Alexander Gombert

Aspirin, but Not Tirofiban Displays Protective Effects in Endotoxin Induced Lung Injury

Background Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. Recruitment of neutrophils into the lungs, regarded as a key mechanism in progression of ALI, depends on signaling between neutrophils and platelets. Consequently we explored the effect of platelet-targeted aspirin and tirofiban treatment in endotoxin induced acute lung injury Methods C57Bl/6 mice were exposed to aerosolized LPS (500μg/ml) for 30min and treated with Aspirin (100μg/g bodyweight via intraperitoneal injection, 30 min before or 1 hour after LPS inhalation) or Tirofiban (0.5μg/ g bodyweight via tail vein injection 30 min before or 1 hour after LPS inhalation). The count of alveolar, interstitial, and intravascular neutrophils was assessed 4h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and protein content in the BAL fluid. Results Aspirin both before and after LPS inhalation reduced neutrophil influx into the lung and lung permeability indicating the protective role of Aspirin in ALI. Tirofiban, however, did not alter neutrophil recruitment after LPS inhalation. Release of platelet-derived chemokines CCL5 and PF4 and neutrophil extracellular traps was reduced by Aspirin but not by Tirofiban. Conclusion Aspirin, but not Tirofiban reduces neutrophil recruitment and displays protective effects during endotoxin induced lung injury.

Redox-mediated mechanisms and biological responses of copper-catalyzed reduction of the nitrite ion in vitro.

During ischemia nitrite may be converted into nitric oxide (NO) by reaction with heme-carrying proteins or thiol-containing enzymes. NO acts as a regulator of vasodilation and protector against oxidative stress-induced tissue injuries. As a result of ischemia-induced oxidative stress, hypoxia and/or acidosis bivalent copper ions (Cu(2+)) can dissociate from their physiological carrier proteins. Reduced by the bodys own antioxidants, the resultant Cu(1+) might represent an effective reductant of nitrite. Here we have evaluated in vitro copper-dissociation from copper/BSA (bovine serum albumin) complexes under ischemic conditions. Furthermore, using physiological concentrations, we have characterized the capacity of antioxidants and bivalent copper ions to serve as Cu(1+)-agitated catalytic sites for nitrite reduction and also the biological responses of this mechanism in vitro. We found that as a consequence of an acidic milieu and/or oxidative stress the copper-binding capacity of serum albumin strongly declined, leading to significant dissociation of copper ions into the ambient solution. At physiologically relevant pH-values Cu(2+) ions in combination with physiologically available copper reductants (i.e., ascorbate, glutathione, Fe(2+)) significantly enhanced nitrite reduction and subsequent non-enzymatic NO generation under hypoxic but also normoxic conditions. Our data demonstrate for the first time that upon ischemic conditions carrier protein-dissociated copper ions combined with appropriate reductants may serve as Cu(1+)-driven catalytic sites for nitrite reduction, leading to the formation of biologically relevant NO formation. Thus, in addition to the action of heme proteins, copper-catalyzed non-enzymatic NO formation from nitrite might represent a further physiologically relevant vasodilating and NO-dependent protective principle to ischemic stress.

Interventional treatment of postthrombotic syndrome.

BackgroundPostthrombotic syndrome (PTS) is the development of symptoms and signs of chronic venous insufficiency following deep vein thrombosis (DVT) and has a significant negative effect on the quality of life. The current understanding is that the clinical manifestation of PTS is related more to venous obstruction than it is to venous reflux. The use of interventional techniques for the treatment of venous obstruction and/or venous occlusion has rapidly increased in recent years.ObjectiveThis article summarizes the current concept of endovenous and hybrid interventions and presents the optimized treatment of choice in patients with chronic symptomatic venous obstruction.MethodsWe performed a systematic literature search in the Medline database to identify relevant studies on the treatment of patients with PTS.ResultsA meta-analysis of the relevant studies showed that this minimally invasive procedure is an effective treatment option with low morbidity and no mortality. Use of the newly developed dedicated venous stents showed promising results with good mid-term patency rates and a significant decrease in related symptoms.ConclusionInterventional therapy for the treatment of symptomatic chronic venous obstruction has become the method of choice in recent years. More studies are needed to evaluate the long-term success rate of dedicated venous stents.ZusammenfassungHintergrundDas postthrombotische Syndrom (PTS) als Langzeitfolge der tiefen Beinvenenthrombose (TVT) kann zu einer erheblichen Beeinträchtigung der Lebensqualität führen. Nach neuerem Erkenntnisstand trägt die obstruktive Komponente mehr zur Entstehung der Symptomatik bei als die refluxive. Interventionelle Verfahren zur Beseitigung der venösen Obstruktion/Okklusion haben im letzten Jahrzehnt rasant an Bedeutung zugenommen.ZielsetzungIn diesem Beitrag wird die endovaskuläre bzw. Hybridbehandlung der symptomatischen chronisch-venösen Obstruktion und unser Konzept zur Optimierung derselben dargestellt.MethodenDie elektronische Datenbank „medline“ wurde systematisch nach Artikeln in deutscher oder englischer Sprache durchsucht, welche die Behandlung des PTS thematisieren.ErgebnisseAlle zugrundeliegenden Studien zeigen, dass es sich bei dieser wenig invasiven Operation um eine effektive Behandlungsmethode ohne Mortalität mit wenig Morbidität handelt. Die Offenheitsraten sind gut. Es lässt sich ein signifikanter Rückgang der Beschwerden erzielen. Unsere Kurzzeitergebnisse mit speziellen venösen Stents sind erfolgversprechend.SchlussfolgerungDie interventionelle Therapie zur Behandlung der symptomatischen chronisch-venösen Obstruktion hat sich in den letzten Jahren zur Therapie der Wahl entwickelt. Die im Kurzzeitverlauf nachgewiesenen Vorteile der speziellen venösen Stents sollten anhand von kontrollierten Vergleichsstudien evaluiert werden.

The Treatment of Post-Thrombotic Syndrome

BACKGROUND Post-thrombotic syndrome (PTS) arises in 20-50% of patients who have sustained a deep vein thrombosis and markedly impairs their quality of life. METHODS This review is based on pertinent publications retrieved by a selective literature search in PubMed and the Cochrane Library, and on the guidelines of the German Societies of Phlebology and Vascular Surgery (Deutsche Gesellschaft für Phlebologie, Deutsche Gesellschaft für Gefässchirurgie). RESULTS The treatment options are conservative treatment with compression and patient exercises, endovascular recanalization with stent angioplasty, and open bypass surgery of the iliac obstructions. The endovascular techniques yield patency rates of 73 to 100%, with thrombotic stent occlusion and hematoma as potential complications. The open operations have only been documented in studies with small case numbers (3 to 85 cases per study, patency rates 58 to 100%). The complications of these invasive procedures can include thrombotic bypass occlusion, hematoma, and wound infection. There have been randomized trials of conservative treatment, but not of surgical treatment. The American Heart Association, in its guidelines, gives the same weak recommendation for all surgical methods (IIb). CONCLUSION All conservative options should be exhausted as the first line of treatment. If PTS symptoms persist and markedly impair the patients quality of life, the possible indication for surgery should be considered. As PTS hardly ever leads to death or limb loss, its treatment should be as uninvasive as possible. Endovascular recanalization is an attractive option in this respect. A conclusive evaluation of the role of endovascular procedures in PTS must await randomized trials of this form of treatment and of the optimal stent configuration.

Wound complications after common femoral vein endophlebectomy: Influence on outcome:

Introduction Venous recanalization of obstructed femoral and iliac veins is associated with good results regarding the feasibility and patency rate. If the common femoral vein with its inflow vessels is involved, open surgical desobliteration or endophlebectomy has been described as a crucial part of the intervention. However, when performing the hybrid procedure, a number of specific complications have been described. We present our results after venous recanalization including an endophlebectomy, focussing on wound complications and its impact on outcome. Material and methods A retrospective analysis of prospective recorded data of all patients who underwent a hybrid procedure for chronic obstruction of iliofemoral veins between 2010 and 2015 was performed. The patients were treated by recanalization of the affected veins combined with endophlebectomy of the common femoral vein and arteriovenous fistula implantation. Data assessment focussed on complications and patency rates. Results This study includes 96 patients, thereof 58 females with a mean age of 44.1 years. The mean procedure time was 344 ± 140 min (range 124–663). Median follow-up time was 12.5 months (2–33 months). Primary patency was 62.5% and secondary patency was 90%. Re-intervention due to early occlusion within the first 30 post-intervention days was necessary in 37.5% of all cases. Besides bleeding complications, wound complications, mainly classified as Szilagyi I, occurred in 33% of all patients. A multivariate analysis showed a significant impact of wound complications on primary as well as secondary patency rate (p = 0.032, respectively 0.015). Conclusion Recanalization of obstructed iliac veins and/or the inferior vena cava combined with endophlebectomy of the common femoral vein and arteriovenous fistula implantation is a safe and feasible treatment option in the post-thrombotic syndrome. As wound complications are a common and associated with a significant impact on patency rate, further attempts to improve the procedure are crucial.

Effect of a new incision management system (PREVENA®) on wound healing after endophlebectomy of the common femoral vein: a case series

BackgroundNew endovascular techniques facilitate treatment of complex deep vein obstructions in cases of post-thrombotic syndrome. In a relevant number of these patients, endophlebectomy including the implantation of an arteriovenous fistula between the common femoral artery and the femoral vein is indispensable in order to establish a good inflow. These procedures display a high risk of wound complications. Despite conservative efforts to prevent these postoperative complications, wound healing problems occur in more than 20 % of cases. The present case report is the first description of wound dressing using a PREVENA® incision management system in cases of endophlebectomy.Case presentationA single center’s experience with the incision management system PREVENA®, which was used after endophlebectomy and venous stenting in complex hybrid procedures in three white men aged 46 years, 53 years, and 61 years is the subject of this case report. Although the surgical procedures were performed under therapeutical anticoagulation and took a couple of hours, no wound complications occurred.ConclusionsThese encouraging results underline a potential benefit of the incision management system PREVENA® in cases of complex venous recanalization including endophlebectomy of the femoral vein as well as the implantation of an arteriovenous fistula.

Treatment of blunt thoracic aortic injury in Germany—Assessment of the TraumaRegister DGU®

Purpose Using the data delivered by the German Trauma Register DGU® from 2002 till 2013, the value of different therapies of blunt thoracic aortic injury (BTAI) in Germany was analyzed. Methods Prospectively collected data of patients suffering from BTAI were retrospectively analyzed with focus on the different treatment modalities for grade I–IV injuries. Results 821 patients suffering from BTAI were identified: 51.6% (424) grade I injury, 35.4% (291) grade II or III injury and 12.9% (106) grade IV injury (77.5% men [44.94 ± 20.6 years]). The main patterns of injury were high- speed accidents and falls (78.0% [n = 640], 21.8% [n = 171] respectively). Significant differences between grade I and grade II/III as well as IV injuries could be assessed for the incidence of cardiopulmonary resuscitation, a Glasgow Coma Scale score below 8 and a systolic blood pressure below 90 mmHg (p-value: <0.001). In the primary admission subgroup, 44.1% (197/447) of the patients received best medical treatment, 55.9% received surgical intervention (250/447): Thereof 37.2% (93/250) received open surgery and 62.8% (147/250) had been treated by endovascular means. Significantly lower 24-h- and in-hospital-mortality rates were encountered after endovascular treatment for all gradings of BTAI (p-value: <0.001). Yet this subgroup of patients showed the lowest incidence of further severe injuries and cardiac arrest. Conclusion Endovascular therapy became the treatment of choice for BTAI in Germany. Patients who have been treated by surgical means showed the highest survival rate, especially endovascular therapy showed a favorable low mortality rate.

Open Thoracic and Thoraco-abdominal Aortic Repair in Patients with Connective Tissue Disease

Retrospective cross-border, single centre study February 2000 to April 2016 72 aortic operations on 65 patients with CTD 41 male, median age 41 years [range 19–70 years] 56 patients (86%) with previous aortic repair (71 open, 4 endovascular) 33 patients (51%) operated before at the site of the procedure reported here Procedures: 8 emergency operations (11%) Aortic arch revision (n = 1; 1%) Descending thoracic aortic repair (n = 11; 15%) TAAA type I repair (n = 12; 17%), Type II repair (n = 29; 40%) Type III repair (n = 12; 17%) Type IV repair (n = 5; 7%). Ascending aorta and/or the aortic arch (n = 2; 3%) and (n = 8; 11%) 7 patients (10%) underwent staged procedures Median follow-up: 42 months (0.5–180 months)

Macrophage Migration Inhibitory Factor Predicts Outcome in Complex Aortic Surgery

The perioperative inflammatory response is associated with outcome after complex aortic repair. Macrophage migration inhibitory factor (MIF) shows protective effects in ischemia-reperfusion (IR), but also adverse pro-inflammatory effects in acute inflammation, potentially leading to adverse outcome, which should be investigated in this trial. This prospective study enrolled 52 patients, of whom 29 (55.7%) underwent open repair (OR) and 23 (44.3%) underwent endovascular repair (ER) between 2014 and 2015. MIF serum levels were measured until 72 h post-operatively. We used linear mixed models and ROC analysis to analyze the MIF time-course and its diagnostic ability. Compared to ER, OR induced higher MIF release perioperatively; at 12 h after ICU admission, MIF levels were similar between groups. MIF course was significantly influenced by baseline MIF level (P = 0.0016) and acute physiology and chronic health evaluation (APACHE) II score (P = 0.0005). MIF level at 24 h after ICU admission showed good diagnostic value regarding patient survival [sensitivity, 80.0% (28.4–99.5%); specificity, 51.2% (35.1–67.1%); AUC, 0.688 (0.534–0.816)] and discharge modality [sensitivity, 87.5% (47.3–99.7%); specificity, 73.7% (56.9–86.6%), AUC, 0.789 (0.644–0.896)]. Increased perioperative MIF-levels are related to an increased risk of adverse outcome in complex aortic surgery and may represent a biomarker for risk stratification in complex aortic surgery.

The β-D-Endoglucuronidase Heparanase Is a Danger Molecule That Drives Systemic Inflammation and Correlates with Clinical Course after Open and Endovascular Thoracoabdominal Aortic Aneurysm Repair : Lessons Learnt from Mice and Men

Thoracoabdominal aortic aneurysm (TAAA) is a highly lethal disorder requiring open or endovascular TAAA repair, both of which are rare, but extensive and complex surgical procedures associated with a significant systemic inflammatory response and high post-operative morbidity and mortality. Heparanase is a β-d-endoglucuronidase that remodels the endothelial glycocalyx by degrading heparan sulfate in many diseases/conditions associated with systemic inflammation including sepsis, trauma, and major surgery. We hypothesized that (a) perioperative serum levels of heparanase and heparan sulfate are associated with the clinical course after open or endovascular TAAA repair and (b) induce a systemic inflammatory response and renal injury/dysfunction in mice. Using a reverse-translational approach, we assessed (a) the serum levels of heparanase, heparan sulfate, and the heparan sulfate proteoglycan syndecan-1 preoperatively as well as 6 and 72 h after intensive care unit (ICU) admission in patients undergoing open or endovascular TAAA repair and (b) laboratory and clinical parameters and 90-day survival, and (c) the systemic inflammatory response and renal injury/dysfunction induced by heparanase and heparan sulfate in mice. When compared to preoperative values, the serum levels of heparanase, heparan sulfate, and syndecan-1 significantly transiently increased within 6 h of ICU admission and returned to normal within 72 h after ICU admission. The kinetics of any observed changes in heparanase, heparan sulfate, or syndecan-1 levels, however, did not differ between open and endovascular TAAA-repair. Postoperative heparanase levels positively correlated with noradrenalin dose at 12 h after ICU admission and showed a high predictive value of vasopressor requirements within the first 24 h. Postoperative heparan sulfate showed a strong positive correlation with interleukin-6 levels day 0, 1, and 2 post-ICU admission and a strong negative correlation with lactate clearance during the first 6 h post-ICU admission. Moreover, systemic administration of heparanase and heparan sulfate induced an inflammatory response and a small degree of renal dysfunction in mice. In conclusion, these results suggest that heparanase and heparan sulfate exhibit a substantial role as clinically relevant danger molecules and may serve as both, promising biomarkers and therapeutic targets in patients undergoing open or endovascular TAAA repair and, indeed, other conditions associated with significant systemic inflammation.