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Aims: The aim of this study is to describe the disposition of tranexamic acid (TXA) in adult trauma patients and derive a dosing regimen that optimizes exposure based on a predefined exposure target., Methods: We performed a population pharmacokinetic (popPK) analysis of participants enrolled in the Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI) trial (≥18 years with traumatic injury, given ≥1 blood product and/or requiring immediate transfer to the operating room) who were randomized to a single dose of either 2 or 4 g of TXA ≤2 h from time of injury. PopPK analysis was conducted using nonlinear mixed-effects modelling (NONMEM). Simulations were then performed using the final model to generate estimated plasma TXA concentrations in 1000 simulated participants. Dosing schemes were evaluated to determine maintenance of TXA plasma concentrations >10 mg/L for ≥8 h after administration of the initial dose., Results: TXA PK was best described by a two-compartment model with proportional residual error and allometric scaling on all parameters. Platelet count, skeletal muscle oxygen saturation measured by near-infrared spectroscopy and interleukin-8 concentration were significant covariates on TXA clearance. Based on simulations, a 2 g IV bolus dose, repeated 3 h later, best achieved the target exposure., Conclusions: According to simulations from a popPK model of TXA, a 2 g IV bolus with a repeated dose 3 h later would be most likely to maintain concentrations >10 mg/L for 8 h in >95% of adult trauma patients and should be considered for patients with ongoing haemorrhage., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Trauma is the leading cause of death in individuals up to 45 years of age. Alterations in platelet function are a critical component of trauma-induced coagulopathy (TIC), yet these changes and the potential resulting dysfunction is incompletely understood. The lack of clinical assays available to explore platelet function in this patient population has hindered detailed understanding of the role of platelets in TIC. The objective of this study was to assess trauma patient ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model. We hypothesized that trauma patients would have flow-regime dependent alterations in platelet function. Blood was collected from trauma patients with level I activations (N = 34) within 60 min of hospital arrival, as well as healthy volunteer controls (N = 10). Samples were perfused through a microfluidic model of injury at venous and arterial shear rates, and a subset of experiments were performed after incubation with fluorescent anti-CD41 to quantify platelets. Complete blood counts were performed as well as plasma-based assays to quantify coagulation times, fibrinogen, and von Willebrand factor (VWF). Exploratory correlation analyses were employed to identify relationships with microfluidic hemostatic parameters. Trauma patients had increased microfluidic bleeding times compared to healthy controls. While trauma patient samples were able to deposit a substantial amount of clot in the model injury site, the platelet contribution to microfluidic hemostasis was attenuated. Trauma patients had largely normal hematology and plasma-based coagulation times, yet had elevated D-Dimer and VWF. Venous microfluidic bleeding time negatively correlated with VWF, D-Dimer, and mean platelet volume (MPV), while arterial microfluidic bleeding time positively correlated with oxygenation. Arterial clot growth rate negatively correlated with red cell count, and positively with mean corpuscular volume (MCV). We observed changes in clot composition in trauma patient samples reflected by significantly diminished platelet contribution, which resulted in reduced hemostatic function in a microfluidic model of vessel injury. We observed a reduction in platelet clot contribution under both venous and arterial flow ex vivo in trauma patient samples. While our population was heterogenous and had relatively mild injury severity, microfluidic hemostatic parameters correlated with different patient-specific data depending on the flow setting, indicating potentially differential mechanistic pathways contributing to platelet hemostatic capacity in the context of TIC. These data were generated with the goal of identifying key features of platelet dysfunction in bleeding trauma patients under conditions of flow and to determine if these features correlate with clinically available metrics, thus providing preliminary surrogate markers of physiological platelet dysfunction to be further studied across larger cohorts. Future studies will continue to explore those relationships and further define mechanisms of TIC and their relationship with patient outcomes., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: PCS: Consultant for Hemanext, Cerus, CSL Behring, Octapharma. Advisory Board, Haima. Co-founder and Chief Medical Officer, Kalocyte. MDN: Chief Medical Officer, Haima Therapeutics, Research funding: Haemonetics, Instrumentation Laboratories, Alexion; Advisory Board and honoraria: Takeda and Haemonetics. RMGR, KAT, RK, DMD, KCR, RF, MC, JA, HA, KB, GVB, and SMS declare that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Thomas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Serial neurological examinations (NEs) are routinely recommended in the intensive care unit (ICU) within the first 24 hours following a traumatic brain injury (TBI). There are currently no widely accepted guidelines for the frequency of NEs. Disruptions to the sleep-wake cycles increase the delirium rate. We aimed to evaluate whether there is a correlation between prolonged hourly (Q1)-NE and development of delirium and to determine if this practice reduces the likelihood of missing the detection of a process requiring emergent intervention., Methods: A retrospective analysis of patients with mild/moderate TBI, admitted to the ICU with serial NEs, was performed. Cohorts were stratified by the duration of exposure to Q1-NE, into prolonged (≥24 hours) and nonprolonged (<24 hours). Our primary outcomes of interest were delirium, evaluated using the Confusion Assessment Method; radiological progression from baseline images; neurological deterioration (focal neurological deficit, abnormal pupillary examination, or Glasgow Coma Scale score decrease >2); and neurosurgical procedures., Results: A total of 522 patients were included. No significant differences were found in demographics. Patients in the prolonged Q1-NE group (26.1%) had higher Injury Severity Score with similar head Abbreviated Injury Score, significantly higher delirium rate (59% vs. 35%, p < 0.001), and a longer hospital/ICU length of stay when compared with the nonprolonged Q1-NE group. No neurosurgical interventions were found to be performed emergently as a result of findings on NEs. Multivariate analysis demonstrated that prolonged Q1-NE was the only independent risk factor associated with a 2.5-fold increase in delirium rate. The number needed to harm for prolonged Q1-NE was 4., Conclusion: Geriatric patients with mild/moderate TBI exposed to Q1-NE for periods longer than 24 hours had nearly a threefold increase in ICU delirium rate. One of five patients exposed to prolonged Q1-NE is harmed by the development of delirium. No patients were found to directly benefit as a result of more frequent NEs., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Necrotizing soft tissue infections (NSTIs) are rare but deadly infections that require early and often extensive surgical debridement. After debridement, patients frequently have substantial morbidity because of large, open wounds. Hypothesis: Negative pressure wound therapy with instillation (NPWTi) results in higher wound closure rates compared with traditional negative pressure wound therapy (NPWT) or wet to dry dressings (moist wound care dressing). Patients and Methods: A prospectively maintained Acute and Critical Care Surgery database spanning 2008-2018 was queried for patients with a diagnosis of necrotizing fasciitis, Fournier gangrene, or gas gangrene. Data were collected on patient comorbidities, operative management, and clinical outcomes. Patients were stratified by use of moist wound care dressing, traditional NPWT, or NPWTi. Data were analyzed using analysis of variance (ANOVA), χ 2 , and logistic regression. Results: During the 10-year study period, patients were treated for NSTI; 173 were managed with moist wound care dressing, 150 with NPWT, and 48 with NPWTi. Patients were similar in terms of demographics, body mass index (BMI), diabetes mellitus, and smoking rates. Overall, complication rates were not substantially different, but mortality was higher in the moist wound care dressing group (16.2% vs. 10.7% NPWT vs. 2.1% NPWTi; p = 0.02). In the moist wound care dressing group, 81.5% of patients had an open wound at discharge compared with 52.7% of the NPWT group and only 14.6% of the NPWTi group (p < 0.001). On multivariable regression, NPWTi was associated with closure rates five times higher than the NPWT group (odds ratio [OR], 5.28; 95% confidence interval [CI], 2.40-11.61; p < 0.001) after controlling for smoking status, intravenous drug use, number of operations, and involvement of the most common region of the body. Conclusions: Negative pressure wound therapy with instillation is associated with higher rates of wound closure without increasing complication rates in patients with NSTI compared with traditional NPWT or moist wound care dressing. Although prospective studies are needed, this indicates the potential to improve patient quality of life through reduced pain and outpatient home health needs.

Background: A notable improvement in the treatment of necrotizing soft tissue infections (NSTIs) is the development of negative pressure wound therapy (NPWT). Clinicians are still debating whether NPWT is as successful as conventional wet-to-dry dressings at removing bacteria. Recent research has revealed potential oxygen deprivation effects of NPWT in underlying wound tissues, although clinical trials regarding the effects of reduced oxygen on anaerobic bacterial soft tissue infections remain noticeably lacking. Hypothesis: We hypothesized that NPWT-treated patients with NSTIs who were solely infected by anaerobic bacteria would have worse outcomes than those who were infected with other bacterial species . Patients and Methods: Our study included a retrospective examination of the 2008-2022 period of our Acute and Critical Care Surgery database. Patients who had been identified as having necrotizing fasciitis, Fournier gangrene, or gas gangrene and who had their conditions verified by positive wound cultures acquired during the initial debridement and subsequently received NPWT made up the study cohort. Comorbidities, surgical techniques, and clinical results were all covered by the data. Based on their wound infections, patients were divided into two groups: those with exclusively anaerobic NSTIs and those with different bacterial groups (such as polymicrobial and aerobic). Multiple regression, χ 2 analysis, and analysis of variance (ANOVA) were among the analytical methods used. Results: One hundred twelve patients with NSTI who had received NPWT comprised the study cohort. Sixteen of these patients (14.3%) had NSTIs that were exclusively anaerobic, whereas the remaining 96 (85.7%) had NSTIs that were mixed aerobic, facultative, or polymicrobial. Between the two groups, there was no difference in the initial wound size. Patients with anaerobic NSTI who underwent NPWT showed a statistically significant increase in the number of debridements (3 [interquartile range {IQR},1-9] vs. 2 [IQR, 1-4]; p = 0.012) and an increased 100-day re-admission rate (37.5% vs. 12.5%; p = 0.012) when compared with patients with non-anaerobic NSTI. The 100-day re-admission rate increased three-fold in NPWT-treated anaerobic NSTIs, according to a logistic regression analysis (odds ratio [OR], 3.63; 95% confidence interval [CI], 1.06-12.44; p = 0.04). Conclusions: In contrast to patients with other bacterial strains, our data show that patients with NSTI treated with NPWT who only have anaerobic bacterial infections have a larger number of debridements and are much more likely to require re-admission within 100 days. We call for additional prospective studies to be conducted to identify additional risk factors and consider alternate treatment options for individuals with exclusively anaerobic NSTIs in light of these findings.

Background: Low-titer group O whole blood (LTOWB) or component therapy (CT) may be used to resuscitate hemorrhaging trauma patients. LTOWB may have clinical and logistical benefits and may improve survival., Objectives: We hypothesized LTOWB would improve 24-hour survival in hemorrhaging patients and would be safe and equally efficacious in non-group O compared with group O patients., Methods: Adult trauma patients with massive transfusion protocol activations were enrolled in this observational study. The primary outcome was 24-hour mortality. Secondary outcomes included 72-hour total blood product use. A Cox regression determined the independent associations with 24-hour mortality., Results: In total, 348 patients were included (CT, n = 180; LTOWB, n = 168). Demographics were similar between cohorts. Unadjusted 24-hour mortality was reduced in LTOWB vs CT: 8% vs 19% (P = .003), but 6-hour and 28-day mortality were similar. In an adjusted analysis with multivariable Cox regression, LTOWB was independently associated with reduced 24-hour mortality (hazard ratio, 0.21; 95% CI, 0.07-0.67; P = .004). LTOWB patients received significantly less 72-hour total blood products (80.9 [41.6-139.3] mL/kg vs 48.9 [25.9-106.9] mL/kg; P < .001). In stratified 24-hour survival analyses, LTOWB was associated with improved survival for patients in shock or with coagulopathy. LTOWB use in non-group O patients was not associated with increased mortality, organ injury, or adverse events., Conclusion: In this hypothesis-generating study, LTOWB use was independently associated with improved 24-hour survival, predominantly in patients with shock or coagulopathy. LTOWB also resulted in a 40% reduction in blood product use which equates to a median 2.4 L reduction in transfused products., Competing Interests: Declaration of competing interests P.C.S. is a consultant for Hemanext, Cerus, Haima, and Co-Founder and Chief Medical Officer for Kalocyte. The authors have no other conflicts of interest to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Ludwig's angina (LA) is a diffuse cellulitis of the submandibular space and adjacent tissues. During the coronavirus disease 2019 (COVID-19) pandemic, odontogenic treatments were often delayed because of the implementation of safety measures to avoid the spread of the virus. We hypothesized that delayed odontogenic treatments associated with the onset of the COVID-19 pandemic would be associated with an increase in the incidence of LA and worse outcomes related to these infections. Patients and Methods: Patients from June 2018 to June 2022 with computed tomography images suggestive of LA and confirmed by ear, nose, throat (ENT) consult were included. We abstracted demographics, outcomes, clinical management, and microbiology. Patients were stratified into pre-COVID and COVID-onset. Our primary outcome, incidence of LA, was defined as: (new LA cases) ÷ (ED evaluations of oral or dental infections × 1.5 years). Results: In the pre-COVID group, we identified 32 of 1,301 patients with LA for an incidence of 0.02 per year. The COVID-onset group consisted of 41 of 641 patients, with an incidence of 0.04 per year. In the COVID-onset group, progression to necrotizing fasciitis was more likely (0% vs. 15%; p < 0.024), and they returned to the operating room for repeated debridement (3% vs. 22%; p < 0.020). Likewise, hospital length of stay, intensive care unit (ICU) length of stay, and ventilator days were higher (4.3 ± 3.5 vs. 9.5 ± 11.3; 1.1 ± 1.2 vs. 9.5 ± 7.1; 0.3 ± 1 vs. 3.6 ± 7.1; p < 0.001). Conclusions: Although the prognosis for dental infections diagnosed early is generally favorable, we observed a notable increase in the incidence of LA after the onset of the COVID-19 pandemic. Moreover, complications stemming from these infections became more severe in the COVID-onset era. Specifically, the likelihood of necrotizing fasciitis showed a substantial increase, accompanied by an increased risk of respiratory failure and mediastinitis.

Objectives: Deep venous thrombosis (DVT) causes significant morbidity and mortality after trauma. Recently, we have shown that blood flow patterns at vein valves induce oscillatory stress genes, which maintain an anticoagulant endothelial phenotype that inhibits spontaneous clotting at vein valves and sinuses, is lost in the presence of DVT in human pathological samples, and is dependent on expression of the transcription factor FOXC2. We describe an assay, modifying our mouse multiple injury system, which shows evidence of clinically relevant microthrombosis and hypercoagulability applicable to the study of spontaneous DVT in trauma without requiring direct vascular injury or ligation. Finally, we investigated whether these model findings are relevant to a human model of critical illness by examining gene expression changes by quantitative polymerase chain reaction and immunofluorescence in veins collected from critically ill., Methods: C57/Bl6 mice were subjected to a modified mouse multiple injury model with liver crush injury, crush and pseudofracture of a single lower extremity, and 15% total blood volume hemorrhage. Serum was assayed for d-dimer at 2, 6, 24, and 48 hours after injury by enzyme-linked immunosorbent assay. For the thrombin clotting assay, veins of the leg were exposed, 100 μL of 1 mM rhodamine (6 g) was injected retro-orbitally, and 450 μg/mL thrombin was then applied to the surface of the vein with examination of real-time clot formation via in vivo immunofluorescence microscopy. Images were then examined for percentage area of clot coverage of visible mouse saphenous and common femoral vein. Vein valve specific knockout of FOXC2 was induced with tamoxifen treatment in PROX1 Ert2Cre FOXC2 fl/fl mice as previously described. Animals were then subjected to a modified mouse multiple injury model with liver crush injury, crush and pseudofracture of a single lower extremity, and 15% total blood volume hemorrhage. Twenty-four hours after injury, we examined the valve phenotype in naive versus multiple injury animals, with and without loss of the FOXC2 gene from the vein valve (FOXC2 del ) via the thrombin assay. Images were then examined for proximity of clot formation to the valve present at the junction of the mouse saphenous, tibial, and superficial femoral vein and presence of spontaneous microthrombi present in the veins before exposure to thrombin. Human vein samples were obtained from excess tissue preserved after harvest for elective cardiac surgery and from organ donors after organ procurement. Sections were submitted for paraffin embedding and then assayed by immunofluorescence for PROX1, FOXC2, thrombomodulin, endothelial protein C receptor, and von Willebrand's factor. All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee, and all human studies reviewed and approved by the institutional review board., Results: After mouse multiple injuries, enzyme-linked immunosorbent assay for d-dimer showed evidence of products of fibrin breakdown consistent with formation of clot related to injury, fibrinolysis, and/or microthrombosis. The thrombin clotting assay demonstrated higher percentage area of vein covered with clot when exposed to thrombin in the multiple injury animals compared with uninjured (45% vs. 27% p = 0.0002) consistent with a phenotype of hypercoagulable state after trauma in our model system. Unmanipulated FoxC2 knockout mice manifest increased clotting at the vein valve as compared with unmanipulated wild type animals. After multiple injuries, wild type mice manifest increase clotting at the vein after thrombin exposure ( p = 0.0033), and equivalent to that of valvular knockout of FoxC2 (FoxC2del), recapitulating the phenotype seen in FoxC2 knockout animals. The combination of multiple injuries and FoxC2 knockout resulted in spontaneous microthrombi in 50% of the animals, a phenotype not observed with either multiple injuries or FoxC2 deficiency alone (χ 2 , p = 0.017). Finally, human vein samples demonstrated the protective vein valve phenotype of increased FOXC2 and PROX1 and showed decreased expression in the critically ill organ donor population by immunofluorescence imaging in organ donor samples., Conclusion: We have established a novel model of posttrauma hypercoagulation that does not require direct restriction of venous flow or direct injury to the vessel endothelium to assay for hypercoagulability and can generate spontaneous microthrombosis when combined with valve-specific FOXC2 knockout. We find that multiple injuries induce a procoagulant phenotype that recapitulates the valvular hypercoagulability seen in FOXC2 knockout and, in critically ill human specimens, find evidence for loss of oscillatory shear stress-induced gene expression of FOXC2 and PROX1 in the valvular endothelium consistent with potential loss of DVT-protective valvular phenotype., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Victims of assault (VOA) often present with fractures of the mandible and maxilla. They represent a complex challenge because of possible compromise of the airway, and infection-related complications because of potential involvement of the oral cavity. We hypothesized that open mandible and maxillary fractures in VOA are associated with a higher rate of infection compared with non-VOA patients with open facial fractures. Patients and Methods: Patients admitted to our level 1 trauma center from 2005 to 2020 with a diagnosis of open mandible and maxillary fractures were included. Demographics, mechanisms of injury, fracture location, cultures, infectious complications, antibiotic treatments, and clinical outcomes were abstracted. Patients were stratified by their mechanism of injury into VOA or non-VOA and were compared using χ 2 and Student t-test using SPSS (IBM Corp, Armonk, NY). Results: We identified 316 patients with open mandible and maxillary fractures. There were 198 patients categorized as being VOA, and 118 as non-VOA. Nineteen of 316 patients were diagnosed with infection related to the fracture (3.8% abscesses, 1.9% cellulitis, and 1.9% osteomyelitis). Although the Injury Severity Score (ISS) was higher in non-VOA patients (5.8 ± 2.6 vs. 4.9 ± 1.8; p < 0.013), most of the infections were in the VOA cohort (17/19; 89.5%; p < 0.013). Conclusions: Open fractures of the mandible and maxilla in VOA are associated with a greater risk of infection compared with non-victims of assault. The relation between VOA and poor SDH has been studied recently; clinicians should be aware of this association and implement special considerations and appropriate follow-up visits to decrease the rate of infection in this currently expanding population.

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19., Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19., Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients., Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor., Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis., Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77)., Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Background: Emergency laparotomy for abdominal trauma is associated with high rates of surgical site infection (SSI). A protocol for antimicrobial prophylaxis (AMP) for trauma laparotomy was implemented to determine whether SSI could be reduced by adhering to established principles of AMP. Patients and Methods: A protocol utilizing ertapenem administered immediately before initiation of trauma laparotomy was adopted. Compliance with measures of adequate AMP were determined before and after protocol implementation, as were rates of SSI and other infections related to abdominal trauma. Univariable and multivariable analyses were performed to determine risk factors for development of infection related to trauma laparotomy. Results: Over a four-year period, 320 patient operations were reviewed. Ertapenem use for prophylaxis increased to 54% in the post-intervention cohort. Compliance with individual measures of appropriate AMP improved modestly. Overall, infections related to trauma laparotomy decreased by 46% (absolute decrease of 13%) in the post-intervention cohort. Multivariable analysis confirmed that treatment during the post-intervention phase was associated with this decrease, with a separate analysis suggesting that ertapenem use was an important factor in this decrease. Conclusions: Development of a standardized protocol for AMP in trauma laparotomy led to decreases in infectious complications after that procedure.

Background: Sepsis induces gut barrier dysfunction characterized by increased gut epithelial apoptosis and increased intestinal permeability. The cytokine IL-22 has been demonstrated to regulate gut barrier function. Type-3 innate lymphoid cells (ILC3) are the predominate source of IL-22 in the GI tract. We hypothesized that sepsis may cause changes to the gut ILC3/IL-22 axis., Materials and Methods: Sepsis was induced in WT and IL-22 KO mice by Pseudomonas aeruginosa pneumonia. Changes in gut-associated leukocyte populations were determined by flow-cytometry and ILC-associated transcripts were measured by RT-PCR. The effect of sepsis on gut permeability, pulmonary microbial burden, gut epithelial apoptosis, and survival was compared between WT and IL-22-/- mice., Results: Sepsis resulted in a significant decrease in the number of ILC3 in the gut, with a reciprocal increase in type-1 ILC (ILC1). Consistent with prior reports, sepsis was associated with increased gut permeability; however there was no difference in gut permeability, gut epithelial apoptosis, pulmonary microbial burden, or survival between WT and IL-22-/- mice., Conclusions: Septic pneumonia causes a decrease in gut-associated ILC3 and an associated reciprocal increase in ILC1. This may reflect inflammation-induced conversion of ILC3 to ILC1. Constitutive systemic IL-22 deficiency does not alter sepsis-induced gut barrier dysfunction., Competing Interests: Decleration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Forty percent of critically ill trauma patients will develop an infectious complication. Pneumonia is the most common cause of death of trauma patients surviving their initial insult. We previously demonstrated that polytrauma (PT), defined as two or more severe injuries in at least two areas of the body, induces emergency hematopoiesis characterized by accelerated myelopoiesis in the bone marrow and increased myeloid cell frequency in the peripheral tissues. We hypothesized that PT alone induces priming of neutrophils, resulting in hyperactivation upon secondary exposure to bacteria and causing acute lung injury and increased susceptibility to secondary exposure to Pseudomonas aeruginosa pneumonia., Methods: C57BL/6 mice were subjected to PT consisting of a lower extremity pseudofracture, liver crush injury, and 15% blood-volume hemorrhage. Pneumonia was induced by intratracheal injection of 5 × 106 CFU live P. aeruginosa or 1 × 107 of heat-killed P. aeruginosa (HKPA). For reactive oxygen species (ROS), studies polymorphonuclear neutrophils (PMNs) were isolated by immunomagnetic bead negative selection and stimulated ex-vivo with HKPA. Reactive oxygen species production was measured by immunofluorescence. For histology, lung sections were stained by hematoxylin-eosin and analyzed by a blinded grader., Results: Polytrauma induced persistent changes in immune function at baseline and to secondary infection. Pneumonia after injury resulted in increased mortality (60% vs. 5% p < 0.01). Blood neutrophils from PT mice had higher resting (unstimulated) ROS production than in naive animals (p < 0.02) demonstrating priming of the neutrophils following PT. After intratracheal HKPA injection, bronchoalveolar lavage PMNs from injured mice had higher ROS production compared with naive mice (p < 0.01), demonstrating an overexuberant immunopathologic response of neutrophils following PT., Conclusion: Polytrauma primes neutrophils and causes immunopathologic PMN ROS production, increased lung injury and susceptibility to secondary bacterial pneumonia. These results suggest that trauma-induced immune dysfunction can cause immunopathologic response to secondary infection and suggests neutrophil-mediated pulmonary damage as a therapeutic target for posttrauma pneumonia., (Copyright © 2021 American Association for the Surgery of Trauma.)

Background: The use of near-continuous blood glucose (BG) monitoring has the potential to improve glycemic control in critically ill patients. The MANAGE IDE trial evaluated the performance of the OptiScanner (OS) 5000 in a multicenter cohort of 200 critically ill patients., Methods: An Independent Group reviewed the BG run charts of all 200 patients and voted whether unblinded use of the OS, with alarms set at 90 and 130 to 150 mg/dL to alert the clinical team to impending hypoglycemia and hyperglycemia, respectively, would have eliminated episodes of dysglycemia: hypoglycemia, defined as a single BG <70 mg/dL; hyperglycemia, defined as >4 hours of BG >150 mg/dL; severe hyperglycemia, defined as >4 hours of BG >200 mg/dL and increased glucose variability (GV), defined as coefficient of variation (CV) >20%., Results: At least one episode of dysglycemia occurred in 103 (51.5%) of the patients, including 6 (3.0%) with hypoglycemia, 83 (41.5%) with hyperglycemia, 18 (9.0%) with severe hyperglycemia, and 40 (20.0%) with increased GV. Unblinded use of the OS with appropriate alarms would likely have averted 97.1% of the episodes of dysglycemia: hypoglycemia (100.0%), hyperglycemia (96.4%), severe hyperglycemia (100.0%), and increased GV (97.5%). Point accuracy of the OS was very similar to that of the point of care BG monitoring devices used in the trial., Conclusion: Unblinded use of the OS would have eliminated nearly every episode of dysglycemia in this cohort of critically ill patients, thereby markedly improving the quality and safety of glucose control.

Background: Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder without gallstones in the setting of critical illness. It represents 2%-15% of acute cholecystitis (AC) cases. Bacteremia is associated with increased morbidity and mortality rates in patients in the intensive care unit (ICU). The incidence of bacteremia in acute calculous cholecystitis (ACC) has been described; however, the incidence of bacteremia in AAC has not been reported. We hypothesized that patients with AAC have higher bacteremia rates, leading to worse outcomes than in those with ACC. Methods: A prospectively collected acute care surgery (ACS) institutional database of patients treated from 2008 through 2018 was queried for patients having ACC using International Classification of Diseases (ICD) 9 and 10 codes. Demographics, microbiology findings, and outcomes were extracted. Only patients with positive blood cultures were included in the study. We defined two cohorts: AAC with bacteremia and ACC with bacteremia. The Student t -test was used for continuous variables and the χ 2 and Fisher exact tests for categorical variables. Multivariable regression was applied, and statistical significance was set at p < 0.05. Results: Of 323 patients with AC, 57 (17.6%) had AAC and 266 (82.4%) had ACC. Of the 19 patients who had a blood culture, 11 (57.8%) were positive. Patients with positive blood cultures had a mean age of 56.7 ± 15.3 years and a mean Body Mass Index (BMI) of 26.7 ± 4.9. The incidence of bacteremia was significantly higher in AAC (n = 6; 10.5% versus n = 5; 1.9 %; p = 0.005), although the time between admission and diagnosis of bacteremia was similar in the two groups (1.2 ± 1.1 versus 0.2 ± 0.5 days; p = 0.128). The patients with AAC and bacteremia were younger (53.8 ± 19.2 versus 60.2 ± 8 years; p = 0.021) and had a longer ICU length of stay (LOS) (12.6 ± 7.2 versus 1.3 ± 2.1 days; p = 0.030). However, there was no difference in the mortality rate in the groups (n = 2; 33.3% versus 1; 20.0%; p = 1.000). After adjusting for age, gender, BMI, and Charlson Comorbidity Index, bacteremia in AAC patients was found to be an independent variable for longer ICU LOS (odds ratio 8.8; 95% confidence interval 1.7-15.9; p = 0.024). Conclusions: The incidence of bacteremia in patients with AAC is five-fold higher and the ICU stay eight days longer than in patients with ACC.

Objectives: A cornerstone of our healthcare system's response to the coronavirus disease 2019 pandemic is widespread testing to facilitate both isolation and early treatment. When patients refuse to undergo coronavirus disease testing, they compromise not only just their own health but also the health of those around them. The primary objective of our review is to identify the most ethical way a given healthcare system may respond to a patient's refusal to undergo coronavirus disease 2019 testing., Data Sources: We apply a systematic approach to a true clinical case scenario to evaluate the ethical merits of four plausible responses to a patient's refusal to undergo coronavirus disease testing. Although our clinical case is anecdotal, it is representative of our experience at our University Tertiary Care Center., Data Extraction: Each plausible response in the case is rigorously analyzed by examining relevant stakeholders, facts, norms, and ethical weight both with respect to individuals' rights and to the interests of public health. We use the "So Far No Objections" method as the ethical approach of choice because it has been widely used in the Ethics Modules of the Surgical Council on Resident Education Curriculum of the American College of Surgeons., Data Synthesis: Two ethically viable options may be tailored to individual circumstances depending on the severity of the patient's condition. Although unstable patients must be assumed to be coronavirus disease positive and treated accordingly even in the absence of a test, stable patients who refuse testing may rightfully be asked to seek care elsewhere., Conclusions: Although patient autonomy is a fundamental principle of our society's medical ethic, during a pandemic we must, in the interest of vulnerable and critically ill patients, draw certain limits to obliging the preferences of noncritically ill patients with decisional capacity., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Recommended treatment for complicated peri-rectal abscess is incision and drainage (I&D) in conjunction with antibiotics. However, there is no standard antibiotic regimen for post-operative therapy described in the published literature. Our hypothesis was that appropriate post-operative antibiotic therapy after emergency I&D of complicated peri-rectal abscess will improve patient outcomes. Methods: Data from 58 patients with complicated peri-rectal abscess who underwent emergency I&D were analyzed retrospectively. Demographic, microbiologic, and antibiotic data were abstracted. Adequateness of antibiotics was judged by susceptibility data when available or by comparing the antibiotic spectrum with the type of organisms grown in culture when susceptibility data were not available. The Student t -test and χ 2 test were used to analyze continuous and categorical variables, respectively. Multivariable analysis was used to adjust for confounding variables influencing recurrence rates. Results: Of the 58 patients reviewed, 12 were excluded because there was no culture information available or the culture showed no growth. Of the remaining 46 patients, 33 (72%) were male and 29 (63%) were African American. The mean age was 39.4 ± 16.4 years and the Body Mass Index was 28.4 ± 6.6 kg/m 2 . Culture data revealed mixed aerobic/anaerobic organisms in 17 (37%), mixed aerobic organisms in 15 (32.6%), gram-positive organisms in 9 (19.6%), gram-negative organisms in 2 (4.4%), and other organisms in 3 (6.6%). Twenty-five patients (54.4%) received adequate antibiotic coverage with the remainder inadequately covered. The inadequate antibiotic therapy cohort had a higher re-admission rate for abscess recurrence (n = 6 [28.6%] versus n = 1 [4%]; p = 0.021). More than half were readmitted 30 days or more after the index procedure. There were no differences in length of stay (LOS), intensive care unit LOS, or Charlson Comorbidity Index between the groups. Conclusion: Inadequate antibiotic coverage after I&D of complicated peri-rectal abscess resulted in a six-fold increase in the re-admission rate. A standard oral protocol combining antibiotics covering typical gram-positive, gram-negative, and anaerobic organisms should provide adequate coverage after surgical drainage. Additional prospective studies are needed to elucidate the optimal antibiotic regimen for these patients.

Background: Fungal infections are associated with increased morbidity and death. Few studies have examined risk factors associated with post-operative fungal intra-abdominal infections (FIAIs) in trauma patients after exploratory laparotomy. In this study, we evaluated potential risk factors for acquiring post-operative FIAIs and their impact on clinical outcomes. Methods: This was a retrospective analysis of trauma patients admitted from 2005 to 2018 who underwent exploratory laparotomy and subsequently had development of intra-abdominal infection (IAI). Demographics, comorbidities, culture data, antimicrobial usage, Injury Severity Scores (ISS), and clinical outcomes were abstracted. All post-operative IAIs were evaluated and stratified as either bacterial, fungal, combined, and with or without colonization. All groups were compared. Risk factors for the development of post-operative IAI and clinical outcomes were analyzed by Student t test and chi-square test. Multi-variable logistic regression was used to determine independent predictors of post-operative FIAIs. Results: There were 1675 patients identified as having undergone exploratory laparotomy in the setting of traumatic injury, 161 of whom were suspected of having IAI. A total of 105 (6.2%) patients had a diagnosis of IAI. Of these patients, 40 (38%) received a diagnosis of FIAI. The most common fungal pathogens were unspeciated yeast (48.3%), followed by Candida albicans (42.7%), C. glabrata (4.5%) , C. dubliniensis (2.25%), and C. tropicalis (2.25%). There were no significant differences in demographics, comorbidities, and percentage of gastric perforations between FIAI and bacterial IAI (BIAI) groups. Patients with FIAIs, however, had a 75% temporary abdominal closure (TAC) rate compared with 51% in BIAIs (p = 0.01). The FIAI group had higher ISS (27 vs. 22, p = 0.03), longer hospital days (34 vs. 25, p = 0.02), and longer intensive care unit (ICU) days (17 vs. 9, p = 0.006) when compared with BIAI. The FIAI group also had a five-fold greater mortality rate. Logistic regression identified TAC as an independent risk factor for the development of post-operative FIAIs (odds ratio [OR] 6.16, confidence interval [CI] 1.14-28.0, p = 0.02). Conclusions: An FIAI after exploratory laparotomy was associated with greater morbidity and death. A TAC was associated independently with increased risk of FIAI after exploratory laparotomy in the setting of traumatic injury. Clinicians should suspect fungal infections in trauma patients in whom post-operative IAI develops after undergoing exploratory laparotomy using TAC techniques.

Background: The hemostatic properties of tranexamic acid (TXA) are well described, but the immunological effects of TXA administration after traumatic injury have not been thoroughly examined. We hypothesized TXA would reduce monocyte activation in bleeding trauma patients with severe injury., Methods: This was a single center, double-blinded, randomized controlled trial (RCT) comparing placebo to a 2 g or 4 g intravenous TXA bolus dose in trauma patients with severe injury. Fifty patients were randomized into each study group. The primary outcome was a reduction in monocyte activation as measured by human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes 72 h after TXA administration. Secondary outcomes included kinetic assessment of immune and hemostatic phenotypes within the 72 h window post-TXA administration., Results: The trial occurred between March 2016 and September 2017, when data collection ended. 149 patients were analyzed (placebo, n = 50; 2 g TXA, n = 49; 4 g TXA, n = 50). The fold change in HLA-DR expression on monocytes [reported as median (Q1-Q3)] from pre-TXA to 72 h post-TXA was similar between placebo [0.61 (0.51-0.82)], 2 g TXA [0.57 (0.47-0.75)], and 4 g TXA [0.57 (0.44-0.89)] study groups ( p = 0.82). Neutrophil CD62L expression was reduced in the 4 g TXA group [fold change: 0.73 (0.63-0.97)] compared to the placebo group [0.97 (0.78-1.10)] at 24 h post-TXA ( p = 0.034). The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group [1.36 (0.87-2.42)] compared to the placebo group [0.46 (0.19-1.69)] at 72 h post-TXA ( p = 0.028). There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points., Conclusion: In trauma patients with severe injury, 4 g intravenous bolus dosing of TXA has minimal immunomodulatory effects with respect to leukocyte phenotypes and circulating cytokine levels., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02535949., (Copyright © 2020 Spinella, Thomas, Turnbull, Fuchs, Bochicchio, Schuerer, Reese, Coleoglou Centeno, Horn, Baty, Shea, Meledeo, Pusateri, Levy, Cap and Bochicchio.)

Background: There is a resurgence in the use of low-titer group O whole blood (LTOWB) for hemorrhagic shock. We hypothesized the use of LTOWB compared to component therapy (CT) would be independently associated with improved 24-hour mortality., Study Design and Methods: In this prospective observational study, trauma patients 18 years of age or older with massive transfusion protocol activations were included from August 17, 2018, to May 14, 2019. The primary outcome was 24-hour mortality. Secondary outcomes included 72-hour blood product totals, multiple organ dysfunction scores (MODS), and 28-day mortality. Multivariable logistic regression (MVLR) and Cox regression were performed to determine independent associations., Results: There were no clinically meaningful differences in measures of injury severity between study groups (CT, n = 42; LTOWB, n = 44). There was no difference in MODS between study groups. The unadjusted mortality was not statistically different between the study groups (9/42 [21%] for CT vs. 7/44 [16%] for LTOWB; p = 0.518). In the MVLR model, LTOWB increased the odds of 24-hour survival by 23% (odds ratio 0.81, 95% confidence interval 0.69-0.96; p = 0.017). Adjusted survival curve analysis indicated improved survival at both 24 hours and 28 days for LTOWB patients (p < 0.001). Further stratification showed an association between LTOWB use and survival when maximum clot firmness (MCF) was 60 mm or less (p = 0.009)., Conclusions: The use of LTOWB is independently associated with improved 24-hour and 28-day survival, and does not increase organ dysfunction at 72 hours. Use of LTOWB most impacted survival of patients with reduced clot firmness (MCF ≤60 mm). Collectively, these data support the clinical use and continued study of LTOWB for hemostatic resuscitation., (© 2020 AABB.)

Background: The link between Helicobacter pylori infection and peptic ulceration is well established. Recent studies have reported a decrease of H. pylori -related peptic ulcer disease; Helicobacter pylori eradication is likely the cause of this decrease. We hypothesized that patients with H. pylori -positive perforated peptic ulcer disease (PPUD) requiring surgical intervention had worse outcomes than patients with H. pylori -negative PPUD. Patients and Methods: A prospectively collected Acute and Critical Care Surgery registry spanning the years 2008 to 2015 was searched for patients with PPUD and tested for H. pylori serum immunoglobulin G (IgG) test. Patients were divided into two cohorts: H. pylori positive (HPP) and H. pylori negative (HPN). Demographics, laboratory values, medication history, social history, and esophagogastroduodenoscopy were collected. Student t-test was used for continuous variables and χ 2 test was used for categorical variables. Linear regression was applied as appropriate. Results: We identified 107 patients diagnosed with PPUD, of whom 79 (74%) patients had H. pylori serum IgG testing. Forty-two (53.2%) tested positive and 37 (46.8%) tested negative. Helicobacter pylori -negative PPUD was more frequent in females (70.27%, p = 0.004), whites (83.78%, p = 0.001) and patients with higher body mass index (BMI) 28.81 ± 8.8 (p = 0.033). The HPN group had a lower serum albumin level (2.97 ± 0.96 vs. 3.86 ± 0.91 p = 0.0001), higher American Society of Anesthesiologists (ASA; 3.11 ± 0.85 vs. 2.60 ± 0.73; p = 0.005), and Charlson comorbidity index (4.81 ± 2.74 vs. 2.98 ± 2.71; p = 0.004). On unadjusted analysis the HPN cohort had a longer hospital length of stay (LOS; 20.20 ± 13.82 vs. 8.48 ± 7.24; p = 0.0001), intensive care unit (ICU) LOS (10.97 ± 11.60 vs. 1.95 ± 4.59; p = 0.0001), increased ventilator days (4.54 ± 6.74 vs. 0.98 ± 2.85; p = 0.004), and higher rates of 30-day re-admission (11; 29.73% vs. 5; 11.91%; p = 0.049). Regression models showed that HPN PPUD patients had longer hospital and ICU LOS by 11 days (p = 0.002) and 8 days (p = 0.002), respectively, compared with HPP PPUD. Conclusion: In contrast to our hypothesis, HPN patients had clinically worse outcomes than HPP patients. These findings may represent a difference in the baseline pathophysiology of the peptic ulcer disease process. Further investigation is warranted.

The inflammatory response to infection or injury dramatically increases the hematopoietic demand on the bone marrow to replace effector leukocytes consumed in the inflammatory response. In the setting of infection, pathogen-associated molecular patterns induce emergency hematopoiesis, activating hematopoietic stem and progenitor cells to proliferate and produce progeny for accelerated myelopoiesis. Sterile tissue injury due to trauma also increases leukocyte demand; however, the effect of sterile tissue injury on hematopoiesis is not well described. We find that tissue injury alone induces emergency hematopoiesis in mice subjected to polytrauma. This process is driven by IL-1/MyD88-dependent production of G-CSF. G-CSF induces the expansion of hematopoietic progenitors, including hematopoietic stem cells and multipotent progenitors, and increases the frequency of myeloid-skewed progenitors. To our knowledge, these data provide the first comprehensive description of injury-induced emergency hematopoiesis and identify an IL-1/MyD88/G-CSF-dependent pathway as the key regulator of emergency hematopoiesis after injury., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: To our knowledge, there is an absence of prospective randomized multicenter controlled trials evaluating both the impact of technique and mesh type on outcomes in complicated ventral hernia repair., Study Design: A prospective randomized multicenter controlled trial of 120 patients at 3 sites was conducted in which patients were randomized to either overlay (anterior component separation) or underlay mesh placement (posterior component separation) and mesh type (human acellular dermis [HADM] vs porcine acellular dermis [PADM]). Key inclusion criteria included hernia size (>200 cm 2 ), BMI < 40 kg/m 2 , hemoglobin A1C < 7%, tobacco free > 6 weeks and primary fascial closure. Primary outcome was hernia recurrence at 1 year, determined by independent examiner/imaging. Secondary outcomes included complications and patient satisfaction (short form [SF]-36v2). Standardized investigator training included a porcine model followed by a proctored first case by the lead investigator., Results: There were no significant differences in demographics between the 4 groups (age 60 ±12 years, BMI 32 ± 5 kg/m 2 , 51% female). The overall 1-year recurrence rate was 10.8%. There was no significant difference in recurrence rate by location of mesh placement (overlay 9.8%, underlay 11.9%) or mesh type (HADM 10.3%, PADM 11.3%). Overlay patients had a significantly lower surgical site infection rate (1.6% vs 11.9% p = 0.03), reported better physical functioning (p = 0.001) and role limitation scores (p = 0.04) in the early postoperative period, and achieved the highest physical functioning score during the 12-month period (p < 0.03)., Conclusions: Recurrence rates were not affected by either anatomic location or type of mesh used. To our knowledge, this represents the first prospective randomized multicenter controlled trial that demonstrates similar clinical outcomes using HADM vs PADM (not inferiority, contrary to previously published literature), with several advantages identified using the overlay technique., (Copyright © 2019 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Clostridium difficile infection (CDI) is an important surgical complication. Emergency general surgery (EGS) is a developing area of the acute care surgical practice. Few studies evaluating the incidence and risk factors of CDI in this patient population are available., Patients and Methods: A prospectively maintained Acute and Critical Care Surgery registry spanning from 2008 to 2015 was queried for cases of operative EGS with clinical suspicion of CDI post-operatively. Diagnosis of CDI was made using toxin A/B assay in stools. Demographics, co-morbidities, surgical procedures, length of stay (LOS), intensive care unit LOS, antibiotic use, and death were obtained. The patients positive and negative for CDI were compared using chi-squared and Student's t-test. Multi-variable logistic regression was used to determine risk factors for CDI., Results: A total of 550 patients were identified. The total incidence of CDI was 12.7%. There was no significant difference in demographics between CDI positive and negative patients. Average time to CDI diagnosis was 10.1 ± 8.5 days post-operatively. Patients who received three or more antibiotic classes were at higher risk of CDI developing post-operatively (83% vs. 75%, p = 0.04). The CDI positive patients underwent an EGS significantly earlier than CDI negative patients (0.9 ± 2.3 vs. 3.2 ± 9.2 days, p < 0.001). The most common procedures were partial colectomies (21.4%); small bowel resections/repairs (12.9%); gastric repair for perforated peptic ulcer (10%); skin and soft tissue procedure (7.1%), and laparotomies (5.7%). There was no difference in outcomes between the groups. On linear regression, an EGS performed later after admission was an independent risk factor for lower CDI (OR 0.87; CI 95% [0.79-0.96], p < 0.01)., Conclusion: Patients undergoing an early EGS have a high incidence of CDI. The number of antibiotic classes administered post-operatively affects CDI status. Bowel resections appear to be at increased risk for CDI. Clinicians should have a high index of suspicion and low threshold for testing C. difficile in high-risk EGS patients.

Aims of the Study: The safety and efficacy of a hemostatic powder (HP) versus a control agent, absorbable gelatin sponge and thrombin (G + T), were assessed, using a validated, quantitative bleeding severity scale., Methods: Subjects were randomized to receive HP (256 subjects) or G + T (132 subjects) for treatment of minimal, mild, or moderate bleeding at 20 investigational sites. The primary efficacy endpoint was non-inferiority of HP relative to G + T for success at achieving hemostasis within 6 minutes. Secondary endpoints in rank order included: superiority of HP relative to G + T in mean preparation time; non-inferiority of HP relative to G + T for achieving hemostasis within 3 min; superiority of HP relative to G + T for achieving hemostasis within 6 min; and superiority of HP relative to G + T for success for achieving hemostasis within 3 min., Results: A total of 388 subjects were included in the primary efficacy analysis. At 6 min, hemostasis was achieved in 93.0% (238/256) of the HP group compared to 77.3% (102/132) of the G + T group (non-inferiority P < 0.0001, superiority P < 0.0001). All secondary endpoints were met. Complications were comparable between treatment groups., Conclusions: HP had superior rates of hemostasis, shorter preparation time, and a similar safety profile compared to G + T in this prospective, randomized trial using quantitative bleeding severity criteria., (© 2019 The Authors. Journal of Cardiac Surgery Published by Wiley Periodicals, Inc.)

Background: With the advent of anti-Helicobacter pylori therapy, hospital admissions for peptic ulcer disease (PUD) have declined significantly since the 1990s. Despite this, operative treatment of PUD still is common. Although previous papers suggest that Candida in peritoneal fluid cultures may be associated with worse outcomes in patients with perforated peptic ulcers (PPUs), post-operative anti-fungal therapy has not been effective. We hypothesized that pre-operative anti-fungal drugs improve outcomes in patients with PPUs undergoing operative management., Patients and Methods: A prospectively maintained Acute and Critical Care Surgery (ACCS) database spanning 2008-2015 and including more than 7,000 patients was queried for patients with PPUs. Demographics and clinical outcomes were abstracted. Pre-operative anti-fungal use, intra-operative peritoneal fluid cultures, and infectious outcomes were abstracted manually. We compared outcomes and the presence of fungal infections in patients receiving peri-operative anti-fungal drugs in the entire cohort and in patients with intra-operative peritoneal fluid cultures. Frequencies were compared by the Fisher exact or χ2 test as appropriate. The Student's t-test was used for continuous variables., Results: There were 107 patients with PPUs who received operative management; 27 (25.2%) received pre-operative anti-fungal therapy; 33 (30.8%) received peritoneal fluid culture, and 17 cultures (51.5%) were positive for fungus. The presence of fungus in the cultures did not affect the outcomes. There were no differences in length of stay (LOS), intensive care unit (ICU) LOS, ventilator days, 30-day re-admission rates, or rates of intra-abdominal abscess formation or fungemia in patients who received pre-operative anti-fungal drugs regardless of the presence of fungi in the peritoneal fluid., Conclusion: Candida has been recovered in 29%-57% of peritoneal fluid cultures in patients with PPUs. However, no studies have evaluated pre-operative anti-fungal therapy in PPUs. Our data suggest that pre-operative anti-fungal drugs are unnecessary in patients undergoing operative management for PPU.

Background: Post colonoscopy blunt splenic injury (PCBSI) is a rarely reported and poorly recognized event. We analyzed cases of PCBSI managed at our hospital and compared them to existing literature., Methods: We identified 5 patients admitted with PCBSI through chart review., Results: There were 5 cases of PCBSI identified from April 2016-July 2017. Four of the patients were older than 65 years, three had prior surgeries, and all were women. CT scans showed splenic laceration in 4 cases, hemoperitoneum in 4 cases, and left pleural effusion in 2 cases. Three patients were treated with coil embolization, 1 had open splenectomy, and 1 was observed., Conclusions: Although blunt splenic injury is an infrequently reported complication of colonoscopy, it can result in high-grade injury requiring transfusion and invasive treatment due to significant hemorrhage. As previously reported, we demonstrate a high rate of PCBSI in women over 55 with a history of prior abdominal surgery. These data suggest that a high index of suspicion for splenic injury post-colonoscopy should be present in this population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Previous studies have suggested that percutaneous drainage and interval appendectomy is an effective treatment for appendicitis with associated abscess. Few studies to date have analyzed risk factors for failed drain management. We hypothesized that older patients with more co-morbidities would be at higher risk for failing conservative treatment., Methods: The 2010-2014 editions of the National Inpatient Sample (NIS) were queried for patients with diagnoses of peri-appendiceal abscesses. Minors and elective admissions were excluded. We identified patients who underwent percutaneous drainage and defined drain failure as undergoing a surgical operation after drainage but during the same inpatient visit to assess for factors associated with failure of drainage alone as a treatment. After univariable analysis, binomial logistic regression was used to assess for independent risk factors. Frequencies were analyzed by χ 2 and continuous variables by Student's t-test., Results: A total of 2,209 patients with appendiceal abscesses received drains; 561 patients (25.4%) failed conservative management and underwent operative intervention. On univariable analysis, patients who failed conservative management were younger, more likely to be Hispanic, have more inpatient diagnoses, and to have undergone drainage earlier in the hospital course. Multivariable regression demonstrated that the number of diagnoses, female sex, and Hispanic race were predictive of failure of drainage alone. Older age, West and Midwest census regions, and later drain placement were predictive of successful treatment with drainage alone. Failure was associated with more charges and longer hospital stay but not with a higher mortality rate., Conclusion: Approximately a quarter of patients will fail management of appendiceal abscess with percutaneous drain placement alone. Risk factors for failure are patient complexity, female sex, earlier drainage, and Hispanic race. Failure of drainage is associated with higher total charges and longer hospital stay; however, no change in the mortality rate was noted.

Background: Appendicitis is the most common intraabdominal surgical emergency in the United States, with over 250,000 cases each year. Several recent studies have evaluated the efficacy of nonoperative management of appendicitis. We measured changes in the treatment of appendicitis in the United States from 1998 to 2014 and evaluated outcomes in the contemporary cohort of appendicitis cases from 2010 to 2014., Methods: The National Inpatient Sample was queried for cases with a principal diagnosis of appendicitis. Cases with peritoneal abscesses were excluded. We determined trends in management and then compared cases managed nonoperatively versus those managed with early operation for demographics and outcomes including mortality, total charges, and length of stay using univariate analysis, binary logistic regression analysis, and case-control matching., Results: Although early operation remains the dominant treatment for acute appendicitis in the United States, there is an accelerating trend in nonoperative management. Nonoperative management is associated with increased age, number of comorbidities, and inpatient diagnoses. In univariate, multiple regression, and case-control analysis, nonoperative management is associated with decreased total charges but significantly increased risk of mortality., Conclusions: Elderly patients and patients with medical comorbidities are more likely to be treated nonoperatively for appendicitis than younger patients. Although previously published data support nonoperative management of appendicitis in low-risk surgical patients, we suggest that elderly or medically complex patients may benefit from early operative treatment of appendicitis and are potentially at risk of poor outcomes from nonoperative management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Antibiotic-impregnated central venous catheters (CVCs) decrease the incidence of infection in high-risk patients. However, use of these catheters carries the hypothetical risk of inducing antibiotic resistance. We hypothesized that routine use of minocycline and rifampin-impregnated catheters (MR-CVC) in a single intensive care unit (ICU) would change the resistance profile for Staphylococcus aureus., Methods: We reviewed antibiotic susceptibilities of S. aureus isolates obtained from blood cultures in a large urban teaching hospital from 2002-2015. Resistance patterns were compared before and after implementation of MR-CVC use in the surgical ICU (SICU) in August 2006. We also compared resistance patterns of S. aureus obtained in other ICUs and in non-ICU patients, in whom MR-CVCs were not used., Results: Data for rifampin, oxacillin, and clindamycin were available for 9,703 cultures; tetracycline resistance data were available for 4,627 cultures. After implementation of MR-CVC use in the SICU, rifampin resistance remained unchanged, with rates the same as in other ICU and non-ICU populations (3%). After six years of use of MR-CVCs in the SICU, the rate of tetracycline resistance was unchanged in all facilities (1%-3%). The use of MR-CVCs was not associated with any change in S. aureus oxacillin-resistance rates in the SICU (66% vs. 60%). However, there was a significant decrease in S. aureus clindamycin resistance (59% vs. 34%; p < 0.05) in SICU patients., Conclusions: Routine use of rifampin-minocycline-impregnated CVCs in the SICU was not associated with increased resistance of S. aureus isolates to rifampin or tetracyclines.

Background: Necrotizing soft-tissue infections (NSTIs) result in significant morbidity and mortality rates, with as many as 76% of patients dying during their index admission. Published data suggest NSTIs rarely involve fungal infections in immunocompetent patients. However, because of the recent recognition of fungal infections in our population, we hypothesized that such infections frequently complicate NSTIs and are associated with higher morbidity and mortality rates., Methods: A prospectively maintained Acute and Critical Care Surgery (ACCS) database spanning 2008-2015 and including more than 7,000 patients was queried for patients with NSTIs. Microbiologic data, demographics, and clinical outcomes were abstracted. Risk factors and outcomes associated with NSTI with positive intra-operative fungal cultures were determined. Frequencies were compared by χ 2 and continuous variables by the Student t-test using SPSS. Because the study included only archived data, no patient permission was needed., Results: A total of 230 patients were found to have NSTIs; 197 had intra-operative cultures, and 21 (10.7%) of these were positive for fungi. Fungal infection was more common in women, patients with higher body mass index (BMI), and patients who had had prior abdominal procedures. There were no significant differences in demographics, co-morbidities, or site of infection. The majority of patients (85.7%) had mixed bacterial and fungal infections; in the remaining patients, fungi were the only species isolated. Most fungal cultures were collected within 48 h of hospital admission, suggesting that the infections were not hospital acquired. Patients with positive fungal cultures required two more surgical interventions and had a three-fold greater mortality rate than patients without fungal infections., Conclusions: This is the largest series to date describing the impact of fungal infection in NSTIs. Our data demonstrate a three-fold increase in the mortality rate and the need for two additional operations. Consideration should be given to starting patients on empiric anti-fungal therapy in certain circumstances.

Background: We have previously demonstrated that tight glycemic control (80-120 mg/dL) improves outcome in critically injured patients. However, many centers have gotten away from aggressive glucose control due to the workload and risk of hypoglycemia. The objective of this pivotal trial is to evaluate the first in human continuous inline glucose monitor (OptiScanner) in critically ill patients., Methods: A multicenter pivotal trial was conducted over a 1-year period (2014-2015) at four major academic centers in 200 critically ill patients. Three thousand seven hundred thirty-five glucose measurements were obtained and measured. A paired blood sample was then collected to coincide with the OptiScan measurement. The OptiScanner withdraws 0.13 mL of blood every 15 minutes from a central venous line, centrifuges the sample, and uses midinfrared spectroscopy to directly measure glucose levels in blood plasma. We plotted a Clarke Error Grid, calculated mean absolute relative difference (MARD) to analyze trend accuracy, and population coefficient of variation (PCV) to measure deviations. OptiScanner and Yellow Springs Instrument values were "blinded" from clinicians. Treatment was guided by the standard point of care meters., Results: 95.4% of the data points were in zone A of the Clarke Error Grid and 4.5% in zone B. The MARD was 7.6%, the PCV 9.6%. The majority of data points achieved the benchmark for accuracy. The MARD was below 10%, which is the first inline continuous glucose monitor to achieve this result in a clinical trial. The PCV was less than 10%. We confirmed that the OptiScanner outperformed every 1- to 3-hour glucose measurements using point of care meters which prevents glucose excursions and variability and achieves a higher amount of time the patient's glucose values remain in range., Conclusion: This pivotal multicenter trial demonstrates that the first inline CGM monitor is safe and accurate for use in critically ill surgical and trauma patients., Level of Evidence: Diagnostic study, level I.

Patients with protracted sepsis develop impaired immunity, which predisposes them to acquiring secondary infections. One of the most common and lethal secondary infections is Pseudomonas aeruginosa pneumonia. Immunoadjuvant therapy is a promising approach to reverse sepsis-induced immunosuppression and improve morbidity and mortality from secondary infections. Interleukin-7 is an immunoadjuvant that improves survival in clinically relevant animal models of polymicrobial peritonitis and in fungal sepsis. This study investigated the effect of recombinant human interleukin-7 (rhIL-7) on survival in a 2-hit model of sublethal cecal ligation and puncture followed by P. aeruginosa pneumonia. Potential immunologic mechanisms responsible for the rhIL-7 putative beneficial effect were also examined, focusing on IL-17, IL-22, IFN-γ, and TNF-α, cytokines that are critical in the control of sepsis and pulmonary Pseudomonas infections. Results showed that rhIL-7 was highly effective in preventing P. aeruginosa-induced death, i.e., 92% survival in rhIL-7-treated mice versus 56% survival in control mice. rhIL-7 increased absolute numbers of immune effector cells in lung and spleen and ameliorated the sepsis-induced loss of lung innate lymphoid cells (ILCs). rhIL-7 also significantly increased IL-17-, IFN-γ-, and TNF-α-producing lung ILCs and CD8 T cells as well as IFN-γ- and TNF-α-producing splenic T cell subsets and ILCs. Furthermore, rhIL-7 enhanced NF-κB and STAT3 signaling in lungs during sepsis and pneumonia. Given the high mortality associated with secondary P. aeruginosa pneumonia, the ability of rhIL-7 to improve immunity and increase survival in multiple animal models of sepsis, and the remarkable safety profile of rhIL-7, clinical trials with rhIL-7 should be considered., (© Society for Leukocyte Biology.)

Following results from the CRASH-2 trial, tranexamic acid (TXA) gained considerable interest for the treatment of hemorrhage in trauma patients. Although TXA is effective at reducing mortality in patients presenting within 3 hours of injury, optimal dosing, timing of administration, mechanism, and pharmacokinetics require further elucidation. The concept of fibrinolysis shutdown in hemorrhagic trauma patients has prompted discussion of real-time viscoelastic testing and its potential role for appropriate patient selection. The results of ongoing clinical trials will help establish high-quality evidence for optimal incorporation of TXA in mature trauma networks in the United States and abroad., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Near-continuous glucose monitoring is expected to increase time in range (TIR) of 80-120mg/dL and to avoid hypoglycemia without increasing workload. We investigated a near-continuous glucose monitor in surgical critically ill and trauma patients., Methods: Patients were enrolled at a surgical intensive care unit associated with a level 1 trauma center. Glucose measurements were compared to the gold standard Yellow Springs Instrument (YSI). The technology withdraws 0.13mL of blood every 15min from a central venous line, centrifuges the sample, and uses mid-infrared spectroscopy to measure glucose. We plotted a Clarke Error Grid, calculated Mean Absolute Relative Deviation (MARD) to analyze trend accuracy, and we present a Bland Altman plot of device versus standard glucose measurements., Results: 24 patients were enrolled. One patient was withdrawn due to poor blood return from central venous line. A total of 347 glucose measurements from 23 patients were compared to the gold standard. 94.8% of the data points were in zone A of the Clarke Error Grid and 5.2% in zone B. The MARD was 8.02%. The majority of data points achieved the benchmark for accuracy. The remaining 5.2% are clinically benign. The MARD was below 10%. The Bland Altman plot shows good agreement between the device and reference glucose measurements. There were no device related adverse events., Conclusion: Our data suggests that near continuous monitoring via infrared spectroscopy is safe and accurate for use in critically ill surgical and trauma patients. A large scale multi-center study is underway to confirm these findings., (Copyright © 2016 Elsevier Inc. All rights reserved.)