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

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

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.

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

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

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

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

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.

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.

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.

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.

Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock.

OBJECTIVE: We hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. BACKGROUND: Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. METHODS: Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, and also in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. RESULTS: After SS/SS, CD33CD11bHLA-DR MDSCs were dramatically increased out to 28 days (P < 0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (P < 0.05). Additionally, septic MDSCs had suppressed HLA gene expression and up-regulated ARG1 expression (P < 0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged intensive care unit stays, and poor functional status at discharge (P < 0.05). CONCLUSIONS: After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome.

OBJECTIVES: To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. DESIGN: Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. MEASUREMENTS AND MAIN RESULTS: Sepsis remains one of the most debilitating and expensive illnesses, and its prevalence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness, rarely fully recover, and often experience an indolent death. Patients with chronic critical illness often exhibit "a persistent inflammation-immunosuppression and catabolism syndrome," and it is proposed here that this state of persisting inflammation, immunosuppression and catabolism contributes to many of these adverse clinical outcomes. The underlying cause of inflammation-immunosuppression and catabolism syndrome is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function, and expansion of immature myeloid-derived suppressor cells are all contributory. CONCLUSIONS: Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with chronic critical illness and persistent inflammation-immunosuppression and catabolism syndrome may require a more complementary approach.

The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level-One Trauma Centers.

OBJECTIVE: To determine the incidence and risk factors of chronic critical illness after severe blunt trauma. DESIGN: Prospective observational cohort study (NCT01810328). SETTING: Two level-one trauma centers in the United States. PATIENTS: One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, -9.2 vs -5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 ± 2.4 vs 0.8 ± 1.1; p < 0.0001) and developed more infectious complications (84% vs 35%; p < 0.0001). Chronic critical illness patients were more likely to be discharged to a long-term care setting (56% vs 34%; p = 0.008) than to a rehabilitation facility/home. At 4 months, chronic critical illness patients had higher mortality (16.0% vs 1.9%; p < 0.05), with survivors scoring lower in general health measures (p < 0.005). Multivariate analysis revealed age greater than or equal to 55 years, systolic hypotension less than or equal to 70 mm Hg, transfusion greater than or equal to 5 units packed red blood cells within 24 hours, and Denver multiple organ failure score at 72 hours as independent predictors of chronic critical illness (area under the receiver operating curve, 0.87; 95% CI, 0.75-0.95). CONCLUSIONS: Although early mortality is low after severe trauma, chronic critical illness is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity, and persistent organ dysfunction are predictive of chronic critical illness. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.

Neural network prediction of severe lower intestinal bleeding and the need for surgical intervention.

BACKGROUND: The prognosis for patients with severe acute lower intestinal bleeding (ALIB) may be assessed by complex artificial neural networks (ANNs) or user-friendly regression-based models. Comparisons between these modalities are limited, and predicting the need for surgical intervention remains elusive. We hypothesized that ANNs would outperform the Strate rule to predict severe bleeding and would also predict the need for surgical intervention. METHODS: We performed a 4-y retrospective analysis of 147 adult patients who underwent endoscopy, angiography, or surgery for ALIB. Baseline characteristics, Strate risk factors, management parameters, and outcomes were analyzed. The primary outcomes were severe bleeding and surgical intervention. ANNs were created in SPSS. Models were compared by area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals. RESULTS: The number of Strate risk factors for each patient correlated significantly with the outcome of severe bleeding (r = 0.29, P < 0.001). However, the Strate model was less accurate than an ANN (AUROC 0.66 [0.57-0.75] versus 0.98 [0.95-1.00], respectively) which incorporated six variables present on admission: hemoglobin, systolic blood pressure, outpatient prescription for Aspirin 325 mg daily, Charlson comorbidity index, base deficit ≥5 mEq/L, and international normalized ratio ≥1.5. A similar ANN including hemoglobin nadir and the occurrence of a 20% decrease in hematocrit was effective in predicting the need for surgery (AUROC 0.95 [0.90-1.00]). CONCLUSIONS: The Strate prediction rule effectively stratified risk for severe ALIB, but was less accurate than an ANN. A separate ANN accurately predicted the need for surgery by combining risk factors for severe bleeding with parameters quantifying blood loss. Optimal prognostication may be achieved by integrating pragmatic regression-based calculators for quick decisions at the bedside and highly accurate ANNs when time and resources permit.

Emergent laparotomy and temporary abdominal closure for the cirrhotic patient.

BACKGROUND: Temporary abdominal closure (TAC) may be performed for cirrhotic patients undergoing emergent laparotomy. The effects of cirrhosis on physiologic parameters, resuscitation requirements, and outcomes following TAC are unknown. We hypothesized that cirrhotic TAC patients would have different resuscitation requirements and worse outcomes than noncirrhotic patients. METHODS: We performed a 3-year retrospective cohort analysis of 231 patients managed with TAC following emergent laparotomy for sepsis, trauma, or abdominal compartment syndrome. All patients were initially managed with negative pressure wound therapy (NPWT) TAC with intention for planned relaparotomy and sequential abdominal closure attempts at 24- to 48-h intervals. RESULTS: At presentation, cirrhotic patients had higher incidence of acidosis (33% versus 17%) and coagulopathy (87% versus 54%) than noncirrhotic patients. Forty-eight hours after presentation, cirrhotic patients had a persistently higher incidence of coagulopathy (77% versus 44%) despite receiving more fresh frozen plasma (10.8 units versus 4.4 units). Cirrhotic patients had higher NPWT output (4427 mL versus 2375 mL) and developed higher vasopressor infusion rates (57% versus 29%). Cirrhotic patients had fewer intensive care unit-free days (2.3 versus 7.6 days) and higher rates of multiple organ failure (64% versus 34%), in-hospital mortality (67% versus 21%), and long-term mortality (80% versus 34%) than noncirrhotic patients. CONCLUSIONS: Cirrhotic patients managed with TAC are susceptible to early acidosis, persistent coagulopathy, large NPWT fluid losses, prolonged vasopressor requirements, multiple organ failure, and early mortality. Future research should seek to determine whether TAC provides an advantage over primary fascial closure for cirrhotic patients undergoing emergency laparotomy.

Antibiotics May be Safely Discontinued Within One Week of Percutaneous Cholecystostomy.

BACKGROUND: For patients with acute cholecystitis managed with percutaneous cholecystostomy (PC), the optimal duration of post-procedural antibiotic therapy is unknown. Our objective was to compare short versus long courses of antibiotics with the hypothesis that patients with persistent signs of systemic inflammation 72 h following PC would receive prolonged antibiotic therapy and that antibiotic duration would not affect outcomes. METHODS: We performed a retrospective cohort analysis of 81 patients who underwent PC for acute cholecystitis at two hospitals during a 41-month period ending November 2014. Patients who received short (≤7 day) courses of post-procedural antibiotics were compared to patients who received long (>7 day) courses. Treatment response to PC was evaluated by systemic inflammatory response syndrome (SIRS) criteria. Logistic and linear regressions were used to evaluate associations between antibiotic duration and outcomes. RESULTS: Patients who received short (n = 30) and long courses (n = 51) of antibiotics had similar age, comorbidities, severity of cholecystitis, pre-procedural vital signs, treatment response, and culture results. There were no differences in recurrent cholecystitis (13 vs. 12%), requirement for open/converted to open cholecystectomy (23 vs. 22%), or 1-year mortality (20 vs. 18%). On logistic and linear regressions, antibiotic duration as a continuous variable was not predictive of any salient outcomes. CONCLUSIONS: Patients who received short and long courses of post-PC antibiotics had similar baseline characteristics and outcomes. Antibiotic duration did not predict recurrent cholecystitis, interval open cholecystectomy, or mortality. These findings suggest that antibiotics may be safely discontinued within one week of uncomplicated PC.

Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis.

Controversy remains whether the leukocyte genomic response to trauma or sepsis is dependent upon the initiating stimulus. Previous work illustrated poor correlations between historical models of murine trauma and sepsis (i.e., trauma-hemorrhage and lipopolysaccharide injection, respectively). The aim of this study is to examine the early genomic response in improved murine models of sepsis [cecal ligation and puncture (CLP)] and trauma [polytrauma (PT)] with and without pneumonia (PT+Pp). Groups of naïve, CLP, PT, and PT+Pp mice were killed at 2 h, 1 or 3 days. Total leukocytes were isolated for genome-wide expression analysis, and genes that were found to differ from control (false discovery rate adjusted P < 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PT+Pp), there were 10,426 total genes that were found to significantly differ from naïve controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (rs) of 0.446 (P < 0.0001) but were less positive thereafter. Correlations were significantly improved when we limited the analysis to common genes whose expression differed by a 1.5 fold-change. Both pathway and upstream analyses revealed the activation of genes known to be associated with pathogen-associated and damage-associated molecular pattern signaling, and early activation patterns of expression were very similar between polytrauma and sepsis at the earliest time points. This study demonstrates that the early leukocyte genomic response to sepsis and trauma are very similar in mice.