Weight-based enoxaparin thromboprophylaxis in young trauma patients: analysis of the CLOTT-1 registry.

Introduction: Optimal venous thromboembolism (VTE) enoxaparin prophylaxis dosing remains elusive. Weight-based (WB) dosing safely increases anti-factor Xa levels without the need for routine monitoring but it is unclear if it leads to lower VTE risk. We hypothesized that WB dosing would decrease VTE risk compared with standard fixed dosing (SFD). Methods: Patients from the prospective, observational CLOTT-1 registry receiving prophylactic enoxaparin (n=5539) were categorized as WB (0.45-0.55 mg/kg two times per day) or SFD (30 mg two times per day, 40 mg once a day). Multivariate logistic regression was used to generate a predicted probability of VTE for WB and SFD patients. Results: Of 4360 patients analyzed, 1065 (24.4%) were WB and 3295 (75.6%) were SFD. WB patients were younger, female, more severely injured, and underwent major operation or major venous repair at a higher rate than individuals in the SFD group. Obesity was more common among the SFD group. Unadjusted VTE rates were comparable (WB 3.1% vs. SFD 3.9%; p=0.221). Early prophylaxis was associated with lower VTE rate (1.4% vs. 5.0%; p=0.001) and deep vein thrombosis (0.9% vs. 4.4%; p<0.001), but not pulmonary embolism (0.7% vs. 1.4%; p=0.259). After adjustment, VTE incidence did not differ by dosing strategy (adjusted OR (aOR) 0.75, 95% CI 0.38 to 1.48); however, early administration was associated with a significant reduction in VTE (aOR 0.47, 95% CI 0.30 to 0.74). Conclusion: In young trauma patients, WB prophylaxis is not associated with reduced VTE rate when compared with SFD. The timing of the initiation of chemoprophylaxis may be more important than the dosing strategy. Further studies need to evaluate these findings across a wider age and comorbidity spectrum. Level of evidence: Level IV, therapeutic/care management.

Predicting high-intensity resuscitation needs in injured patients in the post-hemostasis phase of care following intervention.

BACKGROUND: Best resuscitation practices in the posthemostasis phase of care are poorly defined; this phase of care is characterized by a range of physiologic derangements and multiple therapeutic modalities used to address them. Using a cohort of injured patients who required an immediate intervention in the operating room or angiography suite following arrival to the emergency department, we sought to define high-intensity resuscitation (HIR) in this posthemostasis phase of care; we hypothesized that those who would require HIR could be identified, using only data available at intensive care unit (ICU) admission. METHODS: Clinical data were extracted for consecutive injured patients (2016-2019) admitted to the ICU following an immediate procedure in the operating room or angiography suite. High-intensity resuscitation thresholds were defined as the top decile of blood product (≥3 units) and/or crystalloid (≥4 L) use in the initial 12 hours of ICU care and/or vasoactive medication use between ICU hours 2 and 12. The primary outcome, HIR, was a composite of any of these modalities. Predictive modeling of HIR was performed using logistic regression with predictor variables selected using Least Absolute Shrinkage and Selection Operator (LASSO) estimation. Model was trained using 70% of the cohort and tested on the remaining 30%; model predictive ability was evaluated using area under receiver operator curves. RESULTS: Six hundred five patients were included. Patients were 79% male, young (median age, 39 years), severely injured (median Injury Severity Score, 26), and an approximately 3:2 ratio of blunt to penetrating mechanisms of injury. A total of 215 (36%) required HIR. Predictors selected by LASSO included: shock index, lactate, base deficit, hematocrit, and INR. The area under receiver operator curve for the LASSO-derived HIR prediction model was 0.82. CONCLUSION: Intensive care unit admission data can identify subsequent HIR in the posthemostasis phase of care. Use of this model may facilitate triage, nursing ratio determination, and resource allocation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Evaluation of a Multivalent Transcriptomic Metric for Diagnosing Surgical Sepsis and Estimating Mortality Among Critically Ill Patients.

Importance: Rapid and accurate discrimination of sepsis and its potential severity currently require multiple assays with slow processing times that are often inconclusive in discerning sepsis from sterile inflammation. Objective: To analyze a whole-blood, multivalent, host-messenger RNA expression metric for estimating the likelihood of bacterial infection and 30-day mortality and compare performance of the metric with that of other diagnostic and prognostic biomarkers and clinical parameters. Design, Setting, and Participants: This prospective diagnostic and prognostic study was performed in the surgical intensive care unit (ICU) of a single, academic health science center. The analysis included 200 critically ill adult patients admitted with suspected sepsis (cohort A) or those at high risk for developing sepsis (cohort B) between July 1, 2020, and July 30, 2021. Exposures: Whole-blood sample measurements of a custom 29-messenger RNA transcriptomic metric classifier for likelihood of bacterial infection (IMX-BVN-3) or 30-day mortality (severity) (IMX-SEV-3) in a clinical-diagnostic laboratory setting using an analysis platform (510[k]-cleared nCounter FLEX; NanoString, Inc), compared with measurement of procalcitonin and interleukin 6 (IL-6) plasma levels, and maximum 24-hour sequential organ failure assessment (SOFA) scores. Main Outcomes and Measures: Estimated sepsis and 30-day mortality performance. Results: Among the 200 patients included (124 men [62.0%] and 76 women [38.0%]; median age, 62.5 [IQR, 47.0-72.0] years), the IMX-BVN-3 bacterial infection classifier had an area under the receiver operating characteristics curve (AUROC) of 0.84 (95% CI, 0.77-0.90) for discriminating bacterial infection at ICU admission, similar to procalcitonin (0.85 [95% CI, 0.79-0.90]; P = .79) and significantly better than IL-6 (0.67 [95% CI, 0.58-0.75]; P < .001). For estimating 30-day mortality, the IMX-SEV-3 metric had an AUROC of 0.81 (95% CI, 0.66-0.95), which was significantly better than IL-6 levels (0.57 [95% CI, 0.37-0.77]; P = .006), marginally better than procalcitonin levels (0.65 [95% CI, 0.50-0.79]; P = .06), and similar to the SOFA score (0.76 [95% CI, 0.62-0.91]; P = .48). Combining IMX-BVN-3 and IMX-SEV-3 with procalcitonin or IL-6 levels or SOFA scores did not significantly improve performance. Among patients with sepsis, IMX-BVN-3 scores decreased over time, reflecting the resolution of sepsis. In 11 individuals at high risk (cohort B) who subsequently developed sepsis during their hospital course, IMX-BVN-3 bacterial infection scores did not decline over time and peaked on the day of documented infection. Conclusions and Relevance: In this diagnostic and prognostic study, a novel, multivalent, transcriptomic metric accurately estimated the presence of bacterial infection and risk for 30-day mortality in patients admitted to a surgical ICU. The performance of this single transcriptomic metric was equivalent to or better than multiple alternative diagnostic and prognostic metrics when measured at admission and provided additional information when measured over time.

Sex differences associate with late microbiome alterations after murine surgical sepsis.

BACKGROUND: Sepsis-induced gut microbiome alterations contribute to sepsis-related morbidity and mortality. Given evidence for improved postsepsis outcomes in females compared with males, we hypothesized that female mice maintain microbiota resilience versus males. METHODS: Mixed-sex C57BL/6 mice underwent cecal ligation and puncture (CLP) with antibiotics, saline resuscitation, and daily chronic stress and were compared with naive (nonsepsis/no antibiotics) controls. For this work, the results of young (3-5 months) and old (18-22 months) adult mice were analyzed by sex, independent and dependent of age. Mice were sacrificed at days 7 and 14, and 16S rRNA gene sequencing was performed on fecal bacterial DNA. α and ß diversity were determined by Shannon index and Bray-Curtis with principal coordinate analysis, respectively. False discovery rate (FDR) correction was implemented to account for potential housing effect. RESULTS: In control mice, there was no difference in α or ß diversity between male and female mice (FDR, 0.76 and 0.99, respectively). However, male mice that underwent CLP with daily chronic stress had a decrease in microbiota α diversity at 7 days post-CLP (Shannon FDR, 0.005), which was sustained at 14 days post-CLP (Shannon FDR, 0.001), compared with baseline. In addition, male mice maintained differences in ß diversity even at day 14 compared with controls (FDR, <0.0001). In contrast, female mice had a decreased microbiota α diversity (Shannon FDR, 0.03) and ß diversity (FDR, 0.02) 7 days post-CLP but recovered their α and ß diversity by post-CLP day 14 (Shannon FDR, 0.5, and FDR, 0.02, respectively). Further analysis of females revealed that only young female mice were not different (ß diversity) post-CLP day 14 to controls. CONCLUSION: Although sepsis-induced perturbations of the intestinal microbiota occur initially in both male and female C57BL/6 mice, females demonstrate different microbiota by day 14. This may be seen primarily in younger females. This difference in recovery may play a role in outcome differences between sexes after sepsis.

A core outcome set for damage control laparotomy via modified Delphi method.

OBJECTIVES: Damage control laparotomy (DCL) remains an important tool in the trauma surgeon's armamentarium. Inconsistency in reporting standards have hindered careful scrutiny of DCL outcomes. We sought to develop a core outcome set (COS) for DCL clinical studies to facilitate future pooling of data via meta-analysis and Bayesian statistics while minimizing reporting bias. METHODS: A modified Delphi study was performed using DCL content experts identified through Eastern Association for the Surgery of Trauma (EAST) 'landmark' DCL papers and EAST ad hoc COS task force consensus. RESULTS: Of 28 content experts identified, 20 (71%) participated in round 1, 20/20 (100%) in round 2, and 19/20 (95%) in round 3. Round 1 identified 36 potential COS. Round 2 achieved consensus on 10 core outcomes: mortality, 30-day mortality, fascial closure, days to fascial closure, abdominal complications, major complications requiring reoperation or unplanned re-exploration following closure, gastrointestinal anastomotic leak, secondary intra-abdominal sepsis (including anastomotic leak), enterocutaneous fistula, and 12-month functional outcome. Despite feedback provided between rounds, round 3 achieved no further consensus. CONCLUSIONS: Through an electronic survey-based consensus method, content experts agreed on a core outcome set for damage control laparotomy, which is recommended for future trials in DCL clinical research. Further work is necessary to delineate specific tools and methods for measuring specific outcomes. LEVEL OF EVIDENCE: V, criteria.

Transcriptomic Changes Within Human Bone Marrow After Severe Trauma.

BACKGROUND: Severe trauma is associated with severe systemic inflammation and neuroendocrine activation that is associated with erythroid progenitor growth suppression and refractory anemia. Although distinct transcriptional profiles have been detected in numerous tissue types after trauma, no study has yet characterized this within the bone marrow. This study sought to identify a unique bone marrow transcriptomic response following trauma. METHODS: In a prospective observational cohort study, bone marrow was obtained from severely injured trauma patients with a hip or femur fracture (n = 52), elective hip replacement patients (n = 33), and healthy controls (n = 11). RNA was isolated from bone marrow using a Purelink RNA mini kit. Direct quantification of mRNA copies was performed by NanoString Technologies on a custom gene panel. RESULTS: Trauma patients displayed an upregulation of genes encoding receptors known to have inhibitory downstream effects on erythropoiesis, including ferroportin, interleukin-6 (IL-6) receptor, transforming growth factor-beta (TGF-ß) receptor, and IL-10, as well as genes involved in innate immunity including toll-like receptor 4 (TLR4)-mediated signaling factors. In contrast, hip replacement patients had downregulated transcription of IL-1ß, IL-6, TGF-ß, tumor necrosis factor alpha, and the HAMP gene with no change in TLR4-mediated signaling factors. CONCLUSIONS: A unique transcriptomic response within the bone marrow was identified following severe trauma compared to elective hip replacement. These transcriptomic differences were related to the innate immune response as well as known inhibitors of erythropoiesis. Although confined to just one time point, this differential transcriptional response may be linked to refractory anemia and inflammation after injury.

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.

Challenging Traditional Paradigms in Posttraumatic Pulmonary Thromboembolism.

Importance: Pulmonary clots are seen frequently on chest computed tomography performed after trauma, but recent studies suggest that pulmonary thrombosis (PT) and pulmonary embolism (PE) after trauma are independent clinical events. Objective: To assess whether posttraumatic PT represents a distinct clinical entity associated with the nature of the injury, different from the traditional venous thromboembolic paradigm of deep venous thrombosis (DVT) and PE. Design, Setting, and Participants: This prospective, observational, multicenter cohort study was conducted by the Consortium of Leaders in the Study of Traumatic Thromboembolism (CLOTT) study group. The study was conducted at 17 US level I trauma centers during a 2-year period (January 1, 2018, to December 31, 2020). Consecutive patients 18 to 40 years of age admitted for a minimum of 48 hours with at least 1 previously defined trauma-associated venous thromboembolism (VTE) risk factor were followed up until discharge or 30 days. Exposures: Investigational imaging, prophylactic measures used, and treatment of clots. Main Outcomes and Measures: The main outcomes of interest were the presence, timing, location, and treatment of any pulmonary clots, as well as the associated injury-related risk factors. Secondary outcomes included DVT. We regarded pulmonary clots with DVT as PE and those without DVT as de novo PT. Results: A total of 7880 patients (mean [SD] age, 29.1 [6.4] years; 5859 [74.4%] male) were studied, 277 with DVT (3.5%), 40 with PE (0.5%), and 117 with PT (1.5%). Shock on admission was present in only 460 patients (6.2%) who had no DVT, PT, or PE but was documented in 11 (27.5%) of those with PE and 30 (25.6%) in those with PT. Risk factors independently associated with PT but not DVT or PE included shock on admission (systolic blood pressure <90 mm Hg) (odds ratio, 2.74; 95% CI, 1.72-4.39; P < .001) and major chest injury with Abbreviated Injury Score of 3 or higher (odds ratio, 1.72; 95% CI, 1.16-2.56; P = .007). Factors associated with the presence of PT on admission included major chest injury (14 patients [50.0%] with or without major chest injury with an Abbreviated Injury Score >3; P = .04) and major venous injury (23 [82.1%] without major venous injury and 5 [17.9%] with major venous injury; P = .02). No deaths were attributed to PT or PE. Conclusions and Relevance: To our knowledge, this CLOTT study is the largest prospective investigation in the world that focuses on posttraumatic PT. The study suggests that most pulmonary clots are not embolic but rather result from inflammation, endothelial injury, and the hypercoagulable state caused by the injury itself.

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.

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.

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 after hypothermia in trauma patients.

OBJECTIVES: Chronic critical illness (CCI) is a phenotype that occurs frequently in patients with severe injury. Previous work has suggested that inflammatory changes leading to CCI occur early following injury. However, the modifiable factors associated with CCI are unknown. We hypothesized that hypothermia, an early modifiable factor, is associated with CCI. METHODS: To determine the association of hypothermia and CCI, a secondary analysis of the Inflammation and Host Response to Injury database was performed, and subsequently validated on a similar cohort of patients from a single level 1 trauma center from January 2015 to December 2019. Hypothermia was defined as initial body temperature ≤34.5°C. CCI was defined as death or sustained multiorgan failure ≥14 days after injury. Data were analyzed using univariable analyses with Student's t-test and Pearson's χ2 test, and logistic regression. An arrayed genomic analysis of the transcriptome of circulating immune cells was performed in these patients. RESULTS: Of the initial 1675 patients, 254 had hypothermia and 1421 did not. On univariable analysis, 120/254 (47.2%) of patients with hypothermia had CCI, compared with 520/1421 (36.6%) without hypothermia who had CCI, p<0.001. On multivariable logistic regression, hypothermia was independently associated with CCI, OR 1.61 (95% CI 1.17 to 2.21) but not mortality. Subsequent validation in 1264 patients of which 172 (13.6%) were hypothermic, verified that hypothermia was independently associated with CCI on multivariable logistic regression, OR 1.84 (95% CI 1.21 to 2.41). Transcriptomic analysis in hypothermic and non-hypothermic patients revealed unique cellular-specific genomic changes to only circulating monocytes, without any distinct effect on neutrophils or lymphocytes. CONCLUSIONS: Hypothermia is associated with the development of CCI in severely injured patients. There are transcriptomic changes which indicate that the changes induced by hypothermia may be associated with persistent CCI. Thus, early reversal of hypothermia following injury may prevent the CCI. LEVEL OF EVIDENCE: III.

Association of Postoperative Clinical Outcomes With Sarcopenia, Frailty, and Nutritional Status in Older Patients With Colorectal Cancer: Protocol for a Prospective Cohort Study.

BACKGROUND: Older patients account for a significant proportion of patients undergoing colorectal cancer surgery and are vulnerable to a number of preoperative risk factors that are not often present in younger patients. Further, three preoperative risk factors that are more prevalent in older adults include frailty, sarcopenia, and malnutrition. Although each of these has been studied in isolation, there is little information on the interplay between them in older surgical patients. A particular area of increasing interest is the use of urine metabolomics for the objective evaluation of dietary profiles and malnutrition. OBJECTIVE: Herein, we describe the design, cohort, and standard operating procedures of a planned prospective study of older surgical patients undergoing colorectal cancer resection across multiple institutions in the United Kingdom. The objectives are to determine the association between clinical outcomes and frailty, nutritional status, and sarcopenia. METHODS: The procedures will include serial frailty evaluations (Clinical Frailty Scale and Groningen Frailty Indicator), functional assessments (hand grip strength and 4-meter walk test), muscle mass evaluations via computerized tomography morphometric analysis, and the evaluation of nutritional status via the analysis of urinary dietary biomarkers. The primary feasibility outcome is the estimation of the incidence rate of postoperative complications, and the primary clinical outcome is the association between the presence of postoperative complications and frailty, sarcopenia, and nutritional status. The secondary outcome measures are the length of hospital stay, 30-day hospital readmission rate, and mortality rate at days 30 and 90. RESULTS: Our study was approved by the National Health Service Research Ethics Committee (reference number: 19/WA/0190) via the Integrated Research Application System (project ID: 231694) prior to subject recruitment. Cardiff University is acting as the study sponsor. Our study is financially supported through an external, peer-reviewed grant from the British Geriatrics Society and internal funding resources from Cardiff University. The results will be disseminated through peer-review publications, social media, and conference proceedings. CONCLUSIONS: As frailty, sarcopenia, and malnutrition are all areas of common derangement in the older surgical population, prospectively studying these risk factors in concert will allow for the analysis of their interplay as well as the development of predictive models for those at risk of commonly tracked surgical complications and outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/16846.

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.

Resolution of organ dysfunction as a predictor of long-term survival in necrotizing soft tissue infections: Analysis of the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections trial and a retrospective claims database-linked chart study.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) are an acute surgical condition with high morbidity and mortality. Timely identification, resuscitation, and aggressive surgical management have significantly decreased inpatient mortality. However, reduced inpatient mortality has shifted the burden of disease to long-term mortality associated with persistent organ dysfunction. METHODS: We performed a combined analysis of NSTI patients from the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections randomized-controlled interventional trial (ATB-202) and comprehensive administrative database (ATB-204) to determine the association of persistent organ dysfunction on inpatient and long-term outcomes. Persistent organ dysfunction was defined as a modified Sequential Organ Failure Assessment (mSOFA) score of 2 or greater at Day 14 (D14) after NSTI diagnosis, and resolution of organ dysfunction defined as mSOFA score of 1 or less. RESULTS: The analysis included 506 hospitalized NSTI patients requiring surgical debridement, including 247 from ATB-202, and 259 from ATB-204. In both study cohorts, age and comorbidity burden were higher in the D14 mSOFA ≥2 group. Patients with D14 mSOFA score of 1 or less had significantly lower 90-day mortality than those with mSOFA score of 2 or higher in both ATB-202 (2.4% vs. 21.5%; p < 0.001) and ATB-204 (6% vs. 16%: p = 0.008) studies. In addition, in an adjusted covariate analysis of the combined study data sets D14 mSOFA score of 1 or lesss was an independent predictor of lower 90-day mortality (odds ratio, 0.26; 95% confidence interval, 0.13-0.53; p = 0.001). In both studies, D14 mSOFA score of 1 or less was associated with more favorable discharge status and decreased resource utilization. CONCLUSION: For patients with NSTI undergoing surgical management, persistent organ dysfunction at 14 days, strongly predicts higher resource utilization, poor discharge disposition, and higher long-term mortality. Promoting the resolution of acute organ dysfunction after NSTI should be considered as a target for investigational therapies to improve long-term outcomes after NSTI. LEVEL OF EVIDENCE: Prognostic/epidemiology study, level III.

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.

Distinct immunologic endotypes are associated with clinical trajectory after severe blunt trauma and hemorrhagic shock.

BACKGROUND: The genomic/cytokine "storm" after severe trauma is well described. However, the differing composition, magnitude and resolution of this response, and its relationship to clinical outcomes remain unclear. METHODS: This is a secondary analysis of a prospective longitudinal cohort study of severely injured trauma patients in hemorrhagic shock. Peripheral blood sampling was performed at 0.5, 1, 4, 7, 14, and 28 days after injury for measurement of circulating immune biomarkers. K-means clustering using overall mean and trajectory slope of selected immunologic biomarkers were used to identify distinct temporal immunologic endotypes. Endotypes were compared with known clinical trajectories defined as early death (<14 days), chronic critical illness (CCI) (ICU length of stay of ≥14 days with persistent organ dysfunction), and rapid recovery (RAP) (ICU length of stay of <14 days with organ recovery). RESULTS: The cohort included 102 subjects enrolled across 2 level 1 trauma centers. We identified three distinct immunologic endotypes (iA, iB, and iC), each with unique associations to clinical trajectory. Endotype iA (n = 47) exhibited a moderate initial proinflammatory response followed by a return to immunologic homeostasis, with a primary clinical trajectory of RAP (n = 44, 93.6%). Endotype iB (n = 44) exhibited an early hyperinflammatory response with persistent inflammation and immunosuppression, with the highest incidence of CCI (n = 10, 22.7%). Endotype iC (n = 11) exhibited a similar hyperinflammatory response, but with rapid return to immunologic homeostasis and a predominant trajectory of RAP (n = 9, 81.8%). Patients with endotype iB had the highest severity/duration of organ dysfunction and highest incidence of nosocomial infections (50%, p = 0.001), and endotype iB was the predominant endotype of patients who developed CCI (10 of 13 patients, 76.9%; p = 0.002). CONCLUSION: We identified three distinct immunologic endotypes after severe injury differing the magnitude and duration of the early response. The clinical trajectory of CCI is characterized by an endotype (iB) defined by persistent alteration in inflammation/immunosuppression and is associated with poor clinical outcomes. LEVEL OF EVIDENCE: Prognostic, level III.

Audiovisual Modules to Enhance Informed Consent in the ICU: A Pilot Study.

Obtaining informed consent for commonly performed ICU procedures is often compromised by variability in communication styles and inadequate verbal descriptions of anatomic concepts. The objective of this study was to evaluate the efficacy of an audiovisual module in improving the baseline knowledge of ICU procedures among patients and their caregivers. DESIGN: Prospective, observational study. SETTING: Forty-eight-bed adult surgical ICU at a tertiary care center. SUBJECTS: Critically ill surgical patients and their legally authorized representatives. INTERVENTIONS: An audiovisual module describing eight commonly performed ICU procedures. MEASUREMENTS AND MAIN RESULTS: Fifty-nine subjects were enrolled and completed an 11-question pre- and postvideo test of knowledge regarding commonly performed ICU procedures and a brief satisfaction survey. Twenty-nine percent had a healthcare background. High school was the highest level of education for 37% percent of all subjects. Out of 11 questions on the ICU procedure knowledge test, subjects scored an average 8.0 ± 1.9 correct on the pretest and 8.4 ± 2.0 correct on the posttest (p = 0.055). On univariate logistic regression, having a healthcare background was a negative predictor of improved knowledge (odds ratio, 0.185; 95% CI, 0.045-0.765), indicating that those with a health background had a lower probability of improving their score on the posttest. Among subjects who did not have a healthcare background, scores increased from 7.7 ± 1.9 to 8.3 ± 2.1 (p = 0.019). Seventy-five percent of all subjects indicated that the video was easy to understand, and 70% believed that the video improved their understanding of ICU procedures. CONCLUSIONS: Audiovisual modules may improve knowledge and comprehension of commonly performed ICU procedures among critically ill patients and caregivers who have no healthcare background.