Chronic Critical Illness in Patients With Sepsis is Associated With Persistent Anemia, Inflammation, and Impaired Functional Outcomes.

INTRODUCTION: Survivors of sepsis will progress towards rapid recovery (RAP) or enter a state of persistent organ dysfunction and chronic critical illness (CCI). Independently, anemia is known to be a significant factor in functional recovery of hospitalized patients. This study aims to analyze long-term hemoglobin levels and functional outcomes following RAP and CCI. METHODS: A prospective, cohort study was performed in septic patients who were stratified into RAP (N = 54) with ICU length of stay < 14 days or CCI (N = 63) with ICU length of stay > 14 days. CBC and plasma inflammatory markers were measured on the day of enrollment, weekly until day 42, then at 3 and 6 months. Functional outcomes using Zubrod scale, gait speed test, and total short physical performance battery (SPPB) were assessed at 3, 6, and 12 months. RESULTS: Mean age was 59 years (range: 20-83) and 62% were male. Hemoglobin was significantly decreased at 3 and 6 months in CCI compared to RAP (8.9* and 9.2* vs 10.4 and 11.1 g/dL), despite receiving significantly more red blood cell transfusions. CCI patients had persistent elevation of CRP, IL-6 and TNF-α. CCI patients had worse functional outcome with a significantly higher Zubrod score, and lower SPPB, and gait speed score at 3, 6, and 12 months. CONCLUSION: Despite receiving more pRBC transfusions, CCI patients had a persistent anemia that was associated with chronic systemic inflammation and poor functional outcomes six months following sepsis. Alleviating prolonged inflammation could improve persistent anemia and functional outcomes in CCI patients.

Detection of the Omicron (B.1.1.529) variant of SARS-CoV-2 in aircraft wastewater.

On the 26th of November 2021, the World Health Organization (WHO) designated the newly detected B.1.1.529 lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) the Omicron Variant of Concern (VOC). The genome of the Omicron VOC contains more than 50 mutations, many of which have been associated with increased transmissibility, differing disease severity, and potential to evade immune responses developed for previous VOCs such as Alpha and Delta. In the days since the designation of B.1.1.529 as a VOC, infections with the lineage have been reported in countries around the globe and many countries have implemented travel restrictions and increased border controls in response. We putatively detected the Omicron variant in an aircraft wastewater sample from a flight arriving to Darwin, Australia from Johannesburg, South Africa on the 25th of November 2021 via positive results on the CDC N1, CDC N2, and del(69-70) RT-qPCR assays per guidance from the WHO. The Australian Northern Territory Health Department detected one passenger onboard the flight who was infected with SARS-CoV-2, which was determined to be the Omicron VOC by sequencing of a nasopharyngeal swab sample. Subsequent sequencing of the aircraft wastewater sample using the ARTIC V3 protocol with Nanopore and ATOPlex confirmed the presence of the Omicron variant with a consensus genome that clustered with the B.1.1.529 BA.1 sub-lineage. Our detection and confirmation of a single onboard Omicron infection via aircraft wastewater further bolsters the important role that aircraft wastewater can play as an independent and unintrusive surveillance point for infectious diseases, particularly coronavirus disease 2019.

Ineffective Erythropoietin Response to Anemia in Sepsis.

Background: To determine whether degree of anemia at sepsis onset is predictive of inflammatory cytokine trajectory, erythropoietin response, and recovery. Patients and Methods: Critically ill patients with sepsis were stratified into three groups based on initial hemoglobin (Hgb): Hgb <8 g/dL (severe); 8-10 g/dL (moderate); and >10 g/dL (mild). Granulocyte colony stimulating factor (G-CSF), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), erythropoietin (EPO), and Zubrod scores were measured serially. Results: Thirty-four percent had severe anemia (Hgb, 7.2 ± 0.7g/dL), 35% had moderate anemia (Hgb, 9.1 ± 0.6g/dL), and 31% had mild anemia (Hgb, 11.3 ± 1.1g/dL). All groups experienced persistently high EPO levels without resolution of anemia. IFN-γ and CRP was persistently elevated in all groups. At three, six, and 12 months, the severe anemia group had higher Zubrod scores. Conclusions: Degree of anemia at sepsis onset was not associated with a difference in proinflammatory cytokine trajectory but was associated with a worse functional outcome. Despite initial elevated EPO levels, it did not correlate with resolution of anemia.

Estimated vs measured energy expenditure in ventilated surgical-trauma critically ill patients.

BACKGROUND: The American and European guidelines recommend measuring resting energy expenditure (REE) using indirect calorimetry (IC). Predictive equations (PEs) are used to estimate REE, but there is limited evidence for their use in critically ill patients. The aim of this study is to evaluate the degree of agreement and accuracy between IC-measured REE (REE-IC) and 10 different PEs in mechanically ventilated critically ill patients with surgical trauma who met their estimated energy requirement. METHODS: REE-IC was retrospectively compared with REE-PE by 10 PEs. The degree of agreement between REE-PE and REE-IC was analyzed by the Bland-Altman test (BAt) and the concordance correlation coefficient (CCC). The accuracy was calculated by the percentage of patients whose REE-PE values differ by up to ±10% in relation to REE-IC. All analyses were stratified by gender and body mass index (BMI; <25 vs ≥25). RESULTS: We analyzed 104 patients and the closest estimate to REE-IC was the modified Harris-Benedict equation (mHB) by the BAt with a mean difference of 49.2 overall (61.6 for males, 28.5 for females, 67.5 for BMI <25, and 42.5 for BMI ≥25). The overall CCC between the REE-IC and mHB was 0.652 (0.560 for males, 0.496 for females, 0.570 for BMI <25, and 0.598 for BMI ≥25). The mHB equation was the most accurate with an overall accuracy of 44.2%. CONCLUSION: The effectiveness of PEs for estimating the REE of mechanically ventilated surgical-trauma critically ill patients is limited. [Correction added on 17 February 2022, after first online publication: The word "with" was deleted before "is limited" in the preceding sentence.] Nonetheless, of the 10 equations examined, the closest to REE-IC was the mHB equation.

Older Adults Demonstrate Biomarker Evidence of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) After Sepsis.

BACKGROUND: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression, and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in (i) older (vs young) adults and (ii) older CCI (vs older RAP) patients to gain insight into underlying pathobiology of CCI in older adults. METHOD: Prospective longitudinal study with young (≤45 years) and older (≥65 years) septic adults, who were characterized by (i) baseline predisposition, (ii) hospital outcomes, (iii) serial Sequential Organ Failure Assessment (SOFA) organ dysfunction scores over 14 days, (iv) Zubrod Performance status at 3-, 6-, and 12-month follow-up, and (v) mortality over 12 months, was conducted. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. RESULTS: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status, and mortality over 12 months. Additionally, older (vs young) and older CCI (vs older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism, and antiangiogenesis over 14 days after sepsis. CONCLUSION: Older (vs young) and older CCI (vs older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

Nonocclusive mesenteric ischemia: A rare but lethal complication of enteral nutrition in critically ill patients.

BACKGROUND: The American Society for Parenteral and Enteral Nutrition (ASPEN)/ Society of Critical Care Medicine and the European Society for Clinical Nutrition and Metabolism guidelines recognize that critically ill patients receiving stable, low doses of vasopressors have experienced the advantages of early initiation of enteral nutrition (EN). However, clinical questions remained unanswered including vasopressor combinations associated with complications, the advent of other therapies during hypotensive states, as well as the volume and content of EN that might contribute to the development of a nonocclusive mesenteric ischemia (NOMI). PRESENTATION: A 68-year old male with a history of hypertension, hyperlipidemia, atrial fibrillation, coronary artery disease with two-vessel bypass grafting, and peripheral vascular disease underwent subtotal excision of an infected right axillofemoral-femoral bypass graft. Postoperatively, EN was held because of hemodynamic instability and postsurgical complications. A fiber-free, high-protein, and low-residue formula was started at 10 ml/h while the patient was receiving stable doses of midodrine, norepinephrine, and vasopressin. Despite advancement of tube-feed rates to goal, nasogastric output never exceeded 300 ml. Computerized tomography of the abdomen showed diffuse bowel distention with pneumatosis, concerning for bowel ischemia. No surgical interventions were pursued, and the patient died. CONCLUSIONS: Our patient developed NOMI postoperatively while receiving EN. Further studies addressing EN route, trophic vs full EN, recommended formula, the safety of vasoactive agents, the addition of fiber to EN, and continuous venovenous hemodiafiltration in relation to NOMI are needed, as there continues to be clinical controversy regarding these topics.

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.

A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis.

Background: With the successful implementation of the Surviving Sepsis Campaign guidelines, post-sepsis in-hospital mortality to sepsis continues to decrease. Those who acutely survive surgical sepsis will either rapidly recover or develop a chronic critical illness (CCI). CCI is associated with adverse long-term outcomes and 1-year mortality. Although the pathobiology of CCI remains undefined, emerging evidence suggests a post-sepsis state of pathologic myeloid activation, inducing suboptimal lymphopoiesis and erythropoiesis, as well as downstream leukocyte dysfunction. Our goal was to use single-cell RNA sequencing (scRNA-seq) to perform a detailed transcriptomic analysis of lymphoid-derived leukocytes to better understand the pathology of late sepsis. Methods: A mixture of whole blood myeloid-enriched and Ficoll-enriched peripheral blood mononuclear cells from four late septic patients (post-sepsis day 14-21) and five healthy subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). Results: We identified unique transcriptomic patterns for multiple circulating immune cell subtypes, including B- and CD4+, CD8+, activated CD4+ and activated CD8+ T-lymphocytes, as well as natural killer (NK), NKT, and plasmacytoid dendritic cells in late sepsis patients. Analysis demonstrated that the circulating lymphoid cells maintained a transcriptome reflecting immunosuppression and low-grade inflammation. We also identified transcriptomic differences between patients with bacterial versus fungal sepsis, such as greater expression of cytotoxic genes among CD8+ T-lymphocytes in late bacterial sepsis. Conclusion: Circulating non-myeloid cells display a unique transcriptomic pattern late after sepsis. Non-myeloid leukocytes in particular reveal a host endotype of inflammation, immunosuppression, and dysfunction, suggesting a role for precision medicine-guided immunomodulatory therapy.

A hypolipoprotein sepsis phenotype indicates reduced lipoprotein antioxidant capacity, increased endothelial dysfunction and organ failure, and worse clinical outcomes.

OBJECTIVE: Approximately one-third of sepsis patients experience poor outcomes including chronic critical illness (CCI, intensive care unit (ICU) stay > 14 days) or early death (in-hospital death within 14 days). We sought to characterize lipoprotein predictive ability for poor outcomes and contribution to sepsis heterogeneity. DESIGN: Prospective cohort study with independent replication cohort. SETTING: Emergency department and surgical ICU at two hospitals. PATIENTS: Sepsis patients presenting within 24 h. METHODS: Measures included cholesterol levels (total cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C]), triglycerides, paraoxonase-1 (PON-1), and apolipoprotein A-I (Apo A-I) in the first 24 h. Inflammatory and endothelial markers, and sequential organ failure assessment (SOFA) scores were also measured. LASSO selection assessed predictive ability for outcomes. Unsupervised clustering was used to investigate the contribution of lipid variation to sepsis heterogeneity. MEASUREMENTS AND MAIN RESULTS: 172 patients were enrolled. Most (~ 67%, 114/172) rapidly recovered, while ~ 23% (41/172) developed CCI, and ~ 10% (17/172) had early death. ApoA-I, LDL-C, mechanical ventilation, vasopressor use, and Charlson Comorbidity Score were significant predictors of CCI/early death in LASSO models. Unsupervised clustering yielded two discernible phenotypes. The Hypolipoprotein phenotype was characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1), higher SOFA scores, and worse clinical outcomes (45% rapid recovery, 40% CCI, 16% early death; 28-day mortality, 21%). The Normolipoprotein cluster patients had higher cholesterol levels, less endothelial dysfunction, lower SOFA scores and better outcomes (79% rapid recovery, 15% CCI, 6% early death; 28-day mortality, 15%). Phenotypes were validated in an independent replication cohort (N = 86) with greater sepsis severity, which similarly demonstrated lower HDL-C, ApoA-I, and higher ICAM-1 in the Hypolipoprotein cluster and worse outcomes (46% rapid recovery, 23% CCI, 31% early death; 28-day mortality, 42%). Normolipoprotein patients in the replication cohort had better outcomes (55% rapid recovery, 32% CCI, 13% early death; 28-day mortality, 28%) Top features for cluster discrimination were HDL-C, ApoA-I, total SOFA score, total cholesterol level, and ICAM-1. CONCLUSIONS: Lipoproteins predicted poor sepsis outcomes. A Hypolipoprotein sepsis phenotype was identified and characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1) and organ failure, and worse clinical outcomes.

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.

Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p < 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

The impact of sarcopenia and acute muscle mass loss on long-term outcomes in critically ill patients with intra-abdominal sepsis.

BACKGROUND: Sarcopenia is a known risk factor for poor outcomes across many chronic diseases. The impact on outcomes of both pre-existing sarcopenia and acute muscle wasting (AMW) in acute critical illness caused by sepsis remain unclear. METHODS: We conducted a prospective longitudinal cohort study of critically ill patients with intra-abdominal sepsis utilizing abdominal computed tomography at sepsis onset to determine baseline skeletal muscle index (SMI). Biomarkers of inflammation and catabolism were measured through 28 days while hospitalized. We performed follow-up evaluations of strength and physical function at 3, 6, and 12 months, with interval CT analyses at 3 and 12 months to evaluate changes in muscle mass. Measured clinical outcomes included development of chronic critical illness (≥14 days in intensive care with persistent organ dysfunction), long-term functional status, and 1 year mortality. RESULTS: Among 47 sepsis patients enrolled (mean age 53 ± 14 years), half (n = 23; 49%) were sarcopenic at baseline. Overall, sepsis patients exhibited acute and persistent muscle wasting with an average 8% decrease in SMI from baseline at 3 months (P = 0.0008). Sarcopenic (SAR) and non-sarcopenic (NSAR) groups were similar in regards to age and comorbidity burden. SAR patients had greater acute physiologic derangement (APACHE II, 18 vs. 12.5), higher incidence of multiple organ failure (57% vs. 17%), longer hospital (21 vs. 12 days) and intensive care unit length of stays (13 vs. 4 days), and higher inpatient mortality (17% vs. 0%; all P < 0.05). Pre-existing SAR was a strong independent predictor of early death or developing chronic critical illness (odds ratio 11.87, 95% confidence interval CI 1.88-74.9; P = 0.009, area under the curve 0.880) and was associated with significantly higher risk of 1-year mortality (34.9% vs. 4.2%, p = 0.007). Lower baseline SMI was also predictive of poor functional status at 12 months (OR 0.89, 95% confidence interval 0.80-0.99; p = 0.039, area under the curve 0.867). Additionally, SAR patients had AMW with persistent muscle mass loss at 3 months that was associated with decreased health-related quality of life and SF-36 physical function domains (P < 0.05). Persistent AMW at 3 months was not predictive of mortality or poor functional status, with return to near-baseline muscle mass among sepsis survivors by 6 months. CONCLUSIONS: Critically ill patients have an acute and persistent loss of muscle mass after intra-abdominal sepsis, which is associated with decreased health-related quality of life and physical function at 3 months. However, pre-existing sarcopenia, rather than persistent acute muscle mass loss at 3 months after sepsis, is independently associated with poor long-term functional status and increased 1 year mortality.

Identification of unique microRNA expression patterns in bone marrow hematopoietic stem and progenitor cells after hemorrhagic shock and multiple injuries in young and old adult mice.

BACKGROUND: After severe trauma, the older host experiences more dysfunctional hematopoiesis of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs), and dysfunctional differentiation of circulating myeloid cells into effective innate immune cells. Our main objective was to compare BM HSPC microRNA (miR) responses of old and young mice in a clinically relevant model of severe trauma and shock. METHODS: C57BL/6 adult male mice aged 8 to 12 weeks (young) and 18 to 24 months (old) underwent multiple injuries and hemorrhagic shock (polytrauma [PT]) that engenders the equivalent of major trauma (Injury Severity Score, >15). Pseudomonas pneumonia (PNA) was induced in some young and old adult mice 24 hours after PT. MicroRNA expression patterns were determined from lineage-negative enriched BM HSPCs isolated from PT and PT-PNA mice at 24 and 48 hours postinjury, respectively. Genome-wide expression and pathway analyses were also performed on bronchoalveolar lavage (BAL) leukocytes from both mouse cohorts. RESULTS: MicroRNA expression significantly differed among all experimental conditions (p < 0.05), except for old-naive versus old-injured (PT or PT-PNA) mice, suggesting an inability of old mice to mount a robust early miR response to severe shock and injury. In addition, young adult mice had significantly more leukocytes obtained from their BAL, and there were greater numbers of polymorphonuclear cells compared with old mice (59.8% vs. 2.2%, p = 0.0069). Despite increased gene expression changes, BAL leukocytes from old mice demonstrated a more dysfunctional transcriptomic response to PT-PNA than young adult murine BAL leukocytes, as reflected in predicted upstream functional pathway analysis. CONCLUSION: The miR expression pattern in BM HSPCs after PT (+/-PNA) is dissimilar in old versus young adult mice. In the acute postinjury phase, old adult mice are unable to mount a robust miR HSPC response. Hematopoietic stem and progenitor cell miR expression in old PT mice reflects a diminished functional status and a blunted capacity for terminal differentiation of myeloid cells.

Chronic Critical Illness and PICS Nutritional Strategies.

The nutritional hallmark of chronic critical illness (CCI) after sepsis is persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which results in global resistance to the anabolic effect of nutritional supplements. This ultimately leaves these patients in a downward phenotypic spiral characterized by cachexia with profound weakness, decreased capacity for rehabilitation, and immunosuppression with the propensity for sepsis recidivism. The persistent catabolism is driven by a pathologic low-grade inflammation with the inability to return to homeostasis and by ongoing increased energy expenditure. Better critical care support systems and advances in technology have led to increased intensive care unit (ICU) survival, but CCI due to PICS with poor long-term outcomes has emerged as a frequent phenotype among ICU sepsis survivors. Unfortunately, therapies to mitigate or reverse PICS-CCI are limited, and recent evidence supports that these patients fail to respond to early ICU evidence-based nutrition protocols. A lack of randomized controlled trials has limited strong recommendations for nutrition adjuncts in these patients. However, based on experience in other conditions characterized by a similar phenotype, immunonutrients aimed at counteracting inflammation, immunosuppression, and catabolism may be important for improving outcomes in PICS-CCI patients. This manuscript intends to review several immunonutrients as adjunctive therapies in treating PICS-CCI.

Lipid and lipoprotein predictors of functional outcomes and long-term mortality after surgical sepsis.

RATIONALE: Sepsis is a life-threatening, dysregulated response to infection. Lipid biomarkers including cholesterol are dynamically regulated during sepsis and predict short-term outcomes. In this study, we investigated the predictive ability of lipid biomarkers for physical function and long-term mortality after sepsis. METHODS: Prospective cohort study of sepsis patients admitted to a surgical intensive-care unit (ICU) within 24 h of sepsis bundle initiation. Samples were obtained at enrollment for lipid biomarkers. Multivariate regression models determined independent risk factors predictive of poor performance status (Zubrod score of 3/4/5) or survival at 1-year follow-up. MEASUREMENTS AND MAIN RESULTS: The study included 104 patients with surgical sepsis. Enrollment total cholesterol and high-density lipoprotein (HDL-C) levels were lower, and myeloperoxidase (MPO) levels were higher for patients with poor performance status at 1 year. A similar trend was seen in comparisons based on 1-year mortality, with HDL-C and ApoA-I levels being lower and MPO levels being higher in non-survivors. However, multivariable logistic regression only identified baseline Zubrod and initial SOFA score as significant independent predictors of poor performance status at 1 year. Multivariable Cox regression modeling for 1-year survival identified high Charlson comorbidity score, low ApoA-I levels, and longer vasopressor duration as predictors of mortality over 1-year post-sepsis. CONCLUSIONS: In this surgical sepsis study, lipoproteins were not found to predict poor performance status at 1 year. ApoA-I levels, Charlson comorbidity scores, and duration of vasopressor use predicted 1 year survival. These data implicate cholesterol and lipoproteins as contributors to the underlying pathobiology of sepsis.

Enteral Nutrition Administration Record Prescribing Process Using Computerized Order Entry: A New Paradigm and Opportunities to Improve Outcomes in Critically Ill Patients.

BACKGROUND: Prevalence of malnutrition has been reported in 60% of hospitalized and up to 78% of patients admitted to intensive care units. Malnutrition has been associated with complications, such as infection, increased hospital length of stay, morbidity, and mortality. Nutritional support has been shown to reduce avoidable readmissions, pressure ulcers, malpractice claims, and hospital costs. Creating a new electronic nutrition administration record (ENAR) with a linked nutrition tab within the electronic health record (EHR) would promote enhanced patient outcomes by improving adherence to established institutional enteral nutrition (EN) protocols and achieving early energy goals. Additionally, it would enable a clear and standardized method for documentation and administration of EN therapy. METHODS: The multidisciplinary nutrition support team was established and met on a weekly basis to discuss strategies and barriers, identify stakeholders, evaluate the current state, and establish a process and workflow from the point of order entry, delivery, administration, and electronic documentation of orders of EN supplements. The aim of this article is to describe a systematic approach and process of creating a new ENAR with a linked nutrition tab in the EHR, and to illustrate the order panel built and lessons learned from the process. RESULTS: A separate nutrition tab was created in the EHR with minimal disruption in patient care and end-users' positive feedback for the new order panel. CONCLUSION: ENAR allows for easier data collection and promotes nutrition-related research that may result in enhanced patient care. Utilizing technology to build a full ENAR would result in optimized patient care and safety.

Single-Cell RNA-seq of Human Myeloid-Derived Suppressor Cells in Late Sepsis Reveals Multiple Subsets With Unique Transcriptional Responses: A Pilot Study.

BACKGROUND: Increased circulating myeloid-derived suppressor cells (MDSCs) are independently associated with poor long-term clinical outcomes in sepsis. Studies implicate subsets of MDSCs having unique roles in lymphocyte suppression; however, characterization of these cells after sepsis remains incomplete. We performed a pilot study to determine the transcriptomic landscape in MDSC subsets in sepsis using single-cell RNAseq (scRNA-seq). METHODS: A mixture of whole blood myeloid-enriched and Ficoll-enriched PBMCs from two late septic patients on post-sepsis day 21 and two control subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). RESULTS: We successfully identified the three MDSC subset clusters-granulocytic (G-), monocytic (M-), and early (E-) MDSCs. Sepsis was associated with a greater relative expansion of G-MDSCs versus M-MDSCs at 21 days as compared to control subjects. Genomic analysis between septic patients and control subjects revealed cell-specific and common differential expression of genes in both G-MDSC and M-MDSC subsets. Many of the common genes have previously been associated with MDSC proliferation and immunosuppressive function. Interestingly, there was no differential expression of several genes demonstrated in the literature to be vital to immunosuppression in cancer-induced MDSC. CONCLUSION: This pilot study successfully demonstrated that MDSCs maintain a transcriptomic profile that is immunosuppressive in late sepsis. Interestingly, the landscape in chronic critical illness is partially dependent on the original septic insult. Preliminary data would also indicate immunosuppressive MDSCs from late sepsis patients appear to have a somewhat unique transcriptome from cancer and/or other inflammatory diseases.

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.