Udo Obertacke

Relation of a TNF Gene Polymorphism to Severe Sepsis in Trauma Patients

OBJECTIVE To investigate the relation of the biallelic Nco1 restriction fragment length polymorphism in the first intron of the tumor necrosis factor (TNF) beta gene with the development of severe sepsis in multiply injured patients. SUMMARY BACKGROUND DATA The biallelic Nco1 polymorphism of the TNFbeta gene has been described to be associated with autoimmune diseases and with the mortality rate in severe sepsis. Therefore, the Nco1 polymorphism may be associated with the clinical finding that despite comparable risk factors, posttraumatic sepsis develops in some patients but not others. METHODS The study group consisted of 110 patients with severe blunt trauma (Injury Severity Score > or = 17). Typing of each patient for the biallelic Nco1 polymorphism was performed by analyzing restriction fragments of an Nco1-digested DNA fragment obtained using polymerase chain reaction. Genotypes were then related to the occurrence of severe posttraumatic sepsis and TNFalpha serum concentrations. RESULTS Fifty-seven patients showed an uncomplicated posttraumatic recovery, and severe sepsis developed in 53 patients. The overall allele frequency (TNFB1 0.29, TNFB2 0.71) and genotype distribution (TNFB1 homozygous 7.3%, TNFB1/TNFB2 42.7%, TNFB2 homozygous 50%) were in agreement with the distribution in healthy volunteers. Genotype distribution in patients with an uncomplicated clinical course was significantly different from that in patients with severe posttraumatic sepsis. Development of severe posttraumatic sepsis was significantly increased in patients homozygous for the allele TNFB2. In patients with severe posttraumatic sepsis, TNFalpha serum concentrations were significantly higher in TNFB2-homozygous individuals compared with heterozygous and TNFB1 -homozygous individuals. The age- and injury-matched odds ratio for the homozygous TNFB2 genotype compared with the heterozygous genotype was 5.22 (p = 0.007, 95% confidence interval 1.6 to 17.9). CONCLUSIONS In multiply injured patients, the Nco1 polymorphism within the TNFbeta gene is associated with the development of severe posttraumatic sepsis and with increased TNFalpha serum levels when severe sepsis has occurred. This suggests a genetic determination of the individual inflammatory response after infection or tissue damage, which significantly influences susceptibility to severe nosocomial infections.

HLA-DR expression and soluble HLA-DR levels in septic patients after trauma.

OBJECTIVE To determine if cellular and soluble HLA-DR molecules may be relevant in severely injured patients for the development of gram-positive or gram-negative sepsis. SUMMARY BACKGROUND DATA HLA-DR molecules play a central role in the specific immune response to infection. The reduced HLA-DR expression on monocytes is considered to correlate with infectious complications and the development of sepsis. Data on the role of HLA-DR expression on T cells and soluble HLA-DR molecules are rare. METHODS HLA-DR expression on monocytes and T cells was measured by flow cytometry. Plasma levels of soluble HLA-DR were studied by enzyme-linked immunosorbent assay. RESULTS HLA-DR expression on circulating T cells, calculated as mean fluorescence intensity in channels, was reduced at day 1 after admission in 20 patients with subsequent severe sepsis compared with 46 patients without sepsis. The septic patients immediately after trauma had significantly lower soluble HLA-DR plasma levels than the nonseptic patients. At day 2 after admission, HLA-DR expression on monocytes was significantly lower in the severe sepsis group than in the patients without sepsis, and lasted until day 14 after injury. CONCLUSIONS In severely injured patients, decreased levels of cellular and soluble HLA-DR appear as early indicators of an immune deviation associated with the development of severe sepsis. Moreover, immune alterations of different cell types may promote distinct kinds of septicemia.

Operative chest wall stabilization in flail chest—outcomes of patients with or without pulmonary contusion

BACKGROUND The aim of operative chest wall stabilization in patients with flail chest and respiratory insufficiency is to reduce ventilator time and avoid ventilator associated complications. The purpose of this retrospective study was to analyze the indications and outcomes of operative chest wall stabilization in defined groups of patients sustaining flail chest with and without pulmonary contusion. METHODS The hospital records of 405 patients with multiple trauma (Injury Severity Score > 17) between 1988 and 1994 were reviewed. Forty-two patients sustained flail chest. Twenty of these underwent operative chest wall stabilization for the following indications: 1) flail chest with indication for thoracotomy due to intrathoracic injury (n = 6); 2) flail chest without pulmonary contusion (n = 9); 3) paradoxical movement of a chest wall segment in the weaning period from the respirator (n = 3); and 4) severe deformity of the chest wall (n = 2). For the purpose of analysis the patients were separated into groups: group 1: operative chest wall stabilization in flail chest without pulmonary contusion (n = 10); group 2: operative chest wall stabilization in flail chest with pulmonary contusion (n = 10); group 3: flail chest without pulmonary contusion and without chest wall stabilization (n = 18); group 4: flail chest with pulmonary contusion and without chest wall stabilization (n = 4). Data were coded for time of operation, duration of ventilatory support, and complications. RESULTS There were no significant differences in age, severity of injury, and extent of injury between groups 1, 2, and 3 (p < 0.42). Group 4 was excluded for statistical analysis because of the small number of patients. Patients in group 1 required a shorter ventilatory support time compared to patients in group 3 (6.5+/-7.0 versus 26.7+/-29.0 days) and group 2 (p < 0.02). In group 2 (ventilator time 30.8+/-33.7 days) early extubation was only possible in patients being operated on for chest wall instability during weaning from the ventilator. One patient in group 1, three patients in group 2 and five patients in group 3 developed pneumonia with further disturbance of gas exchange. All patients in group 1 survived; deaths in group 2 were attributed to massive hemorrhage in two and septic multiorgan failure in one patient. Four patients in group 3 died of head injury, one of acute respiratory distress syndrome, one of severe hemorrhage, and one of multiple organ failure. CONCLUSIONS In patients with flail chest and respiratory insufficiency without pulmonary contusion, operative chest wall stabilization permits early extubation. Patients with pulmonary contusion do not benefit from chest wall stabilization. Secondary operative chest wall stabilization in these patients is indicated when progressive collapse of the chest wall is evident during weaning from the ventilator.

Multiple organ failure still a major cause of morbidity but not mortality in blunt multiple trauma.

BACKGROUND Multiple organ failure (OF/MOF) was found to be the major complication after blunt multiple trauma during the last 25 years and was correlated with a high mortality rate. Recently, several publications reported a decreased ARDS-related mortality, but there is little information about mortality rates from posttraumatic MOF. The purpose of this study was to describe the development of MOF-related death after blunt multiple trauma during the last 25 years. METHODS Blunt multiple trauma patients with an Injury Severity Score (ISS) > 15 points were included in this evaluation. According to the year of trauma, the population was divided into five groups: years 1975-1980 (n = 317), years 1981-1985 (n = 308), years 1986-1990 (n = 246), years 1991-1997 (n = 368), and years 1998-1999 (n = 122). Main outcome measurements were death, cause of death, and length of ICU stay. Patients dying within the first 24 hours after trauma were excluded. All data indicated in the Results section are presented as mean +/- SEM. Continuous variables were compared by ANOVA. Ordinal variables were analyzed by chi2 contingency table analysis and, if significant, subsequently by Fishers exact test (two-tailed test, p < 0.05). RESULTS Mean ISS remained unchanged between 1975-1980 (ISS 29 +/- 1) and 1998-1999 (ISS 31 +/- 1) (p = 0.56). During the observation period, the mean age increased from 33 +/- 1 years (1975-1980) to 40 +/- 2 years (1998-1999) (p = 0.03). The overall incidence of OF/MOF slightly increased from 25.6% (1975-1980) to 33.6% (1998-1999) (p = 0.1). Length of ICU stay was not different between 1975-1980 (LOS: 14 +/- 1 d) and 1998-1999 (LOS: 19 +/- 2 d) (p = 1.0). The overall mortality decreased significantly, from 28.7% (1975-1980) to 13.9% (1998-1999) (p < 0.001). While the mortality due to severe head injuries remained unchanged (1975-1980, 8.2%; 1998-1999, 9.0%) (p = 0.85), mortality due to OF/MOF decreased significantly (p < 0.001), from 18.0% (1975-1980) to 4.1% (1998-1999). The age of patients dying from OF/MOF increased significantly (p = 0.04) during the observation period, from 44 +/- 3 years (1975-1980) to 63 +/- 6 years (1998-1999). CONCLUSION Although MOF incidence remains unchanged, there is a significant fall in MOF-related mortality in patients with severe trauma, and death from single organ failure is virtually absent. Severe brain injury is now the leading cause of death in patients with severe multiple injuries admitted to the ICU.

Immuno-inflammatory tissue reaction to stainless-steel and titanium plates used for internal fixation of long bones.

The immuno-inflammatory responses to stainless-steel (21 implants in 20 patients) and titanium plates (22 implants in 20 patients) used in the treatment of long bone fractures were studied immunohistochemically. All fractures healed without complications. In the soft tissue adjacent to the surface of the implants a dark discolouration of the tissue was visible in 18/21 stainless-steel and 20/22 titanium plates. Tissue specimens of all patients contained positive staining for macrophages (CD68-positive cells). Serial sections showed that the majority of cells were found to express the HLA-DR molecule indicating their activation. Many of the macrophages were surrounded by clusters of T-lymphocytes (CD3-positive cells). 17 out of 21 steel specimens and 15 out of 22 titanium specimens showed the infiltration of moderate amounts of cytotoxic T-lymphocytes (CD8-positive cells). Moderate amounts of B-lymphocytes (CD79alpha positive cells) were evident in four patients with steel and six patients with titanium implants. The results of the present study clearly demonstrate the presence of a marked inflammation and tissue reaction in the soft tissue covering stainless-steel and titanium plates used for internal fixation of fractures of long bones independently from the material used.

Tumor Necrosis Factor Gene Polymorphisms, Leukocyte Function, and Sepsis Susceptibility in Blunt Trauma Patients

ABSTRACT The tumor necrosis factor alpha (TNF-α) −308 G/A and TNF-β NcO1 polymorphisms have been described to be associated with an increased risk for sepsis in critically ill patients. Functional consequences associated with these polymorphisms remain unclear. We compared the genotype distribution of these TNF polymorphisms with susceptibility to severe sepsis and leukocyte function in blunt trauma patients (n = 70; mean injury severity score, 24 points [range, 4 to 57). Severe sepsis was defined according to the American College of Chest Physicians-Society of Critical Care Medicine consensus conference criteria. Genotyping for the NcO1 polymorphism (alleles TNFB1 and TNFB2) was performed by PCR and digestion of the products with NcO1, and that for the TNF-α −308 G/A polymorphism (alleles TNF1 and TNF2) was performed by real-time PCR. Leukocyte function was assessed by measurement of the production of endotoxin-induced cytokines (TNF-α, interleukin-6 [IL-6], and IL-8) in whole blood. TNF-α, IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. For the genotypes of the TNF-α −308 G/A polymorphism, differences in the frequency of development of severe sepsis were not detectable. Patients developing severe sepsis after trauma were significantly more likely to posses a homozygous genotype of the TNF-β NcO1 polymorphism. Compared with heterozygotes, the odds ratio for the TNFB2/B2 genotype for the development of severe posttraumatic sepsis was 11 (P = 0.01), and that for the TNFB1/B1 genotype was 13 (P = 0.014). TNF-α −308:TNF-β NcO1 haplotype analysis showed that the TNFB2:TNF2 haplotype is significantly negatively associated with development of severe sepsis. Patients homozygous for the TNFB1 or TNFB2 allele showed a persistently higher cytokine-producing capacity during at least 4 to 8 days after trauma than the heterozygotes. In patients homozygous for the TNF1 allele, a higher TNF-α- and IL-8-producing capacity was found only at day 1 after trauma. Although the TNF-β NcO1 polymorphism appears to be less likely to be causative for development of severe sepsis after trauma, it is thus far the only genetic marker identified which can be used as a relevant risk estimate for severe sepsis in trauma patients immediately after the injury.

Efficiency of chest computed tomography in critically ill patients with multiple traumas

Objective: The efficiency of secondary thoracic computed tomography (TCT) in critically ill patients with multiple traumas was assessed by comparison of TCT with chest radiograph findings. The subsequent therapeutic consequences based on the additional information of TCT were evaluated. Setting: A six‐bed trauma intensive care unit in a university hospital. Design: Prospective, descriptive study. Patients and Interventions: One hundred one computed tomographic (CT) examinations (mean, 2.6 per patient; range, 1‐10) were performed in 39 patients, fulfilling the following indications for TCT: a) sepsis with suspected pulmonary focus (n = 41); b) deterioration of pulmonary gas exchange (n = 35); c) guiding the duration of intermittent prone positioning (n = 25). The information provided by TCT was compared with corresponding chest radiographs (CXR). Therapeutic consequences drawn after TCT were compared with the additional diagnostic information of TCT. The change of therapy was documented that would not have been undertaken or may have been delayed had TCT evaluation not been used. Results: TCT was significantly superior to CXR in detecting pneumothoraces, pleural effusions, and pulmonary abscesses. Furthermore, a significantly higher accuracy regarding pulmonary densities was found. Subsequent therapeutic interventions ensued from 85 (84.2%) CT scans. After TCT, intermittent prone positioning was initiated in 31 patients, chest tubes were inserted in 16 patients, and intermittent prone positioning was terminated in 13 patients and was continued in 12 patients. Eleven thoracotomies were performed because of the TCT findings. The described therapeutic interventions were based on abnormalities seen on CT scans but were not evident in CXR in 58 patients (57.4%). Significant information that influenced therapeutic concepts was obtained in 66% (n = 23) of patients with pulmonary deterioration of gas exchange, in 61% (n = 25) of patients with sepsis, and in 40% (n = 10) of patients to guide the duration of intermittent prone positioning. Thoracotomy and specific drainage by tube thoracostomy was always dependent on the findings of TCT. Conclusion: Performed under the above displayed defined indications, TCT had an overall efficiency of 57%. It provided an increased sensitivity for intrathoracic lesions and a more comprehensive diagnosis of chest abnormalities.

Local and systemic reactions after lung contusion: an experimental study in the pig.

ABSTRACT The present study was designed to investigate the consequences of isolated unilateral lung contusion on local alveolar and systemic inflammatory responses in an animal model in the pig. Isolated unilateral lung contusion was induced by bolt shot in eight mechanically ventilated animals under general anesthesia (sham: n = 4). Plasma and bronchoalveolar lavage fluid were collected during a period of 8 h following lung contusion. Leukocytes, leukocyte neutral protease inhibitor (LNPI), terminal complement complex (TCC), thrombin-antithrombin-complex (TAT) as well as pulmonary microvascular permeability and surfactant function were determined. Within 30 min, lung contusion was found to cause a significant local and systemic increase in TCC and TAT concentrations and a systemic increase in LNPI concentrations. The latter was accompanied by a sequestration of leukocytes in the contused lung. Complement activation and leukocyte sequestration in the contused lung progressively increased during the investigation period. Although surfactant function decreased in the entire lung 30 min after contusion, TCC, TAT, and leukocyte sequestration was unchanged in the contralateral lung. The first indication of an involvement of the contralateral lung was obtained by an increase in leukocyte sequestration 8 h after lung contusion. Unilateral lung contusion initiates an early systemic activation of humoral and cellular defense systems. Involvement of the contralateral lung appears to be a secondary event caused by a systemic inflammatory reaction.

Kypho-IORT - a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases

BackgroundInstable and painful vertebral metastases in patients with progressive visceral metastases present a common therapeutic dilemma. We developed a novel approach to deliver intraoperative radiotherapy (IORT) during kyphoplasty and report the first treated case.Methods/Results60 year old patient with metastasizing breast cancer under chemotherapy presented with a newly diagnosed painful metastasis in the 12th thoracic vertebra. Under general anaesthesia, a bipedicular approach into the vertebra was chosen with insertion of specially designed metallic sleeves to guide the electron drift tube of the miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany). This was inserted with a novel sheet designed for this approach protecting the drift tube. A radiation dose of 8 Gy in 5 mm distance (50 kV X-rays) was delivered. The kyphoplasty balloons (KyphX, Kyphon Inc, Sunnyvale) were inflated after IORT and polymethylmethacrylate cement was injected. The whole procedure lasted less than 90 minutes.ConclusionIn conclusion, this novel, minimally invasive procedure can be performed in standard operating rooms and may become a valuable option for patients with vertebral metastases providing immediate stability and local control. A phase I/II study is under way to establish the optimal dose prescription.

Development of a Novel Method for Intraoperative Radiotherapy During Kyphoplasty for Spinal Metastases (Kypho-IORT)

PURPOSE Approximately 30% of patients with cancer receive bone metastases, of which 50% are in the spine. Approximately 20% present with unstable lesions requiring surgical intervention, followed by fractionated radiotherapy over 2-4 weeks to prevent early regrowth. Because of the limited survival time of patients with metastatic cancer, novel treatment concepts shortening the overall treatment time or hospitalization are desirable. In this study, we established a novel approach for intraoperative radiotherapy during kyphoplasty (Kypho-IORT), a method that combines stabilizing surgery and radiotherapy within one visit, after estimating the percentage of eligible patients for this treatment. METHODS AND MATERIALS To estimate the percentage of eligible patients, 53 planning CTs (897 vertebrae) of patients with spinal metastases were evaluated. The number of infiltrated vertebrae were counted and classified in groups eligible or not eligible for Kypho-IORT. The Kypho-IORT was performed in a donated body during a standard balloon kyphoplasty using the INTRABEAM system and specially designed applicators. A single dose of 10 Gy (in 10 mm) was delivered over 4 min to the vertebra. This was verified using two ionization chambers and a Monte Carlo simulation. RESULTS The estimation of eligible patients resulted in 34% of the evaluated patients, and thus 34% of patients with instable spinal metastases are suitable for Kypho-IORT. This study shows also that, using the approach presented here, it is possible to perform an IORT during kyphoplasty with an additional 15 min operation time. The measurement in the donated body resulted in a maximum dose of 3.8 Gy in the spinal cord. However, the Monte Carlo depth dose simulation in bone tissue showed 68% less dose to the prescription depth. CONCLUSION We present for the first time a system using an x-ray source that can be used for single-dose IORT during kyphoplasty. The described Kypho-IORT can decrease the overall treatment time for up to 34% of patients who usually receive radiotherapy for spinal metastases.