Hans-Peter Simmen

Danger Signals Activating the Immune Response after Trauma

Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immune response. With popularization of the “danger theory,” numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1), interleukin-1α (IL-1α), and interleukin-33 (IL-33) as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.

Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma.

BACKGROUND: We investigated whether hyperfibrinolysis and its severity was associated with outcome of traumatized and nontraumatized patients. METHODS: From April 2008 to April 2010, all emergency patients with hyperfibrinolysis were enrolled in this study. Hyperfibrinolysis patients were divided into traumatized (trauma hyperfibrinolysis group) and nontraumatized (nontrauma hyperfibrinolysis group). The trauma hyperfibrinolysis group was matched with 24 polytrauma patients without hyperfibrinolysis (matched trauma group). Data from rotational thromboelastometry measurements, blood gas analysis (metabolic state), laboratory analysis, injury severity score, and 30-day mortality were collected. RESULTS: Thirty-five patients with hyperfibrinolysis were identified (13 traumatized, 22 nontraumatized). Overall mortality for hyperfibrinolysis was 54%. Mortality in the trauma hyperfibrinolysis group (77% ± 12%) was significantly higher than in the nontrauma hyperfibrinolysis group (41% ± 10%; P = 0.001, 95% CI 5%–67%) and the matched trauma group (33% ± 10%; P = 0.009, 95% CI 13%–74%). Hyperfibrinolysis is significantly (P = 0.017) associated with mortality in trauma patients. In the blood gas analysis representing the metabolic state, only pH (P = 0.02) and potassium (P = 0.01) were significantly lower in the trauma hyperfibrinolysis group compared to the nontrauma hyperfibrinolysis group. CONCLUSIONS: Mortality from hyperfibrinolysis is significantly higher in trauma compared with nontrauma patients, and hyperfibrinolysis is an independent factor predicting mortality in trauma patients. Rotational thromboelastometry provides real-time recognition of hyperfibrinolysis allowing early treatment.

Effects of limb immobilization on brain plasticity

Objective: Little is known about the effects of reduced sensory input and motor output in the human brain. Therefore, we conducted a longitudinal study to investigate whether limb immobilization after unilateral arm injury is reflected in structural plastic changes in gray matter (cortical thickness) and white matter (fractional anisotropy [FA]). Methods: We examined 10 right-handed subjects with injury of the right upper extremity that required at least 14 days of limb immobilization. Subjects underwent 2 MRI examinations, the first within 48 hours postinjury and the second after an average time interval of 16 days of immobilization. Based on the MRI scans, we measured cortical thickness of sensorimotor regions and FA of the corticospinal tracts. Results: After immobilization, we revealed a decrease in cortical thickness in the left primary motor and somatosensory area as well as a decrease in FA in the left corticospinal tract. In addition, the motor skill of the left (noninjured) hand improved and is related to increased cortical thickness and FA in the right motor cortex. Conclusions: The present study illustrates that cortical thickness of the sensorimotor cortex and FA of the corticospinal tract changed during right arm immobilization and that these changes are associated with skill transfer from the right to the left hand. Thus, immobilization induces rapid reorganization of the sensorimotor system. Given that limb immobilization is a standard intervention technique in constraint-induced therapy, therapists should be aware of both the positive and negative effects of this intervention.

Analysis of pH and pO2 in abscesses, peritoneal fluid, and drainage fluid in the presence or absence of bacterial infection during and after abdominal surgery

The diagnostic significance of pH, pO2 (partial pressure of oxygen), and pCO2 (partial pressure of carbon dioxide) was studied in pus, peritoneal fluid, and drainage fluid obtained during or after abdominal surgery. Measurements of these fluids in 59 patients with clinically and bacteriologically documented abdominal or anorectal infection (median pH: 6.75, median pO2: 28 mm Hg, median pCO2: 89 mm Hg) differed significantly (p < 0.001) from data of 105 patients undergoing elective laparotomy for a reason other than infection (median pH: 7.49, median pO2: 144 mm Hg, median pCO2: 92 mm Hg). The combined use of a threshold criterion for pH and pO2 allowed for excellent discrimination between infected (pH less than 7.1, pO2 less than 49 mm Hg) and noninfected patients, with positive and negative predictive values of 98% and 99%, respectively. In conclusion, conditions prevailing during standard in vitro susceptibility tests more closely reflect physiologic conditions as opposed to the conditions prevailing at the site of abdominal infections. Measurements of pH and pO2 allow for an easy, quick, sensitive, and specific diagnosis of bacterial abdominal infection.

Medial support by fibula bone graft in angular stable plate fixation of proximal humeral fractures: an in vitro study with synthetic bone

BACKGROUND Failure to achieve stable fixation with medial support in proximal humeral fractures can result in varus malalignment and cut-through of the proximal screws. The purpose of this study was to investigate the influence of an intramedullary fibula bone graft on the biomechanical properties of proximal humeral fractures stabilized by angular stable plate fixation in a bone model under cyclic loading. METHODS Two fixation techniques were tested in 20 composite analog humeri models. In group F- (n = 10), fractures were fixed by an anatomically formed locking plate system. In group F+ (n = 10), the same fixation system was used with an additional fibular graft model with a length of 6 cm inserted in an intramedullary manner. Active abduction was simulated for 400 cycles by use of a recently established testing setup. Fragment gap distance was measured, and thereby, intercyclic motion, fragment migration, and residual plastic deformation were determined. RESULTS The addition of a fibular graft to the fixation plate led to 5 times lower intercyclic motion, 2 times lower fragment migration, and 2 times less residual plastic deformation. Neither screw pullout, cut-through, nor implant failure was observed. CONCLUSION Medial support with an intramedullary fibular graft in an angular stable fixation of the proximal humerus in vitro increases overall stiffness of the bone-implant construct and reduces migration of the humeral head fragment. This technique might provide a useful tool in the treatment of displaced proximal humeral fractures, especially when there is medial comminution.

Comparative Multiple-Dose Pharmacokinetics of Cefotaxime, Moxalactam, and Ceftazidime

The pharmacokinetics of cefotaxime, moxalactam, and ceftazidime were investigated in six human volunteers who received in a crossover fashion doses of 0.5, 1.0, and 2.0 g of each drug by a 5-min infusion. Doses of 1.0 g were repeated after the administration of probenecid. Serum and urine concentrations were assayed with an agar diffusion method. Serum concentrations of moxalactam exceeded those of ceftazidime at all times and were distinctly higher than those of cefotaxime. The normalized area under the concentration time curve (defined as the ratio of the area under the curve per dose) reflects this relationship: compared with cefotaxime the normalized area under the curve of moxalactam was 3 to 4 times higher, and that of ceftazidime was 2 to 3 times higher. By intra-individual comparisons, the area under the curve of moxalactam was 44% larger than that of ceftazidime. With increasing doses, cefotaxime exhibited a nonlinear increase of the area under the curve. The half-lives of moxalactam, ceftazidime, and cefotaxime were 2.34, 1.95, and 1.16 h, respectively. The volume of distribution averaged 0.20 ± 0.03, 0.23 ± 0.02, and 0.25 ± 0.04 liters per kg, and the mean total body clearance was 84, 131, and 328 ml/min for moxalactam, ceftazidime, and cefotaxime, respectively. The 24-h urinary recovery was highest for moxalactam (75 ± 4%) followed by ceftazidime (68 ± 11%) and cefotaxime (53 ± 6%). The influence of probenecid on serum concentrations, half-life, area under the curve, and clearance was most apparent with cefotaxime, whereas the pharmacokinetics of moxalactam and ceftazidime were only slightly affected. After the 0.5− and 2.0− g doses of cefotaxime, desacetyl-cefotaxime activity (determined by high-pressure liquid chromatography) reached a peak of 2.7 and 9.9 μg/ml and declined with a half-life of 1.9 and 1.4 h. The ratio of the R(−) and S(−) epimers of moxalactam, which could be differentiated by high-pressure liquid chromatography, fell rapidly from 0.81 at 0.17 h to 0.5 at 5 h, indicating the presence of twice as much of the microbiologically less active S(−) epimer. From a pharmacokinetic standpoint it appears reasonable to conclude that moxalactam and possibly ceftazidime could be administered twice daily and that cefotaxime could be administered three or even four times daily.

Bio-corrosion of stainless steel by osteoclasts—in vitro evidence

Most metals in contact with biological systems undergo corrosion by an electrochemical process. This study investigated whether human osteoclasts (OC) are able to grow on stainless steel (SS) and directly corrode the metal alloy leading to the formation of corresponding metal ions, which may cause inflammatory reactions and activate the immune system. Scanning electron microscopy analysis demonstrated long‐term viable OC cultures and evident resorption features on the surface of SS discs on which OC were cultured for 21 days. The findings were confirmed by atomic emission spectrometry investigations showing significantly increased levels of chromium, nickel, and manganese in the supernatant of OC cultures. Furthermore, significant levels of pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α, which are considered to be major mediators of osteolysis, were revealed in the same cultures by cytometric bead array analysis. Within the present study, it was shown that human osteoclast precursors are able to grow and differentiate towards mature OC on SS. The mature cells are able to directly corrode the metal surface and release corresponding metal ions, which induce the secretion of pro‐inflammatory cytokines that are known to enhance osteoclast differentiation, activation, and survival. Enhanced corrosion and the subsequently released metal ions may therefore result in enhanced osteolytic lesions in the peri‐prosthetic bone, contributing to the aseptic loosening of the implant.

Calcar comminution as prognostic factor of clinical outcome after locking plate fixation of proximal humeral fractures

OBJECTIVE In the treatment of proximal humeral fractures, the decision between open fixation and arthroplasty is often difficult. Applicable radiographic prognostic factors would be useful. The purpose of the present study was to investigate the influence of calcar comminution on the clinical and radiologic outcome after locking plate fixation of these fractures. METHODS In patients with proximal humeral fractures that were treated by locking plate fixation, fracture morphology and the presence of comminution of the calcar were documented on preoperative radiographs. Follow-up for at least 2 years with radiologic assessment and functional outcome measurements including Constant score, subjective shoulder value (SSV), disabilities of the arm, shoulder and hand score (DASH), visual analogue scale (VAS) and short form (SF)-36 was performed. RESULTS Follow-up examination (50.8±20.6 months) was possible in 74 patients (46 female, 28 male, age 63.0±15.9 years). Mean absolute Constant score (CS abs), CS adapted to age and gender (CS adap), DASH, SSV and VAS were 72.4±14.5, 85.2±17.3%, 15.7±17.3, 80.3±19.6% and 2.1±2.2. Nonunion was present in 1.3%, cut-out in 5.4% and implant failure in 1.3%. Avascular necrosis (AVN) was seen in 12.2%, in three cases >24 months after the initial trauma. In the presence of calcar comminution, the clinical outcome (CS abs, CS adap, SSV and several parameters of SF-36) was significantly impaired, the odds ratio for these patients to have an absolute CS<65 was 4.4 (95% confidence interval (CI): 1.4-13.7). CONCLUSIONS The treatment of proximal humeral fractures with locking plate fixation achieves good clinical mid-term results. Calcar comminution is a relevant and easy-to-detect prognostic factor for the functional and subjective outcome in these fractures.

Posterior screw fixation in rotationally unstable pelvic ring injuries.

OBJECTIVE Although the stability of the pelvic ring primarily depends on the integrity of the posterior sacroiliac arch, lateral compression fractures with rotational instability are commonly treated by anterior fixation alone. The objective of the present study was to assess the outcome of patients with these fractures treated by posterior iliosacral screw fixation alone. METHODS Patients with rotationally unstable lateral compression fractures of the pelvic ring (Young and Burgess LC I and LC II or AO/Tile B2) treated by percutaneous iliosacral fixation alone were included. Postoperative complications, need for secondary surgery, malunion, secondary fracture displacement and the time to full-weight bearing were documented. RESULTS Twenty-five patients (13 female, 26 male; age: 56±20 years) were treated by percutaneous screw fixation (14 bilaterally, 11 unilaterally). Mean follow-up was 6±4 months, mean time to full weight bearing 9±3 weeks. Revision surgery was necessary in two patients (8%) due to nerve irritation; an additional anterior stabilisation was needed in two other patients (8%) due to secondary dislocation. Wound infection or motor weakness were not encountered, non-union of the posterior arch did not occur. Non-union of the pubic rami, however, occurred in two patients. The presence of malunion of the pubic rami did not affect the time to full weight bearing. CONCLUSIONS Percutanous iliosacral screw fixation alone is a sufficient technique for the stabilisation of rotationally unstable pelvic fractures with low rates of complications or non-unions. It allows for a minimally invasive treatment thus being a useful option in patients who do not qualify for open anterior fixation.

Titanium induced production of chemokines CCL17/TARC and CCL22/MDC in human osteoclasts and osteoblasts

There is increasing evidence that titanium (Ti(IV)) ions are released from orthopedic implants and play a role in aseptic loosening. This study aimed to investigate whether titanium induces expression of chemokines and cytokines that are important in osteoclastogenesis in human osteoclasts and osteoblasts. Incubation of those cells with 1 muM Ti(IV) significantly upregulated expression of CCL17/TARC and CCL22/MDC, RANK-L, M-CSF and pro-inflammatory cytokines as determined by quantitative real-time PCR and ELISA assays. Additionally, flow cytometry was used to show Ti(IV) related increased expression of CCR4, the cognate receptor for CCL17 and CCL22 in challenged osteoclast precursors. These results strongly suggest that Ti(IV) ions play a role in the recruitment of osteoclast precursors to the bone-implant interface by increasing CCL17 and CCL22 expression and by upregulating their cognate receptor. Moreover the increased expression of RANK-L and M-CSF by osteoblasts together with increased levels of pro-inflammatory cytokines may enhance osteoclast differentiation and activity, and subsequently contribute to the pathomechanism of aseptic loosening.