Accelerated tryptophan degradation predicts poor survival in trauma and sepsis patients.

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Immunodeficiency may develop in such patients as one consequence of an activated chronic pro-inflammatory response. According to recent data, degradation of L-tryptophan (TRP) via the kynurenine (KYN) pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could represent an important contributor to the deficient responsiveness of immunocompetent cells. Compared to healthy controls, patients post trauma or with sepsis had increasing KYN concentrations and KYN to TRP ratios (KYN/TRP) whereas TRP concentrations decreased. Likewise, concentrations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and of immune activation marker neopterin increased in patients (all p < 0.001). Furthermore in patients KYN/TRP, KYN and neopterin concentrations were further increasing (all p < 0.001), whereas the changes of TRP, TNF-α and IL-6 concentrations were not significant. Compared to the survivors, the non-survivors had a higher concentration of KYN, neopterin, TNF-α and IL-6 as well as a higher KYN/TRP ratio. KYN/TRP correlated with neopterin (p < 0.001) and also with TNF-α (p < 0.01) and IL-6 concentrations (p < 0.05) and inversely with the in vitro response of stimulated monocytes. We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients.

Circulating NT-proCNP predicts sepsis in multiple-traumatized patients without traumatic brain injury.

OBJECTIVES: C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is produced in vascular endothelium. We assessed the accuracy of natriuretic (NT)-proCNP, the N-terminal fragment of the C-type natriuretic peptide precursor, in predicting development of sepsis in multiple-traumatized patients with/without traumatic brain injury verified by computed tomography. DESIGN: Retrospective clinical study. SETTING: Level II trauma center. PATIENTS: Three patient groups were stratified according to computed tomography results: isolated traumatic brain injury (n = 20), multiple-traumatized with traumatic brain injury (n = 26) and multiple-traumatized without traumatic brain injury (n = 26). During 13 days after multiple trauma, 37 (51%) patients developed sepsis. MEASUREMENTS AND MAIN RESULTS: Circulating plasma NT-proCNP levels were measured daily (days 0-13) in all patients. Without any retrospective stratification of trauma patients, plasma NT-proNCP levels did not differ in septic (n = 37) and nonseptic (n = 35) patients (p = .505). Between days 2 and 6 posttrauma, there was a significant (p = .002) increase of circulating NT-proCNP in multiple-traumatized patients without traumatic brain injury who developed sepsis (n = 19) compared with nonseptic multiple-traumatized patients without traumatic brain injury. Conversely, in septic patients either with traumatic brain injury alone or with multiple trauma and traumatic brain injury, the NT-proCNP showed a trend toward lower levels than in nonseptic patients. Prediction of sepsis (receiver-operating characteristic test) from days 2 to 6 after multiple trauma by NT-proCNP in patients without traumatic brain injury was accurate with an area under the curve of 0.84 +/- 0.03. The optimal cutoff value of 2.3 pmol/L produced sensitivity of 84% to 96% and specificity of 61% to 91% from day 2 to 6 after trauma. CONCLUSIONS: Our data showed that the levels of circulating NT-proCNP between multiple-traumatized patients without traumatic brain injury who do and do not develop sepsis are distinctly different. Plasma NT-proCNP concentration can potentially serve as an accurate predictor of sepsis in this cohort of patients.

Urine toxicology screening in Austrian trauma patients: a prospective study.

INTRODUCTION: The question as to whether the patient consumed drugs prior to the trauma and which drugs were consumed, is of prime importance for the anesthesia required during surgery. However, many patients are unwilling or unable (including those with multiple trauma or impaired consciousness, or unconscious patients) to answer this question. The purpose of our prospective multicenter study was to collect data about drug consumption in Austria to determine whether drugs are identifiable in the urine of recently injured individuals and to establish the types of drugs consumed. MATERIALS AND METHODS: This prospective study included severely and moderately injured patients admitted to the Lorenz Boehler Trauma Hospital (Vienna, Austria), the Trauma Hospital Linz (Linz, Austria) and the Department of Trauma Surgery of the General Hospital Horn (Horn, Austria) during an 18-month period (October 2003-March 2005). All patients were suffering from injuries urgently requiring surgery. Urine samples were gained from all patients immediately after admission. Urinary samples were tested by Immuno-Assay (Triage 8 Immuno-Assay, Biosite, San Diego, USA). Urine samples were screened simultaneously for opiates, methadone, cocaine, barbiturates, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants. RESULTS: Our prospective study included a total of 664 patients (320 from Vienna, 193 from the city of Linz, and 151 from Horn). Six hundred and forty-two patients were moderately injured (ISS < 16), suffering mostly from injuries to the extremities (504 patients) and 22 patients were severely injured (ISS > 16). Of the 664 patients, 178 (26.8%) tested positive for one or more drugs. The drugs most commonly detected were benzodiazepines (111 patients, 16.7%), cannabinoides (39 patients, 6%), tricyclic antidepressants (28, 4.2%) and opiates (26, 3.9%). CONCLUSION: Drug use is widespread in patients presenting to urban trauma centers in Austria. Physicians should maintain a high index of suspicion that their patients may be intoxicated and should perform drug testing routinely.

Cholecystitis after trauma.

BACKGROUND: The goal of this project was to investigate incidence, risk factors, histologic findings, and mortality rate of posttraumatic cholecystitis requiring surgical treatment. METHODS: Retrospective analysis of all patients admitted to the intensive care unit of an urban trauma center between April 1998 and January 2005. Data from the hospital and intensive care documentation systems databases and patients' charts were reviewed. All patients with cholecystitis treated by cholecystectomy were selected for further study. Potential risk factors, diagnostic, and histologic findings were analyzed. RESULTS: Cholecystitis was a fairly frequent finding in critically ill trauma patients (67 of 2,625 patients, 2.6%). Almost 10% of the patients with severe multiple injuries developed cholecystitis. Histologic findings showed a wide variation; three main diagnoses were established: acute acalculous cholecystitis (n = 28), chronic acalculous cholecystitis (n = 25), and cholecystitis with cholecystolithiasis (n = 13). Patients with acute acalculous cholecystitis and chronic acalculous cholecystitis were significantly younger and had significantly higher injury severity scores than patients with either cholecystitis with cholecystolithiasis or without cholecystitis. Noninvasive diagnostic tools such as ultrasonographic signs and laboratory data did not correlate with histologic diagnosis. Well-timed cholecystectomy within 24 hours after clinical suspicion lead to a 4.4% mortality rate in this group of patients. CONCLUSION: Cholecystitis after trauma is not a uniform disease. Although trauma severity seems to play an important role in the development or exacerbation of acalculous cholecystitis or both, cholecystolithiasis may play a significant role in patients with moderate to minor trauma. Intensivists should be aware of this complication in critically ill trauma patients because it seems to occur more frequently than previously assumed. Diagnosis can only be made if clinical signs, laboratory data, and ultrasonographic findings are taken into consideration. If posttraumatic cholecystitis is treated in an early stage by cholecystectomy, mortality rate remains low.

Tryptophan degradation in multiple trauma patients: survivors compared with non-survivors.

Immune dysfunction in trauma patients is associated with immune system activation and inflammation. The cytokine-inducible enzyme IDO (indoleamine 2,3-dioxygenase) initiates the degradation of the essential aromatic amino acid tryptophan via the kynurenine pathway and could contribute to deficient immune responsiveness. Activated IDO is indicated by an increased kyn/trp (kynurenine/tryptophan) ratio. The aim of the present study was to investigate whether tryptophan degradation is associated with outcome in patients post-trauma. Tryptophan and kynurenine concentrations were measured by HPLC in serum specimens of 15 patients post-trauma during 12-14 days of follow-up. Up to five samples within this observation period from each patient were included in this analysis, and a total a 69 samples were available. For further comparisons, concentrations of the immune activation marker neopterin were measured. Compared with healthy controls, the average kyn/trp ratio and kynurenine concentrations were increased in patients, whereas tryptophan concentrations were decreased. During follow-up, increased kyn/trp ratio and kynurenine concentrations (all P<0.001) were observed, whereas the changes in tryptophan concentrations were not significant. Non-survivors had higher kyn/trp ratios and kynurenine concentrations compared with survivors. The kyn/trp ratio correlated with neopterin concentrations (r(s)=0.590, P<0.001). In conclusion, these results imply that increased tryptophan degradation in patients is due to activated IDO, which most probably is a consequence of a host defence response. These findings support a possible role for IDO in the development of immunodeficiency and death in patients.

Assessment of bone union/nonunion in an experimental model using microcomputed technology.

BACKGROUND: High-resolution microcomputed tomography (microCT) is one of the most recent technical developments to visualize and quantify primarily cancellous bone. Regarding bone formation, microCT is becoming increasingly important, although its reliability has not yet been evaluated. Our study had two goals: to develop a reproducible nonunion model and to determine the efficacy of microCT for the assessment of bone healing in this model. METHODS: The designed fracture model in the rat simulates secondary fracture healing. After plate fixation to the femur, diaphysis transverse middiaphyseal osteotomy was performed with a reciprocating saw, resulting in a 0.38-mm gap with a defect of bone and periosteum corresponding to the thickness of the blade. Proximally and distally to this gap, the periosteum was preserved. Thus, three separate zones were defined: proximal femur diaphysis with periosteum, gap, and distal femur diaphysis with periosteum. In the nonunion group (NM group), a model of impaired bone healing (nonunion), silicone foil was wrapped around the femur diaphysis to block any influence from surrounding tissue. Coverage of the bone repair site by thigh muscles was designed for a model of bone union (M group). Four weeks postoperatively, callus formation was determined by conventional anterior-posterior and lateral plain radiographs. Ten weeks later, a second x-ray series was done as the clinical standard evaluation method. Afterward, specimens were harvested for microCT examination (two-dimensional and three-dimensional [3D]). Biomechanical testing was carried out to determine fracture healing. RESULTS: Our model is highly reproducible and results in bone nonunion in five out of six cases (83.3%). In determining fracture site, plain radiographs the least reliable method in comparison to the biomechanical testing which is the most accurate reference method. In contrast, microCT (the 3D reconstruction) showed significant correlation (r = 1) to the results assessed by biomechanical testing, whereas microCT was correct in 100%. We found bone healing in five out of six animals in the M group verified by microCT (in accordance to biomechanical data). In the M group, significantly enhanced bone formation (50%) (p = 0.008) was observed within the osteotomy site (i.e. within the gap), but there was no difference in periosteal bone formation between the groups proximally and distally to the gap. Interestingly, we did not find statistically significant differences in mineralization. CONCLUSION: We conclude that microCT with 3D reconstruction is the optimal method diagnostic tool in fracture healing, especially in nonunion. Furthermore, direct coverage of the fracture site by muscle flaps results in a mineralized enhanced bone formation within the osteotomy site (i.e. within the gap). Skeletal muscle coverage hypothetically might have osteogenic augmentation potential, thus being able to prevent pseudoarthrosis.

Lipopolysaccharide-induced tumor necrosis factor alpha production and not monocyte human leukocyte antigen-DR expression is correlated with survival in septic trauma patients.

Multiple trauma patients have an impaired immune system and thus frequently develop life-threatening septic complications. Because there is an ongoing debate on which are the most predictive immunologic parameters of clinical outcome, we prospectively studied 19 multiple trauma patients with sepsis (mean age, 38.7 +/- 15.8 years; mean Injury Severity Score, 40.6 +/- 11.6) over a period of 14 days. The following parameters were measured daily after admission to the intensive care unit: ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production, monocyte human leukocyte antigen (HLA)-DR expression, constitutive interleukin (IL) 6 secretion, white blood cell count, and C-reactive protein. In addition, procalcitonin, neopterin, LPS-binding protein, and constitutive TNF-alpha secretion were measured every third day. Immediately after trauma, all patients had significantly lower levels of HLA-DR and ex vivo LPS-stimulated TNF-alpha secretion than healthy controls (n = 7; P < 0.001). On the day after clinical diagnosis of sepsis, before any other parameter differed between survivors (n = 13) and nonsurvivors (n = 6), ex vivo LPS-induced TNF-alpha secretion was significantly lower (P < 0.05) in nonsurvivors than in survivors. We conclude that ex vivo LPS-induced TNF-alpha production is an earlier predictor of clinical outcome in multiple trauma patients with sepsis than monocyte HLA-DR expression, constitutive IL-6 secretion, or any other parameter assessed.

Anti-L-selectin antibody therapy does not worsen the postseptic course in a baboon model.

INTRODUCTION: Anti-adhesion molecule therapy prevents leukocytes from extravasating. During exaggerated inflammation, this effect is wanted; however, during infection, blocking diapedesis may be detrimental. In this study, therefore, the potential risks of anti-L-selectin antibody therapy were evaluated in a primate model of sepsis. METHODS: Sixteen baboons were anesthetized and randomized into two groups. The experimental group received 2 mg/kg of the anti-L-selectin antibody HuDREG-55 and the control group received Ringer's solution prior to the onset of a 2 h infusion of Escherichia coli (1-2 x 10(9) colony forming units (CFU)/kg body weight). Serial blood samples were drawn over a 72 h period for the measurement of tumour necrosis factor-alpha, IL-6 and polymorphonuclear elastase. In addition, blood gas analysis, hematology and routine clinical chemistry were determined to monitor cardiovascular status, tissue perfusion and organ function. RESULTS: The three-day mortality rate and the mean survival time after E. coli-induced sepsis were similar in the two groups. The bacterial blood CFU levels were significantly higher in the placebo group than in the anti-L-selectin group. Other parameters measured throughout the 72 h experimental period, including the cardiovascular, immunologic, and hematologic responses as well as indicators of organ function and tissue perfusion, were similar in the two groups, with the exception of serum creatinine and mean arterial pressure at 32 h after E. coli challenge. CONCLUSION: Anti-L-selectin therapy did not adversely affect survival, promote organ dysfunction or result in major side effects in the baboon sepsis model. Additionally, as anti-L-selectin therapy improved the bacterial clearance rate, it appears that this therapy is not detrimental during sepsis. This is in contrast to previous studies using the baboon model, in which antibody therapy used to block CD18 increased mortality.

Nonspecific increase of systemic neuron-specific enolase after trauma: clinical and experimental findings.

The aim of this clinical and experimental study was to determine whether systemic neuron-specific enolase (NSE) is a useful early marker of traumatic brain injury (TBI) and whether NSE is affected by ischemia/reperfusion damage of abdominal organs. Our study included patients with and without TBI (verified by computerized tomography) admitted within 6 h after trauma and male Sprague-Dawley rats with ischemia and reperfusion of the abdominal organs liver, gut, or kidney. Thirty-eight study patients included 13 with isolated TBI and 18 patients with multiple trauma and TBI. Seven patients had multiple trauma but no TBI. Fifteen rats were anaesthetized and subjected to isolated ischemia of the liver, gut, or kidney (n = 5 each) for 1 h, followed by reperfusion for 3 h. In patients, NSE increased over 2-fold versus the upper normal limit (10 microg/L) within 6 h after trauma, regardless of whether TBI had occurred or not. In rats, NSE increased over 3-fold versus laboratory controls during ischemia of the liver and kidney (both P < 0.0005), but not of the gut. NSE increased over 2-fold after onset of reperfusion of the liver and kidney (both P < 0.05), but not of the gut and increased over 3-fold after 3 h of reperfusion of the liver, gut (both P < 0.005), and kidney (P < 0.0005). Our data show that systemic NSE increases to similar degrees with and without TBI. Therefore, NSE is not a useful early marker of TBI in multiple trauma.

Glial fibrillary acidic protein in serum after traumatic brain injury and multiple trauma.

BACKGROUND: This study aimed to determine whether glial fibrillary acidic protein (GFAP) is released after traumatic brain injury (TBI), whether GFAP is related to brain injury severity and outcome after TBI, and whether GFAP is released after multiple trauma without TBI. METHODS: This prospective study enrolled 114 patients who had TBI with or without multiple trauma (n = 101) or multiple trauma without TBI (n = 13), as verified by computerized tomography. Daily GFAP measurement began at admission (<12 hours after trauma) and continued for the duration of intensive care (1-22 days). Documentation included categorization of computerized tomography according to Marshall classification, based on daily highest intracranial pressure (ICP), lowest cerebral perfusion pressure (CPP), lowest mean arterial pressure (MAP), and 3-month Glasgow Outcome Score (GOS). RESULTS: The GFAP concentration was lower for diffuse injury 2 than for diffuse injury 4 (p < 0.0005) or nonevacuated mass lesions larger than than 25 mL (p < 0.005), lower for a ICP less than 25 mm Hg than for a ICP of 25 mm Hg or more, lower for a CPP of 60 mm Hg or more than for a CPP of 60 mm Hg or less, lower for a MAP of 60 mm Hg or more than for a MAP less than 60 mm Hg (all p < 0.0005), and lower for a GOS of 1 or 2 than for a GOS of 3, 4 (p < 0.05), or 5 (p < 0.0005). After TBI, GFAP was higher in nonsurvivors (n = 39) than in survivors (n = 62) (p < 0.005). After multiple trauma without TBI, GFAP remained normal. CONCLUSIONS: The findings showed that GFAP is released after TBI, that GFAP is related to brain injury severity and outcome after TBI, and that GFAP is not released after multiple trauma without brain injury.

Bilateral lower leg replantation versus prosthetic replacement: long-term outcome of amputation after an occupational railroad accident.

BACKGROUND: This retrospective study investigated three very similar cases of bilateral lower leg amputation. The aim was to determine which of two therapeutical procedures is associated with better long-term outcome: replantation or primary treatment of the stumps and subsequent prosthetic replacement. METHODS: Evaluation included clinical examination, gait analysis, and a workup of the psychosocial background. Health problems were documented using the Nottingham Health Profile. Follow-up assessments were performed 6, 7, and 18 years after the trauma. RESULTS: One patient underwent successful bilateral lower leg replantation and continued to work for the same employer. Two patients underwent prosthetic replacement. One became a social outcast confined to a wheelchair. The other patient had a good psychosocial background, similar to that of the patient who underwent replantation. He showed a better gait analysis on even ground than the replantation patient, but the findings were vice versa for uneven ground. CONCLUSIONS: The decision between replantation and prosthetic replacement after bilateral lower leg amputation is case related and cannot be generalized. Patients who have undergone these procedures require long-term psychological and physiotherapeutic care to achieve a good long-term surgical outcome.

Improving risk adjustment in critically ill trauma patients: the TRISS-SAPS Score.

OBJECTIVES: To test (a) the prognostic performance of TRISS and SAPS II scoring systems in a large sample of trauma patients admitted to Austrian ICUs, and (b) the hypothesis that the prognostic performance of TRISS could be improved by adding SAPS II. METHODS: Prospective multicenter cohort study comprising 5,538 trauma patients out of 35,637 patients admitted to 31 ICUs in Austria over a 4-year period. RESULTS: Separately, TRISS and SAPS II showed lack of calibration in the cohort of trauma patients. The database was then split into two equal samples, development and validation. Using the development sample, a new scoring system was developed, with vital status at hospital discharge as the dependent variable and TRISS and SAPS II as independent variables. The prognostic performance of the new TRISS-SAPS system was then assessed in the validation cohort: Both, discrimination (as shown by area under the ROC curve), and calibration (using Hosmer-Lemeshow goodness-of-fit statistics) was excellent. CONCLUSIONS: We improved risk adjustment in critically ill trauma patients by combining TRISS and SAPS II. This new scoring system might aid in evaluating and comparing specialized trauma ICUs.

Elevated serum levels of epithelial cell apoptosis-specific cytokeratin 18 neoepitope m30 in critically ill patients.

Apoptosis of the epithelium is deemed to play a pivotal role in the pathogenesis of sepsis. A neoepitope in cytokeratin 18 (CK18), termed M30 neoantigen, becomes available at an early caspase cleavage event during apoptosis of epithelium-derived cells and is not detectable in vital or necrotic epithelial cells. A monoclonal antibody, M30, specifically recognizes a fragment of CK18 cleaved at Asp396 (M30 neoantigen). We used an enzyme-linked immunosorbent assay (ELISA) to measure M30 antigen levels in the sera of 15 septic patients. Healthy humans and critical ill patients suffering from severe trauma served as controls. Mann-Whitney U test was used to calculate significance, and a P value of <0.01 was considered to be statistically significant. Serum levels of the CK18 neoepitope M30 were significantly increased in septic patients (236.88 +/- 47.4 U/L) versus trauma (97.2 +/- 17.1 U/L) and healthy controls (66.9 +/- 9.2 U/L) (P < 0.01 and P < 0.008, respectively). The increased serum level of the CK18 neoepitope in septic patients indicates a heightened apoptotic turnover in epithelial cells as compared with trauma patients and healthy controls. Interestingly, nonsurviving trauma patients exhibited a significant increase in the M30 neoantigen as compared with survivors and healthy controls (P < 0.003 and P < 0.002, respectively). The detection of CK18 neoepitope M30 in the serum might be a useful marker in tracing apoptotic epithelium in septic patients.

Bystander trauma care--effect of the level of training.

BACKGROUND: The bystander is often the first person present at the scene of an accident. Our aim was to determine how often and how well bystanders perform trauma care and whether trauma care is affected by the bystander's level of training, relationship to the patient and numbers of bystanders present. PATIENTS AND METHODS: In a prospective 1-year study, the emergency medical service in two European cities collected data on trauma calls. Questionnaires were used to document the bystanders' level of training (none, basic, advanced, professional), the bystander's relationship to the patient, and the number of bystanders present, and to assess whether five separate measures of trauma care (ensuring scene safety, extrication of the patient, positioning, control of haemorrhage, prevention of hypothermia) were performed correctly, incorrectly, or not at all. RESULTS: Two thousand nine hundred and thirty-two trauma calls were documented and bystanders were present in 1720 (58.7%). All measures except ensuring scene safety and prevention of hypothermia were affected by the bystander's level of training. Correct extrication, positioning, and control of haemorrhage increased with the level of bystander training while the number of patients who were not attended decreased (P < 0.05, P < 0.005, P < 0.005), respectively. The relationship to the patient did not affect whether, or how well, any measure was performed. The number of bystanders present only affected prevention of hypothermia, which was performed most often when only one bystander was present. CONCLUSION: Improved, more widespread training could increase the frequency and quality of bystander trauma care further.

Neuron-specific-enolase is increased in plasma after hemorrhagic shock and after bilateral femur fracture without traumatic brain injury in the rat.

Neuron-specific enolase (NSE) is an acknowledged marker of traumatic brain injury. Several markers originally considered reliable in the setting of traumatic brain injury have been challenged after having been studied more extensively. The aim of our experimental study was to determine whether NSE is a reliable marker of traumatic brain injury early after trauma. Hemorrhagic shock was achieved by bleeding anesthetized rats to a mean arterial pressure (MAP) of 30-35 mmHg through a femoral catheter until incipient decompensation. MAP was maintained at 30-35 mmHg until 40% of shed blood had been administered as Ringer's solution and was then increased and maintained at 40-45 mmHg for 40 min by further administration of Ringer's solution, mimicking the phase of inadequate preclinical resuscitation. Blood samples were drawn at the end of the 40-min period of inadequate resuscitation. Femur fracture was achieved in anesthetized rats by bilateral application of forceps. Blood samples were drawn 30 and 60 min after fracture. Hemorrhagic shock caused NSE increase versus laboratory controls at the end of inadequate resuscitation (P < 0.01). Bilateral femur fracture caused NSE increase versus laboratory controls 30 min after fracture, which was significant 60 min after fracture (P < 0.01). During femur fracture, MAP remained at a level that is not associated with shock in rats. Our findings show for the first time that NSE increases after hemorrhagic shock as well as after femur fracture without hemorrhagic shock in rats. From a clinical point of view, these findings indicate that NSE cannot be considered a reliable marker of traumatic brain injury early after trauma in cases associated with hemorrhagic shock and/or femur fracture.