Persistence and Sexual Dimorphism of Gut Dysbiosis and Pathobiome after Sepsis and Trauma.

OBJECTIVE: To evaluate the persistence of intestinal microbiome dysbiosis and gut-plasma metabolomic perturbations following severe trauma or sepsis weeks after admission in patients experiencing chronic critical illness (CCI). SUMMARY: Trauma and sepsis can lead to gut dysbiosis and alterations in the plasma and fecal metabolome. However, the impact of these perturbations and correlations between gut dysbiosis and the plasma metabolome in chronic critical illness have not been studied. METHODS: A prospective observational cohort study was performed with healthy subjects, severe trauma patients, patients with sepsis residing in an intensive care unit (ICU) for 2-3 weeks. A high-throughput multi-omics approach was utilized to evaluate the gut microbial and gut-plasma metabolite responses in critically ill trauma and sepsis patients 14-21 days after ICU admission. RESULTS: Patients in the sepsis and trauma cohorts demonstrated strikingly depleted gut microbiome diversity, with significant alterations and specific pathobiome patterns in the microbiota composition compared to healthy subjects. Further subgroup analyses based on sex revealed resistance to changes in microbiome diversity among female trauma patients compared to healthy counterparts. Sex-specific changes in fecal metabolites were also observed after trauma and sepsis, while plasma metabolite changes were similar in both males and females. CONCLUSIONS: Dysbiosis induced by trauma and sepsis persists up to 14-21 days after onset and is sex-specific, underscoring the implication of pathobiome and entero-septic microbial-metabolite perturbations in post-sepsis and post-trauma CCI. This indicates resilience to infection or injury in females' microbiome and should inform and facilitate future precision/personalized medicine strategies in the intensive care unit.

Multicompartmental Trauma Induces Persistent Inflammation and Organ Injury.

INTRODUCTION: Previous preclinical models of multicompartmental injury have investigated its effects for durations of less than 72 h and the long-term effects have not been defined. We hypothesized that a model of multicompartmental injury would result in systemic inflammation and multiorgan dysfunction that persists at 1 wk. METHODS: Male and proestrus female Sprague-Dawley rats (n = 16/group) underwent polytrauma (PT) (unilateral right lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofractures) and were compared to naive controls. Weight, hemoglobin, plasma neutrophil gelatinase-associated lipocalin, and plasma toll-like receptor 4 were evaluated on days two and seven. Bilateral lungs were sectioned, stained and assessed for injury at day seven. Comparisons were performed in Graphpad with significance defined as ∗P <0.05. RESULTS: Rats who underwent PT had significant weight loss and anemia at day 2 (P = 0.001) compared to naïve rats which persisted at day 7 (P = 0.001). PT rats had elevated plasma neutrophil gelatinase-associated lipocalin at day 2 compared to naïve (P <0.0001) which remained elevated at day 7 (P <0.0001). Plasma toll-like receptor 4 was elevated in PT compared to naïve at day 2 (P = 0.03) and day 7 (P = 0.01). Bilateral lungs showed significant injury in PT cohorts at day 7 compared to naïve (P <0.0004). PT males had worse renal function at day seven compared to females (P = 0.02). CONCLUSIONS: Multicompartmental trauma induces systemic inflammation and multiorgan dysfunction without recovery by day seven. However, females demonstrate improved renal recovery compared to males. Long-term assessment of preclinical PT models are crucial to better understand and evaluate future therapeutic immunomodulatory and anti-inflammatory treatments.

Gut mycobiome dysbiosis after sepsis and trauma.

BACKGROUND: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. METHODS: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. RESULTS: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. CONCLUSIONS: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients.

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.

Postoperative Overtriage to an Intensive Care Unit Is Associated With Low Value of Care.

OBJECTIVE: We test the hypothesis that for low-acuity surgical patients, postoperative intensive care unit (ICU) admission is associated with lower value of care compared with ward admission. BACKGROUND: Overtriaging low-acuity patients to ICU consumes valuable resources and may not confer better patient outcomes. Associations among postoperative overtriage, patient outcomes, costs, and value of care have not been previously reported. METHODS: In this longitudinal cohort study, postoperative ICU admissions were classified as overtriaged or appropriately triaged according to machine learning-based patient acuity assessments and requirements for immediate postoperative mechanical ventilation or vasopressor support. The nearest neighbors algorithm identified risk-matched control ward admissions. The primary outcome was value of care, calculated as inverse observed-to-expected mortality ratios divided by total costs. RESULTS: Acuity assessments had an area under the receiver operating characteristic curve of 0.92 in generating predictions for triage classifications. Of 8592 postoperative ICU admissions, 423 (4.9%) were overtriaged. These were matched with 2155 control ward admissions with similar comorbidities, incidence of emergent surgery, immediate postoperative vital signs, and do not resuscitate order placement and rescindment patterns. Compared with controls, overtraiged admissions did not have a lower incidence of any measured complications. Total costs for admission were $16.4K for overtriage and $15.9K for controls ( P =0.03). Value of care was lower for overtriaged admissions [2.9 (2.0-4.0)] compared with controls [24.2 (14.1-34.5), P <0.001]. CONCLUSIONS: Low-acuity postoperative patients who were overtriaged to ICUs had increased total costs, no improvements in outcomes, and received low-value care.

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.

Defining critical illness using immunological endotypes in patients with and without sepsis: a cohort study.

BACKGROUND: Sepsis is a heterogenous syndrome with limited therapeutic options. Identifying immunological endotypes through gene expression patterns in septic patients may lead to targeted interventions. We investigated whether patients admitted to a surgical intensive care unit (ICU) with sepsis and with high risk of mortality express similar endotypes to non-septic, but still critically ill patients using two multiplex transcriptomic metrics obtained both on admission to a surgical ICU and at set intervals. METHODS: We analyzed transcriptomic data from 522 patients in two single-site, prospective, observational cohorts admitted to surgical ICUs over a 5-year period ending in July 2020. Using an FDA-cleared analytical platform (nCounter FLEX®, NanoString, Inc.), we assessed a previously validated 29-messenger RNA transcriptomic classifier for likelihood of 30-day mortality (IMX-SEV-3) and a 33-messenger RNA transcriptomic endotype classifier. Clinical outcomes included all-cause mortality, development of chronic critical illness, and secondary infections. Univariate and multivariate analyses were performed to assess for true effect and confounding. RESULTS: Sepsis was associated with a significantly higher predicted and actual hospital mortality. At enrollment, the predominant endotype for both septic and non-septic patients was adaptive, though with significantly different distributions. Inflammopathic and coagulopathic septic patients, as well as inflammopathic non-septic patients, showed significantly higher frequencies of secondary infections compared to those with adaptive endotypes (p < 0.01). Endotypes changed during ICU hospitalization in 57.5% of patients. Patients who remained adaptive had overall better prognosis, while those who remained inflammopathic or coagulopathic had worse overall outcomes. For severity metrics, patients admitted with sepsis and a high predicted likelihood of mortality showed an inflammopathic (49.6%) endotype and had higher rates of cumulative adverse outcomes (67.4%). Patients at low mortality risk, whether septic or non-septic, almost uniformly presented with an adaptive endotype (100% and 93.4%, respectively). CONCLUSION: Critically ill surgical patients express different and evolving immunological endotypes depending upon both their sepsis status and severity of their clinical course. Future studies will elucidate whether endotyping critically ill, septic patients can identify individuals for targeted therapeutic interventions to improve patient management and outcomes.

Clinical Trajectories of Acute Kidney Injury in Surgical Sepsis: A Prospective Observational Study.

OBJECTIVE: To characterize endothelial function, inflammation, and immunosuppression in surgical patients with distinct clinical trajectories of AKI and to determine the impact of persistent kidney injury and renal non-recovery on clinical outcomes, resource utilization, and long-term disability and survival. SUMMARY OF BACKGROUND DATA: AKI is associated with increased healthcare costs and mortality. Trajectories that account for duration and recovery of AKI have not been described for sepsis patients, who are uniquely vulnerable to renal dysfunction. METHODS: This prospective observational study included 239 sepsis patients admitted and enrolled between January 2015 and July 2017. Kidney Disease: Improving Global Outcomes (KDIGO) and Acute Disease Quality Initiative (ADQI) criteria were used to classify subjects as having no AKI, rapidly reversed AKI, persistent AKI with renal recovery, or persistent AKI without renal recovery. Serial biomarker profiles, clinical outcomes, resource utilization, and long-term physical performance status and survival were compared among AKI trajectories. RESULTS: Sixty-two percent of the study population developed AKI. Only one-third of AKI episodes rapidly reversed within 48 hours; the remaining had persistent AKI, among which 57% did not have renal recovery by discharge. One-year survival and proportion of subjects fully active 1 year after sepsis was lowest among patients with persistent AKI compared with other groups. Long-term mortality hazard rates were 5-fold higher for persistent AKI without renal recovery compared with no AKI. CONCLUSIONS: Among critically ill surgical sepsis patients, persistent AKI and the absence of renal recovery are associated with distinct early and sustained immunologic and endothelial biomarker signatures and decreased long-term physical function and survival.

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis.

Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community-acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human-focused and artificial intelligence-based forms of research in order to improve septic patients' morbidity and mortality.

Biomarker Evidence of the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) in Chronic Critical Illness (CCI) After Surgical Sepsis.

OBJECTIVE: To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. BACKGROUND: Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. METHODS: PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. RESULTS: CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). CONCLUSIONS: Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.

Prolonged Chronic Stress and Persistent Iron Dysregulation Prevent Anemia Recovery Following Trauma.

Introduction Following major trauma, persistent injury-associated anemia is associated with organ failure, increased length of stay and mortality. We hypothesize that prolonged adrenergic stimulation following trauma is directly responsible for persistent iron dysfunction that impairs anemia recovery. Materials and Methods Naïve rodents, lung contusion and hemorrhagic shock followed by daily handling for 13 d (LCHS), LCHS followed by 6 d of restraint stress and 7 d of daily handling (LCHS/CS-7) and LCHS/CS followed by 13 d of restraint stress with day and/or night disruption (LCHS/CS-14) were sacrificed on day 14. Hemoglobin, plasma, urine, bone marrow/liver inflammatory and erythropoietic markers were analyzed. Results LCHS/CS-14 led to a significant decline in weight gain and persistently elevated plasma and urine inflammatory markers. Liver IL-6, IL-1ß and hepcidin expression were significantly increased following LCHS/CS-14. LCHS/CS-14 also had impaired anemia recovery with reduced plasma transferrin and erythropoietin receptor expression. Conclusion Prolonged chronic stress following trauma/hemorrhagic shock led to sustained inflammation with increased expression of IL-1ß, IL-6 and hepcidin with decreased iron availability for uptake into erythroid progenitor cells and a lack of anemia recovery.

Mediators of Prolonged Hematopoietic Progenitor Cell Mobilization After Severe Trauma.

BACKGROUND: This study investigated the molecular mediators of prolonged hematopoietic progenitor cell mobilization a trauma and chronic stress and the role of propranolol in modifying this response. METHODS: Sprague-Dawley rats were randomized to lung contusion (LC), LC plus hemorrhagic shock (LCHS), or LCHS with daily restraint stress (LCHS/CS). Propranolol was administered daily. Bone marrow (BM) and lung expression of high mobility group box 1 (HMGB1), granulocyte colony-stimulating factor (G-CSF), neutrophil elastase, stromal cell-derived factor 1 (SDF-1)/CXR4, and vascular cell adhesion protein 1 (VCAM-1)/very late antigen-4 were measured by real-time polymerase chain reaction. RESULTS: Bone marrow HMGB1, G-CSF, and neutrophil elastase expression were significantly elevated two- to four-fold after LCHS/CS, and all were decreased with the use of propranolol. SDF-1 and VCAM-1 were both significantly decreased after LCHS/CS. CONCLUSIONS: The increased expression of HMGB1 and G-CSF and decreased expression of BM anchoring molecules, SDF-1 and VCAM-1, after LCHS/CS, likely mediates prolonged hematopoietic progenitor cell mobilization. Propranolol's ability to reduce HMGB1, G-CSF, and neutrophil elastase expression suggests that the mobilization of hematopoietic progenitor cells was driven by persistent hypercatecholaminemia.

Impact of Injury Severity on the Inflammatory State and Severe Anemia.

BACKGROUND: Severe traumatic injury is a major cause of morbidity and mortality. Our goal was to analyze blunt traumatic injury by injury severity score (ISS) and compare with elective hip repair, as a transient injury, and healthy control with the hypothesis that more severe injury would lead to an increase in neuroendocrine activation, systemic inflammation, and worse anemia. MATERIALS AND METHODS: A prospective observational cohort study was performed at a level 1 trauma center, comparing blunt trauma patients (n = 37), elective hip replacement patients (n = 26), and healthy controls (n = 8). Bone marrow and plasma were assessed for hyperadrenergic state, erythropoiesis, and systemic inflammation. Trauma patient's ISS ranged from 4 to 41 and were broken down into quartiles for analysis. The ISS quartiles were 4-13, 14-20, 21-26, and 27-41. RESULTS: Plasma norepinephrine, interleukin-6, tumor necrosis factor-alpha, and hepcidin increased progressively as ISS increased. Hemoglobin significantly decreased as ISS increased and packed red blood cell (pRBC) transfusion increased as ISS increased. Elective hip replacement patients had an appropriate increase in the bone marrow expression of erythropoietin and the erythropoietin receptor, which was absent in all trauma patient groups. CONCLUSIONS: Increased neuroendocrine activation, systemic inflammation, and anemia correlated with worsening injury severity, lower age, and increased pRBC transfusions. Elective hip replacement patients have only minimal systemic inflammation with an appropriate bone marrow response to anemia. This study demonstrates a link between injury severity, neuroendocrine activation, systemic inflammation, and the bone marrow response to anemia.

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study.

BACKGROUND: The role of site of infection in sepsis has been poorly characterized. Additionally, sepsis epidemiology has evolved. Early mortality has decreased, but many survivors now progress into chronic critical illness (CCI). This study sought to determine if there were significant differences in the host response and current epidemiology of surgical sepsis categorized by site of infection. STUDY DESIGN: This is a longitudinal study of surgical sepsis patients characterized by baseline predisposition, insult characteristics, serial biomarkers, hospital outcomes, and long-term outcomes. Patients were categorized into five anatomic sites of infection. RESULTS: The 316 study patients were predominantly Caucasian; half were male, with a mean age of 62 years, high comorbidity burden, and low 30-day mortality (10%). The primary sites were abdominal (44%), pulmonary (19%), skin/soft tissue (S/ST, 17%), genitourinary (GU, 12%), and vascular (7%). Most abdominal infections were present on admission and required source control. Comparatively, they had more prolonged proinflammation, immunosuppression, and persistent organ dysfunction. Their long-term outcome was poor with 37% CCI (defined as > 14 in ICU with organ dysfunction), 49% poor discharge dispositions, and 30% 1-year mortality. Most pulmonary infections were hospital-acquired pneumonia. They had similar protracted proinflammation and organ dysfunction, but immunosuppression normalized. Long-term outcomes are similarly poor (54% CCI, 47% poor disposition, 32% 1-year mortality). S/ST and GU infections occurred in younger patients with fewer comorbidities, less perturbed immune responses, and faster resolution of organ dysfunction. Comparatively, S/ST had better long-term outcomes (23% CCI, 39% poor disposition, 13% 1-year mortality) and GU had the best (10% CCI, 20% poor disposition, 10% 1-year mortality). Vascular sepsis patients were older males, with more comorbidities. Proinflammation was blunted with baseline immunosuppression and organ dysfunction that persisted. They had the worst long-term outcomes (38% CCI, 67% poor disposition, 57% 1-year mortality). CONCLUSION: There are notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection in surgical sepsis. While previous studies have focused on differences in hospital mortality, this study provides unique insights into the host response and long-term outcomes associated with different sites of infection.

Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes.

OBJECTIVE: We sought to compare traditional inpatient outcomes to long-term functional outcomes and mortality of surgical intensive care unit (SICU) patients with sepsis. SUMMARY OF BACKGROUND DATA: As inpatient sepsis mortality declines, an increasing number of initial sepsis survivors now progress into a state of chronic critical illness (CCI) and their post-discharge outcomes are unclear. METHODS: We performed a prospective, longitudinal cohort study of SICU patients with sepsis. RESULTS: Among this recent cohort of 301 septic SICU patients, 30-day mortality was 9.6%. Only 13 (4%) patients died within 14 days, primarily of refractory multiple organ failure (62%). The majority (n = 189, 63%) exhibited a rapid recovery (RAP), whereas 99 (33%) developed CCI. CCI patients were older, with greater comorbidities, and more severe and persistent organ dysfunction than RAP patients (all P < 0.01). At 12 months, overall cohort performance status was persistently worse than presepsis baseline (WHO/Zubrod score 1.4 ±â€Š0.08 vs 2.2 ±â€Š0.23, P > 0.0001) and mortality was 20.9%. Of note at 12 months, the CCI cohort had persistent severely impaired performance status and a much higher mortality (41.4%) than those with RAP (4.8%) after controlling for age and comorbidity burden (Cox hazard ratio 1.27; 95% confidence interval, 1.14-1.41, P < 0.0001). Among CCI patients, independent risk factors for death by 12 months included severity of comorbidities and persistent organ dysfunction (sequential organ failure assessment ≥6) at day 14 after sepsis onset. CONCLUSIONS: There is discordance between low inpatient mortality and poor long-term outcomes after surgical sepsis, especially among older adults, increasing comorbidity burden and patients that develop CCI. This represents important information when discussing expected outcomes of surgical patients who experience a complicated clinical course owing to sepsis.

MySurgeryRisk: Development and Validation of a Machine-learning Risk Algorithm for Major Complications and Death After Surgery.

OBJECTIVE: To accurately calculate the risk for postoperative complications and death after surgery in the preoperative period using machine-learning modeling of clinical data. BACKGROUND: Postoperative complications cause a 2-fold increase in the 30-day mortality and cost, and are associated with long-term consequences. The ability to precisely forecast the risk for major complications before surgery is limited. METHODS: In a single-center cohort of 51,457 surgical patients undergoing major inpatient surgery, we have developed and validated an automated analytics framework for a preoperative risk algorithm (MySurgeryRisk) that uses existing clinical data in electronic health records to forecast patient-level probabilistic risk scores for 8 major postoperative complications (acute kidney injury, sepsis, venous thromboembolism, intensive care unit admission >48 hours, mechanical ventilation >48 hours, wound, neurologic, and cardiovascular complications) and death up to 24 months after surgery. We used the area under the receiver characteristic curve (AUC) and predictiveness curves to evaluate model performance. RESULTS: MySurgeryRisk calculates probabilistic risk scores for 8 postoperative complications with AUC values ranging between 0.82 and 0.94 [99% confidence intervals (CIs) 0.81-0.94]. The model predicts the risk for death at 1, 3, 6, 12, and 24 months with AUC values ranging between 0.77 and 0.83 (99% CI 0.76-0.85). CONCLUSIONS: We constructed an automated predictive analytics framework for machine-learning algorithm with high discriminatory ability for assessing the risk of surgical complications and death using readily available preoperative electronic health records data. The feasibility of this novel algorithm implemented in real time clinical workflow requires further testing.

The Development of Chronic Critical Illness Determines Physical Function, Quality of Life, and Long-Term Survival Among Early Survivors of Sepsis in Surgical ICUs.

OBJECTIVES: This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness. DESIGN: Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes. SETTING: Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center. PATIENTS: Adult critically ill patients that survived 14 days or longer after sepsis onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures. CONCLUSIONS: Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.

Old Mice Demonstrate Organ Dysfunction as well as Prolonged Inflammation, Immunosuppression, and Weight Loss in a Modified Surgical Sepsis Model.

OBJECTIVES: Our goal was to "reverse translate" the human response to surgical sepsis into the mouse by modifying a widely adopted murine intra-abdominal sepsis model to engender a phenotype that conforms to current sepsis definitions and follows the most recent expert recommendations for animal preclinical sepsis research. Furthermore, we aimed to create a model that allows the study of aging on the long-term host response to sepsis. DESIGN: Experimental study. SETTING: Research laboratory. SUBJECTS: Young (3-5 mo) and old (18-22 mo) C57BL/6j mice. INTERVENTIONS: Mice received no intervention or were subjected to polymicrobial sepsis with cecal ligation and puncture followed by fluid resuscitation, analgesia, and antibiotics. Subsets of mice received daily chronic stress after cecal ligation and puncture for 14 days. Additionally, modifications were made to ensure that "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" recommendations were followed. MEASUREMENTS AND MAIN RESULTS: Old mice exhibited increased mortality following both cecal ligation and puncture and cecal ligation and puncture + daily chronic stress when compared with young mice. Old mice developed marked hepatic and/or renal dysfunction, supported by elevations in plasma aspartate aminotransferase, blood urea nitrogen, and creatinine, 8 and 24 hours following cecal ligation and puncture. Similar to human sepsis, old mice demonstrated low-grade systemic inflammation 14 days after cecal ligation and puncture + daily chronic stress and evidence of immunosuppression, as determined by increased serum concentrations of multiple pro- and anti-inflammatory cytokines and chemokines when compared with young septic mice. In addition, old mice demonstrated expansion of myeloid-derived suppressor cell populations and sustained weight loss following cecal ligation and puncture + daily chronic stress, again similar to the human condition. CONCLUSIONS: The results indicate that this murine cecal ligation and puncture + daily chronic stress model of surgical sepsis in old mice adhered to current Minimum Quality Threshold in Pre-Clinical Sepsis Studies guidelines and met Sepsis-3 criteria. In addition, it effectively created a state of persistent inflammation, immunosuppression, and weight loss, thought to be a key aspect of chronic sepsis pathobiology and increasingly more prevalent after human sepsis.

Systemic Regulation of Bone Marrow Stromal Cytokines After Severe Trauma.

BACKGROUND: Traumatic injury generates a prolonged hypercatecholamine state that is associated with reduced growth of bone marrow erythroid progenitors mediated by the bone marrow stroma. The bone marrow stroma is made up of many cells including fibroblasts, which respond to inflammatory stimuli and alter the cytokine profile. We hypothesized that trauma plasma would increase bone marrow stromal fibroblast expression of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), stem cell factor (SCF), and activation of nuclear factor kappa-light-chain-enhancer of activated B cells and correlate with injury severity and anemia. MATERIALS AND METHODS: Plasma from 15 trauma patients was cultured with bone marrow fibroblast cells and compared with that from healthy volunteers. At 6, 24, and 48 h, the expression of IL-6, G-CSF, EPO, SCF, and the activation of nuclear factor kappa-light-chain-enhancer of activated B cells were measured using quantitative polymerase chain reaction. The influence of trauma plasma on cytokine expression was further stratified by injury severity score (ISS). RESULTS: The average hemoglobin significantly decreased from admission to discharge (10.7 ± 2.5 to 9.2 ± 1.1 g/dL, P < 0.04). The discharge hemoglobin significantly decreased by 14% from the admission hemoglobin. After 48 h, trauma plasma significantly increased IL-6, G-CSF, and EPO bone marrow fibroblast expression when compared with normal plasma. When stratified by ISS, IL-6, G-CSF, and EPO, bone marrow fibroblast expression was highest in the trauma plasma ISS 27-41 group and was significantly elevated compared with normal plasma. When SCF expression was stratified by ISS, there was a significant increase in expression in ISS 27-41. Higher ISS was also associated with a larger decrease in hemoglobin despite no difference in total blood transfusions. CONCLUSIONS: Severe trauma can systemically increase IL-6, G-CSF, and EPO expression in bone marrow stroma. Increased hematopoietic cytokine expression after traumatic injury correlated with a hypercatecholamine state, anemia, and injury severity.

Prognostic value of NT-proBNP levels in the acute phase of sepsis on lower long-term physical function and muscle strength in sepsis survivors.

BACKGROUND: Sepsis survivors often develop chronic critical illness (CCI) and demonstrate the persistent inflammation, immunosuppression, and catabolism syndrome predisposing them to long-term functional limitations and higher mortality. There is a need to identify biomarkers that can predict long-term worsening of physical function to be able to act early and prevent mobility loss. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-accepted biomarker of cardiac overload, but it has also been shown to be associated with long-term physical function decline. We explored whether NT-proBNP blood levels in the acute phase of sepsis are associated with physical function and muscle strength impairment at 6 and 12 months after sepsis onset. METHODS: This is a retrospective analysis conducted in 196 sepsis patients (aged 18-86 years old) as part of the University of Florida (UF) Sepsis and Critical Illness Research Center (SCIRC) who consented to participate in the 12-month follow-up study. NT-proBNP was measured at 24 h after sepsis onset. Patients were followed to determine physical function by short physical performance battery (SPPB) test score (scale 0 to12-higher score corresponds with better physical function) and upper limb muscle strength by hand grip strength test (kilograms) at 6 and 12 months. We used a multivariate linear regression model to test an association between NT-proBNP levels, SPPB, and hand grip strength scores. Missing follow-up data or absence due to death was accounted for by using inverse probability weighting based on concurrent health performance status scores. Statistical significance was set at p ≤ 0.05. RESULTS: After adjusting for covariates (age, gender, race, Charlson comorbidity index, APACHE II score, and presence of CCI condition), higher levels of NT-proBNP at 24 h after sepsis onset were associated with lower SPPB scores at 12 months (p < 0.05) and lower hand grip strength at 6-month (p < 0.001) and 12-month follow-up (p < 0.05). CONCLUSIONS: NT-proBNP levels during the acute phase of sepsis may be a useful indicator of higher risk of long-term impairments in physical function and muscle strength in sepsis survivors.