Clinical decision-making on spinal cord injury-associated pneumonia: a nationwide survey in Germany

Study design: Survey study. Objectives: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP. Setting: All departments for SCI-care in Germany. Methods: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of ‘clinically defined pneumonia’ were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART). Results: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38–81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7–41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/β-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/β-lactamase inhibitors with fluoroquinolones or carbapenems. Conclusions: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP

protocol of a prospective, longitudinal study

Background Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. Methods and design The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5–9) days, 14 days (11–28) days, and 10 (8–12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8–12 weeks following SCI. Secondary endpoints are the NK cell’s TNF-α and IFN-γ production by the NK cells 8–12 weeks following SCI. Discussion The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. Trial registration DRKS00009855

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI

Expression of survivin detected by immunohistochemistry in the cytoplasm and in the nucleus is associated with prognosis of leiomyosarcoma and synovial sarcoma patients

<p>Abstract</p> <p>Background</p> <p>Survivin, a member of the inhibitor of apoptosis-protein family suppresses apoptosis and regulates cell division. It is strongly overexpressed in the vast majority of cancers. We were interested if survivin detected by immunohistochemistry has prognostic relevance especially for patients of the two soft tissue sarcoma entities leiomyosarcoma and synovial sarcoma.</p> <p>Methods</p> <p>Tumors of leiomyosarcoma (n = 24) and synovial sarcoma patients (n = 26) were investigated for their expression of survivin by immunohistochemistry. Survivin expression was assessed in the cytoplasm and the nucleus of tumor cells using an immunoreactive scoring system (IRS).</p> <p>Results</p> <p>We detected a survivin expression (IRS > 2) in the cytoplasm of 20 leiomyosarcomas and 22 synovial sarcomas and in the nucleus of 12 leiomyosarcomas and 9 synovial sarcomas, respectively. There was no significant difference between leiomyosarcoma and synovial sarcoma samples in their cytoplasmic or nuclear expression of survivin. Next, all sarcoma patients were separated in four groups according to their survivin expression in the cytoplasm and in the nucleus: group 1: negative (IRS 0 to 2); group 2: weak (IRS 3 to 4); group 3: moderate (IRS 6 to 8); group 4: strong (IRS 9 to 12). In a multivariate Cox's regression hazard analysis survivin expression detected in the cytoplasm or in the nucleus was significantly associated with overall survival of patients in group 3 (RR = 5.7; P = 0.004 and RR = 5.7; P = 0.022, respectively) compared to group 2 (reference). Patients whose tumors showed both a moderate/strong expression of survivin in the cytoplasm and a moderate expression of survivin in the nucleus (in both compartments IRS ≥ 6) possessed a 24.8-fold increased risk of tumor-related death (P = 0.003) compared to patients with a weak expression of survivin both in the cytoplasm and in the nucleus.</p> <p>Conclusion</p> <p>Survivin protein expression in the cytoplasma and in the nucleus detected by immunohistochemistry is significantly associated with prognosis of leiomyosarcoma and synovial sarcoma patients.</p

In vivo analysis of skeletal muscle and periosteum microcirculation following fracture and closed soft tissue trauma

Titel, Inhaltsverzeichnis 1. EINLEITUNG 4 1.1 Fraktur und Weichteilschaden 4 1.2 Pathophysiologie des geschlossenen Weichteilschadens 8 1.3 Interaktion von Periostverletzung, Weichteilschaden und Frakturheilung 11 2. WISSENSCHAFTLICHE FRAGESTELLUNG 14 3. EXPERIMENTELLE ARBEITEN 17 3.1 Tierexperimentelle Studien zum geschlossenen Weichteiltrauma 17 3.2 Therapeutische Ansätze zur Reduktion der mikrovaskulären Dysfunktion im Skelettmuskel der Ratte nach geschlossenem Weichteiltrauma 50 4. DISKUSSION 87 4.1 Etablierung und Analyse des Modells zur standardisierten Erzeugung eines geschlossenen Weichteiltraumas 87 4.2 In-vivo-Analyse der mikrovaskulären Perfusion des Skelettmuskels nach geschlossenem Weichteiltrauma 89 4.3 Die Mikrozirkulation des Periostes bei traumatischem Weichteilschaden 91 4.4 Die Mikrozirkulation des Skelettmuskels und Periostes bei geschlossener Fraktur 92 4.5 Die Mikrozirkulation des Skelettmuskels nach Fraktur und Weichteiltrauma und ihre Bedeutung für die Biomechanik der Frakturheilung 94 4.6 Therapie des Weichteiltraumas mit hypertonen-hyperonkotischen Lösungen 96 4.7 Reduktion des Sekundärschadens nach geschlossenem Weichteiltrauma durch N-Acetylcystein 99 4.8 Selektive Cyclooxygenase (COX)-2-Inhibition zur Therapie des geschlossenen Weichteiltraumas 100 5. ZUSAMMENFASSUNG 103 6. LITERATUR 105 7. ANHANG 122 7.1 Verzeichnis der Abkürzungen 122 7.2 Danksagung 123 7.3 Eidesstattliche Versicherung 126Frakturen mit schweren Weichteilschäden und deren Folgezustände bestimmen entscheidend die Prognose komplexer Extremitätenverletzungen. Die Weichteilschädigung besitzt dabei zentrale Bedeutung für das Frakturmanagement. Unklar ist bis heute jedoch, welche spezifischen Pathomechanismen bei Vorliegen eines schweren Weichteilschadens zu einer verzögerten Frakturheilung führen. Vor diesem Hintergrund wurde ein klinisch relevantes tierexperimentelles Modell der geschlossenen Weichteilverletzung etabliert. Mit Hilfe dieses Modells wurde die Mikrozirkulation des Skelettmuskels und des Periostes der Ratte sowohl nach Weichteilschaden als auch nach einfacher Fraktur zuverlässig und mit guter Bildqualität mittels intravitaler Fluoreszenzmikroskopie direkt quantitativ analysiert. Es kommt beim geschlossenen, traumatisch bedingten Weichteilschaden zu einer protrahierten Ausbildung von spezifischen pathologischen Veränderungen in der nutritiven Perfusion des Skelettmuskels und des Periostes. Diese sind mit einer signifikanten Zunahme der mikrovaskulären Permeabilität als Anzeichen eines sich progressiv entwickelnden Endothelzellschadens vergesellschaftet. Weiterhin führt der geschlossene Weichteilschaden zu einer massiven traumatisch-induzierten Entzündungsreaktion, die durch eine drastische Zunahme der Akkumulation und Adhärenz von Leukozyten am mikrovaskulären Endothel postkapillärer Venolen gekennzeichnet ist. Diese Mikrozirkulationsstörungen werden bei kombinierter Fraktur und Weichteilschaden noch akzentuiert. Weitere Untersuchungen konnten den pathogenetischen Einfluss eines schweren Weichteilschadens auf die Biomechanik der Frakturheilung im Tiermodell der Ratte quantitativ ermitteln. Nach Fraktur mit assoziiertem Weichteilschaden wurde im Vergleich zu einfacher Fraktur eine signifikant geringere Versagenslast und Energieabsorption in der Frühphase der Frakturheilung nachgewiesen. Es fand sich ein funktioneller Zusammenhang der initialen mikrovaskulären Dysfunktion mit den biomechanischen Testergebnissen zu 3 Wochen nach Verletzung. Unterschiedliche therapeutische Ansätze zur Reduktion der mikrovaskulären Dysfunktion im Skelettmuskel mit vasoaktiven, anti-inflammatorischen und anti- oxidativ wirksamen Substanzen wie hypertonen-hyperonkotische Lösungen, N-Acetylcystein und COX-2-Inhibitoren wurden in verschiedenen Teilprojekten untersucht. Dabei konnte mit Hilfe intravitalmikroskopischer und Laser- Doppler-103 Flowmetrischer Techniken eine nahezu komplette Restitution der posttraumatisch gestörten kapillären Perfusion sowie eine signifikante Verminderung der mikrovaskulären Permeabilität, Leukozytenadhärenz, Ödemmanifestation und Myonekroserate demonstriert werden. Das verzögerte posttraumatische Auftreten von mikrovaskulärem Perfusionsversagen, endothelialer Permeabilitätsstörung, Leukozytenadhärenz und intramuskulärer Drucksteigerung sowie Ödem lässt somit auf eine pathogenetische Bedeutung der Mikrozirkulationsstörung für die Entwicklung des Sekundärschadens schließen. Außerdem konnte die Korrelation von mikrovaskulärer Dysfunktion und biomechanischer Stabilität die kausale Bedeutung der Mikrozirkulationsstörung für die verzögerte Frakturheilung bei schwerem Weichteilschaden aufzeigen. Es kann gefolgert werden, dass biologisch-kausal wirksame Therapiekonzepte mit der Zielsetzung der Gewebeprotektion und der Minimierung des Sekundärschadens diesen Mikrozirkulationsstörungen früh und effektiv entgegenwirken müssen. Die vorliegenden Ergebnisse könnten langfristig dazu dienen, die Mikrozirkulation von Periost und Skelettmuskel bei effektiven Behandlungsalgorithmen der Fraktur mit schwerem Weichteilschaden zu berücksichtigen. Durch die Kenntnis der spezifischen Pathomechanismen sind wir in der Lage, effektivere therapeutische Ansätze zu erarbeitenMajor loss of tissue is an almost invariable consequence of severe closed soft tissue injury (CSTI). Among the many factors which determine outcome of complex injuries, the role of closed soft tissue damage remains only partly understood. Clinically, the extent of soft tissue trauma determines the outcome of complex injuries and has significant influence on bone healing. The extent and the temporal relationship of periosteal microcirculatory deteriorations after severe closed soft tissue injury (CSTI) are not known. We hypothesized that progressive tissue damage following severe CSTI is secondary to delayed and prolonged microvascular perfusion failure and increased leukocyte recruitment. This study also evaluates the hypothesis that periosteal microcirculation is adversely affected and the manifestation of trauma-initiated microvascular impairment in periosteum is substantially prolonged following CSTI. To test this hypothesis the specific aims of the present study were to quantitatively analyze the skeletal muscle and periosteum microcirculation, i.e. nutritive perfusion and leukocyte-endothelial cell interaction, following standardized fracture and CSTI using a new animal model. Skeletal muscle (extensor digitorum longus muscle) and periosteum (meta-/ diaphyseal tibia) microvascular perfusion were analyzed by intravital multifluorescence microscopy and laser-Doppler flowmetry. The microvascular response to CSTI alone or in combination with fracture was characterized by a significant reduction of capillary perfusion which was paralleled by an increase in capillary diameter throughout the entire 5 day observation period when compared with controls. Trauma-induced inflammatory response was reflected by a markedly increased rolling and adherence of leukocytes, primarily restricted to the endothelium of postcapillary venules. This was accompanied by increased microvascular permeability indicative of substantial loss of endothelial integrity. Following fractures with soft tissue trauma the microvascular deteriorations in skeletal muscle were accompanied by similar qualitative and temporal changes in the periosteum. In addition, a decreased total failure load and energy absorption in the early fracture healing period was found. Regression analysis between initial capillary perfusion disturbances and biomechanical stability (energy absorption at 3 weeks) revealed a positive functional association. Different therapeutic approaches using vasoactive and anti-inflammatory substances designed to reduce microvascular dysfunction and leukocyte adherence in skeletal muscle, e.g. hypertonic-hyperoncotic solutions, N-acetylcysteine, COX-2 inhibitors, were investigated. These studies revealed a marked and rapid restoration of posttraumatically disturbed microcirculation and a significant reduction in trauma-induced edema, leukocyte infiltration and myonecrosis (assessed by loss of desmin immunoreactivity). The delayed manifestation of trauma-induced microcirculatory derangements, leukocyte activation, edema formation, tissue pressure and myonecrosis underscores the underlying and prognostic importance of microvascular dysfunction for evolving secondary tissue damage. Furthermore, the correlation between microvascular perfusion deficits and decrease in biomechanical stability indicate a causative role of microcirculatory disturbances for delayed fracture healing. Therefore, clinical management of CSTI aimed at soft tissue preservation should consider improvement of microvascular perfusion and the inhibition of leukocyte-mediated tissue injury. These results may have further therapeutic implications in terms of supporting microvascular blood supply and tissue viability in the early posttraumatic period, preserving periosteal integrity and considering the interaction of skeletal muscle damage and periosteal microvascular injury during management of muskuloskeletal trauma

Positive outcome after a small-caliber gunshot fracture of the upper cervical spine without neurovascular damage

BACKGROUND: Gunshot wounds to the cervical spine most frequently concur with serious injuries to the spinal cord and cervical vessels and often have a fatal outcome. CASE REPORT: We describe the case of a 35-year-old male with a complex fracture of the C2 vertebra body and a mandibular fracture after a penetration gunshot to the cervical spine. Computed tomography (CT) at admission revealed the exact extent of the fractures and the small caliber bullet lodged next to the C2 vertebra. In this rare and extremely lucky case no collateral vascular or neurological damage was detected. Eighteen months after surgical bullet removal and posterior C1-C3 fusion complete bone healing of the C2 vertebra was achieved and there were no secondary neurovascular deficits. CONCLUSIONS: Immediate surgical C1-C3 fixation resulted in an excellent outcome without secondary neurovascular deficits in this rare case of traumatic complex C2 vertebral fracture caused by a gunshot injury

Simultaneous Periprosthetic Acetabular Fracture and Contralateral B-Type Compression Injury of the Pelvic Ring: A Case Report of a Rare Injury Combination

The periprosthetic fracture of the acetabulum is a rare injury, and its management is only sporadically reported in the literature. A few case reports are available which mainly focus on periprosthetic acetabular fractures in the elderly population. In our case, a 32-year-old patient suffered from a periprosthetic acetabular fracture in combination with a pelvic ring injury following a high velocity accident. The fracture morphology allowed a salvage of the prosthesis with an open reduction and internal fixation with a good radiographic and functional outcome one year after trauma

Locked Internal Fixator- Sensitivity of Screw/Plate Stability to the Correct Insertion Angle of the Screw

Objective: Internal fixators with angular stability have been developed to provide high stability without compression of the plate on to the bone. Angular and axial stability of a plate-screw construct can be achieved using a conically threaded screw head undersurface and a corresponding conically threaded plate hole. Furthermore, the insertion angle of the screw must correspond precisely to the axis of the screw hole. This is not always achieved in clinical practice and may result in screw loosening. The objective of this study was to examine the relationship between the stability of the locked screw-plate on the insertion angle of the screw. Methods: Locking screws were inserted in an isolated (Point Contact Fixator, PC-Fix) or combined (Locking Compression Plate, LCP 4.5) locking hole with the use of an aiming device. The optimal insertion angle for these plates is perpendicular to the plate surface. The screws were inserted with an axis deviation of 0[degrees] (optimal condition), 5[degrees], and 10[degrees] respective to the optimal angle (variance +/- 1[degrees]). The samples were tested under shear or axial (push out) loading conditions until failure occurred. An Instron materials testing machine was used. Results: Locking screws inserted in the isolated locking hole (PC-Fix) showed a significant decrease of failure load if inserted at 5[degrees] and 10[degrees] angle. Using an optimal insertion angle (0[degrees]), failure load was 1480 +/- 390 N, with 5[degrees] axis deviation 780 +/- 160 N, P = 0.0001, and with 10[degrees] axis deviation 550 +/- 110 N, P = 0.0001. Screws inserted in the combined locking hole (LCP) also showed a significant decrease of push-out force of 77% (4960 +/- 1000 N versus 1120 +/- 400 N) with 10[degrees] axis deviation. Compared to optimal insertion angle (0[degrees]), bending load to failure did decrease up to 69% (1240 +/- 210 N vs. 390 +/- 100 N) with 10[degrees] axis deviation. Conclusion: A locking head screw exhibits high stability with a moderate axis deviation in the angle of insertion of up to 5[degrees]. However, there is a significant decrease in stability with increasing axis deviation (>5[degrees]). An aiming device is recommended to provide optimal fixation with angular stability

Microdialysis Reveals Anti-Inflammatory Effects of Sulfated Glycosaminoglycanes in the Early Phase of Bone Healing

Although chronic inflammation inhibits bone healing, the healing process is initiated by an inflammatory phase. In a well-tuned sequence of molecular events, pro-inflammatory cytokines are secreted to orchestrate the inflammation response to injury and the recruitment of progenitor cells. These events in turn activate the secretion of anti-inflammatory signaling molecules and attract cells and mediators that antagonize the inflammation and initiate the repair phase. Sulfated glycosaminoglycanes (sGAG) are known to interact with cytokines, chemokines and growth factors and, thus, alter the availability, duration and impact of those mediators on the local molecular level. sGAG-coated polycaprolactone-co-lactide (PCL) scaffolds were inserted into critical-size femur defects in adult male Wistar rats. The femur was stabilized with a plate, and the defect was filled with either sGAG-containing PCL scaffolds or autologous bone (positive control). Wound fluid samples obtained by microdialysis were characterized regarding alterations of cytokine concentrations over the first 24 h after surgery. The analyses revealed the inhibition of the pro-inflammatory cytokines IL-1β and MIP-2 in the sGAG-treated groups compared to the positive control. A simultaneous increase of IL-6 and TNF-α indicated advanced regenerative capacity of sGAG, suggesting their potential to improve bone healing