The role of adaptive immunity in contributing to post-traumatic neuroinflammation and neuropathology after head injury remains largely unexplored. The present study was designed to investigate the pathophysiological sequelae of closed head injury in Rag1−/− mice devoid of mature B and T lymphocytes. C57BL/6 wild-type and Rag1−/− mice were subjected to experimental closed head injury, using a standardized weight-drop device. Outcome parameters consisted of neurological scoring, quantification of blood–brain barrier (BBB) function, measurement of inflammatory markers and mediators of apoptosis in serum and brain tissue, and assessment of neuronal cell death, astrogliosis, and tissue destruction. There was no difference between wild-type and Rag1−/− mice with regard to injury severity and neurological impairment for up to 7 days after head injury. The extent of BBB dysfunction was in a similar range for both groups. Quantification of complement activation fragments in serum revealed significantly attenuated C3a levels in Rag1−/− mice compared to wild-type animals. In contrast, the levels of pro- and anti-inflammatory cytokines and pro-apoptotic and anti-apoptotic mediators remained in a similar range for both groups, and the histological analysis of brain sections did not reveal a difference in reactive astrogliosis, tissue destruction, and neuronal cell death in Rag1−/− compared to wild-type mice. These findings suggest that adaptive immunity is not of crucial importance for initiating and sustaining the inflammatory neuropathology after closed head injury. The attenuated extent of post-traumatic complement activation seen in Rag1−/− mice implies a cross-talk between innate and adaptive immune responses, which requires further investigation in future studies.
adaptive immunity; closed head injury; complement system; natural antibodies; Rag1
Traumatic brain injury is characterized by neuroinflammatory pathological sequelae which contribute to brain edema and delayed neuronal cell death. Until present, no specific pharmacological compound has been found, which attenuates these pathophysiological events and improves the outcome after head injury. Recent experimental studies suggest that targeting peroxisome proliferator-activated receptors (PPARs) may represent a new anti-inflammatory therapeutic concept for traumatic brain injury. PPARs are “key” transcription factors which inhibit NFκB activity and downstream transcription products, such as proinflammatory and proapoptotic cytokines. The present review outlines our current understanding of PPAR-mediated neuroprotective mechanisms in the injured brain and discusses potential future anti-inflammatory strategies for head-injured patients, with an emphasis on the putative beneficial combination therapy of synthetic cannabinoids (e.g., dexanabinol) with PPARα agonists (e.g., fenofibrate).
The lack of formal training programs for peer reviewers places the scientific quality of biomedical publications at risk, as the introduction of ‘hidden’ bias may not be easily recognized by the reader. The exponential increase in the number of manuscripts submitted for publication worldwide, estimated in the millions annually, overburdens the capability of available qualified referees. Indeed, the workload imposed on individual reviewers appears to be reaching a ‘breaking point’ that may no longer be sustainable. Some journals have made efforts to improve peer review via structured guidelines, courses for referees, and employing biostatisticians to ensure appropriate study design and analyses. Further strategies designed to incentivize and reward peer review work include journals providing continuing medical education (CME) credits to individual referees by defined criteria for timely and high-quality evaluations. Alternative options to supplement the current peer review process consist of ‘post-publication peer review,’ ‘decoupled peer review,’ ‘collaborative peer review,’ and ‘portable peer review’. This article outlines the shortcomings and flaws in the current peer review system and discusses new innovative options on the horizon.
See related article: http://www.biomedcentral.com/content/pdf/s12916-014-0128-z.pdf.
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The online version of this article (doi:10.1186/s12916-014-0179-1) contains supplementary material, which is available to authorized users.
Peer review; Biomedical publications; Evidence-based medicine; Randomized controlled trials
Major trauma results in a strong inflammatory response in injured tissue. This posttraumatic hyperinflammation has been implied in the adverse events leading to a breakdown of host defense mechanisms and ultimately to delayed organ failure. Ligands to peroxisome proliferator-activated receptors (PPARs) have recently been identified as potent modulators of inflammation in various acute and chronic inflammatory conditions. The main mechanism of action mediated by ligand binding to PPARs is the inhibition of the nuclear transcription factor NF-κB, leading to downregulation of downstream gene transcription, such as for genes encoding proinflammatory cytokines. Pharmacological PPAR agonists exert strong anti-inflammatory properties in various animal models of tissue injury, including central nervous system trauma, ischemia/reperfusion injury, sepsis, and shock. In addition, PPAR agonists have been shown to induce wound healing process after tissue trauma. The present review was designed to provide an up-to-date overview on the current understanding of the role of PPARs in the pathophysiology of the inflammatory response after major trauma. Therapeutic options for using recombinant PPAR agonists as pharmacological agents in the management of posttraumatic inflammation will be discussed.
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.
Closed head injury; Neuroinflammation; Complement receptor; Cr2
mice; Secondary brain injury
Background: There is limited information in the literature on the outcomes and complications in elderly patients who sustain high-energy hip fractures. As the population ages, the incidence of high-energy geriatric hip fractures is expected to increase. The purpose of this study was to analyze the outcomes and complications in patients aged 65 years or older, who sustained a high-energy proximal femur fracture. Methods: Retrospective review of a prospective trauma database from January 2000 to April 2011 at a single US academic level-1 trauma center. Inclusion criteria consisted of all patients of age 65 years or older, who sustained a proximal femur fracture related to a high-energy trauma mechanism. Details concerning injury, acute treatment, and clinical course and outcome were obtained from medical records and radiographs. Results: We identified 509 proximal femur fractures in patients older than 65 years of age, of which 32 (6.3%) were related to a high-energy trauma mechanism. The mean age in the study group was 72.2 years (range 65-87), with a mean injury severity score of 20 points (range 9-57). Three patients died before discharge (9.4%), and 22 of 32 patients sustained at least one complication (68.8%). Blunt chest trauma represented the most frequently associated injury, and the main root cause of pulmonary complications. The patients' age and comorbidities did not significantly correlate with the rate of complications and the 1-year mortality. Conclusions: High-energy proximal femur fractures in elderly patients are not very common and are associated with a low in-hospital mortality rate of less than 10%, despite high rate of complications of nearly 70%. This selective cohort of patients requires a particular attention to respiratory management due to the high incidence of associated chest trauma.
geriatric trauma; trauma surgery; fragility fractures; osteoporosis; anesthesia
The Editors of Patient Safety in Surgery would like to thank all our
reviewers who have contributed to the journal in Volume 7 (2013).
Posttraumatic sternoclavicular arthritis related to chronic ligamentous instability after posterior sternoclavicular dislocation represents a rare but challenging problem. The current article in the Journal’s “Safe Surgical Technique” series describes a successful salvage procedure by partial resection of the medial clavicle and ligamentous reconstruction of the sternoclavicular joint with a figure-of-eight semitendinosus allograft interposition arthroplasty.
Traumatic brain injury (TBI) represents a major health care problem and a significant socioeconomic challenge worldwide. In the United States alone, approximately 1.5 million patients are affected each year, and the mortality of severe TBI remains as high as 35%–40%. These statistics underline the urgent need for efficient treatment modalities to improve posttraumatic morbidity and mortality. Despite advances in basic and clinical research as well as improved neurological intensive care in recent years, no specific pharmacological therapy for TBI is available that would improve the outcome of these patients. Understanding of the cellular and molecular mechanisms underlying the pathophysiological events after TBI has resulted in the identification of new potential therapeutic targets. Nevertheless, the extrapolation from basic research data to clinical application in TBI patients has invariably failed, and results from prospective clinical trials are disappointing. We review the published prospective clinical trials on pharmacological treatment modalities for TBI patients and outline future promising therapeutic avenues in the field.
Novel bone substitutes have challenged the notion of autologous bone grafting as the ‘gold standard’ for the surgical treatment of fracture nonunions. The present study was designed to test the hypothesis that autologous bone grafting is equivalent to other bone grafting modalities in the management of fracture nonunions of the long bones.
A retrospective review of patients with fracture nonunions included in two prospective databases was performed at two US level 1 trauma centers from January 1, 1998 (center 1) or January 1, 2004 (center 2), respectively, until December 31, 2010 (n = 574). Of these, 182 patients required adjunctive bone grafting and were stratified into the following cohorts: autograft (n = 105), allograft (n = 38), allograft and autograft combined (n = 16), and recombinant human bone morphogenetic protein-2 (rhBMP-2) with or without adjunctive bone grafting (n = 23). The primary outcome parameter was time to union. Secondary outcome parameters consisted of complication rates and the rate of revision procedures and revision bone grafting.
The autograft cohort had a statistically significant shorter time to union (198 ± 172–225 days) compared to allograft (416 ± 290–543 days) and exhibited a trend towards earlier union when compared to allograft/autograft combined (389 ± 159–619 days) or rhBMP-2 (217 ± 158–277 days). Furthermore, the autograft cohort had the lowest rate of surgical revisions (17%) and revision bone grafting (9%), compared to allograft (47% and 32%), allograft/autograft combined (25% and 31%), or rhBMP-2 (27% and 17%). The overall new-onset postoperative infection rate was significantly lower in the autograft group (12.4%), compared to the allograft cohort (26.3%) (P < 0.05).
Autologous bone grafting appears to represent the bone grafting modality of choice with regard to safety and efficiency in the surgical management of long bone fracture nonunions.
Fracture nonunion; Autograft; Allograft; Bone morphogenetic protein
Occult femoral neck fractures associated with femoral shaft fractures are frequently missed and may lead to adverse outcomes.
A 46-year old female presented to our institution with increasing groin pain one month after antegrade intramedullary nailing of a femoral shaft fracture at an outside hospital. Radiographic evaluation revealed a displaced ipsilateral femoral neck fracture, adjacent to the piriformis starting point of the nail. A revision fixation of the femoral shaft and neck fracture was performed. The patient sustained a series of complications requiring multiple revision surgeries, including a total hip arthroplasty. Despite the cascade of complications, the patient had an uneventful long-term recovery, without additional complications noted at one-year follow-up.
This case report illustrates the necessity of increased awareness with a high level of suspicion for the presence of associated femoral shaft and neck fractures in any patient undergoing antegrade femoral nailing. Arguably, the cascade of complications presented in this paper could have been prevented with early recognition and initial stabilization of the occult femoral neck fracture. Standardized diagnostic protocols include “on table” pelvic radiographs to rule out associated femoral neck fractures. The diagnosis must be enforced in case of equivocal radiographic findings, either by computed tomography scan or magnetic resonance imaging.
Femoral neck fracture; Femoral shaft fracture; Missed injury; Complication
Heterotopic ossification is a rare complication of musculoskeletal injuries, characterized by bone growth in soft tissues. Percutaneous antegrade intramedullary nailing represents the ‘gold standard’ for the treatment of femur shaft fractures. Minor bone growth is frequently seen around the proximal end of reamed femoral nails (so-called ‘callus caps’), which are asymptomatic and lack a therapeutic implication. The occurrence of excessive, symptomatic heterotopic ossification around the entry site of an antegrade femoral nail is rarely described in the literature.
We present the case of a 28-year-old Caucasian woman who developed extensive heterotopic ossification around the reaming seeds of a reamed femoral nail. She developed severe pain and significantly impaired range of motion of the hip joint, requiring revision surgery for heterotopic ossification resection and adjunctive local irradiation. She recovered full function of the hip and remained asymptomatic at her two-year follow-up appointment.
Severe heterotopic ossification represents a rare but potentially detrimental complication after percutaneous femoral nailing of femur shaft fractures. Diligent care during the reaming procedure, including placement of a trocar to protect from osteogenic seeding of the soft tissues, may help decrease the risk of developing heterotopic ossification after reamed antegrade femoral nailing.
Heterotopic ossification; Femoral nailing; Femur fracture; Complication
Inflation bone tamps are becoming increasingly popular as a reduction tool for depressed tibial plateau fractures. A number of recent publications have addressed the technical aspects of balloon inflation osteoplasty. However, no study has yet been published to describe the technical limitations, intraoperative complications, and surgical bailout strategies for this new technology.
Observational retrospective study of all patients managed with inflatable bone tamps for depressed tibial plateau fractures between October 1, 2010 and December 1, 2012. The primary outcome parameter was the rate of complications, which were stratified into “minor” and “major” depending on the necessity for altering the surgical plan intraoperatively, and based on the risk for patient harm. This study was approved by the Institutional Review Board of the State of Colorado.
A consecutive series of 20 patients were managed by balloon inflation osteoplasty for depressed tibial plateau fractures during the 15 months study period. The mean age was 42.8 years (range 20–79), with 9 females and 11 males. A total of 13 patients sustained an adverse intraoperative event (65%), with three patients sustaining multiple technical complications. Minor events (n = 8) included the burst of a balloon with extrusion of contrast dye, and the unintentional posterior wall displacement during balloon inflation. Major events (n = 5) included the intra-articular injection of calcium phosphate in the knee joint, and the inability to elevate the depressed articular fragment with the inflatable bone tamp.
The observed intraoperative complication rate of 65% reflects a steep learning curve for the use of inflation bone tamps to reduce depressed tibial plateau fractures. Specific surgical bailout options are provided in this article, based on our early anecdotal experience in a pilot series of 20 consecutive cases. Patients should be advised on the benefits and risks of this new technology as part of the shared decision-making process during the informed consent.
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.
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.
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.
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.
Severe chest wall injuries are potentially life-threatening injuries which require a standardized multidisciplinary management strategy for prevention of posttraumatic complications and adverse outcome.
We report the successful management of a 55-year old man who sustained a complete “bony disruption” of the thoracic cage secondary to an “all-terrain vehicle” roll-over accident. The injury pattern consisted of a bilateral “flail chest” with serial segmental rib fractures, bilateral hemo-pneumothoraces and pulmonary contusions, bilateral midshaft clavicle fractures, a displaced transverse sternum fracture with significant diastasis, and an unstable T9 hyperextension injury. After initial life-saving procedures, the chest wall injuries were sequentially stabilized by surgical fixation of bilateral clavicle fractures, locked plating of the displaced sternal fracture, and a two-level anterior spine fixation of the T9 hyperextension injury. The patient had an excellent radiological and physiological outcome at 6 months post injury.
Severe chest wall trauma with a complete “bony disruption” of the thoracic cage represents a rare, but detrimental injury pattern. Multidisciplinary management with a staged timing for addressing each of the critical injuries, represents the ideal approach for an excellent long-term outcome.
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.
Sepsis continues to be a poorly understood syndrome with a high mortality rate. While we are beginning to decipher the intricate interplay of the inflammatory response during sepsis, the precise regulation of the hypothalamic-pituitary-adrenal (HPA) axis and its impact on electrolyte homeostasis during sepsis remains incompletely understood.
Sepsis was induced in adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). Plasma samples were obtained as a function of time (6-48 hrs) after CLP and compared with healthy animals (neg ctrl). Samples were analyzed for adrenocorticotropin (ACTH), corticosterone, and aldosterone levels, as well as concentrations of sodium (Na+), potassium (K+), chloride (Cl-), and magnesium (Mg2+).
ACTH levels were found to be significantly reduced 6-24 hrs after CLP in comparison to baseline levels and displayed gradual recovery during the later course (24-48 hrs) of sepsis. Plasma corticosterone concentrations exhibited a bell-shaped response, peaking between 6 and 12 hrs followed by rapid decline and concentrations below negative control levels 48 hrs after injury. Aldosterone levels in septic animals were continuously elevated between 6 and 48 hrs. Whereas plasma Na+ levels were found to be persistently elevated following CLP, levels of K+, Cl- and Mg2+ were significantly reduced as a function of time and gradually recovered during the later course of sepsis.
CLP-induced sepsis resulted in dynamic changes of ACTH, corticosterone, and aldosterone levels. In addition, electrolyte levels showed significant disturbances after CLP. These electrolyte perturbations might be evoked by a downstream effect or a dysfunctional HPA-axis response during sepsis and contribute to severe complications during sepsis.
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.
We report the case of a 28-year old rock climber who survived an "unsurvivable" injury consisting of a vertical free fall from 300 feet onto a solid rock surface. The trauma mechanism and injury kinetics are analyzed, with a particular focus on the relevance of body positioning to ground surface at the time of impact. The role of early patient transfer to a level 1 trauma center, and "damage control" management protocols for avoiding delayed morbidity and mortality in this critically injured patient are discussed.
Patients suffering from polytrauma often present with altered mental status and have varying levels of examinability. This makes evaluation difficult. Physicians are often required to rely on advanced imaging techniques to make prompt and accurate diagnoses. Occasionally, injury detection on advanced imaging studies can be challenging given the subtle findings associated with certain conditions, such as diffuse idiopathic skeletal hyperostosis (DISH). Delayed or missed diagnoses in the setting of spinal fracture can lead to catastrophic neurological injury.
A man struck by a motor vehicle suffered multiple traumatic injuries including numerous rib fractures, a mechanically unstable pelvic fracture, and also had suspicion for an aortic injury. Unfortunately, the upper thoracic segment (T1-5) was only visualized with axial images based on the electronic data. Several days later, a contrast CT scan obtained to check the status of suspected aortic injury revealed T3-T4 subluxation indicative of an unstable extension-type fracture in the setting of DISH. Due to the missed injury and delay in diagnosis, surgery was not performed until eight days after the injury. At surgery, the patient was found to have left T3-T4 facet joint infection as well as infected hematoma surrounding a left T4 transverse process fracture and a traumatic T4 costo-transverse joint fracture-subluxation. Despite presence of infection, an instrumented posterior spinal fusion from T1-T6 was performed and the patient recovered well after antibiotic treatment.
A T3-T4 unstable DISH extension-type fracture was initially missed in a polytrauma patient due to inadequate imaging acquisition, which caused a delay in treatment and bacterial seeding of fracture hematoma. Complete imaging is especially needed in obtunded patients that cannot be thoroughly examined.