Population pharmacokinetic modelling and simulation of tranexamic acid in adult trauma patients.

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.

Prolonged hourly neurological examinations are associated with increased delirium and no discernible benefit in mild/moderate geriatric traumatic brain injury.

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.

Does Negative Pressure Wound Therapy Impact the Outcome for Patients With Necrotizing Soft Tissue Infection Infected With Anaerobic Bacteria?

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, χ2 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.

Negative Pressure Wound Therapy With and Without Instillation in Necrotizing Soft Tissue Infections.

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), χ2, 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.

Doing more with less: low-titer group O whole blood resulted in less total transfusions and an independent association with survival in adults with severe traumatic hemorrhage.

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.

Ludwig's Angina: Higher Incidence and Worse Outcomes Associated With the Onset of the Coronavirus Disease 2019 Pandemic.

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.

Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial.

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.

Defects in vein valve PROX1/FOXC2 antithrombotic pathway in endothelial cells drive the hypercoagulable state induced by trauma and critical illness.

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.

Reduction of Surgical Site Infection After Trauma Laparotomy Through Use of a Specific Protocol for Antibiotic Prophylaxis.

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.

Open Mandible and Maxillary Fractures Associated with Higher Risk of Infection in Victims of Assault.

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 χ2 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.

When REBOA grows wings: Resuscitative endovascular balloon occlusion of the aorta to facilitate aeromedical transport.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a helpful adjunct in the control of non-compressible truncal hemorrhage. Concerns regarding ischemia time limits its applicability in transfer. We describe the first reported case of civilian transfer via aeromedical transport to a higher level of care with a zone 3 REBOA catheter deployed. CASE REPORT: We present the case of a patient in hemorrhagic shock with a complex pelvic fracture exceeding the capability of a rural level-two trauma center requiring the use of REBOA catheter to permit aeromedical transport to a level-one trauma center for definitive embolization. CONCLUSION: Deployment of REBOA catheter to facilitate aeromedical transport to an appropriate level of care may be considered if travel times can be kept brief and there is a process and training in place to empower flight medics to consider transporting with a REBOA deployed.

Pseudomonas aeruginosa Pneumonia Causes a Loss of Type-3 and an Increase in Type-1 Innate Lymphoid Cells in the Gut.

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.

Extrathoracic multiple trauma dysregulates neutrophil function and exacerbates pneumonia-induced lung injury.

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.

Critical Ethics: How to Balance Patient Autonomy With Fairness When Patients Refuse Coronavirus Disease 2019 Testing.

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.

Fifteen-minute Frequency of Glucose Measurements and the Use of Threshold Alarms: Impact on Mitigating Dysglycemia in Critically Ill Patients.

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.

Acute Acalculous Cholecystitis-Associated Bacteremia Has Worse Outcome.

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 χ2 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.

The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI): A Randomized, Double-Blind, Placebo-Controlled, Single-Center Trial.

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.

The use of low-titer group O whole blood is independently associated with improved survival compared to component therapy in adults with severe traumatic hemorrhage.

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.

Inadequate Antibiotic Therapy Results in Higher Recurrence Rate after Drainage of Complicated Peri-Rectal Abscess.

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 χ2 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/m2. 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.

Temporary Abdominal Closure Is Associated with Increased Risk for Fungal Intra-Abdominal Infections in Trauma 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.