Anti-fibrinolytic agent tranexamic acid suppresses the endotoxin-induced expression of Tnfα and Il1α genes in a plasmin-independent manner.

INTRODUCTION: Tranexamic acid (TXA) is widely used as an antifibrinolytic agent in hemorrhagic trauma patients. The beneficial effects of TXA exceed the suppression of blood loss and include the ability to decrease inflammation and edema. We found that TXA suppresses the release of mitochondrial DNA and enhances mitochondrial respiration. These results allude that TXA could operate through plasmin-independent mechanisms. To address this hypothesis, we compared the effects of TXA on lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines in plasminogen (Plg) null and Plg heterozygous mice. METHODS: Plg null and Plg heterozygous mice were injected with LPS and TXA or LPS only. Four hours later, mice were sacrificed and total RNA was prepared from livers and hearts. Real time quantitative polymerase chain reaction with specific primers was used to assess the effects of LPS and TXA on the expression of pro-inflammatory cytokines. RESULTS: LPS enhanced the expression of Tnfα in the livers and hearts of recipient mice. The co-injection of TXA significantly decreased the effect of LPS both in Plg null and heterozygous mice. A similar trend was observed with LPS-induced Il1α expression in hearts and livers. CONCLUSIONS: The effects of TXA on the endotoxin-stimulated expression of Tnfα and Il1α in mice do not depend on the inhibition of plasmin generation. These results indicate that TXA has other biologically important target(s) besides plasminogen/plasmin. Fully understanding the molecular mechanisms behind the extensive beneficial effects of TXA and future identification of its targets may lead to improvement in the use of TXA in trauma, cardiac, and orthopedic surgical patients.

Tranexamic acid: Beyond antifibrinolysis.

Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis.

Ultrasound-Guided Serratus Anterior Plane Block (SAPB) Improves Pain Control in Patients With Rib Fractures.

OBJECTIVES: The serratus anterior plane block (SAPB) is an ultrasound-guided compartment block; limited data suggest that it can decrease pain in patients with rib fractures or chest wall pain. We sought to determine the effect of SAPB on pain and incentive spirometry (IS) maximal vital capacity in adult patients with rib fractures. METHODS: We enrolled a prospective sample of adult patients with at least two unilateral rib fractures who were being admitted for pain control. SAPB was performed by trained emergency physicians. Patients reported pain on an 11-point Numeric Rating Scale at rest and during IS, before, 15, and 60 minutes after SAPB. RESULTS: Mean pain scores decreased by 1.8 (SD 2.17, 95% confidence interval [CI]: 0.79-2.81) at 15 minutes and 2.5 (SD 2.69, 95% CI: 1.24-3.76) at 60 minutes. Compared to pre-block pain scores during IS, mean pain scores decreased by 1.95 (SD 1.99, 95% CI: 1.02-2.88) at 15 minutes and 2.4 (SD 2.42, 95% CI: 1.27-3.53) at 60 minutes. Mean maximum vital capacity increased by 232 mL (SD 406, 95% CI: 36-427) at 60 minutes. Zero SAPB-attributable complications were identified in the 24 hours post-enrollment. CONCLUSIONS: In patients with multiple rib fractures, SAPB reduced pain scores at rest and during IS, and increased maximal vital capacity. The SABP may be a safe and effective modality for pain control in trauma patients with multiple rib fractures.

Prolonged Cardiopulmonary Bypass is Associated With Endothelial Glycocalyx Degradation.

BACKGROUND: The endothelial glycocalyx (EG) is involved in critical regulatory mechanisms that maintain endothelial vascular integrity. We hypothesized that prolonged cardiopulmonary bypass (CPB) may be associated with EG degradation. We performed an analysis of soluble syndecan-1 levels in relation to duration of CPB, as well as factors associated with cell stress and damage, such as mitochondrial DNA (mtDNA) and inflammation. METHODS: Blood samples from subjects undergoing cardiac surgery with CPB (n = 54) were obtained before and during surgery, 4-8 h and 24 h after completion of CPB, and on postoperative day 4. Flow cytometry was used to determine subpopulations of white blood cells. Plasma levels of mtDNA were determined using quantitative polymerase chain reaction and plasma content of shed syndecan-1 was measured. To determine whether syndecan-1 was signaling white blood cells, the effect of recombinant syndecan-1 on mobilization of neutrophils from bone marrow was tested in mice. RESULTS: CPB is associated with increased mtDNA during surgery, increased syndecan-1 blood levels at 4-8 h, and increased white blood cell count at 4-8 h and 24 h. Correlation analysis revealed significant positive associations between time on CPB and syndecan-1 (rs = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (rs = 0.351, P = 0.038) at 4-8 h. Intravenous administration of recombinant syndecan-1 in mice resulted in a 2.5-fold increase in the number of circulating neutrophils, concurrent with decreased bone marrow neutrophil number. CONCLUSIONS: Longer duration of CPB is associated with increased plasma levels of soluble syndecan-1, a signal for EG degradation, which can induce neutrophil egress from the bone marrow. Development of therapy targeting EG shedding may be beneficial in patients with prolonged CPB.

Tranexamic acid suppresses the release of mitochondrial DNA, protects the endothelial monolayer and enhances oxidative phosphorylation.

Damage-associated molecular patterns, including mitochondrial DNA (mtDNA) are released during hemorrhage resulting in the development of endotheliopathy. Tranexamic acid (TXA), an antifibrinolytic drug used in hemorrhaging patients, enhances their survival despite the lack of a comprehensive understanding of its cellular mechanisms of action. The present study is aimed to elucidate these mechanisms, with a focus on mitochondria. We found that TXA inhibits the release of endogenous mtDNA from granulocytes and endothelial cells. Furthermore, TXA attenuates the loss of the endothelial monolayer integrity induced by exogenous mtDNA. Using the Seahorse XF technology, it was demonstrated that TXA strongly stimulates mitochondrial respiration. Studies using Mitotracker dye, cells derived from mito-QC mice, and the ActivSignal IPAD assay, indicate that TXA stimulates biogenesis of mitochondria and inhibits mitophagy. These findings open the potential for improvement of the strategies of TXA applications in trauma patients and the development of more efficient TXA derivatives.

Surgical adjuncts to noncompressible torso hemorrhage as tools for patient blood management.

Despite the tremendous advances and successes in the care of combat casualties over the past 15 years of war, noncompressible torso hemorrhage (NCTH) remains the most likely source of potentially preventable death (approx. 25%) on the battlefield. This is also likely true for civilian victims of blunt and penetrating trauma. Various devices and therapeutic interventions have been, and are being, developed in an attempt to reduce morbidity and mortality for patients with NCTH. Examples include the use of prehospital blood and blood products, tranexamic acid, specially designed tourniquets for junctional hemorrhage control, retrograde endovascular balloon occlusion of the aorta, intracavity foam, expandable hemostatic sponges, and intravascular nanoparticles to suspended animation. Although each of these modalities offer the potential to staunch uncontrolled hemorrhage until an injured patient is able to reach definitive surgical care, further research and advances must be made to further reduce trauma morbidity and mortality and to identify those technologies and modalities that are best suited to rapid movement to the front lines of combat casualty care as well as to emergency medical personnel dealing with civilian trauma victims. The surgical adjuncts for NCTH discussed may all be considered as potential tools for patient blood management programs. If effective they offer the possibility of reduce hemorrhage and blood product exposure and improved patient outcomes.

Tranexamic acid reduces inflammation, edema and burn wound conversion in a rodent model.

Burn wound conversion is the observed process where superficial partial thickness burns convert into deep partial or full thickness burn injuries. This conversion process often involves surgical excision to achieve timely wound healing. Unfortunately, the pathophysiology of this phenomenon is multifactorial and poorly understood. Thus, a therapeutic intervention that may prevent secondary progression and cell death in burn-injured tissue is desirable. Recent work by our group and others has established that tranexamic acid (TXA) has significant anti-inflammatory properties in addition to its well-known anti-fibrinolytic effects. This study investigates TXA as a novel therapeutic treatment to mitigate burn wound conversion and reduce systemic inflammation. Sprague-Dawley rats were subjected to a hot comb burn contact injury. A subset of animals underwent a similar comb burn with an adjacent 30%TBSA contact injury. The interspaces represent the ischemic zones simulating the zone of stasis. The treatment group received injections of TXA (100 mg/kg) immediately after injury and once daily until euthanasia. Animals were harvested for analyses at 6 h and 7 days after injury. Full-thickness biopsies from the ischemic zones and lung tissue were assessed with established histological techniques. Plasma was collected for measurement of damage associated molecular patterns (DAMPs), and liver samples were used to study inflammatory cytokines expression. Treatment with TXA was associated with reduced burn wound conversion and decreased burn-induced systemic inflammatory response syndrome (SIRS). Lung inflammation and capillary leak were also significantly reduced in TXA treated animals. Future research will elucidate the underlying anti-inflammatory properties of TXA responsible for these findings.

"Should We Phenobarb-it-All?" A Phenobarbital-Based Protocol for Non-Intensive Care Unit Trauma Patients at High Risk of or Experiencing Alcohol Withdrawal.

BACKGROUND: Alcohol use is frequent in trauma patients and alcohol withdrawal syndrome (AWS) is associated with significant morbidity. Benzodiazepines are commonly used for AWS, but may cause neurologic and respiratory adverse events (AEs). The objective was to evaluate the effectiveness and safety of a phenobarbital-based protocol for the treatment of AWS in non-intensive care unit (ICU) trauma patients. METHODS: Adult non-ICU trauma patients at high risk of or experiencing AWS PRE and POST implementation of a phenobarbital-based protocol were included. Outcomes were AWS-related complications (AWS-RC), benzodiazepine use, adjunctive medication use, hospital length of stay (HLOS), and medication-related AEs. Subgroup analyses were performed on patients with traumatic brain injury (TBI), rib fractures, and at high risk of severe AWS. RESULTS: Overall, 110 patients were included (51 PRE, 59 POST). AWS-RC developed in 17 PRE patients compared to 10 POST patients (33% vs 17%; P = .05). PRE patients were more likely to receive benzodiazepines (88% vs 42%, P < .0001) and higher total dose (11 vs 4 mg lorazepam equivalent; P = .001). No difference noted in HLOS (8 vs 8 days, P = .27), adjunctive medication use (49% vs 54%, P = .60), or AEs (57% vs 39%, P = .06). There was no difference in AWS-RC in the TBI subgroup (P = .19), less AEs in the rib fracture POST subgroup (P = .04), and less AWS-RC in the high risk of severe AWS POST subgroup (P = .03). DISCUSSION: A phenobarbital-based protocol in trauma patients is effective in preventing AWS-RC and decreasing benzodiazepine use without increasing AEs.

Tranexamic acid in remote damage control resuscitation.

With the advent of remote damage control resuscitation and far-forward surgery, a renewed emphasis has been placed on examining a variety of pharmacologic adjuncts to controlling blood loss before definitive operative intervention. In this paper, the authors review the current state of the art for tranexamic acid (TXA) and its potential benefits to those patients who are in need of a massive transfusion. Specifically addressed are its biologic and pharmacologic properties, as well the results of a number of recent studies. The 2010 CRASH-2 trial randomized in excess of 20,000 patients and demonstrated a reduction in all-cause mortality from 16.0 to 14.5% and death due to bleeding from 5.7 to 4.9%. The 2012 Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study provided a retrospective analysis of 896 wounded cared for at a military hospital in Afghanistan. This study demonstrated a 23.9%-17.4% reduction in all-cause mortality. Finally, they discuss the potential complications associated with TXA use as well as areas of future research, which are needed to solidify our knowledge of TXA and its potential beneficial effects on controlling bleeding.

Management of Decompensated Cirrhosis in the Surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document.

Management of decompensated cirrhosis (DC) can be challenging for the surgical intensivist. Management of DC is often complicated by ascites, coagulopathy, hepatic encephalopathy, gastrointestinal bleeding, hepatorenal syndrome, and difficulty assessing volume status. This Clinical Consensus Document created by the American Association for the Surgery of Trauma Critical Care Committee reviews practical clinical questions about the critical care management of patients with DC to facilitate best practices by the bedside provider.

Study Strategies for General Surgery Residents Preparing for the American Board of Surgery In-Training Examination: What to Keep, Discard, and Adopt.

OBJECTIVE: Undergraduate and graduate education research has stratified study strategies from low-utility to high-utility with respect to durable learning. The purpose of this study was to determine the prevalence of these evidence-based learning strategies among surgery residents in preparation for the American Board of Surgery In-Training Examination (ABSITE). DESIGN: A 23-item survey was administered during individual interviews. It assessed whether they had a study plan, and the average length and frequency of their independent study, both during the year and the month prior to the ABSITE. Data were also collected on their primary resources and study strategies. Residents rated their usage of those strategies based on a 5-point Likert scale. SETTING: Maine Medical Center, an academic tertiary care center located in Portland, ME. PARTICIPANTS: All residents in the Department of Surgery. RESULTS: Residents (n= 23) intensified their preparation for the ABSITE in the month prior to the exam compared to the remainder of the year, adopting study plans (87% vs 61%, p = 0.53) and increasing the time spent studying (median, 420 vs 120 minutes per week, p < 0.001). Primary resources used were textbooks (65%), ABSITE review books (26%) and online question banks (9%). All residents (100%) often or always used testing, but fewer residents often or always used spacing (24%), both considered high-utility strategies. Most residents (60%) often or always used highlighting, considered a low-utility strategy. There were no relationships between study strategies and ABSITE scores. CONCLUSIONS: All residents use self-testing as a study strategy. Most underuse spacing and overuse highlighting. Further research is needed to establish the relationship between these study strategies and ABSITE scores.

Transdiaphragmatic Chest Wall Herniation.

BACKGROUND: The combination of traumatic simultaneous diaphragmatic rupture and chest wall herniation remains rare, with 42 cases of traumatic transdiaphragmatic intercostal hernia (TDIH) reported in the literature since 1946. An accurate count of cases is difficult to obtain, as TDIH nomenclature has been variable.1-5 Risk factors for traumatic TDIH are not well established. As these injuries are uncommon, best management techniques have yet to be established. Reported repair techniques include primary closure, closure with mesh, and implantation of prosthetic or autologous material. We present our single-center series of 7 patients, the largest reported to our knowledge, and discuss the challenges of repairing these difficult injuries. METHODS: After obtaining institutional review board approval, data were abstracted from the electronic medical record on all adults who underwent evaluation and treatment for traumatic TDIH between July 2014 and January 2019. RESULTS: Of the 7 cases of traumatic TDIH, 6 patients developed TDIH secondary to cough; the seventh patient presented with chronic chest wall pain after an episode of heavy lifting. All patients were obese or overweight. Pain and a "popping sensation" were the most common presenting symptoms. All patients underwent operative intervention with primary repair of the diaphragm and suture approximation of the ribs. 3 patients had onlay mesh repair of the chest wall and/or abdominal wall. 1 patient had plating of his rib fracture. 3 patients had a recurrence of the intercostal portion of the hernia No patients have undergone reoperation thus far. DISCUSSION: While previously thought to more commonly occur on the left side due to the protective effects of the diaphragm,2 the majority in this series had right-sided injuries. Herniation through the ninth-10th interspace remains the most common location.4 Computed tomography imaging should be used for diagnosis and operative planning. It is best to manage these hernias acutely to re-establish normal anatomy. Mesh may be required in delayed reconstructions of if the chest wall cannot be re-approximated. Rib plating should be considered in cases of instability or flail. High rates of complications are not unexpected given the complicated and rare nature of the injury. Given the high rate of intercostal hernia recurrence, it is likely that mesh repair or should be more often used in the treatment of this injury.

Venous thromboembolism prophylaxis in the trauma intensive care unit: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document.

Venous thromboembolism (VTE) is a potential sequela of injury, surgery, and critical illness. Patients in the Trauma Intensive Care Unit are at risk for this condition, prompting daily discussions during patient care rounds and routine use of mechanical and/or pharmacologic prophylaxis measures. While VTE rightfully garners much attention in clinical patient care and in the medical literature, optimal strategies for VTE prevention are still evolving. Furthermore, trauma and surgical patients often have real or perceived contraindications to prophylaxis that affect the timing of preventive measures and the consistency with which they can be applied. In this Clinical Consensus Document, the American Association for the Surgery of Trauma Critical Care Committee addresses several practical clinical questions pertaining to specific or unique aspects of VTE prophylaxis in critically ill and injured patients.

Comparison of intraoperative tranexamic acid and epsilon-aminocaproic acid in cardiopulmonary bypass patients.

Objective: To compare tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: Over a consecutive 2-year period, 824 adult cardiac surgery patients who received TXA during an EACA shortage were compared with 778 patients who received EACA postshortage. Patient characteristics and process and outcome variables were collected through chart review and database queries. This retrospective analysis used inverse probability of treatment weighting to control for confounding by indication, and propensity scores were calculated using a logistic regression model. Results: In adjusted models, overall transfusion rates for the TXA cohort (odds ratio [OR], 0.94; 95% confidence interval [95% CI], 0.81-1.10) and administration of platelets (OR, 1.04; 95% CI, 0.85-1.27), red blood cells (OR, 0.93; 95% CI, 0.80-1.09), fresh frozen plasma (OR, 1.00; 95% CI, 0.79-1.25), and cryoprecipitate (OR, 1.08; 95% CI, 0.71-1.64) were equivalent to the EACA cohort. In addition, there was no statistical difference with respect to stroke, seizure, mortality, reoperation for bleeding, chest tube drainage, and acute kidney injury. Patients who received TXA had shorter ventilator times (difference in medians -1.33 hours [95% CI, -1.86 to -0.80]) and lower postsurgical charges (difference of medians -$2913 [95% CI, -5147 to -679]). Conclusions: Substituting TXA for EACA during cardiac surgery with cardiopulmonary bypass did not change transfusion rate or amount, nor was there a significant difference in chest tube drainage. Patients who received TXA had a statistically significant but not clinically significant lower postoperative ventilator times and charges without an increase in mortality, stroke, reoperation for bleeding, acute kidney injury, or seizures.

Risk of Harm Associated With Using Rapid Sequence Induction Intubation and Positive Pressure Ventilation in Patients With Hemorrhagic Shock.

Based on limited published evidence, physiological principles, clinical experience, and expertise, the author group has developed a consensus statement on the potential for iatrogenic harm with rapid sequence induction (RSI) intubation and positive-pressure ventilation (PPV) on patients in hemorrhagic shock. "In hemorrhagic shock, or any low flow (central hypovolemic) state, it should be noted that RSI and PPV are likely to cause iatrogenic harm by decreasing cardiac output." The use of RSI and PPV leads to an increased burden of shock due to a decreased cardiac output (CO)2 which is one of the primary determinants of oxygen delivery (DO2). The diminishing DO2 creates a state of systemic hypoxia, the severity of which will determine the magnitude of the shock (shock dose) and a growing deficit of oxygen, referred to as oxygen debt. Rapid accumulation of critical levels of oxygen debt results in coagulopathy and organ dysfunction and failure. Spontaneous respiration induced negative intrathoracic pressure (ITP) provides the pressure differential driving venous return. PPV subsequently increases ITP and thus right atrial pressure. The loss in pressure differential directly decreases CO and DO2 with a resultant increase in systemic hypoxia. If RSI and PPV are deemed necessary, prior or parallel resuscitation with blood products is required to mitigate post intervention reduction of DO2 and the potential for inducing cardiac arrest in the critically shocked patient.

'Step Up' approach to the application of REBOA technology in a rural trauma system.

Our group has developed a 'Step Up' approach to the application of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in a rural trauma system. This incorporates viewing REBOA as a spectrum of technology. Examples of REBOA technology use to improve outcomes and provision of our system's clinical practice guideline for the Step-Up application of REBOA technology in the care of trauma patients are presented.

Tranexamic acid suppresses the release of mitochondrial DAMPs and reduces lung inflammation in a murine burn model.

BACKGROUND: Severe burn injuries are known to initiate a profound systemic inflammatory response (SIRS) that may lead to burn shock and other SIRS-related complications. Damage-associated molecular patterns (DAMPs) are important early signaling molecules that initiate SIRS after burn injury. Previous work in a rodent model has shown that application of a topical immune modulator (p38MAPK inhibitor) applied directly to the burn wound decreases cytokine expression, reduces pulmonary inflammation and edema. Our group has demonstrated that tranexamic acid (TXA)-in addition to its use as an antifibrinolytic-has cell protective in vitro effects. We hypothesized that administration of TXA after burn injury would attenuate DAMP release and reduce lung inflammation. METHODS: C57/BL6 male mice underwent a 40% Total Body Surface Area (TBSA) scald burn. Sham animals underwent the same procedure in room temperature water. One treatment group received the topical application of p38MAPK inhibitor after burn injury. The other treatment group received an intraperitoneal administration of TXA after burn injury. Animals were sacrificed at 5 hours. Plasma was collected by cardiac puncture. MtDNA levels in plasma were determined by quantitative Polymerase Chain Reaction (qPCR). Syndecan-1 levels in plasma were measured by ELISA. Lungs were harvested, fixed, and paraffin-embedded. Sections of lungs were stained for antigen to detect macrophages. RESULTS: Topical p38MAPK inhibitor and TXA significantly attenuated mtDNA release. Both TXA and the topical p38MAPK inhibitor reduced lung inflammation as represented by decreased macrophage infiltration. Syndecan-1 levels showed no difference between burn and treatment groups. CONCLUSION: Both p38 MAPK inhibitor and TXA demonstrated the ability to attenuate burn-induced DAMP release and lung inflammation. Beyond its role as an antifibrinolytic, TXA may have significant anti-inflammatory effects pertinent to burn resuscitation. Further study is required; however, TXA may be a useful adjunct in burn resuscitation.