Plasminogen Degradation by Neutrophil Elastase in Pleural Infection, Not High Plasminogen Activator Inhibitor 1, Is the Cause of Intrapleural Lytic Failure.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation. RESEARCH QUESTION: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure? STUDY DESIGN AND METHODS: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of 0.05. RESULTS: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03583931; URL: www. CLINICALTRIALS: gov.

Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS.

OBJECTIVES: Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients. METHODS: Untargeted metabolomics profiling of 67 critically injured patients was completed to establish a metabolic signature associated with ARDS development. Metabolites that significantly increased were assayed for PMN priming activity in vitro. The metabolites that primed PMNs were tested in a 2-event animal model of ARDS to identify a molecular link between circulating metabolites and clinical risk for ARDS. RESULTS: After controlling for confounders, 4 metabolites significantly increased: creatine, dehydroascorbate, fumarate, and succinate in trauma patients who developed ARDS ( P < 0.05). Succinate alone primed the PMN oxidase in vitro at physiologically relevant levels. Intravenous succinate-induced PMN sequestration in the lung, a first event, and followed by intravenous lipopolysaccharide, a second event, resulted in ARDS in vivo requiring PMNs. SUCNR1 inhibition abrogated PMN priming, PMN sequestration, and ARDS. Conclusion: Significant increases in plasma succinate post-injury may serve as the first event in ARDS. Targeted inhibition of the SUCNR1 may decrease ARDS development from other disease states to prevent ARDS globally.

Trauma Resuscitation Consideration: Sex Matters.

BACKGROUND: Sex dimorphisms in coagulation have been recognized, but whole blood assessment of these dimorphisms and their relationship to outcomes in trauma have not been investigated. This study characterizes the viscoelastic hemostatic profile of severely injured patients by sex, and examines how sex-specific coagulation differences affect clinical outcomes, specifically, massive transfusion (MT) and death. We hypothesized that severely injured females are more hypercoagulable and therefore, have lower rates of MT and mortality. STUDY DESIGN: Hemostatic profiles and clinical outcomes from all trauma activation patients from 2 level I trauma centers were examined, with sex as an experimental variable. As part of a prospective study, whole blood was collected and thrombelastography (TEG) was performed. Coagulation profiles were compared between sexes, and association with MT and mortality were examined. Poisson regression with robust standard errors was performed. RESULTS: Overall, 464 patients (23% female) were included. By TEG, females had a more hypercoagulable profile, with a higher angle (clot propagation) and maximum amplitude (MA, clot strength). Females were less likely to present with hyperfibrinolysis or prolonged activating clotting time than males. In the setting of depressed clot strength (abnormal MA), female sex conferred a survival benefit, and hyperfibrinolysis was associated with higher case-fatality rate in males. CONCLUSIONS: Severely injured females have a more hypercoagulable profile than males. This hypercoagulable status conferred a protective effect against mortality in the setting of diminished clot strength. The mechanism behind these dimorphisms needs to be elucidated and may have treatment implications for sex-specific trauma resuscitation.

Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients.

BACKGROUND: Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. Plasminogen activation inhibitor (PAI-1) degradation by activated protein C has been proposed as a mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tissue plasminogen activator (tPA) has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA. METHODS: Eighty-six consecutive trauma activation patients had blood collected at the earliest time after injury and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared with 14 healthy controls using enzyme-linked immunosorbent assays for active tPA, active PAI-1, and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA challenge as a functional assay for PAI-1 reserve. RESULTS: Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median, 104 pM (interquartile range [IQR], 48-201 pM) versus 115 pM (IQR, 54-202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolytic patients than in controls. Conversely, total tPA levels (active + complex) were significantly higher in hyperfibrinolytic patients than in controls: 139 pM (IQR, 68-237 pM) versus 32 pM (IQR, 16-37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA (median LY30 of 66.8% compared with 9.6% for controls). CONCLUSION: Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA-challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of up-regulation of tPA is critical to an understanding of hyperfibrinolysis in trauma. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level II.

Exploring ethical conflicts in emergency trauma research: the COMBAT (Control of Major Bleeding after Trauma) study experience.

BACKGROUND: Up to 25% of severely injured patients develop trauma-induced coagulopathy. To study interventions for this vulnerable population for whom consent cannot be obtained easily, the Food and Drug Administration issued regulations for emergency research with an exception from informed consent (ER-EIC). We describe the community consultation and public disclosure (CC/PD) process in preparation for an ER-EIC study, namely the Control Of Major Bleeding After Trauma (COMBAT) study. METHODS: The CC/PD was guided by the four bioethical principles. We used a multimedia approach, including one-way communications (newspaper ads, brochures, television, radio, and web) and two-way communications (interactive in-person presentations at community meetings, printed and online feedback forms) to reach the trials catchment area (Denver County's population: 643,000 and the Denver larger metro area where commuters reside: 2.9 million). Particular attention was given to special-interests groups (eg, Jehovah Witnesses, homeless) and to Spanish-speaking communities (brochures and presentations in Spanish). Opt-out materials were available during on-site presentations or via the COMBAT study website. RESULTS: A total of 227 community organizations were contacted. Brochures were distributed to 11 medical clinics and 3 homeless shelters. The multimedia campaign had the potential to reach an estimated audience of 1.5 million individuals in large metro Denver area, the majority via one-way communication and 1900 in two-way communications. This resource intensive process cost more than $84,000. CONCLUSION: The CC/PD process is resource-intensive, costly, and complex. Although the multimedia CC/PD reached a large audience, the effectiveness of this process remains elusive. The templates can be helpful to similar ER-EIC studies.

It's not your grandfather's field plasma.

Initiating prehospital resuscitation with plasma in patients with trauma-associated hemorrhagic shock will result in more rapid and durable clot formation and, thus, the need for fewer packed cell infusions, less frequent use of cryoprecipitate, and more ventilator-free hospital days compared with those of patients randomized to standard crystalloid field resuscitation.

Elderly patients may benefit from tight glucose control.

BACKGROUND: While minimizing hyperglycemia in critically injured patients improves outcomes, it is debatable whether postinjury glucose control should aim for conventional glucose control levels (≤180 mg/dL) or tight glucose control levels (81-108 mg/dL). We queried our 17-year prospective database of patients at risk for postinjury multiple organ failure to examine the association between glucose levels and adverse outcomes. METHODS: Acutely injured patients admitted to a Level I trauma center intensive care unit from 1992 to 2008 who were more than 15 years of age, had Injury Severity Scores >15, and who survived >48 hours were eligible for the study. Multiple logistic regression was used to determine the independent association of glucose control with adverse outcomes (death, ventilator-free days, intensive care unit-free days, and major infections), adjusted for Injury Severity Score, age, and red blood cell transfusion in the first 12 hours. RESULTS: Overall, 2,231 patients were eligible, of whom 153 (6.9%) died. The mean age was 37.8 ± 0.4 years, and the median Injury Severity Score was 27 (interquartile range, 21-35). The majority (77%) of these patients maintained mean glucose within conventional glucose control levels and only 10% achieved mean glucose levels within tight glucose control levels. Nonsurvivors required greater doses of insulin to control glucose levels and had greater mean insulin to glucose ratios (t test; P = .025). After adjusting for confounders, mean glucose remained significantly associated with the studied adverse outcomes. Age significantly modified all these associations with older patients seeming to benefit more from tight glucose control levels than their younger counterparts. CONCLUSION: Age is an effect modifier of the association between glucose levels and adverse outcomes. Future studies including larger samples of elderly trauma patients are needed to determine the ideal levels for glucose control in this growing population.

Military medical surge capacity in times of war and natural disaster.

BACKGROUND: The military medical services need demand-based strategies to ensure the best possible care of the injured in combat and natural disasters without compromising peacetime health care commitments at home and abroad. METHODS: A review of steps that have already been taken suggests that they are being used to their fullest extent commensurate with the public will. In fact, the situation has driven preliminary exploration of a special health care personnel draft. We believe the answer lies not in expanding the full-time, active duty US medical and nursing corps, but rather in tapping identifiable reservoirs of trained trauma care physicians, nurses, and allied health care workers in the United States and elsewhere. RESULTS: A rudimentary analysis suggests the most promising novel considerations are: developing special, trauma-trained reserve units within the US civilian trauma care community; seeking temporary attachments of an allied country's military medical officers, or a complete medical battalion; and contracting with US and foreign trauma surgeons, nurses and allied health personnel through a medical private military firm, analogous to those that have provided food, housing, transportation, and special combat units in support of our major military campaigns and peacekeeping operations. CONCLUSION: These considerations have important pros and cons that deserve in-depth evaluation by the best military and civilian trauma/critical care and organizational minds within a structured organization committed to the needs of military medicine. We believe that a Military Medical Think Tank within the Uniformed Services University's postgraduate division should be that organization.

Patient characteristics and physician-determined variables affecting saphenofemoral reflux recurrence after ligation and stripping of the great saphenous vein.

OBJECTIVE: To identify patient and physician-controlled treatment variables that might predict the persistence or redevelopment of saphenofemoral junction (SFJ) reflux. METHODS: Thirteen European centers, with substantial lower extremity venous disease practices, examined their experience with SFJ ligation and GSV stripping for primary varicose veins in patients followed for > or =2 years, entering their data into a protocol-driven matrix that stipulated duplex Doppler imaging as an essential component of follow-up examinations and required a complete review of all peri-operative examinations, as well as all operative procedure and anesthesia notes. Matrix entries were centrally audited for consistency and credibility, and queried for correction or clarification before being accepted into the study database. Presence or absence of Doppler-detectable SFJ reflux was the dependent variable and principal outcome measure. RESULTS: Among 1,638 limbs, 315 (19.2%) had SFJ reflux. After adjustment for follow-up length and inputting for missing values, multivariable analysis identified seven significant predictors. Ultrasonic groin mapping (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.20 to 0.40) and <3-cm groin incisions at or immediately below the groin crease (OR, 0.50; 95% CI, 0.32 to 0.78) were both uniquely associated with diminished probability of follow-up SFJ reflux. Prior parity (OR, 2.69; 95% CI, 1.45 to 4.97), body mass index >29 kg/m(2) (OR, 1.65; 95% CI, 1.12 to 2.43), <3-cm suprainguinal incisions (OR, 3.71; 95% CI, 1.70 to 5.88), stripping to the ankle (OR, 2.43; 95% CI, 1.71 to 3.46), and interim pregnancy during follow-up (OR, 4.74; 95% CI, 2.47 to 9.12), were each independent predictors of a greater probability of having SFJ reflux. CONCLUSIONS: The findings suggest that ultrasound groin mapping, reticence for short suprainguinal or longer groin incisions and extended stripping, and counseling women about the effect of future pregnancy are prudent clinical choices, especially for obese or previously parous patients.

Duplex ultrasound scan findings two years after great saphenous vein radiofrequency endovenous obliteration.

OBJECTIVE: To assess the clinical and duplex ultrasound scan findings in the groin and thigh 2 years after great saphenous vein (GSV) radiofrequency endovenous obliteration (RFO). METHODS: Sixty-three limbs in 56 patients with symptomatic varicose veins and GSV incompetence were treated with RFO, usually with adjunctive stab-avulsion phlebectomies, and examined at a median follow-up of 25 months, by using a color-coded, duplex sonography protocol that mandated views in at least two planes of the saphenofemoral junction (SFJ) and its tributaries and at three GSV levels in the thigh. RESULTS: The commonest duplex finding in the groin was an open, competent, SFJ with a < or =5-cm patent terminal GSV segment conducting prograde tributary flow through the SFJ (82%). Despite the presence of a total of 104 patent junctional tributaries, SFJ reflux was uncommon, affecting only five limbs. GSV truncal occlusion was observed in 90% of treated GSVs. Limited segmental treatment was successful in three limbs with a midthigh reflux source well below competent terminal and subterminal valves. Six GSV trunks had partial or no occlusion, but only one refluxed. These were anatomical RFO failures (9.5%) but were clinically improved, including the refluxing limb. Neovascularity was not identified in any groin. Thigh varicosities were observed in 12 limbs, including telangiectasias and isolated small tributary branches. New varicosities, linked to refluxing thigh perforators (two), or patent SFJ tributaries (three), were present in five limbs. CONCLUSION: RFO is the ideological opposite of high ligation without GSV stripping. It leaves physiologic tributary flow relatively undisturbed, does not incite groin neovascularity, eliminates the GSV as a refluxing conduit in >90% of limbs and has a 2-year, postadjunctive phlebectomy varicosity prevalence of 7.9%, with symptom score improvement in 95% of limbs with an initial score higher than zero.

Great saphenous vein stripping with liberal use of subfascial endoscopic perforator vein surgery (SEPS).

This study is based on a unique registry of 632 patients who underwent great saphenous vein (GSV) stripping and liberal use of subfascial endoscopic perforator vein surgery (SEPS) for minimal to severe lower limb venous insufficiency. Clinical examinations and color-coded duplex scanning were performed on a randomly selected, manageable sample of 170 limbs to assess the affect of early SEPS on junctional (saphenofemoral [SFJ] and/or saphenopopliteal [SPJ]) and perforator vein (PV) insufficiencies and superficial varicosities at a median of 6.5 years. PV incompetence was present in 68 legs (40%), as the sole transfascial insufficiency in 28 limbs and combined with SFJ or SPJ incompetence in 40 limbs. Junction incompetence alone characterized an additional 38 limbs, bringing the total transfascial insufficiency prevalence to 62%. Superficial varicosities affected 46% of limbs. Overall CEAP clinical class was unimproved beyond preoperative values. PV incompetence was associated with higher CEAP and clinical venous severity scores than were junctional insufficiencies alone. We concluded that PV incompetence alone or combined with junctional insufficiency is associated with increased symptoms and disease progression. The prevalence of SFJ, SPJ, and PV incompetence (62%) and recurrent varicosities (46%) suggests that early use of SEPS does not prevent disease progression and offers no benefit over GSV stripping in the absence of deep vein insufficiency or threatened ulceration.