Contemporary management and time to revascularization in upper extremity arterial injury.

INTRODUCTION: Upper extremity arterial injury is associated with significant morbidity and mortality for trauma patients, but there is a paucity of data to guide the clinician in the management of these injuries. The goals of this review were to characterize the demographics, presentation, clinical management, and outcomes, and to evaluate how time to intervention associates with outcomes in trauma patients with upper extremity vascular injuries. METHODS: The National Trauma Data Bank (NTDB) Research Data Set for the years 2007-2016 was queried in order to identify adult patients (age ≥ 18) with an upper extremity arterial injury. Patients with brachiocephalic, subclavian, axillary, or brachial artery injury using the 1998 and 2005 versions of the Abbreviated Injury Scale were included. Patients with non-survivable injuries to the brain, traumatic amputation, or other major arterial injuries to the torso or lower extremities were excluded. RESULTS: The data from 7908 patients with upper extremity arterial injuries was reviewed. Of those, 5407 (68.4%) underwent repair of the injured artery. The median Injury Severity Score (ISS) was 10 (IQR = 7-18), and 7.7% of patients had a severe ISS (≥ 25). Median time to repair was 120 min (IQR = 60-240 min). Management was open repair in 52.3%, endovascular repair in 7.3%, and combined open and endovascular repairs in 8.8%; amputation occurred in 1.8% and non-operative management was used in 31.6% of patients. Blunt mechanism of injury, crush injury, concomitant fractures/dislocations, and nerve injuries were associated with amputation, whereas simultaneous venous injury was not. There was a significant decrease in the rate of amputation when patients undergoing surgical revascularization did so within 90 min of injury (P = 0.007). CONCLUSION: Injuries to arteries of the upper extremity are managed with open repair, endovascular repair, and, rarely, amputation. Expeditious transport to the operating room for revascularization is the key for limb salvage.

Resuscitative Endovascular Balloon Occlusion of Aaorta Use in Nontrauma Emergency General Surgery: A Multi-institutional Experience.

BACKGROUND: The aim of this study was to determine the current utilization patterns of resuscitative endovascular balloon occlusion of aorta (REBOA) for hemorrhage control in nontrauma patients. METHODS: Data on REBOA use in nontrauma emergency general surgery patients from six centers, 2014-2019, was pooled for analysis. We performed descriptive analyses using Fisher's exact, Student's t, chi-squared, or Mann-Whitney U tests as appropriate. RESULTS: Thirty-seven patients with acute hemorrhage from nontrauma sources were identified. REBOA placement was primarily performed by trauma attendings (20/37, 54%) and vascular attendings (13/37, 35%). In seven patients (19%), balloons were positioned prophylactically but never inflated. In 24 (65%) of 37 patients, REBOA was placed in the operating room. 28/37 balloons (76%) were advanced to zone 1, 8/37 (22%) were advanced to zone 3, and there was one REBOA use in the inferior vena cava. Most common indications were gastrointestinal and peripartum bleeding. In the 30 cases of balloon inflation, 24 of 30 (80%) resulted in improved hemodynamics. Eleven of 30 patients (37%) died before discharge. One patient developed a distal embolism, but there were no reports of limb loss. Twelve patients (40% of all REBOA inflations and 63% of survivors) were discharged to home. CONCLUSIONS: REBOA has been used in a range of acutely hemorrhaging emergency general surgery patients with low rates of access-related complications. Mortality is high in this patient population and further research is needed; however, appropriate patient selection and early use may improve survival in these life-threatening cases.

Appetitive cue-evoked ERK signaling in the nucleus accumbens requires NMDA and D1 dopamine receptor activation and regulates CREB phosphorylation.

Conditioned stimuli (CS) can modulate reward-seeking behavior. This modulatory effect can be maladaptive and has been implicated in excessive reward seeking and relapse to drug addiction. We previously demonstrated that exposure to an appetitive CS causes an increase in the activation of extracellular signal-regulated kinase (ERK) and cyclic-AMP response-element binding protein (CREB) in the nucleus accumbens (NAc) of rats, and that CS-evoked ERK activation is critical for CS control over reward seeking. To elucidate the mechanism that mediates CS-driven ERK activation in the NAc, we selectively blocked NMDA glutamate or D1 dopamine receptors in the NAc. To determine whether CS-driven ERK and CREB activation are linked, we selectively blocked ERK signaling in the NAc. We found that both NMDA and D1 receptors are critical for CS-driven ERK signaling in the NAc, and that this recruitment of the ERK cascade is responsible for increased CREB activation in the presence of the CS. Our findings suggest that activation of the NMDAR-D1R/ERK/CREB signal transduction pathway plays a critical role in the control of reward-seeking behavior by reward-predictive cues.

Biomarkers of endothelial cell dysfunction persist beyond resuscitation in patients with hemorrhagic shock.

BACKGROUND: It has been shown that microRNA-19b (miR-19b) binds to and degrades syndecan-1 after hemorrhagic shock (HS) and contributes to endothelial dysfunction in vitro and in vivo. The objective of the current study was to assess longitudinal changes in miR-19b and syndecan-1 in HS patients. METHODS: Blood samples from HS patients (blood pressure <90 mm Hg and ≥2 U blood) were collected upon admission, completion of hemostasis, and after 24 hours for miR-19b (quantitative reverse transcription PCR) and syndecan-1 (enzyme-linked immunosorbent assay) and compared with controls and minimally injured (Injury Severity Score, ≤9). Inflammatory cytokines were measured (Luminex [Thermo Fisher, Waltham, MA]). Correlations between syndecan-1, miR-19b, inflammatory markers, and patient outcomes were performed. Logistic regression models were developed for outcomes. RESULTS: Thirty-four HS patients were studied: age, 46 (19-89) years; male, 82%; penetrating, 35%; Injury Severity Score, 24 ± 10; and blood products at 24 hours, 21 ± 19 U. MicroRNA-19b was increased upon arrival and further increased over time: 4.6 → 6.7 → 24.1-fold change compared with 0.1 and 1.2 for minimally injured patients and controls, respectively. Syndecan-1 was increased to 42.6 → 50 → 51.5 ng/mL over time compared with 14.7 and 23.5 for minimally injured and controls, respectively. Values for both biomarkers remained significantly increased through 24 hours and were associated with a persistent increase in inflammatory cytokines. Admission syndecan-1 significantly predicted mortality, coagulopathy, and massive transfusion. CONCLUSION: We have shown for the first time that miR-19b and syndecan-1 were biomarkers for endothelial dysfunction independent of resuscitation. MicroRNA-19b did not demonstrate a strong correlation with syndecan-1 nor outcomes. Admission syndecan-1, however, remains a strong prognostic marker, but its elevation over time suggests a versatile role following HS that requires further investigation. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level II.

Effect of Antibiotic Duration in Emergency General Surgery Patients with Intra-Abdominal Infection Managed with Open vs Closed Abdomen.

BACKGROUND: Data on duration of antibiotics in patients managed with an open abdomen (OA) due to intra-abdominal infection (IAI) are scarce. We hypothesized that patients with IAI managed with OA rather than closed abdomen (CA) would have higher rates of secondary infections (SIs) independent of the duration of the antibiotic treatment. METHODS: This was an observational, prospective, multicenter, international study of patients with IAI requiring laparotomy for source control. Demographic and antibiotic duration values were collected. Primary outcomes were SI (surgical site, bloodstream, pneumonia, urinary tract) and mortality. Statistical analysis included ANOVA, chi-square/Fisher's exact test, and logistic regression. RESULTS: Twenty-one centers contributed 752 patients. The average age was 59.6 years, 43.6% were women, and 43.9% were managed with OA. Overall mortality was 16.1%, with higher rates among OA patients (31.6% vs 4.4%, p < 0.001). OA patients had higher Sequential Organ Failure Assessment (4.7 vs 1.8, p < 0.001), American Society of Anesthesiologists Physical Status (3.6 vs 2.7, p < 0.001), and APACHE II scores (16.1 vs 9.4, p < 0.001). The mean duration of antibiotics was 6.5 days (8.0 OA vs 5.4 CA, p < 0.001). A total of 179 (23.8%) patients developed SI (33.1% OA vs 16.8% CA, p < 0.001). Longer antibiotic duration was associated with increased rates of SI: 1 to 2 days, 15.8%; 3 to 5 days, 20.4%; 6 to 14 days, 26.6%; and more than 14 days, 46.8% (p < 0.001). CONCLUSIONS: Patients with IAI managed with OA had higher rates of SI and increased mortality compared with CA. A prolonged duration of antibiotics was associated with increased rates of SI. Increased antibiotic duration is not associated with improved outcomes in patients with IAI and OA.

Fibrinogen inhibits microRNA-19b, a novel mechanism for repair of haemorrhagic shock-induced endothelial cell dysfunction.

BACKGROUND: The benefits of plasma as an adjunct to the treatment of haemorrhagic shock are well established; however, the mechanism by which plasma modulates the endotheliopathy of trauma remains unclear. Our recent data demonstrated a novel role of microRNA-19b in post-haemorrhagic shock endothelial dysfunction via targeting of syndecan-1. Additionally, fibrinogen, as a key component of plasma or an isolated haemostatic protein, protects the endothelium by stabilizing syndecan-1. We therefore hypothesized that fibrinogen would inhibit microRNA-19b to mitigate the endotheliopathy of trauma in a murine model of haemorrhagic shock. MATERIALS AND METHODS: C57BL/6J mice were subjected to haemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 minutes) followed by resuscitation with lactated Ringer's, fresh frozen plasma, fibrinogen or no resuscitation. MicroRNA-19b and syndecan-1 mRNA were measured in lung tissue by qRT-PCR. Lungs were stained for histopathologic injury, and broncheoalveolar lavage was collected for protein as a permeability indicator. RESULTS: Pulmonary microRNA-19b was increased after haemorrhagic shock and lactated Ringers, but reduced to sham levels by plasma and fibrinogen. Conversely, pulmonary syndecan-1 mRNA was downregulated by haemorrhagic shock and lactated Ringers, but returned to sham levels by plasma and fibrinogen. Plasma and fibrinogen-based resuscitation reduced lung injury compared to haemorrhagic shock and lactated Ringers while fibrinogen also reduced broncheoalveolar lavage protein. DISCUSSION: We have demonstrated a novel mechanism by which fibrinogen, a key component of plasma and haemostatic agent, inhibits miR-19b, possibly by mitigating the endotheliopathy of trauma. Complete demonstration of the mechanism of fibrinogen inhibition of endotheliopathy via microRNA, however, remains to be elucidated. These findings support the early and empiric use of fibrinogen in post-haemorrhagic shock resuscitation.

Outcomes after ultramassive transfusion in the modern era: An Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: Despite the widespread institution of modern massive transfusion protocols with balanced blood product ratios, survival for patients with traumatic hemorrhage receiving ultramassive transfusion (UMT) (defined as ≥20 U of packed red blood cells [RBCs]) in 24 hours) remains low and resource consumption remains high. Therefore, we aimed to identify factors associated with mortality in trauma patients receiving UMT in the modern resuscitation era. METHODS: An Eastern Association for the Surgery of Trauma multicenter retrospective study of 461 trauma patients from 17 trauma centers who received ≥20 U of RBCs in 24 hours was performed (2014-2019). Multivariable logistic regression and Classification and Regression Tree analysis were used to identify clinical characteristics associated with mortality. RESULTS: The 461 patients were young (median age, 35 years), male (82%), severely injured (median Injury Severity Score, 33), in shock (median shock index, 1.2; base excess, -9), and transfused a median of 29 U of RBCs, 22 U of fresh frozen plasma (FFP), and 24 U of platelets (PLT). Mortality was 46% at 24 hours and 65% at discharge. Transfusion of RBC/FFP ≥1.5:1 or RBC/PLT ≥1.5:1 was significantly associated with mortality, most pronounced for the 18% of patients who received both RBC/PLT and RBC/FFP ≥1.5:1 (odds ratios, 3.11 and 2.81 for mortality at 24 hours and discharge; both p < 0.01). Classification and Regression Tree identified that age older than 50 years, low initial Glasgow Coma Scale, thrombocytopenia, and resuscitative thoracotomy were associated with low likelihood of survival (14-26%), while absence of these factors was associated with the highest survival (71%). CONCLUSION: Despite modern massive transfusion protocols, one half of trauma patients receiving UMT are transfused with either RBC/FFP or RBC/PLT in unbalanced ratios ≥1.5:1, with increased associated mortality. Maintaining focus on balanced ratios during UMT is critical, and consideration of advanced age, poor initial mental status, thrombocytopenia, and resuscitative thoracotomy can aid in prognostication. LEVEL OF EVIDENCE: Prognostic, level III.

Contemporary resuscitation of hemorrhagic shock: What will the future hold?

Resuscitation of the critically ill patient with fluid and blood products is one of the most widespread interventions in medicine. This is especially relevant for trauma patients, as hemorrhagic shock remains the most common cause of preventable death after injury. Consequently, the study of the ideal resuscitative product for patients in shock has become an area of great scientific interest and investigation. Recently, the pendulum has swung towards increased utilization of blood products for resuscitation. However, pathogens, immune reactions and the limited availability of this resource remain a challenge for clinicians. Technologic advances in pathogen reduction and innovations in blood product processing will allow us to increase the safety profile and efficacy of blood products, ultimately to the benefit of patients. The purpose of this article is to review the current state of blood product based resuscitative strategies as well as technologic advancements that may lead to safer resuscitation.

Is all plasma created equal? A pilot study of the effect of interdonor variability.

BACKGROUND: Clinical benefits of plasma as an adjunct for treatment of hemorrhagic shock (HS) have been well established. However, its use is not without risk. Little is understood regarding the clinical implications of plasma variability. We hypothesized there to be interdonor variability in plasma that would impact endothelial and organ function postinjury. METHODS: Pulmonary endothelial cells (ECs) were incubated with plasma from 24 random donors, and transendothelial electrical resistance was measured. Plasma units with a more or less protective effect on reducing EC permeability were selected for testing in vivo. Syndecan-1 and cytokines were measured. Mice underwent laparotomy and then HS followed by resuscitation with the selected plasma units and were compared with mice receiving no resuscitation and shams. Lung tissue was sectioned and stained for myeloperoxidase and pulmonary syndecan-1 and scored for lung histopathologic injury. RESULTS: Plasma from 24 donors revealed variability in the reversal of EC monolayer hyperpermeability; transendothelial electrical resistance for the more protective plasma was significantly higher than that for the less protective plasma (0.801 ± 0.022 vs. 0.744 ± 0.035; p = 0.002). Syndecan-1 was also markedly increased in the less protective compared with the more protective plasma (38427 ± 1257 vs. 231 ± 172 pg/mL, p < 0.001), while cytokines varied. In vivo, the more protective plasma mitigated lung histopathologic injury compared with the less protective plasma (1.56 ± 0.27 vs. 2.33 ± 0.47, respectively; p = 0.005). Similarly, myeloperoxidase was significantly reduced in the more protective compared with the less protective plasma group (2.590 ± 0.559 vs. 6.045 ± 1.885; p = 0.02). Lastly, pulmonary syndecan-1 immunostaining was significantly increased in the more protective compared with the less protective plasma group (20.909 ± 8.202 vs. 9.325 ± 3.412; p = 0.018). CONCLUSION: These data demonstrate significant interdonor variability in plasma that can adversely influence the protective effects of plasma-based resuscitation on HS-induced lung injury. This may have important implications for patient safety and clinical outcomes.

Fresh frozen plasma attenuates lung injury in a novel model of prolonged hypotensive resuscitation.

BACKGROUND: Hemorrhagic shock remains a leading cause of early death among severely injured in both civilian and military settings. As future military operations will require strategies allowing prolonged field care of the injured, we sought to develop an in vivo model of prolonged hypotensive resuscitation (PHR) and to evaluate the role of plasma-based resuscitation in this model. We hypothesized that resuscitation with fresh frozen plasma (FFP) would mitigate lung injury when compared with Hextend in a rodent model of PHR. METHODS: Mice underwent laparotomy and hemorrhagic shock (mean arterial blood pressure, 35 ± 5 mm Hg × 90 minutes) followed by PHR with either FFP or Hextend to maintain a mean arterial blood pressure of 55 mm Hg to 60 mm Hg for 6 hours. Sham animals underwent cannulation only. At the end of 6 hours, animals were euthanized, and lung tissue harvested for measurement of histopathologic injury, inflammation and permeability using hematoxylin and eosin staining, myeloperoxidase immunofluorescence staining and Evans Blue dye. Pulmonary syndecan-1 immunostaining was assessed as an indicator of endothelial cell integrity. RESULTS: All animals in the FFP, Hextend, and sham groups survived to the end of resuscitation. Resuscitation with FFP mitigated lung histopathologic injury compared with Hextend (histologic injury score of 4.38 ± 2.07 vs. 7.5 ± 0.93, scale of 0-9, p = 0.002) and was comparable to shams (histologic injury score of 4.0 ± 1.93, scale of 0-9, p = 0.99). Fresh frozen plasma also reduced lung inflammation (0.116 ± 0.044 vs. 0.308 ± 0.054 relative fluorescence of myeloperoxidase, p = 0.002) and restored pulmonary syndecan-1 (0.514 ± 0.061 vs. 0.059 ± 0.021, relative syndecan-1 fluorescence, p < 0.001) when compared with Hextend. Consistently, FFP mitigated lung hyperpermeability compared with Hextend (7.30 ± 1.34 µg vs. 14.91 ± 5.55 µg Evans blue/100 mg lung tissue, p = 0.005). CONCLUSION: We have presented a novel model of PHR of military relevance to the prolonged field care environment. In this model, FFP maintains its pulmonary protective effects using a PHR strategy compared with Hextend, which supports the need for further development and implementation of plasma-based resuscitation in the forward environment. LEVEL OF EVIDENCE: Basic science.

Therapeutic anticoagulation in patients with traumatic brain injuries and pulmonary emboli.

BACKGROUND: Patients with traumatic intracranial hemorrhage (ICH) and concomitant pulmonary embolus (PE) have competing care needs and demand a careful balance of anticoagulation (AC) versus potential worsening of their ICH. The goal of this study is to determine the safety of therapeutic AC for PE in patients with ICH. METHODS: This is a retrospective single-center study of patients older than 16 years with concomitant ICH and PE occurring between June 2013 and December 2017. Early AC was defined as within 7 days of injury or less; late was defined as after 7 days. Primary outcomes included death, interventions for worsening ICH following AC, and pulmonary complications. Multivariate logistic regression was used to evaluate for clinical and demographic factors associated with worsening traumatic brain injury (TBI), and recursive partitioning was used to differentiate risk in groups. RESULTS: Fifty patients met criteria. Four did not receive any AC and were excluded. Nineteen (41.3%) received AC early (median, 4.1; interquartile range, 3.1-6) and 27 (58.7%) received AC late (median, 14; interquartile range, 9.7-19.5). There were four deaths in the early group, and none in the late cohort (21.1% vs. 0%, p = 0.01). Two deaths were due to PE and the others were from multi-system organ failure or unrecoverable underlying TBI. Three patients in the early group, and two in the late, had increased ICH on computed tomography (17.6% vs. 7.4%, p = 0.3). None required intervention. CONCLUSION: This retrospective study failed to find instances of clinically significant progression of TBI in 46 patients with computed tomography-proven ICH after undergoing AC for PE. Therapeutic AC is not associated with worse outcomes in patients with TBI, even if initiated early. However, two patients died from PE despite AC, underlining the severity of the disease. Intracranial hemorrhage should not preclude AC treatment for PE, even early after injury. LEVEL OF EVIDENCE: Care management, Level IV.

Appetitive Pavlovian conditioned stimuli increase CREB phosphorylation in the nucleus accumbens.

The transcription factor cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc) has been shown to regulate an animal's behavioral responsiveness to emotionally salient stimuli, and an increase in CREB phosphorylation in the NAc has been observed during exposure to rewarding stimuli, such as drugs of abuse. Here we show that CREB phosphorylation increases in the NAc also during exposure to cues that an animal has associated with delivery of natural rewards. Adult male Sprague-Dawley rats (rattus norvegicus) were trained to associate an auditory stimulus with delivery of food pellets, and CREB phosphorylation was examined in the striatum following training. We found that repeated tone-food pairings resulted in an increase in CREB phosphorylation in the NAc but not in the adjacent dorsal striatum or in the NAc 3h after the final training session. We further found that the cue itself, as opposed to the food pellets, the training context, or tone-food pairings, was sufficient to increase CREB phosphorylation in the NAc. These results suggest that the processing of primary rewarding stimuli and of environmental cues that predict them triggers similar accumbal signaling mechanisms.