Guido A. Wanner

Liver Ischemia And Reperfusion Induces A Systemic Inflammatory Response Through Kupffer Cell Activation

To study the role of Kupffer cells (KC) as a cellular source of proinflammatory cytokines in hepatic ischemia/reperfusion, Sprague-Dawley rats were subjected to 20 min global hepatic ischemia. Sham-operated animals served as controls. Blood levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interleukin 6 (IL-6) were determined after 10, 30, 60, 120, and 240 min of reperfusion and compared with spontaneous cytokine release by KC isolated after 60 min of reperfusion. Hepatic ischemia/reperfusion resulted in an enhanced (p < .01) spontaneous release of TNF-alpha (+482%), IL-1 alpha (+33%), and IL-6 (+175%) by KC. Kinetic analysis of cytokinemia revealed an early increase (p < .01) of TNF-alpha and IL-1 alpha within minutes upon reperfusion, while an elevation of IL-6 serum levels was observed with a delay of 2 h. Early cytokinemia was associated with dysfunction/injury of the liver, lung, and kidney after 4 and 24 h of reperfusion, respectively. These data indicate that hepatic ischemia/reperfusion results in Kupffer cell activation and increased cytokine levels, which may produce systemic inflammation and may be responsible for tissue injury locally and on remote sites.

Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients.

Objective: To compare procalcitonin (PCT) plasma levels of injured patients with the incidence and severity of systemic inflammatory response syndrome (SIRS), infection, and multiple organ dysfunction syndrome (MODS) and to assess the predictive value of PCT for these posttraumatic complications. Design: Retrospective study comparing patients with mechanical trauma in terms of severity of injury, development of infectious complications, and organ dysfunctions. Setting: Level I trauma center with emergency room, intensive care unit, and research laboratory. Patients: Four hundred five injured patients with an Injury Severity Score of ≥9 points were enrolled in this study from January 1994 to February 1996. Interventions: Blood samples were collected on the day of admission and on days 1, 3, 5, 7, 10, 14, and 21 thereafter. Measurements and Main Results: We determined PCT serum levels using a specific immunoluminometric assay. We retrospectively evaluated the occurrence of SIRS, sepsis, and MODS using patients’ charts. Mechanical trauma led to increased PCT plasma levels dependent on the severity of injury, with peak values on days 1 and 3 (p < .05) and a continuous decrease within 21 days after trauma. Patients who developed SIRS demonstrated a significant (p < .05) increase of peak PCT plasma levels compared with patients without SIRS. The highest PCT plasma concentrations early after injury were observed in patients with sepsis (6.9 ± 2.5 ng/mL; day 1) or severe MODS (5.7 ± 2.2 ng/mL; day 1) with a sustained increase (p < .05) for 14 days compared with patients with an uneventful posttraumatic course (1.1 ± 0.2 ng/mL). Moreover, these increased PCT plasma levels during the first 3 days after trauma predicted (p < .0001; logistic regression analysis) severe SIRS, sepsis, and MODS. Conclusions: These data indicate that PCT represents a sensitive and predictive indicator of sepsis and severe MODS in injured patients. Routine analysis of PCT levels seems to aid early recognition of these posttraumatic complications. Thus, PCT may represent a useful marker to monitor the inflammatory status of injured patients at risk.

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.

Internal fixation of displaced proximal humeral fractures with two one-third tubular plates.

BACKGROUND Operative treatment of displaced proximal humeral fractures often results in poor functional outcome. We report a technique that provides improved rotational stability of the fracture and thus allows early functional treatment. METHODS Seventy-one consecutive patients (67 +/- 18 years) with displaced fractures of the proximal humerus (two-part, n = 10; three-part, n = 41; four-part, n = 20) were treated by open reduction and internal fixation using two one-third tubular plates on the anterior and lateral aspects of the proximal humerus. Passive motion was started on the third postoperative day, followed by actively assisted exercises on day 6. RESULTS Seven patients (12%) had complications (fracture redisplacement, avascular necrosis of the humeral head, frozen shoulder, subacromial impingement, and implant loosening) that required further surgical intervention. Sixty patients (85%) were available for follow-up evaluation 17 +/- 10 months after the injury. Using the Constant score, 34% of the patients had very good results, 29% had good results, 25% had fair results, and 12% had poor results. Age (< 60 years or > or = 60 years) and fracture type had no influence on functional outcome. CONCLUSION These results demonstrate the high stability of internal fixation with two one-third tubular plates that allowed early mobilization of the shoulder in all patients and emphasize this technique as a preferred treatment option for displaced fractures of the proximal humerus.

Effect of Intravenous Anesthetics on Spontaneous and Endotoxin-stimulated Cytokine Response in Cultured Human Whole Blood

Background Various anesthetics have been suggested to interfere with the immune system. The ability of leukocytes to express surface receptors and mediators is fundamental to a successful host defense. Therefore, the effects of intravenous anesthetics on cytokine release by leukocytes and expression of surface molecules known to modulate this response were determined. Methods Concentration‐dependent effects of thiopentone, etomidate, propofol, ketamine, midazolam, and fentanyl on spontaneous and endotoxin (lipopolysaccharide; 1 [micro sign]g/ml)‐stimulated cytokine release were studied in whole blood from volunteers (n = 6) cultured for 25 h. In addition, expression of the lipopolysaccharide‐recognition molecule CD14 and the major histocompatibility complex class II molecule human leukocyte locus A system‐DR (HLA‐DR) on monocytes were assessed using flow cytometry. Results All anesthetics studied elicited only minor effects on spontaneous cytokine release even at pharmacologic concentrations. However, expression density of CD14 was reduced in the presence of thiopentone, etomidate, and propofol, whereas HLA‐DR was unaffected. lipopolysaccharide‐stimulated tumor necrosis factor response was inhibited by thiopentone (12.8% [median]; 7.6‐18.8 [25‐75 percentile]) of control, and ketamine (46.4% [median]; 44.4‐56.4 [25‐75 percentile]), at pharmacologic concentrations, whereas it was augmented even in the presence of low concentrations of propofol (172.3% [median]; 120.5‐200.7 [25‐75 percentile]). Ketamine additionally decreased the concentration of interleukin (IL)‐1 [small beta, Greek] (14.8% [median]; 12.0‐18.0 [25‐75 percentile]). Release of IL‐1 receptor antagonist (IL‐1ra) was inhibited by thiopentone, etomidate, and propofol, whereas the same anesthetics increased IL‐10 concentration simultaneously. Midazolam and fentanyl did not alter the concentrations of any cytokine. Conclusions These results suggest a complex modulation of the cytokine response by the studied anesthetics in cultured whole blood. Although effects on spontaneous cytokine release by leukocytes were negligible, some anesthetics affected their ability to respond to lipopolysaccharide.

Modulation of kupffer cell activity by gadolinium chloride in endotoxemic rats.

Gadolinium chloride (GdCI3) has been reported to block Kupffer cell (KC) phagocytic activity in rats. In this study, we investigated the action of GdCI3 on Kupffer cells and related effects in response to lipopolysaccharide (LPS) exposure of rats. Using intravital fluorescence microscopy (IVFM), the hepatic microcirculation (phagocytic activity and zonal distribution of KC, sinusoidal perfusion, leukocyte-endothelial cell interaction) of rats pretreated with either saline or GdCI3 (10 mg/kg i.v. for 2 days) was studied at 1 h (n = 14) and 16 h (n = 16) after exposure to Escherichia coli LPS (10 mg/kg i.v.). LPS-exposure (1 h) resulted in KC activation with increased phagocytic activity (IVFM), intracellular enrichment of phagocytic vacuoles, and marked rise of cytokines (tumor necrosis factor-α, interleukin-6) in serum, whereas GdCI3-pretreatment completely inhibited the LPS-related KC response. 16 h after LPS-exposure, saline-treated animals revealed high serum levels of LPS, associated with microvascular perfusion deficits, marked KC destruction, and hepatocellular disintegration, which finally resulted in a mortality rate of 47% (7/15). In contrast, none of the GdCI3-treated animals died (0/8). GdCI3-pretreatment significantly attenuated LPS-induced hepatic microvascular perfusion failure and parenchymal cell injury at 16 h after LPS exposure. Intact KC morphology and low serum levels of LPS indicated adequate clearance capacity. Based on these results, we propose that modulation of LPS-induced KC phagocytic activity and KC function by GdCI3 is effective to protect from LPS-induced hepatic injury and systemic toxicity, probably by inhibition of overwhelming inflammatory response.

Functional results of angular-stable plate fixation in displaced proximal humeral fractures

INTRODUCTION The availability of angular-stable plate/screw systems led to a euphoric use of these implants for the treatment of displaced proximal humerus fractures. The high implant costs seem to be justified by a potentially improved outcome. PATIENTS AND METHODS Thirty one patients (20 female, 11 male, mean age: 62+/-16 years) with two-, three- and four-part proximal humerus fractures (Neer classification) were operated using the proximal humeral internal locking system (PHILOS). The mean follow-up time was 19+/-3 postoperative months (range: 340-720 days). Functional results (Constant score, UCLA-score) were analysed and compared to an equivalent historic control group of 60 patients operated for the same fracture types using two one-third tubular plates. Additionally, total implant costs for each technique were compared. RESULTS Complications in the PHILOS group included one implant failure with refracture, one secondary dislocation, two cases of subacromial impingement, and two cases of partial avascular necrosis of the humeral head. The mean Constant score (age- and sex-matched) was 80+/-11% for the affected side and 104+/-13% for the healthy side. The UCLA scores were excellent in 10%, good in 67%, and fair in 23% of the patients. Complication rate and functional results did not differ significantly from the control group treated with one-third tubular plates. Implant costs were significantly higher for the PHILOS group (684+/-40 Euro vs. 158+/-20 Euro, p<0.05). CONCLUSION Our study showed similar functional results using either plate. Although the PHILOS plate may provide important advantages in specific situations, such as osteoporotic bone, its use as a standard must be carefully judged under the economic aspect of the significant higher implant costs.

Reduction of Metal Artifacts from Hip Prostheses on CT Images of the Pelvis: Value of Iterative Reconstructions

PURPOSE To assess the value of iterative frequency split-normalized (IFS) metal artifact reduction (MAR) for computed tomography (CT) of hip prostheses. MATERIALS AND METHODS This study had institutional review board and local ethics committee approval. First, a hip phantom with steel and titanium prostheses that had inlays of water, fat, and contrast media in the pelvis was used to optimize the IFS algorithm. Second, 41 consecutive patients with hip prostheses who were undergoing CT were included. Data sets were reconstructed with filtered back projection, the IFS algorithm, and a linear interpolation MAR algorithm. Two blinded, independent readers evaluated axial, coronal, and sagittal CT reformations for overall image quality, image quality of pelvic organs, and assessment of pelvic abnormalities. CT attenuation and image noise were measured. Statistical analysis included the Friedman test, Wilcoxon signed-rank test, and Levene test. RESULTS Ex vivo experiments demonstrated an optimized IFS algorithm by using a threshold of 2200 HU with four iterations for both steel and titanium prostheses. Measurements of CT attenuation of the inlays were significantly (P < .001) more accurate for IFS when compared with filtered back projection. In patients, best overall and pelvic organ image quality was found in all reformations with IFS (P < .001). Pelvic abnormalities in 11 of 41 patients (27%) were diagnosed with significantly (P = .002) higher confidence on the basis of IFS images. CT attenuation of bladder (P < .001) and muscle (P = .043) was significantly less variable with IFS compared with filtered back projection and linear interpolation MAR. In comparison with that of FBP and linear interpolation MAR, noise with IFS was similar close to and far from the prosthesis (P = .295). CONCLUSION The IFS algorithm for CT image reconstruction significantly reduces metal artifacts from hip prostheses, improves the reliability of CT number measurements, and improves the confidence for depicting pelvic abnormalities.

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.