Acute Care Surgery and Surgical Rescue: Expanding the Definition.

BACKGROUND: Surgical rescue (SR) is the recovery of patients with surgical complications. Patients transferred (TP) for surgical diagnoses to higher-level care or inpatients (IP) admitted to nonsurgical services may develop intra-abdominal infection (IAI) and require emergency surgery (ES). The aims were to characterize the SR population by the site of ES consultation, open abdomen (OA), and risk of mortality. STUDY DESIGN: This was an international, multi-institutional prospective observational study of patients requiring ES for IAI. Laparotomy before the transfer was an exclusion criterion. Patients were divided into groups: clinic/ED (C/ED), IP, or TP. Data collected included demographics, the severity of illness (SOI), procedures, OA, and number of laparotomies. The primary outcome was mortality. Multivariable logistic regression models were constructed. RESULTS: There were 752 study patients (C/ED 63.8% vs TP 23.4% and IP 12.8%), with a mean age of 59 years and 43.6% women. IP had worse SOI scores (Charlson Comorbidity Index, American Society of Anesthesiologists Physical Status Classification System, and Sequential Organ Failure Assessment). The most common procedures were small and large bowel (77.3%). IP and TP had similar rates of OA (IP 52.1% and TP 52.3 %) vs C/ED (37.7%, p < 0.001), and IP had more relaparotomies (3 or 4). The unadjusted mortality rate was highest in IP (n = 24, 25.0%) vs TP (n = 29, 16.5%) and C/ED (n = 68, 14.2%, p = 0.03). Adjusting for age and SOI, only SOI had an impact on the risk of mortality (area under the curve 86%). CONCLUSIONS: IP had the highest unadjusted mortality after ES for IAI and was followed by the TP; SOI drove the risk of mortality. SR must be extended to IP for timely recognition of the IAI.

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.

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.

Lyophilized plasma resuscitation downregulates inflammatory gene expression in a mouse model of sepsis.

BACKGROUND: Plasma resuscitation may improve outcomes by targeting endotheliopathy induced by severe sepsis or septic shock. Given the logistical constraints of using fresh frozen plasma in military settings or areas with prolonged prehospital care, dried products such as lyophilized plasma (LP) have been developed. We hypothesized that resuscitation with LP would decrease lung injury, inflammation, and mortality in a mouse sepsis model. METHODS: Adult male C57BL/6J mice received an intraperitoneal injection of cecal slurry. Twenty-two hours later, the mice were anesthetized, the femoral artery was cannulated, and the mice were randomized to receive resuscitation with LP (10 mL/kg) or lactated Ringer's (LR; 30 mL/kg) for 1 hour. At 48-hours post-cecal slurry injection, bronchoalveolar lavage fluid was collected, the lungs were harvested, and plasma was obtained. Mortality and bronchoalveolar lavage total protein concentration (as an indicator of permeability) were compared between groups. The lungs were analyzed for histopathology and inflammatory gene expression using NanoString, and the plasma was analyzed for biomarkers of inflammation and endothelial function. RESULTS: There was no significant difference in short-term mortality between LR and LP mice, 38% versus 47%, respectively ( p = 0.62). Bronchoalveolar lavage protein levels were similar among mice resuscitated with LR or LP, and there was a lack of significant histopathologic lung injury in all groups. However, LP resuscitation resulted in downregulation of pulmonary inflammatory genes, including signaling pathways such as Janus kinase-signal transducer and activator of transcription and nuclear factor κB, and a circulating inflammatory biomarker profile similar to sham animals. CONCLUSION: Resuscitation with LP did not improve mortality or reduce permeability or injury in this model compared with LR. However, LP downregulated pulmonary inflammatory gene signaling and may also reduce circulating biomarkers of inflammation. Future studies should evaluate LP resuscitation in combination with antibiotics and other therapeutics to determine whether the anti-inflammatory effects of LP may improve outcomes in sepsis.

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.

Vaginal microbiota differences associated with pelvic organ prolapse risk during late gestation in commercial sows†.

During the last decade, sow mortality due to pelvic organ prolapse (POP) has increased. To better understand the biology associated with POP, sows were phenotypically assessed and assigned a perineal score (PS) based on presumed POP risk and categorized as PS1 (low), PS2 (moderate), or PS3 (high). The study objective was to identify changes in sow vaginal microbiota that may be associated with POP. The hypothesis is that vaginal microbiota differs between sows with variable risk for POP, and changes in microbiota during late gestation exist between sows with differing risk. Of the 2864 sows scored during gestation week 15, 1.0, 2.7, and 23.4% of PS1, PS2, and PS3 sows, respectively, subsequently experienced POP. Vaginal swabs subjected to 16S rRNA gene sequencing revealed differences in community composition (Bray-Curtis; P < 0.05) and individual operational taxonomic unit (OTU) comparisons between vaginal microbiota of PS1 and PS3 sows at gestation week 15. Further, differences (P < 0.05) in community composition and OTUs (Q < 0.05) were observed in PS3 sows that either did or did not subsequently experience POP. Differences in community structure (alpha diversity measurements; P < 0.05), composition (P < 0.05), and OTUs (Q < 0.05) were observed in gestation week 12 sows scored PS1 compared to week 15 sows scored PS1 or PS3, suggesting that sow vaginal microbiota shifts during late gestation differently as POP risk changes. Collectively, these data demonstrate that sows with greater POP risk have unique vaginal microflora, for which a better understanding could aid in the development of mitigation strategies.

Circulating biomarkers associated with pelvic organ prolapse risk in late gestation sows.

Sow mortality, as the result of pelvic organ prolapse (POP), has been increasing in the last decade in the U.S. swine industry. The objective of this study was to identify potential biological markers associated with risk of POP in sows. We hypothesized that sows differing in perineal score (PS) from PS1-PS3 (PS1-a presumed low POP risk; PS2-a presumed moderate POP risk; and PS3-a presumed high POP risk) would differ in circulatory biomarkers of inflammation and hormonal profiles. On gestation week 15, 2,864 individual sows were assigned a PS, and subsequently, 1.0%, 2.7%, and 23.4% of PS1, PS2, or PS3 sows, respectively, experienced POP. During PS assignment at days 107-116 of gestation, blood samples were collected from sows on two farms of similar genetics, feed sources, and health status. Whole blood was subjected to complete blood count (CBC) analysis (n = 212) and steroid hormones were measured in serum from a subset (n = 110) of animals assigned PS3 parity matched to PS1. Lipopolysaccharide-binding protein (LBP), tumor necrosis factor-alpha (TNF-α), haptoglobin, C-reactive protein (CRP), and creatine kinase (CK) levels were also evaluated. Complete blood count analysis revealed decreased (P ≤ 0.05) mean platelet volume (3.9%), lymphocytes (6.5%), and monocytes (7.5%) in PS3 compared to PS1 sows. Increased (P ≤ 0.02) abundance of androstenedione (13.4%), androsterone (18.2%), estrone (24.8%), and 17ß-estradiol (26.2%) was observed in PS3 compared to PS1 sows. Additionally, a 25.8% increase (P = 0.04) in LBP in PS3 compared to PS1 sows was observed. Many dynamic physiological changes occur in sows during late gestation as they approach farrowing. The data presented herein demonstrate that distinct differences in concentrations of circulating biomarkers exist between late gestation sows at high or low risk for POP and may serve as a useful tool for understanding the etiology of POP and evaluation of mitigation strategies.

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.

Vaginal microbiome and serum metabolite differences in late gestation commercial sows at risk for pelvic organ prolapse.

Sow mortality attributable to pelvic organ prolapse (POP) has increased in the U.S. swine industry and continues to worsen. Two main objectives of this study were, (1) to develop a perineal scoring system that can be correlated with POP risk, and (2) identify POP risk-associated biological factors. To assess POP risk during late gestation, sows (n = 213) were scored using a newly developed perineal scoring (PS) system. Sows scored as PS1 (low), PS2 (moderate), or PS3 (high) based on POP risk. Subsequently, 1.5, 0.8, and 23.1% of sows scored PS1, PS2, or PS3, respectively, experienced POP. To identify biomarkers, serum and vaginal swabs were collected from late gestation sows differing in PS. Using GC-MS, 82 serum metabolite differences between PS1 and PS3 animals (P < 0.05) were identified. Vaginal swabs were utilized for 16S rRNA gene sequencing and differences in vaginal microbiomes between PS1 and PS3 animals were detected on a community level (P < 0.01) along with differences in abundances of 89 operational taxonomic units (P < 0.05). Collectively, these data demonstrate that sows with greater POP risk have differential serum metabolites and vaginal microflora. Additionally, an initial and novel characterization of the sow vaginal microbiome was determined.

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.

Fibrinogen Activates PAK1/Cofilin Signaling Pathway to Protect Endothelial Barrier Integrity.

INTRODUCTION: We recently demonstrated that fibrinogen stabilizes syndecan-1 on the endothelial cell (EC) surface and contributes to EC barrier protection, though the intracellular signaling pathway remains unclear. P21 (Rac1) activated kinase 1 (PAK1) is a protein kinase involved in intracellular signaling leading to actin cytoskeleton rearrangement and plays an important role in maintaining endothelial barrier integrity. We therefore hypothesized that fibrinogen binding to syndecan-1 activated the PAK1 pathway. METHODS: Primary human lung microvascular endothelial cells were incubated in 10% lactated Ringers (LR) solution or 10% fibrinogen saline solution (5 mg/mL). Protein phosphorylation was determined by Western blot analysis and endothelial permeability measured by fluorescein isothiocyanate (FITC)-dextran. Cells were silenced by siRNA transfection. Protein concentration was measured in the lung lavages of mice. RESULTS: Fibrinogen treatment resulted in increased syndecan-1, PAK1 activation (phosphorylation), cofilin activation (dephosphorylation), as well as decreased stress fibers and permeability when compared with LR treatment. Cofilin is an actin-binding protein that depolymerizes F-actin to decrease stress fiber formation. Notably, fibrinogen did not influence myosin light chain activation (phosphorylation), a mediator of EC tension. Silencing of PAK1 prevented fibrinogen-induced dephosphorylation of cofilin and barrier integrity. Moreover, to confirm the in vitro findings, mice underwent hemorrhagic shock and were resuscitated with either LR or fibrinogen. Hemorrhage shock decreased lung p-PAK1 levels and caused significant lung vascular leakage. However, fibrinogen administration increased p-PAK1 expression to near sham levels and remarkably prevented the lung leakage. CONCLUSION: We have identified a novel pathway by which fibrinogen activates PAK1 signaling to stimulate/dephosphorylate cofilin, leading to disassembly of stress fibers and reduction of endothelial permeability.

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.

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.

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.

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.

Resuscitative Strategies to Modulate the Endotheliopathy of Trauma: From Cell to Patient.

Clinical data has supported the early use of plasma in high ratios of plasma to red cells to patients in hemorrhagic shock. The benefit from plasma seems to extend beyond its hemostatic effects to include protection to the post-shock dysfunctional endothelium. Resuscitation of the endothelium by plasma and one of its major constituents, fibrinogen, involves cell surface stabilization of syndecan-1, a transmembrane proteoglycan and the protein backbone of the endothelial glycocalyx. The pathogenic role of miRNA-19b to the endothelium is explored along with the PAK-1-mediated intracellular pathway that may link syndecan-1 to cytoskeletal protection. Additionally, clinical studies using fibrinogen and cyroprecipitate to aid in hemostasis of the bleeding patient are reviewed and new data to suggest a role for plasma and its byproducts to treat the dysfunctional endothelium associated with nonbleeding diseases is presented.

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.

Patellofemoral pain syndrome in female athletes: A review of diagnoses, etiology and treatment options.

Patellofemoral pain syndrome (PFPS) is one of the most common causes of knee pain and is present in females disproportionately more relative to males. PFPS causes tend to be multifactorial in nature and are described in this review. From a review of the current literature, it is clear that there needs to be further research on PFPS in order to better understand the complex etiology of this disorder in both males and females. It is known that females with patellofemoral pain syndrome demonstrate a decrease in abduction, external rotation and extension strength of the affected side compared with healthy patients. Conservative management, including optimizing muscle balance between the vastus medialis and lateralis around the patella along with formal therapy should be the first line of treatment in patients presenting with PFPS. Surgery should be reserved for patients in which all conservative management options have failed. This review aims to guide physicians in accurate clinicaldecision making regarding conservative and surgical treatment options when specifically faced with PFPS in a female athlete. Furthermore, we will discuss the anatomic variants, incidence and prevalence, etiology, diagnosis and treatment of PFPS.

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.