Muscle Mass Depletion Associated with Poor Outcome of Sepsis in the Emergency Department

Lee, Yoonje; Park, Hyun Kyung; Kim, Won Young; Kim, Myung Chun; Jung, Woong; Ko, Byuk Sung

doi:10.1159/000488994

Cited by 20 publications

(34 citation statements)

References 26 publications

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“…Low skeletal muscle mass is frequently seen in critically ill patients, and it has an adverse impact on clinical outcomes, including a higher mortality, a longer ventilator duration, increased hospital length-of-stay, and delirium (18)(19)(20)(21). Previous studies have mainly focused on the impact of low skeletal muscle mass on short-term outcomes of sepsis (5,6). In this study, 81.6% of patients with sepsis had low skeletal muscle mass at admission.…”

Section: Discussionmentioning

confidence: 75%

“…Many survivors are exposed to post-intensive care syndrome, such as intensive care unit (ICU)-acquired weakness and delirium, which leads to readmission and late-mortality (4). Notably, muscle wasting is seen in 50-100% of septic patients in ICU and has adverse impacts on clinical outcomes, including quality of life, as well as short-term and long-term prognosis (5,6). The mechanisms of muscle wasting in sepsis are complex and multifactorial (7).…”

Section: Introductionmentioning

confidence: 99%

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ICU rehabilitation is associated with reduced long-term mortality from sepsis in patients with low skeletal muscle mass: a case control study

Kim¹,

Huh²,

Kim³

et al. 2019

Ann. Transl. Med.

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Background: It is unclear whether intensive care unit (ICU)-rehabilitation reduces mortality from sepsis in low skeletal muscle mass. We evaluated whether the association of ICU-rehabilitation with mortality from sepsis differs between patients with and without low skeletal muscle mass. Methods: We retrospectively reviewed 516 patients with sepsis who were admitted to the ICU between June 2011 and August 2017. The skeletal muscle area at the level of the third lumbar vertebra was measured with CT on admission. Patients were divided into two groups (low skeletal muscle mass and non-low skeletal muscle mass), and clinical outcomes were compared in patients treated with ICU-rehabilitation and without ICU-rehabilitation within each subgroup. We used Cox regression to examine factors associated with 1-year mortality in each subgroup. Results: Low skeletal muscle mass was diagnosed in 421 (81.6%). ICU-rehabilitation was conducted to 51.1% low skeletal muscle mass patients and 54.7% non-low skeletal muscle mass patients. In the low skeletal muscle mass subgroup, in-hospital mortality (26.0% vs. 39.8%, P=0.003) and 6-month mortality (38.6% vs.51.5%, P=0.008) were lower in the ICU-rehabilitation group. However, there were no differences in the non-low skeletal muscle mass group. In the multivariate analysis, ICU-rehabilitation was independently associated with reduced 1-year mortality in low skeletal muscle mass patients (HR: 0.66, 95% CI: 0.49-0.87, P=0.003), but not in non-low skeletal muscle mass patients.Conclusions: ICU-rehabilitation was independently associated with reduced 1-year mortality from sepsis among low skeletal muscle mass patients, but not among non-low skeletal muscle mass patients. Therefore, the delayed initiation of ICU-rehabilitation should be avoided, especially in low skeletal muscle mass patients.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

ICU rehabilitation is associated with reduced long-term mortality from sepsis in patients with low skeletal muscle mass: a case control study

Kim¹,

Huh²,

Kim³

et al. 2019

Ann. Transl. Med.

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“…53 In a separate retrospective review of 627 patients with a diagnosis of sepsis and an available abdominal computed tomography scan of the psoas muscle, muscle mass depletion was associated with 28day mortality in both univariate and multivariate logistic regression (odds ratio [OR] = 2.79, p=0.01). 54 Given the extent of protein catabolism, the sepsis-obesity paradox, and the known sequestering of carnitine into muscle tissue, morphomics and variability in body composition offers a currently untapped field that could aid in explaining the observed variability in response to supplemental L-carnitine and patient mortality in sepsis broadly (Table 1).…”

Section: Morphomicsmentioning

confidence: 99%

Using l‐Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis

et al. 2020

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Objective The objective of this review is to discuss the therapeutic use and differential treatment response to Levo‐carnitine (l‐carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l‐carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity. Methods A narrative review was conducted that focused on explaining interpatient variability in l‐carnitine treatment response. Relevant biological and patient‐level characteristics considered include genetic, metabolic, and morphomic phenotypes; potential drug interactions; and pharmacokinetics (PKs). Main Results Despite promising results in a phase I study, a recent phase II clinical trial of l‐carnitine treatment in septic shock showed a nonsignificant reduction in mortality. However, l‐carnitine treatment induces significant interpatient variability in l‐carnitine and acylcarnitine concentrations over time. In particular, administration of l‐carnitine induces a broad, dynamic range of serum concentrations and measured peak concentrations are associated with mortality. Applied systems pharmacology may explain variability in drug responsiveness by using patient characteristics to identify pretreatment phenotypes most likely to derive benefit from l‐carnitine. Moreover, provocation of sepsis metabolism with l‐carnitine offers a unique opportunity to identify metabolic response signatures associated with patient outcomes. These approaches can unmask latent metabolic pathways deranged in the sepsis syndrome and offer insight into the pathophysiology, progression, and heterogeneity of the disease. Conclusions The compiled evidence suggests there are several potential explanations for the variability in carnitine concentrations and clinical response to l‐carnitine in septic shock. These serve as important confounders that should be considered in interpretation of l‐carnitine clinical studies and broadly holds lessons for future clinical trial design in sepsis. Consideration of these factors is needed if precision medicine in sepsis is to be achieved.

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“…6 Analogous to cachexia syndrome, muscle and fat wasting post-sepsis can result in many detrimental outcomes that directly impact long-term mortality and quality of life including decreased locomotive capacity, respiratory dysfunction, and altered systemic metabolism. 7,8 Fundamentally, tissue homeostasis involves balancing pro-growth anabolic processes with breakdown-associated catabolism. In the context of sepsis, acute loss of muscle and fat mass often occurs due to hyper-catabolism linked to infection-associated inflammation, decreased nutrient intake, disuse, or altered systemic metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…Skeletal muscle and adipose tissue are two key metabolic tissues that exhibit major functional and histological changes in sepsis survivors 6 . Analogous to cachexia syndrome, muscle and fat wasting post‐sepsis can result in many detrimental outcomes that directly impact long‐term mortality and quality of life including decreased locomotive capacity, respiratory dysfunction, and altered systemic metabolism 7,8 . Fundamentally, tissue homeostasis involves balancing pro‐growth anabolic processes with breakdown‐associated catabolism.…”

Section: Introductionmentioning

confidence: 99%

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

Cho

Schmitt

Dasgupta

et al. 2020

J cachexia sarcopenia muscle

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Background Persistent loss of skeletal muscle mass and function as well as altered fat metabolism are frequently observed in severe sepsis survivors. Studies examining sepsis-associated tissue dysfunction from the perspective of the tissue microenvironment are scarce. In this study, we comprehensively assessed transcriptional changes in muscle and fat at single-cell resolution following experimental sepsis induction. Methods Skeletal muscle and visceral white adipose tissue from control mice or mice 1 day or 1 month following faecal slurry-induced sepsis were used. Single cells were mechanically and enzymatically prepared from whole tissue, and viable cells were further isolated by fluorescence activated cell sorting. Droplet-based single-cell RNA-sequencing (scRNA-seq; 10× Genomics) was used to generate single-cell gene expression profiles of thousands of muscle and fat-resident cells. Bioinformatics analyses were performed to identify and compare individual cell populations in both tissues. Results In skeletal muscle, scRNA-seq analysis classified 1438 single cells into myocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages, neutrophils, T-cells, B-cells, and dendritic cells. In adipose tissue, scRNA-seq analysis classified 2281 single cells into adipose stem cells, preadipocytes, endothelial cells, fibroblasts, macrophages, dendritic cells, Bcells, T-cells, NK cells, and gamma delta T-cells. One day post-sepsis, the proportion of most non-immune cell populations was decreased, while immune cell populations, particularly neutrophils and macrophages, were highly enriched. Proportional changes of endothelial cells, neutrophils, and macrophages were validated using faecal slurry and cecal ligation and puncture models. At 1 month post-sepsis, we observed persistent enrichment/depletion of cell populations and further uncovered a cell-type and tissue-specific ability to return to a baseline transcriptomic state. Differential gene expression analyses revealed key genes and pathways altered in post-sepsis muscle and fat and highlighted the engagement of infection/inflammation and tissue damage signalling. Finally, regulator analysis identified gonadotropin-releasing hormone and Bay 11-7082 as targets/compounds that we show can reduce sepsis-associated loss of lean or fat mass. Conclusions These data demonstrate persistent post-sepsis muscle and adipose tissue disruption at the single-cell level and highlight opportunities to combat long-term post-sepsis tissue wasting using bioinformatics-guided therapeutic interventions.

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Muscle Mass Depletion Associated with Poor Outcome of Sepsis in the Emergency Department

Cited by 20 publications

References 26 publications

ICU rehabilitation is associated with reduced long-term mortality from sepsis in patients with low skeletal muscle mass: a case control study

ICU rehabilitation is associated with reduced long-term mortality from sepsis in patients with low skeletal muscle mass: a case control study

Using l‐Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

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