Mixed Methods Assessment of Incivility During Surgical Mortality and Morbidity Conference.

OBJECTIVE: This study assessed incivility during Mortality and Morbidity (M&M) Conference. BACKGROUND: A psychologically safe environment at M&M Conference enables generative discussions to improve care. Incivility and exclusion demonstrated by "shame and blame" undermine generative discussion. METHODS: We used a convergent mixed-methods design to collect qualitative data through non-participant observations of M&M conference and quantitative data through standardized survey instruments of M&M participants. The M&M conference was attended by attending surgeons (all academic ranks), fellows, residents, medical students on surgery rotation, advanced practice providers, and administrators from the department of surgery. A standardized observation guide was developed, piloted and adapted based on expert non-participant feedback. The Positive and Negative Affect Schedule Short-Form (PANAS) and the Uncivil Behavior in Clinical Nursing Education (UBCNE) survey instruments were distributed to the Department of Surgery clinical faculty and categorical general surgery residents in an academic medical center. RESULTS: We observed 11 M&M discussions of 30 cases, over six months with four different moderators. Case presentations (virtual format) included clinical scenario, decision-making, operative management, complications, and management of the complications. Discussion was free form, without a standard structure. The central theme that limited discussion participation from attending surgeon of record, as well as absence of a systems-approach discussion led to blame and blame then set the stage for incivility. Among 147 eligible to participate in the survey, 54 (36.7%) responded. Assistant professors had a 2.60 higher Negative Affect score (p-value=0.02), a 4.13 higher Exclusion Behavior score (p-value=0.03), and a 7.6 higher UBCNE score (p-value=0.04) compared to associate and full professors. Females had a 2.7 higher Negative Affect Score compared to males (p-value=0.04). CONCLUSION: Free-form M&M discussions led to incivility. Structuring discussion to focus upon improving care may create inclusion and more generative discussions to improve care.

A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis.

BACKGROUND: Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis. METHODS: We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith. RESULTS: In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50). CONCLUSIONS: For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).

Rapid single-molecule digital detection of protein biomarkers for continuous monitoring of systemic immune disorders.

Digital protein assays have great potential to advance immunodiagnostics because of their single-molecule sensitivity, high precision, and robust measurements. However, translating digital protein assays to acute clinical care has been challenging because it requires deployment of these assays with a rapid turnaround. Herein, we present a technology platform for ultrafast digital protein biomarker detection by using single-molecule counting of immune-complex formation events at an early, pre-equilibrium state. This method, which we term "pre-equilibrium digital enzyme-linked immunosorbent assay" (PEdELISA), can quantify a multiplexed panel of protein biomarkers in 10 µL of serum within an unprecedented assay incubation time of 15 to 300 seconds over a 104 dynamic range. PEdELISA allowed us to perform rapid monitoring of protein biomarkers in patients manifesting post-chimeric antigen receptor T-cell therapy cytokine release syndrome, with ∼30-minute sample-to-answer time and a sub-picograms per mL limit of detection. The rapid, sensitive, and low-input volume biomarker quantification enabled by PEdELISA is broadly applicable to timely monitoring of acute disease, potentially enabling more personalized treatment.

Professionalism of Admitting and Consulting Services and Trauma Patient Outcomes.

OBJECTIVE: To determine whether trauma patients managed by an admitting or consulting service with a high proportion of physicians exhibiting patterns of unprofessional behaviors are at greater risk of complications or death. SUMMARY BACKGROUND DATA: Trauma care requires high-functioning interdisciplinary teams where professionalism, particularly modeling respect and communicating effectively, is essential. METHODS: This retrospective cohort study used data from 9 level I trauma centers that participated in a national trauma registry linked with data from a national database of unsolicited patient complaints. The cohort included trauma patients admitted January 1, 2012 through December 31, 2017. The exposure of interest was care by 1 or more high-risk services, defined as teams with a greater proportion of physicians with high numbers of patient complaints. The study outcome was death or complications within 30 days. RESULTS: Among the 71,046 patients in the cohort, 9553 (13.4%) experienced the primary outcome of complications or death, including 1875 of 16,107 patients (11.6%) with 0 high-risk services, 3788 of 28,085 patients (13.5%) with 1 high-risk service, and 3890 of 26,854 patients (14.5%) with 2+ highrisk services (P < 0.001). In logistic regression models adjusting for relevant patient, injury, and site characteristics, patients who received care from 1 or more high-risk services were at 24.1% (95% confidence interval 17.2% to 31.3%; P < 0.001) greater risk of experiencing the primary study outcome. CONCLUSIONS: Trauma patients who received care from at least 1 service with a high proportion of physicians modeling unprofessional behavior were at an increased risk of death or complications.

Druggable Transcriptional Networks in the Human Neurogenic Epigenome.

Chromosome conformation capture methods have revealed the dynamics of genome architecture which is spatially organized into topologically associated domains, with gene regulation mediated by enhancer-promoter pairs in chromatin space. New evidence shows that endogenous hormones and several xenobiotics act within circumscribed topological domains of the spatial genome, impacting subsets of the chromatin contacts of enhancer-gene promoter pairs in cis and trans Results from the National Institutes of Health-funded PsychENCODE project and the study of chromatin remodeling complexes have converged to provide a clearer understanding of the organization of the neurogenic epigenome in humans. Neuropsychiatric diseases, including schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and other neuropsychiatric disorders are significantly associated with mutations in neurogenic transcriptional networks. In this review, we have reanalyzed the results from publications of the PsychENCODE Consortium using pharmacoinformatics network analysis to better understand druggable targets that control neurogenic transcriptional networks. We found that valproic acid and other psychotropic drugs directly alter these networks, including chromatin remodeling complexes, transcription factors, and other epigenetic modifiers. We envision a new generation of CNS therapeutics targeted at neurogenic transcriptional control networks, including druggable parts of chromatin remodeling complexes and master transcription factor-controlled pharmacogenomic networks. This may provide a route to the modification of interconnected gene pathways impacted by disease in patients with neuropsychiatric and neurodegenerative disorders. Direct and indirect therapeutic strategies to modify the master regulators of neurogenic transcriptional control networks may ultimately help extend the life span of CNS neurons impacted by disease.

Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in Pseudomonas aeruginosa Pneumonia-Induced Sepsis.

BACKGROUND: Pseudomonas aeruginosa (PA) is a pathogenic bacterium that causes severe pneumonia in critically ill and immunocompromised patients. Peptidylarginine deiminase (PAD) 2, PAD4, and caspase-1 are important enzymes in mediating host response to infection. The goal of this study was to determine the interplay between PAD2, PAD4, and caspase-1 in PA pneumonia-induced sepsis. METHODS: Pneumonia was produced in wild-type, Pad2-/-, and Pad4-/- mice by intranasal inoculation of PA (2.5 × 106 colony-forming units per mouse), and survival (n = 15/group) was monitored for 10 days. Bone marrow-derived macrophages (BMDMs) were isolated for in vitro studies. Samples were collected at specific timepoints for Western blot, bacterial load determination, and flow cytometry analysis. RESULTS: Caspase-1-dependent inflammation was diminished in PA-inoculated Pad2-/- mice, contributing to reduced macrophage death and enhanced bacterial clearance. In addition, Pad2-/- mice exhibited improved survival and attenuated acute lung injury after PA infection. In contrast, Pad4-/- mice did not display diminished caspase-1 activation, altered bacterial loads, or improved survival. CONCLUSIONS: Peptidylarginine deiminase 2 plays an essential role in the pathogenesis of pulmonary sepsis by mediating caspase-1 activation. This goes against previous findings of PAD4 in sepsis. Our study suggests that PAD2 is a potential therapeutic target of PA pneumonia-induced sepsis.

Delay in Hip Fracture Repair in the Elderly: A Missed Opportunity Towards Achieving Better Outcomes.

BACKGROUND: Hip fractures are a major cause of morbidity and mortality in the elderly. The American Academy of Orthopedic Surgeons (AAOS) recommends surgical repair within 48 hours of admission, as this is associated with lower postoperative mortality and complications. This study demonstrates the association between patient demographics, level of care, and hospital region to delay in hip fracture repair in the elderly. METHODS: The National Trauma Data Bank (NTDB) was queried for elderly patients (age >65 years) who underwent proximal femoral fracture repair. Identified patients were subcategorized into two groups: hip fracture repair in <48 hours, and hip fracture repair > 48 hours after admission. Patient and hospital characteristics were collected. Outcome variables were timed from the day of admission to surgery and inpatient mortality. RESULTS: Out of 69,532 patients, 28,031 were included after inclusion criteria were applied. 23,470 (83.7%) patients underwent surgical repair within 48 hours. The overall median time to procedure was 21 (interquartile range [IQR] 7-38) hours. Females were less likely to undergo a delay in hip fracture repair (odds ratio [OR; 95% confidence interval {CI}]: 0.82 [0.76-0.88], P< 0.05), and patients with higher Injury Severity Score (ISS ≥25) had higher odds of delay in surgical repair (OR; 95% CI: 1.56 [1.07-2.29], P< 0.05). Patients treated at hospitals in the Western regions of the United States had lower odds of delay, and those treated in the Northeast and the South had higher odds of delay compared to the hospitals in the Midwest (taken as standard). There was no association between trauma level designation and odds of undergoing delay in hip fracture repair. CONCLUSION: Variables related to patient demographic and hospital characteristics are associated with delay in hip fracture repair in the elderly. This study delineates key determinants of delay in hip fracture repair in the elderly patients.

Teamwork at the Bench: Strategies for Collaborative Surgical Science in a Pandemic.

The Center for Basic and Translational Science was formed to address the unique challenges faced by surgeon-scientists. Shortly after its inception, COVID-19 upended research workflows at our institution. We discuss how the collaborative Center for Basic and Translational Science framework was adapted to support laboratories during the pandemic by assisting with ramp-down, promoting mentorship and community building, and maintaining research productivity.

Surgery Provider Perceptions on Telehealth Visits During the COVID-19 Pandemic: Room for Improvement.

BACKGROUND: COVID-19 has mandated rapid adoption of telehealth for surgical care. However, many surgical providers may be unfamiliar with telehealth. This study evaluates the perspectives of surgical providers practicing telehealth care during COVID-19 to help identify targets for surgical telehealth optimization. MATERIALS AND METHODS: At a single tertiary care center with telehealth capabilities, all department of surgery providers (attending surgeons, residents, fellows, and advanced practice providers) were emailed a voluntary survey focused on telehealth during the pandemic. Descriptive statistics and Mann-Whitney U analyses were performed as appropriate on responses. Text responses were thematically coded to identify key concepts. RESULTS: The completion rate was 41.3% (145/351). Providers reported increased telehealth usage relative to the pandemic (P < 0.001). Of respondents, 80% (116/145) had no formal telehealth training. Providers estimated that new patient video visits required less time than traditional visits (P = 0.001). Satisfaction was high for several aspects of video visits. Comparatively lower satisfaction scores were reported for the ability to perform physical exams (sensitive and nonsensitive) and to break bad news. The largest barriers to effective video visits were limited physical exams (55.6%; 45/81) and lack of provider or patient internet access/equipment/connection (34.6%; 28/81). Other barriers included ineffective communication and difficulty with fostering rapport. Concerns regarding video-to-telephone visit conversion were loss of physical exam/visual cues (34.3%; 24/70), less personal interactions (18.6%; 13/70), and reduced efficiency (18.6%; 13/70). CONCLUSIONS: Telehealth remains a new experience for surgical providers despite its expansion. Optimization strategies should target technology barriers and include specialized virtual exam and communication training.

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

INTRODUCTION: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury. METHODS: We analyzed data from two separate experiments where swine were subjected to lethal insults.  Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy. RESULTS: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment. CONCLUSIONS: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

Assessment of the Cytoprotective Effects of High-Dose Valproic Acid Compared to a Clinically Used Lower Dose.

OBJECTIVE: Valproic acid (VPA) treatment improves survival in animal models of injuries on doses higher than those allowed by Food and Drug Administration (FDA). We investigated the proteomic alterations induced by a single high-dose (140mg/kg) of VPA (VPA140) compared to the FDA-approved dose of 30mg/kg (VPA30) in healthy humans. We also describe the proteomic and transcriptomic changes induced by VPA140 in an injured patient. We hypothesized that VPA140 would induce cytoprotective changes in the study participants. METHODS: Serum samples were obtained from healthy subjects randomized to two groups; VPA140 and VPA30 at 3 timepoints: 0h(baseline), 2h, and 24h following infusion(n = 3/group). Samples were also obtained from an injured patient that received VPA140 at 0h, 6h and 24h following infusion. Proteomic analyses were performed using liquid chromatography-mass spectrometry (LC-MS/MS), and transcriptomic analysis was performed using RNA-sequencing. Differentially expressed (DE) proteins and genes were identified for functional annotation and pathway analysis using iPathwayGuide and gene set enrichment analysis (GSEA), respectively. RESULTS: For healthy individuals, a dose comparison was performed between VPA140 and VPA30 groups at 2 and 24 h. Functional annotation showed that top biological processes in VPA140 versus VPA30 analysis at 2 h included regulation of fatty acid (P = 0.002) and ATP biosynthesis (P = 0.007), response to hypoxia (P = 0.017), cell polarity regulation (P = 0.031), and sequestration of calcium ions (P = 0.031). Top processes at 24 h in VPA140 versus VPA30 analysis included amino acid metabolism (P = 0.023), collagen catabolism (P = 0.023), and regulation of protein breakdown (P = 0.023). In the injured patient, annotation of the DE proteins in the serum showed that top biological processes at 2 h included neutrophil chemotaxis (P = 0.002), regulation of cellular response to heat (P = 0.008), regulation of oxidative stress (P = 0.008) and regulation of apoptotic signaling pathway (P = 0.008). Top biological processes in the injured patient at 24 h included autophagy (P = 0.01), glycolysis (P = 0.01), regulation of apoptosis (P = 0.01) and neuron apoptotic processes (P = 0.02). CONCLUSIONS: VPA140 induces cytoprotective changes in human proteome not observed in VPA30. These changes may be responsible for its protective effects in response to injuries.

Serum citrullinated histone H3 concentrations differentiate patients with septic verses non-septic shock and correlate with disease severity.

PURPOSE: Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes. METHODS: Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted. RESULTS: Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p < 0.0001). The area under the curve (95% CI) for distinguishing septic shock from NIC using CitH3 was 0.76 (0.65-0.86). CitH3 was positively correlated with PAD2 and PAD4 concentrations and Sequential Organ Failure Assessment Scores [total score (r = 0.36, p < 0.0001)]. The serum levels of CitH3 at 24 h (p < 0.01) and 48 h (p < 0.05) were significantly higher in the septic patients that did not survive. CONCLUSION: CitH3 is increased in patients with septic shock. Its serum concentrations correlate with disease severity and prognosis, which may yield vital insights into the pathophysiology of sepsis.

Twelve tips for the integration of medical students into telemedicine visits.

The use of telemedicine in clinical care has grown significantly in the last few years and has only increased during the COVID-19 pandemic. Given that many physicians will be expected to deliver virtual care moving forward, it is important for medical students to gain exposure via this modality during their clinical training. Many medical schools are actively working to integrate students into telemedicine. This article aims to provide guidance for readers incorporating medical students in telemedicine visits at an institutional or departmental level. This article covers essential topics such as coordinating key stakeholders, conducting needs assessments, addressing technological or software considerations, and creating appropriate workflows for students and physicians.

An Integrated Plasmo-Photoelectronic Nanostructure Biosensor Detects an Infection Biomarker Accompanying Cell Death in Neutrophils.

Bacterial infections leading to sepsis are a major cause of deaths in the intensive care unit. Unfortunately, no effective methods are available to capture the early onset of infectious sepsis near the patient with both speed and sensitivity required for timely clinical treatment. To fill the gap, the authors develop a highly miniaturized (2.5 × 2.5 µm2 ) plasmo-photoelectronic nanostructure device that detected citrullinated histone H3 (CitH3), a biomarker released to the blood circulatory system by neutrophils. Rapidly detecting CitH3 with high sensitivity has the great potential to prevent infections from developing life-threatening septic shock. To this end, the author's device incorporates structurally engineered arrayed hemispherical gold nanoparticles that are functionalized with high-affinity antibodies. A nanoplasmonic resonance shift induces a photoconduction increase in a few-layer molybdenum disulfide (MoS2 ) channel, and it provides the sensor signal. The device achieves label-free detection of serum CitH3 with a 5-log dynamic range from 10-4 to 101 ng mL and a sample-to-answer time <20 min. Using this biosensor, the authors longitudinally measure the dynamic CitH3 profiles of individual living mice in a sepsis model at high resolution over 12 hours. The developed biosensor may be poised for future translation to personalized management of systemic bacterial infections.

Defining the Burden of Emergency General Surgery in Transplant Patients: A Nationwide Examination.

BACKGROUND: Transplant patients are at the risk of serious sequelae from medical and surgical intervention. The incidence and burden of emergency general surgery (EGS) in transplant patients are scarcely known. This study aims to identify predictors of outcomes in transplant patients with EGS needs. METHODS: The Nationwide Inpatient Sample (2007-2011) was queried for adult patients (aged ≥16 y) who underwent abdominal visceral transplantation. These were further queried for a secondary diagnosis of an American Association for the Surgery of Trauma-defined EGS condition. Outcome measures included mortality, complications, length of stay, and cost of care. Propensity scores were used to match patients across baseline characteristics. Multivariate analysis was used to further adjust propensity score quintiles and hospital-level characteristics. RESULTS: A total of 35,573 transplant patients were identified. Of these, 30% (n = 10,676) developed an EGS condition. Most common EGS conditions were resuscitation (7.7%), intestinal obstruction (7.3%), biliary conditions (3.9%), and hernias (3.2%). Patients with public insurance, those in the highest income quartile, and those treated at larger hospitals had a lower likelihood of developing an EGS condition (P < 0.05). Patients with an EGS condition had a ninefold higher likelihood of mortality and a threefold higher likelihood of developing complications (odds ratio [95% confidence interval (CI)]: 9.21 [1.80-10.89] and 3.17 [3.02-3.34], respectively). Transplant patients after EGS had a longer risk-adjusted length of stay and cost of index hospitalization (Absolute difference [95% CI]: 12.70 [12.14-13.26] and $57,797 [55,415-60,179], respectively]). CONCLUSIONS: Transplant patients fare poorly after developing an EGS condition. The results of this study will help in identifying at-risk patients and determining outcomes.

Pilot Study to Evaluate the Safety, Feasibility, and Financial Implications of a Postoperative Telemedicine Program.

BACKGROUND: Telemedicine in surgery holds promise for improving access and decreasing costs, but its role remains ill-defined. This pilot study was performed to investigate the safety, feasibility, and financial implications of providing postoperative care using an electronic clinic (eClinic) at a university hospital. METHODS: An easy-to-use and secure eClinic platform was constructed in Epic (Epic Systems Corporation, Verona, WA). Patients undergoing laparoscopic cholecystectomy, appendectomy, and hernia repairs on an adult acute care surgery service were enrolled in this program over an 11-month period (March 2017 to January 2018). Patients with prolonged hospitalizations (greater than 4 nights), perioperative complications, drains, and open wounds were excluded. Demographics, clinical outcomes, encounter time, patient satisfaction survey results, and cost analysis were compared with the traditional clinic (tClinic) patient population. RESULTS: Two hundred thirty-three eligible patients (61% female; mean age 41 ±â€Š16 years) were enrolled in this program. Their demographics were no different than the tClinic. Frequencies of readmission, reoperation, and emergency department visits (2.7%, 0%, and 4.2%, respectively) in the eClinic group were also similar to the tClinic group. However, total visit time was significantly shorter in the eClinic group (14 vs 145 minutes, P < 0.01). Anonymous surveys demonstrated a high degree of satisfaction, with 85% of patients expressing desire to utilize the eClinic again. This program enhanced the capacity for new visits to tClinic, with a resultant projected increase in additional operative cases and revenue for the health care system. CONCLUSIONS: A safe and efficient postoperative telemedicine program can be constructed utilizing a widely available electronic medical record system, which can improve patient satisfaction, optimize throughput, and increase gross charges for the healthcare system.

Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death in young adults, and effective treatment strategies have the potential to save many lives. TBI results in coagulopathy, endothelial dysfunction, inflammation, cell death, and impaired epigenetic homeostasis, ultimately leading to morbidity and/or mortality. Commonly used resuscitation fluids such as crystalloids or colloids have several disadvantages and might even be harmful when administered in large quantities. There is a need for next-generation treatment strategies (especially in the prehospital setting) that minimize cellular damage, improve survival, and enhance neurological recovery. Pharmacologic treatment with histone deacetylase inhibitors, such as valproic acid, has shown promising results in animal studies of TBI and may therefore be an excellent example of next-generation therapy. This review briefly describes traditional resuscitation strategies for TBI combined with hemorrhagic shock and describes preclinical studies on valproic acid as a new pharmacologic agent in the treatment of TBI. It finally discusses limitations and future directions on the use of histone deacetylase inhibitors for the treatment of TBI.

Improvement of Blood-Brain Barrier Integrity in Traumatic Brain Injury and Hemorrhagic Shock Following Treatment With Valproic Acid and Fresh Frozen Plasma.

OBJECTIVE: Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. DESIGN: Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). SUBJECTS: Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). INTERVENTIONS: Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. MEASUREMENTS AND MAIN RESULTS: Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. CONCLUSIONS: Resuscitation with fresh frozen plasma results in improved expression of proteins essential for blood-brain barrier integrity. The addition of valproic acid provides significant improvement to these protein expression profiles. This is likely secondary to activation of key pathways related to endothelial functions.