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Funding:

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[email protected].

No financial support was provided for the study. Conflicts of interest:

The authors report no conflicts of interest.

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ABSTRACT Purpose: This study aimed to investigate the association between sarcopenic obesity and 30-day mortality in critically ill patients with intra-abdominal sepsis. Material and methods: We analyzed 236 surgical ICU patients with sepsis due to intra-abdominal

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infection who underwent urgent surgical intervention. Sarcopenia, visceral obesity and sarcopenic

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obesity were analyzed by computed tomography scans using the third lumbar vertebrae skeletal muscle

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index and visceral adipose tissue area, using previously reported cutoff values.

Results: The cohort was divided into 4 groups: 52 were diagnosed with sarcopenic obesity, 62 with

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sarcopenia only, 58 with visceral obesity only, and 64 with no sarcopenia or visceral obesity. 57 (24.2%)

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patients died within 30 days. The frequency of 30-day mortality differed significantly among the groups. Multivariate analysis showed that only sarcopenic obesity was associated with increased risk for 30-day

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mortality. Sarcopenic patients were older than non-sarcopenic patients. To address this limitation,

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subgroup analyses stratified by age showed that the risk of 30-day mortality increased significantly in sarcopenic patients, both in patients with age ≤70 years and in those with age ＞70 years.

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Conclusion: Sarcopenic obesity is an independent risk factor for 30-day mortality in critically ill patients

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with intra-abdominal sepsis.

Keywords: Body composition Computed tomography Critical illness Sarcopenia Visceral obesity

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1. Introduction Sepsis continues to be a common problem in clinical practice [1]. Despite advances in care, a recent systematic review suggests that sepsis may contribute to up to 5.3 million deaths worldwide per year [2]. Therefore, identifying which patients with sepsis are at high risk of adverse outcomes is a clinical priority.

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Two novel prognostic body composition parameters receiving attention in sepsis are sarcopenia (low

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skeletal muscle mass) and visceral obesity [3, 4]. Sarcopenia predicts higher hospital mortality [3].

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Similarly, visceral obesity predicts adverse outcome [4]. By using diagnostic imaging such as abdominal computed tomography (CT), muscle mass and fat mass can be quantified precisely to reveal sarcopenia

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and visceral obesity that would otherwise go undetected [5]. However, if there is an additional effect on

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outcome of these two prognostic parameters present at the same time, i.e. sarcopenic obesity [6], is unknown.

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Given that preoperative abdominal CT evaluation in patients with intra-abdominal sepsis is prevalent,

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opportunistic screening for sarcopenia, visceral obesity, and sarcopenic obesity can be applied in this patient group. Thus, we focused on patients with sepsis of intra-abdominal origin who underwent urgent

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surgical intervention and were treated in the intensive care unit (ICU). This study aimed to investigate

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the association between sarcopenic obesity and 30-day mortality in critically ill patients with intraabdominal sepsis.

2. Material and methods 2.1. Study design, setting, and participants This is a retrospective cohort study of patients admitted to a tertiary-level, surgical ICU of the Second Affiliated Hospital Zhejiang University College of Medicine, a large academic medical center, between 3

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August 1, 2012, and July 31, 2016. We enrolled patients aged 18 years or older with severe sepsis or septic shock due to intra-abdominal infection who underwent urgent surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) before ICU admission. Severe sepsis and septic shock were defined following the criteria of the American College of Chest

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Physicians/Society of Critical Care Medicine [7]. Patients without preoperative abdominal CT imaging

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or without adequate CT images were excluded. The institutional review board for the Second Affiliated

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Hospital Zhejiang University College of Medicine approved the study and provided a waiver of consent.

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2.2. Exposure variables

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The primary exposure variables were sarcopenia, visceral obesity, and sarcopenic obesity. For sarcopenia, we used previously reported skeletal muscle index thresholds of 40.8 cm 2/m2 for male and 34.9 cm2/m2

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for female [8], which are calculated from cross-sectional skeletal muscle area at the level of the third

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lumbar vertebra. These cutoff values were used because they were based on the characteristics of the Chinese population [8]. We chose skeletal muscle index to define sarcopenia because it has been widely

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accepted for use in research [9]. Visceral obesity was defined as a visceral adipose tissue area exceeding

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100 cm2 in both sexes [10]. This value is widely used as a cutoff value to define visceral obesity for Asian population [11,12]. Based on these thresholds, the cohort was split into four groups: those with no sarcopenia or visceral obesity (neither), those with visceral obesity only (VO), those with sarcopenia only (SR), and those with sarcopenic obesity (SO).

2.3. Imaging analysis CT images were retrieved from the institutional Picture Archiving and Communication System (PACS). 4

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CT image analysis using ImageJ version 1.51g software (National Institutes of Health, Bethesda, USA) [13] was performed as described previously [5,14]. Representative images used for analysis are shown in Figure 1. A single axial CT slice at the mid third lumbar vertebra level was selected and assessed for each patient. For sarcopenia, cross-sectional skeletal muscle area was measured using a Hounsfield unit

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threshold from −29 to 150. The cross-sectional skeletal muscle area measurements included the following

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muscles: the psoas, erector spinae, quadratus lumborum, transversus abdominis, internal and external

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obliques and rectus abdominis. Skeletal muscle index was calculated by normalizing the cross-sectional skeletal muscle area by height (m) squared and reported as cm2/m2. For visceral obesity, we measured

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the visceral adipose tissue area using a Hounsfield unit threshold from −190 to −30. The same researcher

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who conducted the image analysis (Y.J.) was blinded to clinical outcomes during the analysis period. The measurement of cross-sectional skeletal muscle and visceral adipose tissue area was performed two

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times for each image, at least 1 week apart. Intra-observer reproducibility was evaluated based on the

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two measurements by the same researcher (Y.J.) by calculating the intra-class correlation coefficient

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2.4. Covariates

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(ICC=0.99).

Demographic characteristics (age, sex, and body mass index [BMI]), Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score on ICU admission, and clinical data (use of vasopressor, use of mechanical ventilation, diagnosis of intraabdominal infection, type of surgical intervention, and pathogen type in peritoneal fluid culture) were obtained from patient medical records.

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2.5. Outcome measures The primary outcome measure was 30-day mortality after ICU admission. Secondary outcome measures included ICU and hospital lengths of stay, and hospital costs.

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2.6. Statistical analysis

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Data are expressed as median with interquartile range for continuous variables or number with percentage

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for categorical variables. The Kruskal-Wallis test was used for continuous variables, and the chi-square test was used for categorical variables. Kaplan-Meier curves were used to evaluate 30-day mortality.

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Testing for differences in mortality between groups was by the log-rank test. Cox proportional hazards

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regression analyses was used to examine covariate-adjusted associations between body composition parameters and 30-day mortality. Variables with known clinical influence or exhibiting significant

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associations after univariate analyses were included in the multivariate analysis. Diagnosis of intra-

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abdominal infection, type of surgical intervention, and pathogen type in peritoneal fluid culture were dichotomized into perforated hollow viscus vs all other diagnosis, open surgery vs other surgical

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intervention, mixed organism vs all other pathogen types, respectively, for inclusion in the models.

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Statistical analyses were performed using SPSS for Windows version 24.0 (SPSS, Chicago, IL, USA). A P value of < 0.05 was considered statistically significant.

3. Results Between August 1, 2012, and July 31, 2016, 287 patients aged 18 years and older with intra-abdominal sepsis admitted to the surgical ICU of the Second Affiliated Hospital Zhejiang University College of Medicine who had urgent surgical intervention. A total of 51 patients (17.8%) were excluded (33 [64.7%] 6

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because of no preoperative abdominal CT images, 12 [23.5%] because of missing data, and 6 [11.8%] because of low-quality CT images). Among the 236 patients included in this study, 172 (72.9%) had at least 1 prognostic body composition parameter (i.e. VO, SR, or SO), including 64 (27.1%) in the neither group, 58 (24.6%) in the VO group, 62 (26.3%) in the SR group, and 52 (22.0%) in the SO group. Figure

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2 shows the flow diagram of patient enrolment and exclusion. The demographics and baseline

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characteristics are shown in Table 1.

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In the study cohort, 57 (24.2%) died within 30 days. The frequency of 30-day mortality differed significantly among the groups (Table 2). Pairwise comparisons revealed significant differences between

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the neither group and the SO group (5 death [7.8%] vs 23 [44.2%]; P＜0.001), between the neither group

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and the SR group (5 [7.8%] vs 18 [29.0%]; P=0.002), and between the VO group and the SO group (11 [19.0%] vs 23 [44.2%]; P=0.004). Crude Kaplan-Meier 30-day survival curves corroborated these

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differences (Figure 3; log-rank χ2=22.0; P＜0.001). Pairwise comparisons again revealed significant

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differences between the curve of the neither group and the curve of the SO group, between the curve of the neither group and the curve of the SR group, and between the curve of VO group and the curve of

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SO group. Further analysis adjusted for covariates of age, use of vasopressor, mixed organism and

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APACHE II score or SOFA score using Cox models. The adjusted regression analysis showed that sarcopenic obesity was the only body composition parameter independently associated with increased risk for 30-day mortality (Table 3). Comparisons among the 4 groups over 3 secondary outcomes are listed in Table 2. ICU lengths of stay differed significantly among the groups (P ＜ 0.001). Pairwise comparisons revealed significant differences only when comparing the group without sarcopenia or visceral obesity (3 days [2-5]) with any of the remaining 3 groups (SO: 6 [3-14], P＜0.001; SR: 5 [3-10], P=0.002; VO: 5 [2-10], P=0.013). 7

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Hospital costs also differed significantly among the groups (P=0.034). Pairwise comparisons revealed significant differences only between the group without sarcopenia or visceral obesity and the VO group (12 thousands US $ [6-18] vs 20 [9-30], P = 0.041). Hospital lengths of stay did not differ among the groups.

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In addition to the above analysis based on 4 groups, patients were also divided into two groups using

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the cutoff values described above: sarcopenic patients (n = 114)/non-sarcopenic patients (n = 122);

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visceral obese patients (n = 110)/non-visceral obese patients (n = 126). The adjusted regression analysis showed that sarcopenia was significantly associated with increased risk for 30-day mortality

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(Supplemental Table 1). Another adjusted regression analysis showed that visceral obesity was

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borderline significantly associated with increased risk for 30-day mortality (Supplemental Table 1). Age is similar between visceral obese patients and non-visceral obese patients, nevertheless, age is

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significantly higher in sarcopenic patients than non-sarcopenic patients (p ＜0.001). To address this

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limitation, we conducted subgroup analyses stratified by age. In subgroup analyses, the risk of 30-day mortality still increased significantly in sarcopenic patients, both in patients with age ≤70 years (hazard

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ratio [HR] 2.5; 95% confidence interval [CI] 1.1-5.7; P = 0.035) and in those with age ＞70 years (HR

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2.8; 95% CI 1.1-7.3; P = 0.031).

4. Discussion

In this study, we found that sarcopenic obesity was the only independent risk factor for 30-day mortality in critically ill patients with intra-abdominal sepsis. To our knowledge, this is the first study to demonstrate this relationship in critically ill patients with intra-abdominal sepsis. The findings suggest that sarcopenic obesity assessment should become part of the risk stratification in critically ill patients 8

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with intra-abdominal sepsis. Sarcopenia and visceral obesity are considered as the multifactorial syndromes with various overlapping causes and feedback mechanisms supposed to be strongly interconnect and aggravate each other [6, 15]. Loss of skeletal muscle induces a decline in basal metabolic rate [16], and reduce total

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energy expenditure, which might lead to visceral obesity [17]. On the other hand, increased visceral

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adiposity secretes more pro-inflammatory cytokines and induces chronic inflammation, which can

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contribute to the development and progression of sarcopenia [18]. Sarcopenia and visceral obesity may act synergistically thus maximizing their health threatening effects [11, 19]. For example, Lim et al [11]

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found in a community-based elderly cohort an OR of 2.64 for metabolic syndrome for subjects with pure

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sarcopenia compared with healthy peers, an OR of 5.51 for subjects with pure visceral obesity, but an OR of 8.28 for sarcopenic obesity.

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Up to now, only a small amount of studies has examined the effect of sarcopenia or visceral obesity

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on the outcomes of critically ill patients [20-22]. For sarcopenia, a recent study by Moisey et al. [20] in 149 injured elderly ICU patients found that sarcopenia is an independent predictor of ventilator-free days,

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ICU-free days, and mortality. Another recent study by Mueller et.al [21] in 102 surgical ICU patients

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showed that sarcopenia predicts adverse discharge disposition equally well as frailty. For visceral obesity, Shashaty et al [22] found that visceral obesity to be an independent predictor of acute kidney injury in 327 critically injured trauma patients. It is worth noting that in these studies, some patients with sarcopenia or visceral obesity may be sarcopenic-obese, but the number of sarcopenic-obese patients is unknown. In this study, critically ill intra-abdominal septic patients were classified into one of four body composition categories according to the presence or absence of sarcopenia or visceral obesity. This study’s results showed that only sarcopenic obesity was associated with increased risk for 30-day 9

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mortality. Therefore, it is vital to assess both visceral adipose tissue and muscle areas at the same time in terms of prognostication. In the present study, the BMI values in the SO and VO group are seemingly low (SO: 23 kg/m2; VO: 26 kg/m2). However, the values are similar to that reported by Kobayashi et. al [23] in Asian populations.

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In their study of the impact of sarcopenic obesity on outcomes in patients undergoing hepatectomy for

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hepatocellular carcinoma, Kobayashi et. al [23] reported the BMI values in SO group and VO group were

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22.5 kg/m2 and 25.6 kg/m2, respectively. They also reported that BMI did not identify more than half of the patients with excess visceral adipose tissue in their study [23]. In addition, other studies have shown

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that for the similar BMI values, Asians have a prominent visceral obesity compared to Caucasians [24,

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25]. Therefore, the seemingly low BMI values in the SO and VO group in the present study may be partly due to the limitation of BMI in accurately measuring adiposity and partly due to the different body

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compositions in Asian individuals versus Caucasians.

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In the present study, sarcopenic patients were older than non-sarcopenic patients. Age may therefore be a confounder. Therefore, we included age as a covariate in all Cox regression models. More

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importantly, to address this limitation, we conducted subgroup analyses stratified by age (≤70 and ＞

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70 years) and observed results similar to the combined analysis. This study has several advantages. First, this cohort was not limited to elderly patients because sarcopenia or visceral obesity is not only a condition of the elderly [26]. Second, previous studies usually used BMI for the definition of obesity [27]. In this study, the visceral adipose tissue area was used to define visceral obesity, which has greater health consequence than peripheral obesity [28]. This study has several limitations. First, the retrospective nature of this study makes it impossible to establish a cause-effect relationship. Second, skeletal muscle quality was not considered in this study. 10

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Low skeletal muscle quality as assessed by CT-derived skeletal muscle density was reported to be associated with higher 6-month mortality in mechanically ventilated critically ill patients [29]. Third, larger multicenter studies would be needed to validate the present findings.

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5. Conclusion

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In conclusion, sarcopenic obesity is an independent risk factor for 30-day mortality in critically ill

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Funding: No financial support was provided for the study.

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patients with intra-abdominal sepsis.

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Conflicts of interest: The authors report no conflicts of interest.

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Figure Legends

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Fig. 1. This image shows computed tomography scans at the level of the third lumbar vertebra of four

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intra-abdominal septic patients. The red shadows show the skeletal muscle area and the white shadows in the abdominal cavity show visceral adipose tissue (VAT) area. Skeletal muscle index (SMI) = skeletal

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muscle area/ height2 (cm2/m2). (A) A man patient with no sarcopenia or visceral obesity (neither). SMI

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= 57.6 cm2/m2, VAT area = 51.3 cm2. (B) A man patient with visceral obesity only (VO). SMI = 49.7 cm2/m2, VAT area = 163.3 cm2. (C) A man patient with sarcopenia only (SR). SMI = 33.1 cm2/m2, VAT

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cm2.

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area = 53.5 cm2. (D) A man patient with sarcopenic obesity (SO). SMI = 32.0 cm2/m2, VAT area = 148.7

Fig. 2. Study participant flow diagram. Fig. 3. Kaplan-Meier survival estimates stratified by body composition parameters. Patients were divided into groups with no sarcopenia or visceral obesity (neither), with visceral obesity only (VO), with sarcopenia only (SR), and with sarcopenic obesity (SO), which were significantly different (log-rank χ2=22.0; P＜0.001).

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ACCEPTED MANUSCRIPT Table 1 Demographics and baseline characteristics NO. (%) No

sarcopenia

or

visceral obesity

Visceral obesity

Sarcopenia

Sarcopenic obesity (n

(n = 58)

(n = 62)

= 52)

(n = 64)

Age (years)

58 (44-69)

66 (53-74)

76 (65-81)

75 (69-83)

Female

27 (42.2)

16 (27.6)

32 (51.6)

22 (42.3)

BMI (kg/m )

22 (20-24)

26 (24-28)

19 (18-21)

23 (21-25)

APACHE II score

13 (8-16)

13 (10-16)

14 (12-17)

15 (12-18)

SOFA score

5 (3-7)

5 (3-7)

5 (4-8)

6 (5-9)

Use of vasopressor

26 (40.6)

28 (48.3)

40 (64.5)

34 (65.4)

Use of mechanical ventilation

56 (87.5)

54 (93.1)

56 (90.3)

48 (92.3)

Complicated appendicitis

4 (6.3)

6 (10.3)

Complicated cholecystitis

4 (6.3)

5 (8.6)

Gastro-duodenal perforations

14 (21.9)

10 (17.2)

Small bowel perforation

15 (23.4)

10 (17.2)

Colonic or rectal perforation

7 (10.9)

Postsurgical peritonitis

7 (10.9)

Others

13 (20.3)

2 (3.1)

Percutaneous

3 (4.7)

Pathogen type in peritoneal fluid culture

7 (13.5)

3 (4.8)

11 (21.2)

12 (19.4)

7 (13.5)

22 (35.5)

9 (17.3)

10 (17.2)

13 (21.0)

8 (15.4)

5 (8.6)

2 (3.2)

4 (7.7)

12 (20.7)

6 (9.7)

6 (11.5)

49 (84.5)

55 (88.7)

50 (96.2)

3 (5.2)

2 (3.2)

2 (3.8)

6 (10.3)

5 (8.1)

0

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4 (6.5)

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Laparoscopic

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59 (92.2)

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Surgical intervention Open

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Diagnosis

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2

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Characteristic

3 (4.7)

10 (17.2)

3 (4.8)

5 (9.6)

Gram-negative alone

22 (34.4)

25 (43.1)

23 (37.1)

19 (36.5)

11 (17.2)

5 (8.6)

10 (16.1)

6 (11.5)

6 (9.4)

3 (5.2)

14 (22.6)

6 (11.5)

22 (34.4)

15 (25.9)

12 (19.4)

16 (30.8)

Others None

AC

Mixed organism

CE

Gram-positive alone

APACHE II indicates Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; SOFA, Sequential Organ Failure Assessment.

16

ACCEPTED MANUSCRIPT

Table 2 Primary and secondary outcome measures NO. (%) No sarcopenia or

Visceral obesity

Sarcopenia

Sarcopenic

visceral obesity

(n = 58)

(n = 62)

obesity (n = 52)

(n = 64) Outcome

P value 5 (7.8)

11 (19.0)

18 (29.0)

23 (44.2)

＜0.001

ICU LOS (days)

3 (2-5)

5 (2-10)

5 (3-10)

6 (3-14)

＜0.001

Hospital LOS (days)

17 (11-29)

23 (16-43)

19 (12-30)

20 (11-29)

0.139

Hospital costs (US $ in thousands) a

12 (6-18)

20 (9-30)

13 (7-22)

15 (10-29)

0.034

RI SC

ICU indicates intensive care unit; LOS, lengths of stay.

CE

PT E

D

MA

NU

Data available in 224 patients.

AC

a

PT

30-day mortality

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ACCEPTED MANUSCRIPT

Table 3 Unadjusted and adjusted analyses for 30-day mortality Model 1a

Unadjusted

Model 2b

Body composition parameter P value

HR (95% CI)

P value

HR (95% CI)

P value

No sarcopenia or visceral obesity

1 [Reference]

NA

1 [Reference]

NA

1 [Reference]

NA

Visceral obesity only

2.5 (0.9-7.3)

0.084

2.2 (0.7-6.4)

0.155

2.0 (0.7-6.0)

0.210

Sarcopenia only

4.0 (1.5-10.9)

0.006

2.7 (0.9-7.5)

0.065

2.3 (0.8-6.6)

0.129

Sarcopenic obesity

6.8 (2.6-17.8)

＜0.001

4.6 (1.7-12.8)

0.003

4.2 (1.5-11.6)

0.007

RI

PT

HR (95% CI)

Adjusted by age, use of vasopressor, mixed organism, and Acute Physiology and Chronic Health Evaluation II score.

b

Adjusted by age, use of vasopressor, mixed organism, and Sequential Organ Failure Assessment score.

AC

CE

PT E

D

MA

NU

SC

a

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ACCEPTED MANUSCRIPT

Highlights Sarcopenic obesity has attracted much attention. We investigate the association between sarcopenic obesity and 30-day mortality in critically ill patients with intra-abdominal sepsis. Sarcopenic obesity is

AC

CE

PT E

D

MA

NU

SC

RI

PT

an independent risk factor for 30-day mortality in critically ill patients with intra-abdominal sepsis.

19

Figure 1

Figure 2

Figure 3