OpTrust: An Effective Educational Bundle for Enhancing Faculty-resident Intraoperative Entrustment.

OBJECTIVE: The purpose of this study was to measure the efficacy of a novel faculty and resident educational bundle focused on development of faculty-resident behaviors and entrustment in the operating room. SUMMARY BACKGROUND DATA: As surgical training environments are orienting to entrustable professional activities (EPAs), successful transitions to this model will require significant faculty and resident development. Identifying an effective educational initiative which prepares faculty and residents for optimizing assessment, teaching, learning, and interacting in this model is critical. METHODS: From September 2015 to June 2017, an experimental study was conducted in the Department of Surgery at the University of Michigan Health System (UMHS). Case observations took place across general, plastic, thoracic, and vascular surgical specialties. A total of 117 operating room observations were conducted during Phase I of the study and 108 operating room observations were conducted during Phase II following the educational intervention. Entrustment behaviors were rated for 56 faculty and 73 resident participants using OpTrust, a validated intraoperative entrustment instrument. RESULTS: Multiple regression analysis showed a significant increase in faculty entrustment (Phase I = 2.32 vs Phase II = 2.56, P < 0.027) and resident entrustability (Phase I = 2.16 vs Phase II = 2.40, P < 0.029) scores following exposure to the educational intervention. CONCLUSIONS: Our study shows improved intraoperative entrustment following implementation of faculty and resident development, indicating the efficacy of this innovative educational bundle. This represents a crucial component in the implementation of a competency-based assessment framework like EPAs.

Alignment of Personality Is Associated With Increased Intraoperative Entrustment.

OBJECTIVE: To determine the association between intraoperative entrustment and personality alignment. SUMMARY BACKGROUND DATA: For surgical residents, achieving operative autonomy has become increasingly difficult. The impact of faculty-resident operative interactions in accomplishing this goal is not well understood. We hypothesized that if operative dyads (faculty and resident) had personality alignment or congruency, then resident entrustment in the operating room would increase. METHODS: We completed a retrospective analysis of 63 operations performed from September 2015 to August 2016. Operations were scored using OpTrust, a validated tool that assesses progressive entrustment of responsibility to surgical residents in the operating room. All dyads were classified as having congruent or incongruent personality alignment as measured by promotion or prevention orientation using the regulatory focus questionnaire. The association between personality congruence and OpTrust scores was identified using multivariable linear regression. RESULTS: A total of 35 congruent dyads and 28 incongruent dyads were identified. Congruent dyads had a higher percentage of "very difficult" cases (33.3 vs. 7.4%, P = 0.017), female residents (37.1 vs. 14.3%, P = 0.042) and faculty with fewer years of experience (10.4 vs. 14.8%, P = 0.028) than incongruent dyads. In addition to post-graduate year level, dyad congruency was independently associated with a 0.88 increase (95% CI [0.27-1.49], P = 0.006) in OpTrust scores (overall range 2-8), after adjusting for case difficulty, faculty experience, and post-graduate year. CONCLUSIONS: Congruent operative dyads are associated with increased operative entrustment as demonstrated by increased OpTrust scores. Developing awareness and strategies for addressing incongruence in personality in the operative dyad is needed.

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.

The association of venous thromboembolism chemoprophylaxis timing on venous thromboembolism after major vascular surgery.

OBJECTIVE: Venous thromboembolism (VTE) is reported to occur in up to 33% of patients undergoing major vascular surgery. Despite this high incidence, patients inconsistently receive timely VTE chemoprophylaxis. The true incidence of VTE among patients receiving delayed VTE chemoprophylaxis is unknown. We sought to identify the association of VTE chemoprophylaxis timing on VTE risk, postoperative transfusion rates, and 30-day mortality and morbidity in patients undergoing major open vascular surgery. METHODS: Patients undergoing major open vascular surgery (open abdominal aortic aneurysm [oAAA] repair, aortofemoral bypass, and lower extremity infrainguinal bypass [LEB]) were identified using the Michigan Surgical Quality Collaborative (MSQC) between July 2012 and June 2015. The VTE rate was compared between patients receiving early versus delayed VTE chemoprophylaxis. VTE chemoprophylaxis delay was defined as therapy initiation more than 24 hours after surgery. The risk-adjusted association of the chemoprophylaxis timing and VTE development was determined using multivariable logistic regression. Blood transfusion rates, 30-day mortality, and postoperative complications were compared across groups. RESULTS: A total of 2421 patients underwent major open vascular surgery, including 196 oAAA repair, 259 aortofemoral bypass, and 1966 LEB. The overall incidence of 30-day VTE was 1.40%, ranging from 1.12% for LEB to 3.57% for oAAA repair. Among patients receiving early VTE chemoprophylaxis, the rate of VTE was 0.78% versus 2.26% among those with a delay in VTE chemoprophylaxis (P = .002). When accounting for the preoperative risk of VTE, delayed chemoprophylaxis was associated with a significantly higher risk of VTE (odds ratio, 2.38; 95% confidence interval, 1.12-5.06; P = .024). The early VTE chemoprophylaxis group was associated with a significantly decreased risk of bleeding compared with those with a delay (14.31% vs 18.90%; P = .002). Overall 30-day mortality and postoperative complications were similar with the exception of an associated higher rate of infectious complications in the delayed VTE chemoprophylaxis group, including superficial surgical site infection (6.00% vs 4.06%; P = .028), pneumonia (3.25% vs 1.85%; P = .028), urinary tract infection (2.95% vs 1.57%; P = .020), and severe sepsis (3.05% vs 1.71%; P = .029). CONCLUSIONS: Although patients undergoing major open vascular surgery have a low risk of VTE at baseline, there is a significantly greater risk of developing VTE among patients who have a delay in the administration of VTE chemoprophylaxis. Postoperative transfusion rates were significantly lower among patients receiving early chemoprophylaxis. There were no differences in the 30-day mortality and postoperative complications, except for infectious complications. Given these findings, surgeons should consider early chemoprophylaxis in the postoperative setting after major open vascular surgery without contraindication.

Rapid valproic acid-induced modulation of the traumatic proteome in a porcine model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: Histone deacetylase inhibitors such as valproic acid (VPA) improve survival in lethal models of hemorrhagic shock and polytrauma. Although VPA is known to modulate transcription, its ability to reduce mortality within minutes of administration suggests involvement of a rapid, posttranslational mechanism. We hypothesized that VPA treatment would cause proteomic changes within minutes of treatment including quantitative and/or posttranslational differences in structural and/or effector proteins. MATERIALS AND METHODS: We used a porcine model of traumatic brain injury (computer-controlled cortical impact, 12 mm depth) and hemorrhagic shock (40% hemorrhage). Animals were kept in shock for 2 h and randomized to two groups (n = 3): normal saline (volume = 3:1 hemorrhage volume) or normal saline + VPA (150 mg/kg, single dose). Peripheral blood mononuclear cells were collected at baseline, postshock, and postresuscitation. Intracellular protein profiles were assessed using 1 dimensional gel electrophoresis, liquid chromatography, mass spectrometry, and analyzed with Ingenuity Pathway Analysis software. RESULTS: Animals treated with VPA demonstrated significant proteomic changes. Quantitative differences were found in over 200 proteins including effector, regulatory, and structural proteins in critical cell signaling pathways. Posttranslational modification analysis demonstrated differential VPA-induced acetylation of lysine residues in histone and nonhistone proteins. Pathway analysis correlated these changes with significant increases in numerous prosurvival and cytoskeletal intracellular pathways, including Rho GTPase signaling (P = 1.66E-11), integrin signaling (P = 4.19E-21), and a decrease in Rho guanosine nucleotide dissociation inhibitor signaling (P = 4.83E-12). CONCLUSIONS: In a porcine model of severe injuries, a single dose of VPA is associated with protective changes in the proteome that are measurable within minutes of treatment.

Assessment of clinical feedback given to medical students via an electronic feedback system.

BACKGROUND: The feedback medical students receive during clinical rotations, traditionally verbal and not formally captured, plays a critical role in student development. This study evaluates written daily feedback given to students through a novel web-based feedback system. METHODS: A Minute Feedback System was used to collect feedback given to medical students during their surgery clerkship from May 2015-April 2016. Using qualitative content analysis, feedback comments were categorized as: encouraging, corrective, specific, and nonspecific. Effective feedback was a combination of specific and either corrective or encouraging feedback; ineffective feedback contained only nonspecific comments; mediocre feedback contained elements of both effective and ineffective comments. RESULTS: 3191 feedback requests were sent by medical students and 2029 faculty/resident feedback responses were received. The overall response rate was 62%. Nonspecific feedback comprised 80% of faculty, 83% of senior resident, and 78% of junior resident comments. Specific feedback was given by only 35% of faculty, 17% of senior residents, and 26% of junior residents. Faculty provided Effective feedback in only 16% of comments, senior residents 8%, and junior residents 17%. Mediocre feedback comprised 13% of faculty, 9% of senior resident, and 7% of junior resident comments. Ineffective feedback comprised 67% of all feedback: 60% of faculty, 72% of senior resident, and 68% of junior resident feedback. CONCLUSIONS: The majority of resident and faculty feedback to medical students using an electronic, email-based application during their surgery clerkship was nonspecific and encouraging and therefore of limited effectiveness. This presents an opportunity for resident/faculty development and education regarding optimal feedback techniques.

Greater faculty familiarity with residents improves intraoperative entrustment.

BACKGROUND: Longitudinal contact between faculty and residents facilitates greater faculty entrustment. The purpose of this study is to assess the relationship between faculty familiarity with residents and faculty entrustment. MATERIALS AND METHODS: Researchers observed and rated entrustment behaviors using OpTrust, September 2015-June 2017 at Michigan Medicine. Faculty familiarity with resident was measured on a 1-4 scale (1 = not familiar, 4 = extremely familiar). ANOVA and Sidak adjusted multiple comparisons were used to assess the relationship between faculty familiarity and faculty entrustment. RESULTS: 56 faculty and 73 residents were observed across 225 surgical cases. Faculty entrustment scores increased to 2.48 when resident familiarity was reported as "slightly familiar". Faculty entrustment scores for "moderately familiar" increased to 2.57. Faculty entrustment scores for "extremely familiar" increased to 2.84. CONCLUSIONS: We found a positive relationship between faculty familiarity and entrustment. These findings support greater continuity in faculty/resident relationships. Longitudinal contact allows learners to be granted progressive entrustment. SUMMARY: This study demonstrates a positive relationship between faculty familiarity with residents and an increase in intraoperative entrustment. These findings support greater continuity in faculty/resident relationships.

The 'Omics' of Epigenetic Modulation by Valproic Acid Treatment in Traumatic Brain Injury-What We Know and What the Future Holds.

Traumatic brain injury (TBI) is a heterogeneous injury that is a major cause of morbidity and mortality worldwide. Epigenetic modulation through the alteration of cellular acetylation by valproic acid (VPA) administration has shown promise as a novel pharmacological treatment for TBI. It improves clinical outcomes through multiple mechanisms, many of which are still poorly understood. In recent years, omics technologies have emerged as a promising strategy to detect molecular changes at the cellular level. This review highlights the use of these high throughput technologies in advancing the understanding of epigenetic modulation by VPA in TBI. It also describes the future role of omics techniques in developing a point of care test to guide patient selection for VPA administration.

Four-extremity amputation following disseminated intravascular coagulation and purpura fulminans.

Purpura fulminans (PF) is a rare but serious complication of septic shock in adults. The complex disease course makes it challenging to manage the condition. Here, we present the case of a healthy young woman who presented with sepsis and new-onset erythematous lesions 4 days after the vaginal delivery of a healthy baby. The infectious source could not be identified, and the patient was started on antibiotics and resuscitated. However, her condition worsened, and she developed disseminated intravascular coagulation and PF. The septic episode slowly decreased in severity, but she sustained extensive ischaemic injuries to her extremities, for which she underwent four-limb amputation.

Management of a Persistent Cystic Duct Stump Leak Following Cholecystectomy With Percutaneous Transabdominal Cystic Duct Stump Embolization.

Cystic duct stump leak remains a difficult clinical problem despite advancements in endoscopic techniques. When these minimally invasive strategies fail, patients are often subject to high morbidity and mortality associated with open surgical exploration. We report the successful treatment of persistent biliary leak from the cystic duct stump following cholecystectomy using percutaneous transabdominal access of the cystic duct and coil embolization.

Bridging the gap: The intersection of entrustability and perceived autonomy for surgical residents in the OR.

BACKGROUND: Faculty entrustment decisions affect resident entrustability behaviors and surgical autonomy. The relationship between entrustability and autonomy is not well understood. This pilot study explores that relationship. METHODS: 108 case observations were completed. Entrustment behaviors were rated using OpTrust. Residents completed a Zwisch self-assessment to measure surgical autonomy. Resident perceived autonomy was collected for 67 cases used for this pilot study. RESULTS: Full entrustability was observed in 5 of the 108 observed cases. Residents in our study did not report full autonomy. Spearman's rank correlation coefficient identified that resident entrustability was positively correlated with perceived resident autonomy (ρ = 0.66, p < 0.05). Ordinal logistic regression assessed the relationship between resident entrustability and autonomy. The relationship persisted while controlling for PGY level, gender, and case complexity (OR = 8.42, SEM = 4.54, p < 0.000). CONCLUSIONS: Resident entrustability is positively associated with perceived autonomy, yet full entrustability is not translating to the perception of full autonomy for residents.

Evaluating the performance of the Minute Feedback System: A web-based feedback tool for medical students.

BACKGROUND: Medical students often report dissatisfaction with the feedback they receive on their clerkships. This study evaluates the performance of the Minute Feedback System (MFS), a web-based tool designed to facilitate medical student acquisition of same day written feedback from surgery residents and faculty. METHODS: System-generated data, targeted surveys, and end of clerkship questionnaires were used to evaluate MFS performance over a one-year period. RESULTS: 170 students made 3190 feedback requests and received 1978 responses (62% response rate). Students felt the system was easy to use (90%), provided useful feedback (74%), and allowed them to obtain more feedback than they would have in its absence (81%). Concerns were raised regarding the quality of electronic feedback and whether the data generated would be used for summative assessment. CONCLUSIONS: The MFS encourages same-day assessment and increases documented medical student feedback. Further development is required to improve feedback quality, response rates, and feedback application.

Impact of a resident's sex on intraoperative entrustment of surgery trainees.

BACKGROUND: Optimizing intraoperative education is critical for development of autonomous residents. Faculty decisions concerning intraoperative entrustment determine the degree to which a resident gains intraoperative responsibility. Accordingly, residents exhibit entrustable behaviors that further faculty entrustment in the operating room. Little empiric evidence exists evaluating how the sex of a resident influences faculty-resident decisions of entrustment. Studies involving perception-based measurements of autonomy report inequities for women residents. We sought to assess faculty behaviors in entrustment in relation to resident sex using OpTrust, a third-party objective measurement tool. METHODS: From September 2015 to June 2017 at the University of Michigan, surgical cases were observed and entrustment behaviors were rated using OpTrust. Critical case sampling was used to generate variation in operation type, case difficulty, faculty-resident pairings, faculty experience, and the level of the resident's training. Independent sample t-tests were conducted to compare faculty entrustment scores, as well as resident entrustability scores. RESULTS: A total of 56 faculty and 73 residents were observed across 223 surgical cases from 4 surgical specialties: general, plastic, thoracic, and vascular. There was no difference in faculty entrustment or entrustability scores between women and men (2.54 vs 2.35, P = .117 and 2.32 vs 2.22, P = .393, respectively). CONCLUSION: Using OpTrust scores, we found that a resident's sex does not appear to influence faculty entrustment in the OR. Faculty entrustment scores for women and men residents are similar across cases. This observation suggests that during the intraoperative interaction, faculty are not extending entrustment or opportunities for autonomy differently to women or men. Future research is needed to identify and measure perioperative elements that inform resident autonomy, which may contribute to inequities for women residents.

Improving the feasibility and utility of OpTrust-A tool assessing intraoperative entrustment.

BACKGROUND: Changes in the surgical training landscape have sparked an interest in developing new educational models anchored on entrustment assessment. We sought to optimize the validated OpTrust entrustment assessment tool by comparing ratings from short-course video reviews to previously validated intraoperative assessments. METHODS: Entrustment assessment scores for video-based and 1-h (short-course) observations were compared to previously validated intraoperative assessment scores. Faculty and residents were surveyed for their perceptions related to operative observation. RESULTS: There was a strong association between entrustment scores when comparing in-person to video-based observations (R2 = 0.76-0.84, p < 0.01) as well as short-course to full-duration observations (R2 = 0.65-0.76, p < 0.01). The majority of faculty and residents (>97%) felt observation did not negatively impact operative experience. CONCLUSIONS: Assessment of entrustment behaviors using short-course video review provides a feasible approach to intraoperative assessment. This latest application of OpTrust allows for the tool to be incorporated into surgical training programs across a variety of environments.

Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for valproic acid and divalproex.

Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (Cmax) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.

Valproic acid induces prosurvival transcriptomic changes in swine subjected to traumatic injury and hemorrhagic shock.

BACKGROUND: Valproic acid (VPA) is a histone deacetylase inhibitor that improves outcomes in large animal models of trauma. However, its protective mechanism of action is not completely understood. We sought to characterize the genetic changes induced by VPA treatment following traumatic injuries. METHODS: Six female Yorkshire swine were subjected to traumatic brain injury (controlled cortical impact), polytrauma (liver and splenic laceration, rib fracture, rectus crush), and hemorrhagic shock (HS, 40% total blood volume). Following 2 hours of HS, animals were randomized to resuscitation with normal saline (NS) or NS + 150 mg/kg of intravenous VPA (n = 3/cohort, 18 samples total). Blood samples were collected for isolation of peripheral blood mononuclear cells at three distinct time points: baseline, 6 hours following injuries, and on postinjury day 1. RNA was extracted from peripheral blood mononuclear cells and sequenced. Differential expression analysis (false discovery rate < 0.001 and p value <0.001) and gene set enrichment (Panther Gene Ontology and Ingenuity Pathway Analysis) was used to compare VPA to non-VPA-treated animals. RESULTS: A total of 628 differentially expressed RNA transcripts were identified, 412 of which were used for analysis. There was no difference between treatment groups at baseline. The VPA-induced genetic changes were similar at 6 hours and on postinjury day 1. Upregulated genes were associated with gene expression (p 2.13E-34), cellular development (1.19E-33), cellular growth and proliferation (1.25E-30), and glucocorticoid receptor signaling (8.6E-21). Downregulated genes were associated with cell cycle checkpoint regulation (3.64E-22), apoptosis signaling (6.54E-21), acute phase response signaling (5.84E-23), and the inflammasome pathway (1.7E-19). CONCLUSION: In injured swine, VPA increases the expression of genes associated with cell survival, proliferation, and differentiation and decreases those associated with cell death and inflammation. These genetic changes could explain the superior clinical outcomes in VPA-treated animals, including smaller brain lesion size and improved neurologic recovery.

Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury.

BACKGROUND: Early treatment with valproic acid (VPA) has demonstrated benefit in preclinical models of traumatic brain injury, including smaller brain lesion size, decreased edema, reduced neurologic disability, and faster recovery. Mechanisms underlying these favorable outcomes are not fully understood. We hypothesized that VPA treatment would upregulate genes involved in cell survival and proliferation and downregulate those associated with cell death and the inflammatory response. METHODS: Ten female swine were subjected to a protocol of traumatic brain injury and hemorrhagic shock. They were assigned to two groups (n = 5): normal saline (NS; 3× volume of shed blood), or NS + VPA (150 mg/kg). Following 6 hours of observation, brain tissue was harvested to evaluate lesion size and edema. Brain tissue was processed for RNA sequencing. Gene set enrichment and pathway analysis was performed to determine the differential gene expression patterns following injury. RESULTS: Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. Valproic acid significantly upregulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. The VPA treatment downregulated pathways related to apoptosis, glial cell proliferation, and neuroepithelial cell differentiation. Ingenuity Pathway Analysis identified VPA as the top upstream regulator of activated transcription, supporting it as a direct cause of these transcriptional changes. Master transcriptional regulator NEUROD1 was also significantly upregulated, suggesting that VPA may induce additional transcription factors. CONCLUSION: Administration of VPA attenuated brain lesion size, reduced brain edema, and induced significant changes in the transcriptome of injured brain within 6 hours. Patterns of differential expression were consistent with the proposed neurogenic and prosurvival effects of VPA treatment.

Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial.

BACKGROUND: Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans. METHODS: A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid. RESULTS: Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg. The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration-time profiles, with a strong correlation (R 2 = 0.56) observed between the number of reported adverse events and the dose level. CONCLUSIONS: The maximum tolerated dose of intravenous valproic acid in healthy subjects is 140 mg/kg. This is significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Next, the safety and tolerability of high-dose valproic acid will be tested in trauma patients in hemorrhagic shock. ClinicalTrials.gov Identifier: NCT01951560.

Resuscitation with Lyophilized Plasma Is Safe and Improves Neurological Recovery in a Long-Term Survival Model of Swine Subjected to Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma.

We have shown previously that fresh frozen plasma (FFP) and lyophilized plasma (LP) decrease brain lesion size and improve neurological recovery in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). In this study, we examine whether these findings can be validated in a clinically relevant model of severe TBI, HS, and polytrauma. Female Yorkshire swine were subjected to TBI (controlled cortical impact), hemorrhage (40% volume), grade III liver and splenic injuries, rib fracture, and rectus abdominis crush. The animals were maintained in a state of shock (mean arterial pressure 30-35 mm Hg) for 2 h, and then randomized to resuscitation with normal saline (NS), FFP, or LP (n = 5 swine/group). Animals were recovered and monitored for 30 d, during which time neurological recovery was assessed. Brain lesion sizes were measured via magnetic resonance imaging (MRI) on post-injury days (PID) three and 10. Animals were euthanized on PID 30. The severity of shock and response to resuscitation was similar in all groups. When compared with NS-treated animals, plasma-treated animals (FFP and LP) had significantly lower neurologic severity scores (PID 1-7) and a faster return to baseline neurological function. There was no significant difference in brain lesion sizes between groups. LP treatment was well tolerated and similar to FFP. In this clinically relevant large animal model of severe TBI, HS, and polytrauma, we have shown that plasma-based resuscitation strategies are safe and result in neurocognitive recovery that is faster than recovery after NS-based resuscitation.

Valproic acid modulates platelet and coagulation function ex vivo.

: Trauma-induced coagulopathy is associated with adverse patient outcome. Animal models demonstrate that histone deacetylase inhibitors, such as valproic acid (VPA), improve survival following injury. While in-vivo data suggest that improved survival may in part be because of an attenuation of coagulopathy, it remains unknown whether this is a direct effect of the drug, or the establishment of an overall prosurvival phenotype. We thus conducted an ex-vivo experiment to determine if VPA has an effect on coagulation and platelet function. Ten swine were subjected to traumatic brain injury (TBI) and hemorrhagic shock (HS). Blood samples were drawn prior to TBI+HS insult (Healthy group) and 2 h following TBI+HS (Shock group). Samples were incubated with VPA or vehicle controls for 1 h. Platelet aggregation was analyzed via impedance aggregometry and coagulation was measured using thromboelastography. Addition of VPA to the healthy blood did not affect platelet aggregation or coagulation parameters. In shock blood, incubation with VPA significantly reduced collagen-(P = 0.050), arachidonic acid-(P = 0.005), and adenosine diphosphate-(P = 0.023) induced platelet aggregation. VPA also significantly increased the clot strength (P = 0.002) and clot formation rate (P = 0.011). This is the first study to investigate the effect of VPA on platelet function ex vivo. Our results suggest that VPA has no effect on normal blood, but it decreases platelet activation and improves clot dynamics (strength and rate of formation) in blood from shocked animals. This suggests that VPA is capable of exerting a selective platelet sparing effect while enhancing the clot integrity.