Charting the course for improved outcomes in chronic critical illness: therapeutic strategies for persistent inflammation, immunosuppression, and catabolism syndrome (PICS).

Enhanced critical care delivery has led to improved survival rates in critically ill patients, yet sepsis remains a leading cause of multiorgan failure with variable recovery outcomes. Chronic critical illness, characterised by prolonged ICU stays and persistent end-organ dysfunction, presents a significant challenge in patient management, often requiring multifaceted interventions. Recent research, highlighted in a comprehensive review in the British Journal of Anaesthesia, focuses on addressing the pathophysiological drivers of chronic critical illness, such as persistent inflammation, immunosuppression, and catabolism, through targeted therapeutic strategies including immunomodulation, muscle wasting prevention, nutritional support, and microbiome modulation. Although promising avenues exist, challenges remain in patient heterogeneity, treatment timing, and the need for multimodal approaches.

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection.

Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE.

Precision Medicine Approach Using Triple Combination Antifungal Therapy for Fusarium Brain Abscesses and Endocarditis in an Adult Burn Patient.

We report a management strategy for disseminated Fusarium solani fungal infection in an adult 35% total body surface area burn patient with brain abscesses and concomitant pulmonic valve endocarditis resulting in the longest survival reported in a burn patient. Early in his hospital course, the patient was diagnosed with a Fusarium burn wound infection with concomitant fungemia and was treated with a prolonged course of intravenous (IV) antifungal monotherapy. Shortly thereafter, he developed focal neurologic deficits and was found to have brain abscesses on MRI. He underwent emergent craniotomy with debridement, and triple antifungal therapy was initiated. Transesophageal echocardiography demonstrated pulmonic valve vegetations, which resolved with triple antifungal therapy. Disseminated Fusarium solani infection is quite rare with mortality approaching 100%. Given the rarity of this disease process, there are no established antifungal treatment guidelines. However, this patient survived for approximately 1 year after diagnosis with treatment including source control via craniotomy and debridement coupled with prolonged courses of combination antifungal therapy (given the near pan-resistance of his fungal infection). Pharmacogenomic testing was utilized to establish the patient's metabolism of voriconazole and dosing adjusted accordingly to improve the efficacy of the combination therapy. To our knowledge, an adult burn patient surviving this length of time after Fusarium brain abscesses with disseminated infection has not been previously described.

Exosomal microRNA following severe trauma: Role in bone marrow dysfunction.

INTRODUCTION: Severe trauma disrupts bone marrow function and is associated with persistent anemia and altered hematopoiesis. Previously, plasma-derived exosomes isolated after trauma have been shown to suppress in vitro bone marrow function. However, the cargo contained in these vesicles has not been examined. We hypothesized that trauma plasma-derived exosomes exhibit microRNA (miRNA) changes that impact bone marrow function after severe injury. METHODS: Plasma was collected from a prospective cohort study of trauma patients (n = 15; 7 males, 8 females) with hip and/or femur fractures and an Injury Severity Score of ≥15; elective total hip arthroplasty (THA) patients (n = 8; 4 males, 4 females) served as operative controls. Exosomes were isolated from plasma with the Invitrogen Total Exosome Isolation Kit (Thermo Fisher Scientific, Waltham, MA), and RNA was isolated using a miRNeasy Mini Kit (Qiagen, Hilden, Germany). Direct quantification of miRNA was performed by NanoString Technologies on a human miRNA gene panel and analyzed with nSolver with significance defined as p < 0.05. RESULTS: There were no differences in age or sex distribution between trauma and THA groups; the average Injury Severity Score was 23. Trauma plasma-derived exosomes had 60 miRNA identities that were significantly downregulated and 3 miRNAs that were upregulated when compared with THA ( p < 0.05). Twelve of the downregulated miRNAs have a direct role in hematopoiesis regulation. Furthermore, male trauma plasma-derived exosomes demonstrated downregulation of 150 miRNAs compared with male THA ( p < 0.05). Female trauma plasma-derived exosomes demonstrated downregulation of only four miRNAs and upregulation of two miRNAs compared with female THA ( p < 0.05). CONCLUSION: We observed downregulation of 12 miRNAs linked to hematopoiesis along with sexual dimorphism in miRNA expression from plasma-derived exosomes following severe trauma. Understanding sexually dimorphic miRNA expression provides new insight into sex-based changes in postinjury systemic inflammation, immune system dysregulation, and bone marrow dysfunction and will aid us in more precise future potential therapeutic strategies. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Severe trauma leads to sustained muscle loss, induced frailty, and distinct temporal changes in myokine and chemokine profiles of older patients.

INTRODUCTION: Sarcopenia is a known risk factor for adverse outcomes across multiple disease states, including severe trauma. Factors such as age, hyperinflammation, prolonged immobilization, and critical illness may not only exacerbate progression of this disease but may also contribute to the development of induced sarcopenia, or sarcopenia secondary to hospitalization. This study seeks to (1) determine the effects of severe traumatic injury on changes in skeletal muscle mass in older adults; (2) test whether changes in skeletal muscle mass are associated with clinical frailty, physical performance, and health-related quality of life; and (3) examine trauma-induced frailty and temporal changes in myokine and chemokine profiles. METHODS: A prospective, longitudinal cohort study of 47 critically ill, older (≥45 years) adults presenting after severe blunt trauma was conducted. Repeated measures of computed tomography-based skeletal muscle index, frailty, and quality of life were obtained in addition to selected plasma biomarkers over 6 months. RESULTS: Severe trauma was associated with significant losses in skeletal muscle mass and increased incidence of sarcopenia from 36% at baseline to 60% at 6 months. Severe trauma also was associated with a transient worsening of induced frailty and reduced quality of life irrespective of sarcopenia status, which returned to baseline by 6 months after injury. Admission biomarker levels were not associated with skeletal muscle index at the time points studied but demonstrated distinct temporal changes across our entire cohort. CONCLUSIONS: Severe blunt trauma in older adults is associated with increased incidence of induced sarcopenia and reversible induced frailty. Despite muscle wasting, functional decline is transient, with a return to baseline by 6 months, suggesting a need for holistic definitions of sarcopenia and further investigation into long-term functional outcomes in this population.

TRANSCRIPTOMIC DIFFERENCES IN PERIPHERAL MONOCYTE POPULATIONS IN SEPTIC PATIENTS BASED ON OUTCOME.

ABSTRACT: Postsepsis early mortality is being replaced by survivors who experience either a rapid recovery and favorable hospital discharge or the development of chronic critical illness with suboptimal outcomes. The underlying immunological response that determines these clinical trajectories remains poorly defined at the transcriptomic level. As classical and nonclassical monocytes are key leukocytes in both the innate and adaptive immune systems, we sought to delineate the transcriptomic response of these cell types. Using single-cell RNA sequencing and pathway analyses, we identified gene expression patterns between these two groups that are consistent with differences in TNF-α production based on clinical outcome. This may provide therapeutic targets for those at risk for chronic critical illness in order to improve their phenotype/endotype, morbidity, and long-term mortality.

The post-septic peripheral myeloid compartment reveals unexpected diversity in myeloid-derived suppressor cells.

Introduction: Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. Methods: Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering. Results: We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome. Discussion: The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity.

Surviving septic patients endotyped with a functional assay demonstrate active immune responses.

Introduction: Sepsis is a complex clinical syndrome characterized by a heterogenous host immune response. Historically, static protein and transcriptomic metrics have been employed to describe the underlying biology. Here, we tested the hypothesis that ex vivo functional TNF expression as well as an immunologic endotype based on both IFNγ and TNF expression could be used to model clinical outcomes in sepsis patients. Methods: This prospective, observational study of patient samples collected from the SPIES consortium included patients at five health systems enrolled over 17 months, with 46 healthy control patients, 68 ICU patients without sepsis, and 107 ICU patients with sepsis. Whole blood was collected on day 1, 4, and 7 of ICU admission. Outcomes included in-hospital and 180-day mortality and non-favorable discharge disposition defined by skilled nursing facility, long-term acute care facility, or hospice. Whole blood ELISpot assays were conducted to quantify TNF expression [stimulated by lipopolysaccharide (LPS)] and IFNγ expression (stimulated by anti-CD3/CD28 mAb), which were then used for assignment to one of four subgroups including an 'immunocompetent', 'immunosuppressed endotype', and two 'mixed' endotypes. Results: Whole blood TNF spot-forming units were significantly increased in septic and CINS patients on days 4 and 7 compared to healthy subjects. In contrast, TNF expression per cell on days 1, 4, and 7 was significantly lower in both septic and critically ill non-septic (CINS) patients compared to healthy subjects. Early increases in total TNF expression were associated with favorable discharge disposition and lower in-hospital mortality. 'Immunocompetent' endotype patients on day 1 had a higher proportion of favorable to non-favorable discharges compared to the 'immunosuppressed' endotype. Similarly, 'immunocompetent' endotype patients on day 4 had a higher in-hospital survival compared to the 'immunosuppressed' endotype patients. Finally, among septic patients, decreased total TNF and IFNγ expression were associated with 180-day mortality. Conclusions: Increased ex vivo whole blood TNF expression is associated with improved clinical outcomes. Further, the early 'immunocompetent' endotype is associated with favorable discharge and improved in-hospital and 180-day survival. The ability to functionally stratify septic patients based on blood cell function ex vivo may allow for identification of future immune modulating therapies.

Adverse outcomes and an immunosuppressed endotype in septic patients with reduced IFN-γ ELISpot.

BACKGROUNDSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.METHODSAn ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 following ICU admission.RESULTSCompared with 46 healthy participants, unstimulated and stimulated whole-blood IFN-γ expression was either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole-blood IFN-γ expression was significantly reduced on ICU days 1, 4, and 7 (all P < 0.05), due to both significant reductions in total number of IFN-γ-producing cells and amount of IFN-γ produced per cell (all P < 0.05). Importantly, IFN-γ total expression on days 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6, and procalcitonin. Septic patients with low IFN-γ expression were older and had lower ALCs and higher soluble PD-L1 and IL-10 concentrations, consistent with an immunosuppressed endotype.CONCLUSIONSA whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients.TRIAL REGISTRYN/A.FUNDINGThis prospective, observational, multicenter clinical study was directly supported by National Institute of General Medical Sciences grant R01 GM-139046, including a supplement (R01 GM-139046-03S1) from 2022 to 2024.

Perisplenitis ("Sugar Spleen") Associated With Malrotation of the Intestine in an Elderly Man.

Intestinal non-rotation is an exceedingly rare clinical entity, especially as the etiology for small bowel obstruction following open-heart surgery in an elderly patient. Perisplenitis (also known as "sugar spleen") is also rarely identified during exploratory laparotomy, and is more often encountered post-mortem due to its benign disease course. These two entities were encountered in the same acutely decompensating patient, and while unrelated, serve as a reminder of the importance of recognizing variations in anatomy and understanding subsequent clinical significance.

VARIABLES INFLUENCING THE DIFFERENTIAL HOST RESPONSE TO BURNS IN PEDIATRIC AND ADULT PATIENTS.

ABSTRACT: Burn injury is a significant source of morbidity and mortality in the pediatric population. Although 40,000 pediatric patients in the United States are admitted to the hospital with burn wounds annually, significant differences exist in the management and treatment of these patients, even among highly specialized burn centers. Some aspects of pediatric burn research, such as metabolic changes and nutritional support after burn injury, have been studied extensively; however, in many aspects of burn care, pediatric research lags behind the study of adult populations. This review compares and contrasts a wide array of physiologic and immune responses between children and adults after burn injury. Such a review elucidates where robust research has been conducted, where adult research is applicable to pediatric patients, and where additional pediatric burn research needs to be conducted.

TRAINED IMMUNITY: A POTENTIAL APPROACH FOR IMPROVING HOST IMMUNITY IN NEONATAL SEPSIS.

ABSTRACT: Sepsis, a dysregulated host immune response to infection, is one of the leading causes of neonatal mortality worldwide. Improved understanding of the perinatal immune system is critical to improve therapies to both term and preterm neonates at increased risk of sepsis. Our narrative outlines the known and unknown aspects of the human immune system through both the immune tolerant in utero period and the rapidly changing antigen-rich period after birth. We will highlight the key differences in innate and adaptive immunity noted through these developmental stages and how the unique immune phenotype in early life contributes to the elevated risk of overwhelming infection and dysregulated immune responses to infection upon exposure to external antigens shortly after birth. Given an initial dependence on neonatal innate immune host responses, we will discuss the concept of innate immune memory, or "trained immunity," and describe several potential immune modulators, which show promise in altering the dysregulated immune response in newborns and improving resilience to sepsis.

A narrative review of ergonomic problems, principles, and potential solutions in surgical operations.

BACKGROUND: Ergonomic development and awareness are critical to the long-term health and well-being of surgeons. Work-related musculoskeletal disorders affect an overwhelming majority of surgeons, and various operative modalities (open, laparoscopic, and robotic surgery) differentially affect the musculoskeletal system. Previous reviews have addressed various aspects of surgical ergonomic history or methods of ergonomic assessment, but the purpose of this study is to synthesize ergonomic analysis by surgical modality while discussing future directions of the field based on current perioperative interventions. METHODS: pubmed was queried for "ergonomics," "work-related musculoskeletal disorders," and "surgery," which returned 124 results. From the 122 English-language papers, a further search was conducted via the articles' sources for relevant literature. RESULTS: Ninety-nine sources were ultimately included. Work-related musculoskeletal disorders culminate in detrimental effects ranging from chronic pain and paresthesias to reduced operative time and consideration for early retirement. Underreporting symptoms and a lack of awareness of proper ergonomic principles substantially hinder the widespread utilization of ergonomic techniques in the operating room, reducing the quality of life and career longevity. Therapeutic interventions exist at some institutions but require further research and development for necessary widespread implementation. CONCLUSION: Awareness of proper ergonomic principles and the detrimental effects of musculoskeletal disorders is the first step in protecting against this universal problem. Implementing ergonomic practices in the operating room is at a crossroads, and incorporating these principles into everyday life must be a priority for all surgeons.