Early detection of muscle wasting assessed by ultrasound and analysis of growth factor and systemic inflammation mediators in critically ill trauma patients: an observational study

Khattar G., Bou Sanayeh E.

This editorial explores the significant challenge of intensive care unit-acquired weakness (ICU-AW), a prevalent condition affecting critically ill patients, characterized by profound muscle weakness and complicating patient recovery. Highlighting the paradox of modern medical advances, it emphasizes the urgent need for early identification and intervention to mitigate ICU-AW's impact. Innovatively, the study by Wang et al is showcased for employing a multilayer perceptron neural network model, achieving high accuracy in predicting ICU-AW risk. This advancement underscores the potential of neural network models in enhancing patient care but also calls for continued research to address limitations and improve model applicability. The editorial advocates for the development and validation of sophisticated predictive tools, aiming for personalized care strategies to reduce ICU-AW incidence and severity, ultimately improving patient outcomes in critical care settings.

Kangalgil M., Ulusoy H., Ayaz S.

Abstract Background Acute muscle wasting is common in critically ill patients, and this can lead to unfavorable clinical outcomes. The aim of this study was to identify factors associated with muscle wasting and to investigate the association between skeletal muscle wasting and prolonged hospital stay in critically ill patients with acute brain injury. Methods This single-center prospective observational study was conducted in critically ill patients with acute brain injury who stayed in the intensive care unit for at least 1 week. The rectus femoris cross-sectional area was measured via ultrasound at baseline and a week after the first assessment. Univariate and multivariate logistic regression analyses were performed to identify factors that predicted prolonged hospital stay. Results A total of 86 patients were included in the study. Their mean age was 49.4 ± 16.9 years, 57% were male, and 46.5% had an admission diagnosis of subarachnoid hemorrhage. The percentage change in the rectus femoris cross-sectional area was 15.8% (95% confidence interval [CI] − 19.8% to − 12.0%; p < 0.001), and 57% of all patients had acute muscle wasting. According to the univariate analysis, there was a significant association between prolonged hospital stay and acute muscle wasting (odds ratio [OR] 3.677; 95% CI 1.487–9.043; p = 0.005), mechanical ventilation status (OR 3.600; 95% CI 1.455–8.904; p = 0.006), and Glasgow Coma Scale score (OR 0.888; 95% CI 0.808–0.976; p = 0.014) at intensive care unit admission. The multivariate analysis demonstrated that acute muscle wasting (OR 3.449; 95% CI 1.344–8.853; p = 0.010) was an independent risk factor for prolonged hospital stay. Conclusions There was considerable muscle wasting in critically ill patients with brain injuries over a 1-week period. Acute muscle wasting was associated with prolonged hospital stay in critically ill patients with acute brain injury.

Di Ludovico A., La Bella S., Ciarelli F., Chiarelli F., Breda L., Mohn A.

AbstractPreviously regarded as a movement and posture control agent, the skeletal muscle is now recognized as an endocrine organ that may affect systemic inflammation and metabolic health. The discovery of myokines such as IL-6, released from skeletal muscle in response to physical exercise, is now one of the most recent insights. Myokines are the mediators of the balance between the pro-inflammatory and anti-inflammatory responses. This underscores the muscle function as a determinant of good health and prevention of diseases. Advances in ultrasound technology improved evaluation of muscle thickness, composition, and determining fat distribution. Combining imaging with molecular biology, researchers discovered the complicated interplay between muscle function, cytokine production and general health effects.The production of myokines with exercise showcasing the adaptability of muscles to high-stress conditions and contributing to metabolism and inflammation regulation. These findings have significant implications in order to provide improvement in metabolic and inflammatory diseases.

Yanar K.E., Gür C., Değirmençay Ş., Aydın Ö., Aktaş M.S., Baysal S.

The objective of this study was to investigate the mRNA expression of insulin-like growth factor-1 (IGF-1), pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α), serum immunoglobulin profiles (IgG and IgM), and lipid peroxidation status (MDA) in relation to pro-inflammatory cytokines. A case-controlled, prospective, and observational investigation was completed on 85 calves. Total RNA was isolated from whole blood samples of both the SIRS and healthy calves, followed by reverse transcription into cDNA. The resulting cDNAs were mixed with iTaq Universal SYBR Green Supermix and primers specific to the relevant genes using the Rotor-Gene Q instrument. After the reaction was completed, gene expressions were normalised against β-actin using the 2-ΔΔCT method. The mRNA levels of pro-inflammatory cytokines namely (IL-1β [SIRS: 2.15 ± 0.55, Control: 1.13 ± 0.62; P = 0.001], IL-6 [SIRS: 2.82 ± 0.52, Control: 0.91 ± 0.11; P < 0.001], IL-18 [SIRS: 1.92 ± 0.41, Control: 0.99 ± 0.13; P < 0.001], and TNF-α [SIRS: 2.59 ± 0.28, Control: 0.93 ± 0.09; P < 0.001]) and IGF-1 (SIRS: 3.55 ± 0.55, Control: 0.91 ± 0.15; P < 0.001) were up-regulated in calves with SIRS, while serum IgG (SIRS: 4.16 ± 0.26, Control: 1.73 ± 0.17; P < 0.001), IgM (SIRS: 1.55 ± 0.11, Control: 1.09 ± 0.13; P < 0.001), and MDA levels (SIRS: 41.12 ± 3.48, Control: 3.76 ± 0.81; P < 0.001) increased significantly in these calves. Furthermore, significant (P < 0.01) positive correlations were found in calves with SIRS in relation to the expression levels of IL-1β, IL-6, IL-18, TNF-α, IGF-1, serum immunoglobulins, and MDA levels. These results suggest that IGF-1 could be a valuable pro-inflammatory marker, considering its high positive correlation with the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) and markers (MDA, IgG, and IgM) in calves with SIRS.

Chen J., Huang M.

Intensive care unit-acquired weakness (ICU-AW) is a common complication in critically ill patients and is associated with a variety of adverse outcomes. These include the need for prolonged mechanical ventilation and ICU stay; higher ICU, in-hospital, and 1-year mortality; and increased in-hospital costs. ICU-AW is associated with multiple risk factors including age, underlying disease, severity of illness, organ failure, sepsis, immobilization, receipt of mechanical ventilation, and other factors related to critical care. The pathological mechanism of ICU-AW remains unclear and may be considerably varied. This review aimed to evaluate recent insights into ICU-AW from several aspects including risk factors, pathophysiology, diagnosis, and treatment strategies; this provides new perspectives for future research.

Stanley B., Greig C., Jackson T., Lewis D., Moorey H., Majid Z., Masud T., Pinkney T., Welch C.

Abstract Background Sarcopenia is a clinical manifestation of adverse ageing, characterised by progressive loss of muscle mass and function. Diagnosis requires assessment of muscle quantity and quality; ultrasound represents an emerging tool for this. However, ultrasound muscle assessment may be impacted by fluid balance. This is particularly important when assessing for acute sarcopenia in hospitalised patients, where fluid disturbance often occurs. The primary aim of this study was to characterise the impact of fluid status on ultrasound muscle assessment, such that this may be accounted for in sarcopenia diagnostics. Methods This Multidimensional Cross-sectional study involved 80 participants, who were inpatients at QEHB, a large UK tertiary centre. Fluid status was evaluated clinically and quantified using Bioelectrical Impedance Analysis (BIA). Muscle quantity was measured using Bilateral Anterior Thigh Thickness (BATT) with Rectus Femoris (RF) echogenicity used to assesses muscle adiposity and hence provide an inverse measure of muscle quality. Results A significant positive correlation was found between fluid status, measured using BIA, and BATT as a measure of muscle quantity, in males (rs = 0.662, p < 0.001) and females (rs = 0.638, p < 0.001). A significant negative correlation was found between fluid status and RF echogenicity (rs=-0.448, p < 0.001). Conclusions These findings demonstrate associations between fluid balance and ultrasound assessment of muscle quantity and quality. Given the emerging use of ultrasound muscle assessment in sarcopenia diagnosis, there is a need to account for this in clinical practice. Future research should focus on the development of a corrective equation allowing assessment of muscle quantity and quality which account for changes in fluid status, hence aiding accurate diagnosis of sarcopenia.

Vieira L., Silva P.E., de Melo P.F., Maldaner V., Durigan J.Q., Marqueti R.D., Nobrega O., Mathur S., Burtin C., Barin F., Machado-Silva W., Ramalho S., Chiappa G.R., Gomes N.O., Carvalho C.R., et. al.

Objective. To investigate the effects of an early neuromuscular electrical stimulation (NMES) protocol on muscle quality and size as well as signaling mediators of muscle growth and systemic inflammation in patients with traumatic brain injury (TBI). Design. Two-arm, single-blinded, parallel-group, randomized, controlled trial with a blinded assessment. Setting. Trauma intensive care unit at a university hospital. Participants. Forty consecutive patients on mechanical ventilation (MV) secondary to TBI were prospectively recruited within the first 24 hours following admission. Interventions. The intervention group (NMES; n = 20) received a daily session of NMES on the rectus femoris muscle for five consecutive days (55 min/each session). The control group (n = 20) received usual care. Main Outcome Measures. Muscle echogenicity and thickness were evaluated by ultrasonography. A daily blood sample was collected to assess circulating levels of insulin-like growth factor I (IGF-I), inflammatory cytokines, and matrix metalloproteinases (MMP). Results. Both groups were similar at baseline. A smaller change in muscle echogenicity and thickness (difference between Day 1 and Day 7) was found in the control group compared to the NMES group (29.9 ± 2.1 vs. 3.0 ± 1.2, p < 0.001 ; −0.79 ± 0.12 vs. −0.01 ± 0.06, p < 0.001 , respectively). Circulating levels of IGF-I, pro-inflammatory cytokines (IFN-y), and MMP were similar between groups. Conclusion. An early NMES protocol can preserve muscle size and quality and maintain systemic levels of signaling mediators of muscle growth and inflammation in patients with TBI. This trial is registered with https://www.ensaiosclinicos.gov.br under number RBR-2db.

Guarino M., Perna B., Cesaro A.E., Maritati M., Spampinato M.D., Contini C., De Giorgio R.

Background: Sepsis/septic shock is a life-threatening and time-dependent condition that requires timely management to reduce mortality. This review aims to update physicians with regard to the main pillars of treatment for this insidious condition. Methods: PubMed, Scopus, and EMBASE were searched from inception with special attention paid to November 2021–January 2023. Results: The management of sepsis/septic shock is challenging and involves different pathophysiological aspects, encompassing empirical antimicrobial treatment (which is promptly administered after microbial tests), fluid (crystalloids) replacement (to be established according to fluid tolerance and fluid responsiveness), and vasoactive agents (e.g., norepinephrine (NE)), which are employed to maintain mean arterial pressure above 65 mmHg and reduce the risk of fluid overload. In cases of refractory shock, vasopressin (rather than epinephrine) should be combined with NE to reach an acceptable level of pressure control. If mechanical ventilation is indicated, the tidal volume should be reduced from 10 to 6 mL/kg. Heparin is administered to prevent venous thromboembolism, and glycemic control is recommended. The efficacy of other treatments (e.g., proton-pump inhibitors, sodium bicarbonate, etc.) is largely debated, and such treatments might be used on a case-to-case basis. Conclusions: The management of sepsis/septic shock has significantly progressed in the last few years. Improving knowledge of the main therapeutic cornerstones of this challenging condition is crucial to achieve better patient outcomes.

Chapela S.P., Simancas-Racines D., Montalvan M., Frias-Toral E., Simancas-Racines A., Muscogiuri G., Barrea L., Sarno G., Martínez P.I., Reberendo M.J., Llobera N.D., Stella C.A.

Sarcopenia in critically ill patients is a highly prevalent comorbidity. It is associated with a higher mortality rate, length of mechanical ventilation, and probability of being sent to a nursing home after the Intensive Care Unit (ICU). Despite the number of calories and proteins delivered, there is a complex network of signals of hormones and cytokines that affect muscle metabolism and its protein synthesis and breakdown in critically ill and chronic patients. To date, it is known that a higher number of proteins decreases mortality, but the exact amount needs to be clarified. This complex network of signals affects protein synthesis and breakdown. Some hormones regulate metabolism, such as insulin, insulin growth factor glucocorticoids, and growth hormone, whose secretion is affected by feeding states and inflammation. In addition, cytokines are involved, such as TNF-alpha and HIF-1. These hormones and cytokines have common pathways that activate muscle breakdown effectors, such as the ubiquitin–proteasome system, calpain, and caspase-3. These effectors are responsible for protein breakdown in muscles. Many trials have been conducted with hormones with different results but not with nutritional outcomes. This review examines the effect of hormones and cytokines on muscles. Knowing all the signals and pathways that affect protein synthesis and breakdown can be considered for future therapeutics.

Takahashi Y., Morisawa T., Okamoto H., Matsumoto N., Saitoh M., Takahashi T., Fujiwara T.

Early risk assessment of functional decline in patients with sepsis is clinically challenging. Recently, there is increasing interest in the nonvolitional evaluation of skeletal muscle quality.The aim of this study was to assess the relationship between skeletal muscle quality and functional decline after intensive care.This pilot study was a single-center prospective observational study conducted from March 2021 to February 2022. We included consecutive patients with sepsis who were admitted to our ICU.The primary outcome was hospital-acquired disability (HAD), which is defined as a decrease in the Barthel index score of at least 5 points from pre-hospital to hospital discharge. Muscle quality was assessed by: 1) muscle echogenicity with ultrasound and 2) phase angle (PhA) with bioelectrical impedance analysis, both of which were measured on ICU days less than 3, 3-5, 5-7, 7-10, and 10-14. We compared longitudinal changes in muscle echogenicity and PhA between the HAD and non-HAD groups using two-way repeated measures analysis of variance with mixed models.Among the 22 patients, 7 (31.8%) had HAD. Muscle echogenicity was higher in the HAD group than in the non-HAD group (p < 0.001); however, no interaction effects were found between the two groups (p = 0.189). PhA showed a main effect on each evaluation day in patients (p = 0.040) and a significant interaction effect between the groups, including an early decreased pattern in the HAD group (p = 0.036).Higher muscle echogenicity and a decreased PhA pattern are related to HAD. Noninvasive assessment of muscle quality using ultrasound and bioelectrical impedance analysis may be useful in predicting the functional prognosis of patients with sepsis.

Tu H., Li Y.

Responding to tissue injury, skeletal muscles undergo the tissue destruction and reconstruction accompanied with inflammation. The immune system recognizes the molecules released from or exposed on the damaged tissue. In the local minor tissue damage, tissue-resident macrophages sequester pro-inflammatory debris to prevent initiation of inflammation. In most cases of the skeletal muscle injury, however, a cascade of inflammation will be initiated through activation of local macrophages and mast cells and recruitment of immune cells from blood circulation to the injured site by recongnization of damage-associated molecular patterns (DAMPs) and activated complement system. During the inflammation, macrophages and neutrophils scavenge the tissue debris to release inflammatory cytokines and the latter stimulates myoblast fusion and vascularization to promote injured muscle repair. On the other hand, an abundance of released inflammatory cytokines and chemokines causes the profound hyper-inflammation and mobilization of immune cells to trigger a vicious cycle and lead to the cytokine storm. The cytokine storm results in the elevation of cytolytic and cytotoxic molecules and reactive oxygen species (ROS) in the damaged muscle to aggravates the tissue injury, including the healthy bystander tissue. Severe inflammation in the skeletal muscle can lead to rhabdomyolysis and cause sepsis-like systemic inflammation response syndrome (SIRS) and remote organ damage. Therefore, understanding more details on the involvement of inflammatory factors and immune cells in the skeletal muscle damage and repair can provide the new precise therapeutic strategies, including attenuation of the muscle damage and promotion of the muscle repair.

Fazzini B., Märkl T., Costas C., Blobner M., Schaller S.J., Prowle J., Puthucheary Z., Wackerhage H.

Abstract Background Patients with critical illness can lose more than 15% of muscle mass in one week, and this can have long-term detrimental effects. However, there is currently no synthesis of the data of intensive care unit (ICU) muscle wasting studies, so the true mean rate of muscle loss across all studies is unknown. The aim of this project was therefore to systematically synthetise data on the rate of muscle loss and to identify the methods used to measure muscle size and to synthetise data on the prevalence of ICU-acquired weakness in critically ill patients. Methods We conducted a systematic literature search of MEDLINE, PubMed, AMED, BNI, CINAHL, and EMCARE until January 2022 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD420222989540. We included studies with at least 20 adult critically ill patients where the investigators measured a muscle mass-related variable at two time points during the ICU stay. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the study quality using the Newcastle–Ottawa Scale. Results Fifty-two studies that included 3251 patients fulfilled the selection criteria. These studies investigated the rate of muscle wasting in 1773 (55%) patients and assessed ICU-acquired muscle weakness in 1478 (45%) patients. The methods used to assess muscle mass were ultrasound in 85% (n = 28/33) of the studies and computed tomography in the rest 15% (n = 5/33). During the first week of critical illness, patients lost every day −1.75% (95% CI −2.05, −1.45) of their rectus femoris thickness or −2.10% (95% CI −3.17, −1.02) of rectus femoris cross-sectional area. The overall prevalence of ICU-acquired weakness was 48% (95% CI 39%, 56%). Conclusion On average, critically ill patients lose nearly 2% of skeletal muscle per day during the first week of ICU admission.

Maas A.I., Menon D.K., Manley G.T., Abrams M., Åkerlund C., Andelic N., Aries M., Bashford T., Bell M.J., Bodien Y.G., Brett B.L., Büki A., Chesnut R.M., Citerio G., Clark D., et. al.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research. In LMICs, the occurrence of TBI is driven by road traffic incidents, often involving vulnerable road users such as motorcyclists and pedestrians. In HICs, most TBI is caused by falls, particularly in older people (aged ≥65 years), who often have comorbidities. Risk factors such as frailty and alcohol misuse provide opportunities for targeted prevention actions. Little evidence exists to inform treatment of older patients, who have been commonly excluded from past clinical trials—consequently, appropriate evidence is urgently required. Although increasing age is associated with worse outcomes from TBI, age should not dictate limitations in therapy. However, patients injured by low-energy falls (who are mostly older people) are about 50% less likely to receive critical care or emergency interventions, compared with those injured by high-energy mechanisms, such as road traffic incidents. Mild TBI, defined as a Glasgow Coma sum score of 13–15, comprises most of the TBI cases (over 90%) presenting to hospital. Around 50% of adult patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health by 6 months after their injury. Fewer than 10% of patients discharged after presenting to an emergency department for TBI in Europe currently receive follow-up. Structured follow-up after mild TBI should be considered good practice, and urgent research is needed to identify which patients with mild TBI are at risk for incomplete recovery. The selection of patients for CT is an important triage decision in mild TBI since it allows early identification of lesions that can trigger hospital admission or life-saving surgery. Current decision making for deciding on CT is inefficient, with 90–95% of scanned patients showing no intracranial injury but being subjected to radiation risks. InTBIR studies have shown that measurement of blood-based biomarkers adds value to previously proposed clinical decision rules, holding the potential to improve efficiency while reducing radiation exposure. Increased concentrations of biomarkers in the blood of patients with a normal presentation CT scan suggest structural brain damage, which is seen on MR scanning in up to 30% of patients with mild TBI. Advanced MRI, including diffusion tensor imaging and volumetric analyses, can identify additional injuries not detectable by visual inspection of standard clinical MR images. Thus, the absence of CT abnormalities does not exclude structural damage—an observation relevant to litigation procedures, to management of mild TBI, and when CT scans are insufficient to explain the severity of the clinical condition. Although blood-based protein biomarkers have been shown to have important roles in the evaluation of TBI, most available assays are for research use only. To date, there is only one vendor of such assays with regulatory clearance in Europe and the USA with an indication to rule out the need for CT imaging for patients with suspected TBI. Regulatory clearance is provided for a combination of biomarkers, although evidence is accumulating that a single biomarker can perform as well as a combination. Additional biomarkers and more clinical-use platforms are on the horizon, but cross-platform harmonisation of results is needed. Health-care efficiency would benefit from diversity in providers. In the intensive care setting, automated analysis of blood pressure and intracranial pressure with calculation of derived parameters can help individualise management of TBI. Interest in the identification of subgroups of patients who might benefit more from some specific therapeutic approaches than others represents a welcome shift towards precision medicine. Comparative-effectiveness research to identify best practice has delivered on expectations for providing evidence in support of best practices, both in adult and paediatric patients with TBI. Progress has also been made in improving outcome assessment after TBI. Key instruments have been translated into up to 20 languages and linguistically validated, and are now internationally available for clinical and research use. TBI affects multiple domains of functioning, and outcomes are affected by personal characteristics and life-course events, consistent with a multifactorial bio-psycho-socio-ecological model of TBI, as presented in the US National Academies of Sciences, Engineering, and Medicine (NASEM) 2022 report. Multidimensional assessment is desirable and might be best based on measurement of global functional impairment. More work is required to develop and implement recommendations for multidimensional assessment. Prediction of outcome is relevant to patients and their families, and can facilitate the benchmarking of quality of care. InTBIR studies have identified new building blocks (eg, blood biomarkers and quantitative CT analysis) to refine existing prognostic models. Further improvement in prognostication could come from MRI, genetics, and the integration of dynamic changes in patient status after presentation. Neurotrauma researchers traditionally seek translation of their research findings through publications, clinical guidelines, and industry collaborations. However, to effectively impact clinical care and outcome, interactions are also needed with research funders, regulators, and policy makers, and partnership with patient organisations. Such interactions are increasingly taking place, with exemplars including interactions with the All Party Parliamentary Group on Acquired Brain Injury in the UK, the production of the NASEM report in the USA, and interactions with the US Food and Drug Administration. More interactions should be encouraged, and future discussions with regulators should include debates around consent from patients with acute mental incapacity and data sharing. Data sharing is strongly advocated by funding agencies. From January 2023, the US National Institutes of Health will require upload of research data into public repositories, but the EU requires data controllers to safeguard data security and privacy regulation. The tension between open data-sharing and adherence to privacy regulation could be resolved by cross-dataset analyses on federated platforms, with the data remaining at their original safe location. Tools already exist for conventional statistical analyses on federated platforms, however federated machine learning requires further development. Support for further development of federated platforms, and neuroinformatics more generally, should be a priority. This update to the 2017 Commission presents new insights and challenges across a range of topics around TBI: epidemiology and prevention (section 1); system of care (section 2); clinical management (section 3); characterisation of TBI (section 4); outcome assessment (section 5); prognosis (Section 6); and new directions for acquiring and implementing evidence (section 7). Table 1 summarises key messages from this Commission and proposes recommendations for the way forward to advance research and clinical management of TBI.Table 1Key messages and recommendationsKey messagesRecommendationsSection 1Worldwide, TBI is a leading cause of injury-related death and disability, with devastating effects on patients and their familiesContinue concerted efforts to address this vast global health problem and focus on better prevention, improved access to care, and promotion of clinical research to improve treatment standardsSection 1More than 90% of patients presenting to hospital with TBI have so-called mild TBI (GCS 13–15), but evidence to inform treatment of patients with mild TBI is scarceIncrease public health interest and establish a research focus on mild TBISection 1In HICs, older patients (≥65 years) who are mostly injured by falls account for 30–40% of hospital admissions for TBI. Frailty and alcohol abuse contribute to falls causing TBI in older peopleTarget fall prevention for older citizens in HICsSections 1, 2People in LMICs are disproportionately affected by TBI, with most injuries caused by road traffic incidents. Substantial disparities in care exist, with little infrastructure available for emergency pre-hospital care and very little access to post-acute careDeliver on implementation of road safety goals, described in WHO's Decade for Action on Road Safety plan launched in 2021. Improve emergency pre-hospital care and develop an infrastructure for post-acute careSection 2Disparities in care also exist in HICs and relate to: older people injured by low-energy mechanisms (falls); access to rehabilitation for patients with moderate to severe TBI (GCS ≤12); and follow-up in patients with mild TBIAddress disparities through close collaboration between policymakers and clinicians; Approaches to consider include: critical appraisal of triage tools used in emergency settings; involvement of rehabilitation services at an early stage of the in-hospital treatment for TBI; and establishment of structured follow-up after mild TBI as good practiceSections 2, 4Use of blood-based biomarkers is on the verge of a breakthrough for diagnostic and prognostic use in TBI, but few assay platforms have been approved for clinical use and substantial variability exists between platformsStimulate the development, validation, and approval of clinical-use platforms, and facilitate cross-platform harmonisation of biomarker assaysSection 3Older patients often have co-morbidities, but very little evidence exists to inform their treatmentStimulate a research focus on older patients with TBISection 3Access to rehabilitation services is inconsistent and no protocols for treating long-term problems existImprove access to rehabilitation services and develop evidence-based treatments for long-term problems—including fatigue, and cognitive and behavioural changesSection 4Substantial advances have been made towards individualised management with improved characterisation and understanding of disease processes in TBI, but physicians are not yet sufficiently able to match therapies to subgroups of patientsStimulate research to identify subgroups of patients who would be most likely to benefit from specific interventionsSection 5Around 50% of patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health and wellbeing by 6 months after injuryImplement care pathways to ensure structured follow-up of patients with mild TBI, and stimulate research to identify patients with mild TBI at high risk for incomplete recovery, which would allow timely evaluation and treatmentSection 5Outcome in women after TBI is poorer than in menFacilitate research to help explain this sex and gender difference and inform intervention strategiesSection 6Prognostic models have been developed and extensively validated for moderate and severe TBI. No well-validated models exist for mild TBI, nor do models exist that are applicable across all ranges of TBI severityInitiatives should be stimulated to develop models applicable across the range of TBI severity. Availability of such models would constitute a huge step forward and facilitate implementation into clinical practiceSection 6Quality indicators developed for TBI are restricted to the ICU setting and are not yet ready for translation into practiceResearch should be stimulated to refine, validate, and implement quality indicators for TBISection 7Costs of data curation and deep harmonisation in preparation for sharing research data are underestimated and can amount to up to 20% of a study budgetFor completed studies, mechanisms should be developed to facilitate maintenance of the data and to provide guidance to external researchers wishing to analyse the data. For new studies, inclusion of an appropriate budget to prepare data for sharing should be foreseen in the grant awardSection 7TBI is often characterised by both an acute mental incapacity of patients to provide informed consent for participation in research and an emergency situation. Although GDPR recognises the issue of absence of capacity to provide consent, no provisions are included that are relevant to patients with an acute absence of capacity or to emergency situationsDevelop better regulatory guidance. Consider mandating that researchers obtain objective proof of mental capacity of the study participant, who might have been temporarily mentally incapacitated, before requesting informed consent.Section 7Data sharing and analyses across different datasets do not necessarily require data transfer and can be done on a federated platform. Use of a federated platform facilitates broad use of data and reduces the risks for violation of data security and privacy regulationSupport is required for the development of platforms for federated analysis, particularly for development and implementation of machine-learning techniques on such platformsTBI=traumatic brain injury. HICs=high-income countries. LMICs=low-income and middle-income countries. GCS=Glasgow Coma sum score. ICU=intensive care unit. GDPR=general data protection regulation. Open table in a new tab TBI=traumatic brain injury. HICs=high-income countries. LMICs=low-income and middle-income countries. GCS=Glasgow Coma sum score. ICU=intensive care unit. GDPR=general data protection regulation.

Liu D., Huang S., Sun J., Zhang H., Cai Q., Gao C., Li L., Cao J., Xu F., Zhou Y., Guan C., Jin S., Deng J., Fang X., Jiang J., et. al.

Sepsis is a common complication of combat injuries and trauma, and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is also one of the significant causes of death and increased health care costs in modern intensive care units. The use of antibiotics, fluid resuscitation, and organ support therapy have limited prognostic impact in patients with sepsis. Although its pathophysiology remains elusive, immunosuppression is now recognized as one of the major causes of septic death. Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis. It is characterized by the release of anti-inflammatory cytokines, abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, and expression of immune checkpoints. By targeting immunosuppression, especially with immune checkpoint inhibitors, preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance. Here, we comprehensively discuss recent findings on the mechanisms, regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

Ji Y., Li M., Chang M., Liu R., Qiu J., Wang K., Deng C., Shen Y., Zhu J., Wang W., Xu L., Sun H.

Various diseases can cause skeletal muscle atrophy, usually accompanied by inflammation, mitochondrial dysfunction, apoptosis, decreased protein synthesis, and enhanced proteolysis. The underlying mechanism of inflammation in skeletal muscle atrophy is extremely complex and has not been fully elucidated, thus hindering the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy. In this review, we elaborate on protein degradation pathways, including the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), the calpain and caspase pathways, the insulin growth factor 1/Akt protein synthesis pathway, myostatin, and muscle satellite cells, in the process of muscle atrophy. Under an inflammatory environment, various pro-inflammatory cytokines directly act on nuclear factor-κB, p38MAPK, and JAK/STAT pathways through the corresponding receptors, and then are involved in muscle atrophy. Inflammation can also indirectly trigger skeletal muscle atrophy by changing the metabolic state of other tissues or cells. This paper explores the changes in the hypothalamic-pituitary-adrenal axis and fat metabolism under inflammatory conditions as well as their effects on skeletal muscle. Moreover, this paper also reviews various signaling pathways related to muscle atrophy under inflammatory conditions, such as cachexia, sepsis, type 2 diabetes mellitus, obesity, chronic obstructive pulmonary disease, chronic kidney disease, and nerve injury. Finally, this paper summarizes anti-amyotrophic drugs and their therapeutic targets for inflammation in recent years. Overall, inflammation is a key factor causing skeletal muscle atrophy, and anti-inflammation might be an effective strategy for the treatment of skeletal muscle atrophy. Various inflammatory factors and their downstream pathways are considered promising targets for the treatment and prevention of skeletal muscle atrophy.