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.

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.

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.

Development of a Simple Sequential Organ Failure Assessment Score for Risk Assessment of Emergency Department Patients With Sepsis.

OBJECTIVES: Sepsis-3 recommends using the quick Sequential Organ Failure Assessment (qSOFA) score followed by SOFA score for sepsis evaluation. The SOFA is complex and unfamiliar to most emergency physicians, while qSOFA is insensitive for sepsis screening and may result in missed cases of sepsis. The objective of this study was to devise an easy-to-use simple SOFA score for use in the emergency department (ED). METHODS: Retrospective study of ED patients with sepsis with in-hospital mortality as the primary outcome. A simple SOFA score was derived and validated and compared with SOFA and qSOFA. RESULTS: A total of 3297 patients with sepsis were included, and in-hospital mortality was 10.1%. Simple SOFA had a sensitivity and specificity of 88% and 44% in the derivation set and 93% and 44% in the validation set for in-hospital mortality, respectively. The sensitivity and specificity of qSOFA was 38% and 86% and for SOFA was 90% and 50%, respectively. There were 2760 (84%) of 3297 qSOFA-negative (<2) patients. In this group, simple SOFA had a sensitivity and specificity of 86% and 48% in the derivation set and 91% and 48% in the validation set, respectively. Sequential Organ Failure Assessment was 86% sensitive and 57% specific in qSOFA-negative patients. For all encounters, the areas under the receiver-operator characteristic curves (AUROC) were 0.82 for SOFA, 0.78 (derivation) and 0.82 (validation) for simple SOFA, and 0.68 for qSOFA. In qSOFA-negative patients, the AUROCs were 0.80 for SOFA and 0.76 (derivation) and 0.82 (validation) for simple SOFA. CONCLUSIONS: Simple SOFA demonstrates similar predictive ability for in-hospital mortality from sepsis compared to SOFA. External validation of these findings is indicated.

Sequential Organ Failure Assessment Component Score Prediction of In-hospital Mortality From Sepsis.

OBJECTIVES: Early organ dysfunction in sepsis confers a high risk of in-hospital mortality, but the relative contribution of specific types of organ failure to overall mortality is unclear. The objective of this study was to assess the predictive ability of individual types of organ failure to in-hospital mortality or prolonged intensive care. METHODS: Retrospective cohort study of adult emergency department patients with sepsis from October 1, 2013, to November 10, 2015. Multivariable regression was used to assess the odds ratios of individual organ failure types for the outcomes of in-hospital death (primary) and in-hospital death or ICU stay ≥ 3 days (secondary). RESULTS: Of 2796 patients, 283 (10%) experienced in-hospital mortality, and 748 (27%) experienced in-hospital mortality or an ICU stay ≥ 3 days. The following components of Sequential Organ Failure Assessment (SOFA) score were most predictive of in-hospital mortality (descending order): coagulation (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.32-1.93), hepatic (1.58, 95% CI: 1.32-1.90), respiratory (OR: 1.33, 95% CI: 1.21-1.47), neurologic (OR: 1.20, 95% CI: 1.07-1.35), renal (OR: 1.14, 95% CI: 1.02-1.27), and cardiovascular (OR: 1.13, 95% CI: 1.01-1.25). For mortality or ICU stay ≥3 days, the most predictive SOFA components were respiratory (OR: 1.97, 95% CI: 1.79-2.16), neurologic (OR: 1.72, 95% CI: 1.54-1.92), cardiovascular (OR: 1.38, 95% CI: 1.23-1.54), coagulation (OR: 1.31, 95% CI: 1.10-1.55), and renal (OR: 1.19, 95% CI: 1.08-1.30) while hepatic SOFA (OR: 1.16, 95% CI: 0.98-1.37) did not reach statistical significance (P = .092). CONCLUSION: In this retrospective study, SOFA score components demonstrated varying predictive abilities for mortality in sepsis. Elevated coagulation or hepatic SOFA scores were most predictive of in-hospital death, while an elevated respiratory SOFA was most predictive of death or ICU stay >3 days.

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.

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.

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.

Myeloid-derived suppressor cell function and epigenetic expression evolves over time after surgical sepsis.

BACKGROUND: Sepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host immunologic response to sepsis is the increase in circulating myeloid-derived suppressor cells (MDSCs), which have been demonstrated to be present and independently associated with poor long-term clinical outcomes. MDSCs are plastic cells and potentially modifiable, particularly through epigenetic interventions. The objective of this study was to determine how the suppressive phenotype of MDSCs evolves after sepsis in surgical ICU patients, as well as to identify epigenetic differences in MDSCs that may explain these changes. METHODS: Circulating MDSCs from 267 survivors of surgical sepsis were phenotyped at various intervals over 6 weeks, and highly enriched MDSCs from 23 of these samples were co-cultured with CD3/CD28-stimulated autologous T cells. microRNA expression from enriched MDSCs was also identified. RESULTS: We observed that MDSC numbers remain significantly elevated in hospitalized sepsis survivors for at least 6 weeks after their infection. However, only MDSCs obtained at and beyond 14 days post-sepsis significantly suppressed T lymphocyte proliferation and IL-2 production. These same MDSCs displayed unique epigenetic (miRNA) expression patterns compared to earlier time points. CONCLUSIONS: We conclude that in sepsis survivors, immature myeloid cell numbers are increased but the immune suppressive function specific to MDSCs develops over time, and this is associated with a specific epigenome. These findings may explain the chronic and persistent immune suppression seen in these subjects.

The Impact of Prior Laparotomy and Intra-abdominal Adhesions on Bowel and Mesenteric Injury Following Blunt Abdominal Trauma.

BACKGROUND: Early recognition of bowel and mesenteric injury following blunt abdominal trauma remains difficult. We hypothesized that patients with intra-abdominal adhesions from prior laparotomy would be subjected to visceral sheering deceleration forces and increased risk for bowel and mesenteric injury following blunt abdominal trauma. METHODS: We performed a multicenter retrospective cohort analysis of 267 consecutive adult trauma patients who underwent operative exploration following moderate-critical (abdominal injury score 2-5) blunt abdominal trauma, comparing patients with prior laparotomy (n = 31) to patients with no prior laparotomy (n = 236). Multivariable regression was performed to identify predictors of bowel or mesenteric injury. RESULTS: There were no significant differences between groups for injury severity scores or findings on abdominal ultrasound, diagnostic peritoneal aspirate/lavage, pelvic radiography, or preoperative CT scan. The prior laparotomy cohort had greater incidence of full thickness bowel injury (26 vs. 9%, p = 0.010) and mesenteric injury (61 vs. 31%, p = 0.001). The proportion of bowel and mesenteric injuries occurring at the ligament of Treitz or ileocecal region was greater in the no prior laparotomy group (52 vs. 25%, p = 0.003). Prior laparotomy was an independent predictor of bowel or mesenteric injury (OR 5.1, 95% CI 1.6-16.8) along with prior abdominal inflammation and free fluid without solid organ injury (model AUC: 0.81, 95% CI 0.74-0.88). CONCLUSIONS: Patients with a prior laparotomy are at increased risk for bowel and mesenteric injury following blunt abdominal trauma. The distribution of bowel and mesenteric injuries among patients with no prior laparotomy favors embryologic transition points tethering free intraperitoneal structures to the retroperitoneum.

The Postinjury Inflammatory State and the Bone Marrow Response to Anemia.

RATIONALE: The pathophysiology of persistent injury-associated anemia is incompletely understood, and human data are sparse. OBJECTIVES: To characterize persistent injury-associated anemia among critically ill trauma patients with the hypothesis that severe trauma would be associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, and decreased erythropoiesis. METHODS: A translational prospective observational cohort study comparing severely injured, blunt trauma patients who had operative fixation of a hip or femur fracture (n = 17) with elective hip repair patients (n = 22). Bone marrow and plasma obtained at the index operation were assessed for circulating catecholamines, systemic inflammation, erythropoietin, iron trafficking pathways, and erythroid progenitor growth. Bone marrow was also obtained from healthy donors from a commercial source (n = 8). MEASUREMENTS AND MAIN RESULTS: During admission, trauma patients had a median of 625 ml operative blood loss and 5 units of red blood cell transfusions, and Hb decreased from 10.5 to 9.3 g/dl. Compared with hip repair, trauma patients had higher median plasma norepinephrine (21.9 vs. 8.9 ng/ml) and hepcidin (56.3 vs. 12.2 ng/ml) concentrations (both P < 0.05). Bone marrow erythropoietin and erythropoietin receptor expression were significantly increased among patients undergoing hip repair (23% and 14% increases, respectively; both P < 0.05), but not in trauma patients (3% and 5% increases, respectively), compared with healthy control subjects. Trauma patients had lower bone marrow transferrin receptor expression than did hip repair patients (57% decrease; P < 0.05). Erythroid progenitor growth was decreased in trauma patients (39.0 colonies per plate; P < 0.05) compared with those with hip repair (57.0 colonies per plate; P < 0.05 compared with healthy control subjects) and healthy control subjects (66.5 colonies per plate). CONCLUSIONS: Severe blunt trauma was associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, erythroid progenitor growth suppression, and persistent injury-associated anemia. Clinical trial registered with www.clinicaltrials.gov (NCT 02577731).

Successful nonoperative management of uncomplicated appendicitis: predictors and outcomes.

BACKGROUND: Our objective was to identify predictors of successful nonoperative management (NOM) of uncomplicated appendicitis. We hypothesized that the absence of diabetes, absence of an appendicolith, short duration of symptoms, absence of systemic inflammation, and low modified Alvarado score would predict successful NOM. METHODS: We performed a retrospective cohort analysis of 81 consecutive patients who underwent NOM of uncomplicated appendicitis. Successful NOM was defined as resolution of appendicitis with antibiotics alone and no recurrent appendicitis within 180 days. Patients with successful NOM (n = 36) were compared with patients who failed NOM (n = 45). Multivariable logistic regression was used to identify predictors of successful NOM, expressed as odds ratios (ORs) with 95% confidence intervals. Model strength was assessed by calculating area under the receiver operating characteristic curve (AUC). RESULTS: Patient age (35 years), the American Society of Anesthesiologists class (2.0), and Charlson comorbidity index (0.0) were similar between groups. Independent predictors of successful NOM were duration of symptoms prior to admission >25 hours: OR 4.17 (1.42-12.24), maximum temperature within 6 hours of admission <37.3°C: OR 8.07 (1.79-36.38), modified Alvarado score <4: OR 9.06 (1.26-64.93), and appendiceal diameter <13 mm: OR 17.55 (1.30-237.28); model AUC: 0.81 (0.72-0.90). CONCLUSIONS: Patients with a longer duration of symptoms prior to admission were more likely to have successful NOM. Other independent predictors of successful NOM included lower temperature, lower modified Alvarado score, and smaller appendiceal diameter. These findings provide a framework for clinical decision-making and large-scale derivation and validation of a model to predict successful NOM of uncomplicated appendicitis.

The effects of beta blockade and clonidine on persistent injury-associated anemia.

BACKGROUND: Nonselective beta blockade (BB) and clonidine may abrogate catecholamine-mediated persistent injury-associated anemia. We hypothesized that critically ill trauma patients who received BB or clonidine would have favorable hemoglobin (Hb) trends when adjusting for operative blood loss (OBL), phlebotomy blood loss (PBL), and red blood cell (RBC) transfusion volumes, and that the effect would be greatest among the elderly, who have higher catecholamine levels. METHODS: We performed a 4-y retrospective cohort analysis of 280 consecutive trauma patients with ICU stay ≥48 h and moderate/severe anemia. Patients who received BB or clonidine for ≥25% of their hospital stay were grouped as the BB/clonidine cohort (n = 84); all other patients served as controls (n = 196). Admission and discharge Hb were used to calculate ΔHb. OBL, PBL, and RBC volume were used to calculate adjusted ΔHb assuming 300 mL RBC = 1 g/dL Hb. RESULTS: BB/clonidine and control patients had similar age, injury severity, comorbid illness, and admission Hb. BB/clonidine patients received fewer RBCs despite greater OBL, though neither association was statistically significant. BB/clonidine patients had higher discharge Hb (9.9 versus 9.5, P = 0.029) and adjusted ΔHb (+1.0 versus -0.8, P = 0.003). Hb curves separated after hospital day 10. The difference in adjusted ΔHb between groups increased with advanced age (all patients: 1.7, ≥50 y: 1.8, ≥60 y: 2.4, ≥70 y: 3.7). CONCLUSIONS: Critically ill trauma patients receiving BB or clonidine had favorable Hb trends when accounting for OBL, PBL, and RBC transfusions. These findings support the hypothesis that BB and clonidine alleviate persistent injury-associated anemia, with strongest effects among the elderly.

Anemia and blood transfusion in elderly trauma patients.

BACKGROUND: The natural history of postinjury among elderly trauma patients has not been well described. We hypothesized that elderly trauma patients would have lower admission hemoglobin (Hb) levels, higher transfusion rates, and worse outcomes than young trauma patients. METHODS: We performed a propensity-matched retrospective cohort analysis comparing elderly (age ≥65 y) to young (age 18-64) trauma patients matched by sex, mechanism of injury, Injury Severity Score, base deficit, comorbidities, operative blood loss, and phlebotomy blood loss (n = 41/group). Outcomes included Hb trends, packed red blood cell (PRBC) transfusion, length of stay, and mortality. RESULTS: Elderly patients had lower admission Hb (11.3 versus 10.2 g/dL, P = 0.012), received more PRBC transfusions within 24 h (3.6 versus 1.8 units, P = 0.046), and during admission (6.9 versus 4.3 units, P = 0.008). Despite receiving more PRBC transfusions and having similar operative and phlebotomy blood loss, elderly subjects had lower discharge Hb (9.0 versus 9.7 g/dL, P = 0.013). Elderly subjects had fewer ICU-free days (2.0 versus 6.0 d, P < 0.001) and higher in-hospital mortality (15% versus 0%, P = 0.026). CONCLUSIONS: Elderly trauma patients had lower admission Hb, received more transfusions, and had persistently lower Hb on discharge when controlling for injury severity, comorbid conditions, and blood loss. Aging may have a negative impact on postinjury anemia.

Autophagy: should it play a role in ICU management?

PURPOSE OF REVIEW: This review is to discuss the role of autophagy in the critically ill patient population. As the understanding of autophagy continues to expand and evolve, there are certain controversies surrounding whether intensivist should allow the benefit of autophagy to supersede gold standard of insulin therapy or early nutritional support. RECENT FINDINGS: The review is relevant as the current literature seems to support under-feeding patients, and perhaps the reason these studies were positive could be prescribed to the mechanisms of autophagy. It is well understood that autophagy is a physiologic response to stress and starvation, and that the inducible form could help patients with end-organ dysfunction return to homeostasis. SUMMARY: The jury is still out as to how autophagy will play into clinical practice as we review several gold standard therapies for the critically ill.

Can Specialized Pro-resolving Mediators Deliver Benefit Originally Expected from Fish Oil?

PURPOSE OF THE REVIEW: Fish oil (FO) supplementation has historically been used by individuals suffering from cardiovascular disease and other inflammatory processes. However, a meta-analysis of several large randomized control trials (RCTs) suggested FO conferred no benefit in reducing cardiovascular risk. Skeptics surmised that the lack of benefit was related to FO dose or drug interactions; therefore, the widely accepted practice of FO consumption was brought into question. RECENT FINDINGS: Thereafter, Serhan et al. identified specialized pro-resolving mediators (SPMs) to be one of the bioactive components and mechanisms of action of FO. SPMs are thought to enhance resolution of inflammation, as opposed to classic anti-inflammatory agents which inhibit inflammatory pathways. Numerous diseases, including persistent Inflammation, immunosuppression, and catabolic syndrome (PICS), are rooted in a burden of chronic inflammation. SPMs are gaining traction as potential therapeutic agents used to resolve inflammation in cardiovascular disorders, inflammatory bowel disease, sepsis, pancreatitis, and acute respiratory distress syndrome (ARDS). This narrative reviews the history of FO and the various studies that made the health benefits of FO inconclusive, as well as an overview of SPMs and their use in specific disease states.

Effect of Time to Operation on Value of Care in Acute Care Surgery.

BACKGROUND: As reimbursement models evolve, there is increasing emphasis on maximizing value-based care for inpatient conditions. We hypothesized that longer intervals between admission and surgery would be associated with worse outcomes and increased costs for acute care surgery patients, and that these associations would be strongest among patients with high-risk conditions. METHODS: We performed a 5-year retrospective analysis of three risk cohorts: appendectomy (low-risk for morbidity and mortality, n = 618), urgent hernia repair (intermediate-risk, n = 80), and laparotomy for intra-abdominal sepsis with temporary abdominal closure (sTAC; high-risk, n = 102). Associations between the interval from admission to surgery and outcomes including infectious complications, mortality, length of stay, and hospital charges were assessed by regression modeling. RESULTS: Median intervals between admission and surgery for appendectomy, hernia repair, and sTAC were 9.3, 13.5, and 8.1 h, respectively, and did not significantly impact infectious complications or mortality. For appendectomy, each 1 h increase from admission to surgery was associated with increased hospital LOS by 1.1 h (p = 0.002) and increased intensive care unit (ICU) LOS by 0.3 h (p = 0.011). For hernia repair, each 1 h increase from admission to surgery was associated with increased antibiotic duration by 1.6 h (p = 0.007), increased hospital LOS by 3.3 h (p = 0.002), increased ICU LOS by 1.5 h (p = 0.001), and increased hospital charges by $1918 (p < 0.001). For sTAC, each 1 h increase from admission to surgery was associated with increased antibiotic duration by 5.0 h (p = 0.006), increased hospital LOS by 3.9 h (p = 0.046), increased ICU LOS by 3.5 h (p = 0.040), and increased hospital charges by $3919 (p = 0.002). CONCLUSIONS: Longer intervals from admission to surgery were associated with prolonged antibiotic administration, longer hospital and ICU length of stay, and increased hospital charges, with strongest effects among high-risk patients. To improve value of care for acute care surgery patients, operations should proceed as soon as resuscitation is complete.