Functional immune monitoring in severely injured patients-A pilot study.

After severe trauma, the resulting excessive inflammatory response is countered by compensatory anti-inflammatory mechanisms. The systemic inflammatory response to trauma enhanced by inappropriately timed surgical second hits may be detrimental for the patient. On the other hand, overwhelming anti-inflammatory mechanisms may put patients at increased risk from secondary local and systemic infections. The ensuing sepsis and organ dysfunction due to immune dysregulation remain the leading causes of death after injury. To date, there are no clinically applicable techniques to monitor the pro-/anti-inflammatory immune status of the patients and the remaining ability to react to microbial stimuli. Therefore, in the present study, we used a highly standardized and easy-to-use system to draw peripheral whole blood from polytraumatized patients (ISS ≥ 32, n = 7) and to challenge it with bacterial lipopolysaccharide. Secreted cytokines were compared with those in samples from healthy volunteers. We observed a significant decrease in the release of monocyte-derived mediators. Surprisingly, we detected stable or even increased concentrations of cytokines related to T cell maturation and function. For clinical practicability, we reduced the incubation time before supernatants were collected. Even after an abbreviated stimulation period, a stable release of almost all analysed parameters in patient blood could be detected. In conclusion, the data are indicative of a clinically well-applicable approach to monitor the immune status in severely injured patients in a short time. This may be used to optimize the timing of necessary surgical interventions to avoid a boost of proinflammation and reduce risk of secondary infections.

Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects.

During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pHi), we propose a direct mechanistic link between complement activation and neutrophil pHi In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

Early Detection of Junctional Adhesion Molecule-1 (JAM-1) in the Circulation after Experimental and Clinical Polytrauma.

Severe tissue trauma-induced systemic inflammation is often accompanied by evident or occult blood-organ barrier dysfunctions, frequently leading to multiple organ dysfunction. However, it is unknown whether specific barrier molecules are shed into the circulation early after trauma as potential indicators of an initial barrier dysfunction. The release of the barrier molecule junctional adhesion molecule-1 (JAM-1) was investigated in plasma of C57BL/6 mice 2 h after experimental mono- and polytrauma as well as in polytrauma patients (ISS ≥ 18) during a 10-day period. Correlation analyses were performed to indicate a linkage between JAM-1 plasma concentrations and organ failure. JAM-1 was systemically detected after experimental trauma in mice with blunt chest trauma as a driving force. Accordingly, JAM-1 was reduced in lung tissue after pulmonary contusion and JAM-1 plasma levels significantly correlated with increased protein levels in the bronchoalveolar lavage as a sign for alveolocapillary barrier dysfunction. Furthermore, JAM-1 was markedly released into the plasma of polytrauma patients as early as 4 h after the trauma insult and significantly correlated with severity of disease and organ dysfunction (APACHE II and SOFA score). The data support an early injury- and time-dependent appearance of the barrier molecule JAM-1 in the circulation indicative of a commencing trauma-induced barrier dysfunction.

Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.

The C5 convertase is not required for activation of the terminal complement pathway in murine experimental cerebral malaria.

Cerebral malaria (CM) is the most severe manifestation of clinical malaria syndromes and has a high fatality rate especially in the developing world. Recent studies demonstrated that C5(-/-) mice are resistant to experimental CM (ECM) and that protection was due to the inability to form the membrane attack complex. Unexpectedly, we observed that C4(-/-) and factor B(-/-) mice were fully susceptible to disease, indicating that activation of the classical or alternative pathways is not required for ECM. C3(-/-) mice were also susceptible to ECM, indicating that the canonical C5 convertases are not required for ECM development and progression. Abrogation of ECM by treatment with anti-C9 antibody and detection of C5a in serum of C3(-/-) mice confirmed that C5 activation occurs in ECM independent of C5 convertases. Our data indicate that activation of C5 in ECM likely occurs via coagulation enzymes of the extrinsic protease pathway.

A new experimental polytrauma model in rats: molecular characterization of the early inflammatory response.

BACKGROUND: The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. METHODS: Male Wistar rats (250 g, 6-10/group) were anesthetized and exposed to chest trauma (ChT), closed head injury (CHI), or Tib/Fib fracture including a soft tissue trauma (Fx + STT) or to the following combination of injuries: (1) ChT; (2) ChT + Fx + STT; (3) ChT + CHI; (4) CHI; (5) polytrauma (PT = ChT + CHI + Fx + STT). Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of "key" inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL) fluid samples. RESULTS: Polytraumatized (PT) rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. CONCLUSION: This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma.

Introducing standardized "readbacks" to improve patient safety in surgery: a prospective survey in 92 providers at a public safety-net hospital.

BACKGROUND: Communication breakdowns represent the main root cause of preventable complications which lead to harm to surgical patients. Standardized readbacks have been successfully implemented as a main pillar of professional aviation safety for decades, to ensure a safe closed-loop communication between air traffic control and individual pilots. The present study was designed to determine the perception of staff in perioperative services regarding the role of standardized readbacks for improving patient safety in surgery at a single public safety-net hospital and level 1 trauma center. METHODS: A 12-item questionnaire was sent to 180 providers in perioperative services at Denver Health Medical Center. The survey was designed to determine the individual participants' perception of (1) appropriateness of current readback processes; (2) willingness to attend a future training module on this topic; (3) specific scenarios in which readbacks may be effective; and (4) perceived major barriers to the implementation of standardized readbacks. Survey results were compared between departments (surgery versus anesthesia) and between specific staff roles (attending or midlevel provider, resident physician, nursing staff), using non-parametric tests. RESULTS: The response rate to the survey was 50.1% (n=92). Respondents overwhelmingly recognized the role of readbacks in reducing communication errors and improving patient safety. There was a strong agreement among respondents to support participation in a readbacks training program. There was no difference in the responses between the surgery and anesthesia departments.There was a statistically significant difference in the healthcare providers willingness to attend a short training module on readbacks (p<0.001). Resident physicians were less likely to endorse the importance of readbacks in reducing communication errors (p=0.01) and less willing to attend a short training module on readbacks (p<0.001), as compared to staff providers and nursing staff.The main challenge for respondents, which emanated from their responses, appeared to relate to determining the ideal scenarios in which readbacks may be most appropriately used. Overall, respondents strongly felt that readbacks had an important role in patient handoffs, patient orders regarding critical results, counting and verifying surgical instruments, and delegating multiple perioperative tasks. CONCLUSION: The majority of all respondents appear to perceive standardized readbacks as an effective tool for reducing and/or preventing adverse events in the care of surgical patients, derived from a breakdown in communication among perioperative caregivers. Further work needs to be done to define the exact clinical scenarios in which readbacks may be most efficiently implemented, including the definition of a uniform set of scripted quotes and phrases, which should likely be standardized in concert with the aviation safety model.

Octenidine in combination with polymethylmethacrylate: a new option for preventing infection?

BACKGROUND: Orthopedic implant infections represent a serious complication for both patient and surgeon. In order to minimize this risk, it has become standard practice in surgery and orthopedics to add antimicrobial substances to the polymethylmethacrylate (PMMA) bone cement. The aim of this study is to find new options for preventing infection by using alternative adjuvants in combination with PMMA. We hypothesized, that Octenidine, after being combined with PMMA, can be released in vitro and an antimicrobial efficacy of discharged Octenidine can be shown. METHODS: The release of Octenidine from PMMA was assessed in high pressure liquid chromatography of the supernatant. In order to assess the efficacy of Octenidine on Staphylococcus aureus and Pseudomonas aeruginosa in vitro, a nutrient solution for these bacteria was incubated with a defined number of these bacteria (10(6) colony forming units) and cement pellets containing the antiseptic Octenidine for 24 h. After the incubation the number of bacteria in the solution was determined by counting the colony forming units on blood agar plates. RESULTS: Octenidine was shown to be released in a concentration-dependent manner from PMMA in the elution experiment. The experimental procedure using S. aureus demonstrated a bactericidal effect for bone cement containing Octenidine. For P. aeruginosa, bone cement containing 5-8% Octenidine was associated with tenfold reduction in bacterial count. CONCLUSION: These results suggest that Octenidine is released after combining it with PMMA and reaches working concentrations in vitro. These findings suggest a new and effective alternative for prevention of infection in cemented implants. Further investigations on the biocompatibility of this combination is needed.

Molecular mechanisms of inflammation and tissue injury after major trauma--is complement the "bad guy"?

Trauma represents the leading cause of death among young people in industrialized countries. Recent clinical and experimental studies have brought increasing evidence for activation of the innate immune system in contributing to the pathogenesis of trauma-induced sequelae and adverse outcome. As the "first line of defense", the complement system represents a potent effector arm of innate immunity, and has been implicated in mediating the early posttraumatic inflammatory response. Despite its generic beneficial functions, including pathogen elimination and immediate response to danger signals, complement activation may exert detrimental effects after trauma, in terms of mounting an "innocent bystander" attack on host tissue. Posttraumatic ischemia/reperfusion injuries represent the classic entity of complement-mediated tissue damage, adding to the "antigenic load" by exacerbation of local and systemic inflammation and release of toxic mediators. These pathophysiological sequelae have been shown to sustain the systemic inflammatory response syndrome after major trauma, and can ultimately contribute to remote organ injury and death. Numerous experimental models have been designed in recent years with the aim of mimicking the inflammatory reaction after trauma and to allow the testing of new pharmacological approaches, including the emergent concept of site-targeted complement inhibition. The present review provides an overview on the current understanding of the cellular and molecular mechanisms of complement activation after major trauma, with an emphasis of emerging therapeutic concepts which may provide the rationale for a "bench-to-bedside" approach in the design of future pharmacological strategies.

Eosinophilic granuloma of the spine involving C1 and pulmonary infiltration in young children - Presentation of two cases with a follow-up over 10 years including review of the literature.

OBJECTIVES: The incidence of spinal eosinophilic granuloma in children is low. METHODS: Clinical case presentation of two children (♀ 18 months old, ♂ 16 months old) complaining of acute torticollis. Follow-up period was 11 years in the female patient and 13 years in the male patient. RESULTS: The diagnostics certified a spinal eosinophilic granuloma: the girl had a multilevel spinal disease including the atlas, the boy a thoracic and pulmonary manifestation. Both were treated with chemotherapy with good clinical results. CONCLUSIONS: Overall, the above described is a very rare clinical entity. However, persisting torticollis in children should be clearly diagnosed.

Role of Hemorrhagic Shock in Experimental Polytrauma.

Hemorrhagic shock (HS) after tissue trauma increases the complication and mortality rate of polytrauma (PT) patients. Although several murine trauma models have been introduced, there is a lack of knowledge about the exact impact of an additional HS. We hypothesized that HS significantly contributes to organ injury, which can be reliably monitored by detection of specific organ damage markers. Therefore we established a novel clinically relevant PT plus HS model in C57BL/6 mice which were randomly assigned to control, HS, PT, or PT+HS procedure (n = 8 per group). For induction of PT, anesthetized animals received a blunt chest trauma, head injury, femur fracture, and soft tissue injury. HS was induced by pressure-controlled blood drawing (mean arterial blood pressure of 30 mmHg for 60 min) and mice then resuscitated with ionosterile (4 × volume drawn), monitored, and killed for blood and organ harvesting 4 h after injury. After HS and resuscitation, PT+HS mice required earlier and overall more catecholamine support than HS animals to keep their mean arterial blood pressure. HS significantly contributed to the systemic release of interleukin-6 and high mobility group box 1 protein. Furthermore, the histological lung injury score, pulmonary edema, neutrophil influx, and plasma clara cell protein 16 were all significantly enhanced in PT animals in the presence of an additional HS. Although early morphological changes were minor, HS also contributed functionally to remote acute kidney injury but not to early liver damage. Moreover, PT-induced systemic endothelial injury, as determined by plasma syndecan-1 levels, was significantly aggravated by an additional HS. These results indicate that HS adds to the systemic inflammatory reaction early after PT. Within hours after PT, HS seems to aggravate pulmonary damage and to worsen renal and endothelial function which might overall contribute to the development of early multiple organ dysfunction.

Modified technique of transforaminal lumbar interbody fusion for segmental correction of lumbar kyphosis: a safe alternative to osteotomies?

BACKGROUND: Sagittal rebalancing of a fixated lumbar hypolordosis (kyphosis) is very important to gain satisfactory results. To correct a misalignment vertebral column resection or pedicle subtraction osteotomies are favored, disregarding the relatively high complication rates. The aim of this study was to evaluate the efficiency and safety of a new modified transforaminal lumbar fusion technique as an alternative. METHODS: We conducted a retrospective review (06/2011-06/2015 ) of a prospective database at an University hospital. Inclusion criteria were adult patients with a fixated lumbar hypolordosis and the need of monosegmental correction of more than 10° with an mTLIF. Exclusion criteria consisted of minor aged patients and polysegmental corrections. Study parameters were the perioperative complications and the achieved postsurgical lordosis. The follow up period was 6 months. RESULTS: A total of 11 patients could be included. The mean segmental lordosis was -2.3° ± 12.4° (range -22° to 14°) preoperative and 15.5° ± 10.5° (range 0° to 29°) postoperative. The degree of correction was 17° ± 5.7° in mean per treated segment (range 12° to 29°). No neurologic or vascular complications occurred. No substantial loss of correction or implant failure was noted during the 6-month follow-up. CONCLUSION: The modified transforaminal lumbar fusion technique is a safe method to correct a fixated lumbar kyphosis. The potential of segmental correction is comparable to pedicle subtraction osteotomies but sparing potentially healthy segments.

The history of risk: a review.

In the USA alone, around 22 million patients annually discuss the need for surgical procedure with their surgeon. On a global scale, more than 200 million patients are exposed to the risk of undergoing a surgical procedure every year. A crucial part of the informed consent process for surgery is the understanding of risk, the probability of complications, and the predicted occurrence of adverse events. Ironically, risk quantification, risk stratification, and risk management are not necessarily part of a surgeon's core skillset, considering the lengthy surgical training curriculum towards technical excellence. The present review was designed to provide a concise historic perspective on the evolution of our current understanding of risk and probability, which represent the key underlying pillars of the shared decision-making process between surgeons and patients when discussing surgical treatment options.

Early Definitive Fracture Fixation is Safely Performed in the Presence of an Open Abdomen in Multiply Injured Patients.

OBJECTIVE: To investigate the safety and feasibility of performing definitive fracture fixation in multiply injured patients in the presence of an open abdomen after laparotomy. DESIGN: Retrospective observational cohort study. SETTING: Level-I academic trauma center. PATIENTS: Adult polytrauma patients with the presence of an open abdomen after "damage control" laparotomy and associated major fractures of long bones, acetabulum, pelvis, or spine, requiring surgical repair (n = 81). INTERVENTION: Timing of definitive fracture fixation in relation to the timing of abdominal wall closure. MAIN OUTCOME MEASURE: Incidence of orthopedic surgical site infections. RESULTS: During a 15-year time window from January 1, 2000 until December 31, 2014, we identified a cohort of 294 consecutive polytrauma patients with an open abdomen after laparotomy. Surgical fixation of associated fractures was performed after the index laparotomy in 81 patients. In group 1 (n = 32), fracture fixation occurred significantly sooner despite a concurrent open abdomen, compared with group 2 (n = 49) with abdominal wall closure before fixation (mean 4.4 vs. 11.8 days; P = 0.01). The incidence of orthopaedic surgical site infections requiring a surgical revision was significantly lower in group 1 (3.1%) compared to group 2 (30.6%; P = 0.002). CONCLUSIONS: Definitive fracture fixation in the presence of an open abdomen is performed safely and associated with a significant decrease in clinically relevant surgical site infections, compared with delaying fracture fixation until abdominal wall closure. These data suggest that the strategy of imposing a time delay in orthopaedic procedures while awaiting abdominal wall closure is unjustified. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Early structural changes of the heart after experimental polytrauma and hemorrhagic shock.

Evidence is emerging that systemic inflammation after trauma drives structural and functional impairment of cardiomyocytes and leads to cardiac dysfunction, thus worsening the outcome of polytrauma patients. This study investigates the structural and molecular changes in heart tissue 4 h after multiple injuries with additional hemorrhagic shock using a clinically relevant rodent model of polytrauma. We determined mediators of systemic inflammation (keratinocyte chemoattractant, macrophage chemotactic protein 1), activated complement component C3a and cardiac troponin I in plasma and assessed histological specimen of the mouse heart via standard histomorphology and immunohistochemistry for cellular and subcellular damage and ongoing apoptosis. Further we investigated spatial and quantitative changes of connexin 43 by immunohistochemistry and western blotting. Our results show significantly increased plasma levels of both keratinocyte chemoattractant and cardiac troponin I 4 h after polytrauma and 2 h after induction of hypovolemia. Although we could not detect any morphological changes, immunohistochemical evaluation showed increased level of tissue high-mobility group box 1, which is both a damage-associated molecule and actively released as a danger response signal. Additionally, there was marked lateralization of the cardiac gap-junction protein connexin 43 following combined polytrauma and hemorrhagic shock. These results demonstrate a molecular manifestation of remote injury of cardiac muscle cells in the early phase after polytrauma and hemorrhagic shock with marked disruption of the cardiac gap junction. This disruption of an important component of the electrical conduction system of the heart may lead to arrhythmia and consequently to cardiac dysfunction.

A survey on patients' knowledge and expectations during informed consent for spinal surgery: can we improve the shared decision-making process?

BACKGROUND: The informed medical consent in surgery requires to some point basic medical knowledge. The treating physicians while explaining the details and risks of the recommended procedure often imply this. We hypothesized, that patients do not have adequate medical understanding to decide about the ongoing therapy and its potential complications based on knowledge jeopardizing the patients' safety. METHODS: We conducted a retrospective analysis of a prospective database using a multiple choice questionnaire with 10 basic questions about anatomy, clinical symptoms and therapies of spinal diseases in our spine clinic at a German university hospital. Included were all patients at the spine clinic who agreed to the study and to fill in the questionnaire. Furthermore the patients age, mother tongue, the past spinal surgical history, the length of duration of symptoms and the patients education were inquired. The data were analyzed descriptive. RESULTS: Included were 248 patients with an average age of 59 years (16-88 a). 70 % of all patients used German as their mother tongue. 30 % of the included patients already had spinal surgery and suffered on average for 13.4 years because of their spinal disorder. Overall 32.6 % of all questions were answered correctly (range 0.8-68 %). A correlation of correctly answered questions and the patients' age, duration of symptoms, mother tongue, education and past surgical history could not be described. CONCLUSION: The percentage of correctly answered questions is almost as low as the likelihood of nearness in guessing. Having this in mind the patients do not choose any treatment option based on knowledge. The physicians need to provide more basic knowledge to the patients. This would increase the amount of successful therapies, content patients and the patients safety.

Accuracy of screw placement and radiation dose in navigated dorsal instrumentation of the cervical spine: a prospective cohort study.

BACKGROUND: Dorsal cervical spinal fusion is a challenging procedure in fracture fixation. There is limited information in the literature about computer navigation using lateral mass screws in cases of spinal trauma. METHODS: Retrospective analysis of a prospective database covering an 8 year period. All patients who received a dorsal spinal fusion due to a fracture of the cervical spine were included. Outcome parameters were screw accuracy, duration of surgery, the radiation emitted and intra-/postoperative complications. RESULTS: Sixteen patients, who received 67 screws (44 navigated vs 23 conventionally inserted screws) were included. Three-dimensional (3D)-based computer navigation prolonged the duration of surgery but helped to reduce the radiation emitted and led to significantly increased accuracy of screw positioning. CONCLUSION: Computer navigation can increase the accuracy of lateral mass screws in spinal trauma. It prolongs the surgical procedure but reduces the emission of radiation significantly.