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Significance: Sepsis is a major public health concern, with high mortality and morbidity, especially among patients undergoing trauma. It is characterized by a systemic inflammatory response syndrome (SIRS) occurring in response to infection. Although classically associated with pathogens, many patients with SIRS do not have infection. The variability of the disease course cannot be fully explained by our current understanding of its pathogenesis. Thus, other factors are likely to play key roles in the development and progression of SIRS/sepsis. Recent Advances: Circulating levels of damage-associated molecular patterns (DAMPs) seem to correlate with SIRS/sepsis morbidity and mortality. Of the known DAMPs, those of mitochondrial (mt) origin have been of particular interest, since their DNA (mtDNA) and formyl peptides (mtFPs) resemble bacterial DNA and peptides, and hence, when released, may be recognized as “danger signals.” Critical Issues: mtDAMPs released after tissue injury trigger immune responses similar to those induced by pathogens. Thus, they can result in systemic inflammation and organ damage, similar to that observed in SIRS/sepsis. We will discuss recent findings on the roles of mtDAMPs, particularly regarding the less recognized mtFPs, in the activation of inflammatory responses and development of SIRS/sepsis. Future Directions: There are no established methods to predict the course of SIRS/sepsis, but clinical studies reveal that plasma levels of mtDAMPs may correlate with the outcome of the disease. We propose that non-pathogen-initiated, mtDAMPs-induced SIRS/sepsis events need further studies aimed at early clinical recognition and better treatment of this disease.

Background Trauma and sepsis both increase the risk for secondary infections. Injury mobilizes mitochondrial (MT) danger-associated molecular patterns (mtDAMPs) directly from cellular necrosis. It is unknown, however, whether sepsis can cause active MT release and whether mtDAMPs released by sepsis might affect innate immunity. Methods Mitochondrial release from human monocytes (Mo) was studied after LPS stimulation using electron microscopy and using fluorescent video-microscopy of adherent Mo using Mito-Tracker Green (MTG) dye. Release of MTG+ microparticles was studied using flow cytometry after bacterial stimulation by size exclusion chromatography of supernatants with polymerase chain reaction (PCR) for mitochondrial DNA (mtDNA). Human neutrophil (PMN), chemotaxis, and respiratory burst were studied after PMN incubation with mtDNA. Results LPS caused Mo to release mtDAMPs. Electron microscopy showed microparticles containing MT. mtDNA was present both in microvesicles and exosomes as shown by PCR of the relevant size exclusion chromatography bands. In functional studies, PMN incubation with mtDNA suppressed chemotaxis in a dose-dependent manner, which was reversed by chloroquine, suggesting an endosomal, toll-like receptor-9-dependent mechanism. In contrast, PMN respiratory burst was unaffected by mtDNA. Conclusion In addition to passive release of mtDAMPs by traumatic cellular disruption, inflammatory and infectious stimuli cause active mtDAMP release via microparticles. mtDNA thus released can have effects on PMN that may suppress antimicrobial function. mtDAMP-mediated "feed-forward" mechanisms may modulate immune responses and potentially be generalizable to other forms of inflammation. Where they cause immune dysfunction the effects can be mitigated if the pathways by which the mtDAMPs act are defined. In this case, the endosomal inhibitor chloroquine is benign and well tolerated. Thus, it may warrant study as a prophylactic antiinfective after injury or prior sepsis.

Infection is a common complication of major trauma that causes significantly increased morbidity and mortality. The mechanisms, however, linking tissue injury to increased susceptibility to infection remain poorly understood. To study this relationship, we present a potentially novel murine model in which a major liver crush injury is followed by bacterial inoculation into the lung. We find that such tissue trauma both impaired bacterial clearance and was associated with significant elevations in plasma heme levels. While neutrophil (PMN) recruitment to the lung in response to Staphylococcus aureus was unchanged after trauma, PMN cleared bacteria poorly. Moreover, PMN show > 50% less expression of TLR2, which is responsible, in part, for bacterial recognition. Administration of heme effectively substituted for trauma. Finally, day 1 trauma patients (n = 9) showed similar elevations in free heme compared with that seen after murine liver injury, and circulating PMN showed similar TLR2 reduction compared with volunteers (n = 6). These findings correlate to high infection rates.

Significance Septic shock commonly leads to multiorgan injury both directly via tissue inflammation and secondarily via hypoperfusion, but both can result in mitochondrial N-formyl peptide (mtFP) release into the circulation. However, no studies have evaluated the role of circulating mtFPs during septic shock. We found that a relatively high plasma nicotinamide adenine dinucleotide dehydrogenase subunit-6 (the most potent human mtFP) level was independently associated with the development of secondary infection in patients with septic shock and that the increased susceptibility to secondary infection is partly attributed to the suppression of polymorphonuclear leukocyte (PMN) chemotaxis by mtFP occupancy of formyl peptide receptor-1. Incorporation of these findings into therapeutic strategies may improve clinical outcomes in septic shock patients by preventing PMN chemotactic anergy., Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial N-formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, P = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, P = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.

Background Trauma induces neutrophil migration toward injury sites, both initiating wound healing and protecting against local bacterial infection. We have previously shown that mitochondrial formyl peptides (mtFPs) released by injured tissues act as chemoattractants by ligating neutrophil (PMN) formyl peptide receptor 1 (FPR1). But this process can also internalize multiple neutrophil chemoattractant receptors and thus might limit neutrophil migration to the lung in response to bacteria. Our objective was to better understand susceptibility to pneumonia after injury and thus find ways to reverse it. Methods and results We modeled the alveolar chemotactic environment in pulmonary infections by incubating Staphylococcus aureus or Escherichia coli with peripheral blood mononuclear cells (PBMC). Survey of the chemotactic mediators in the resultant conditioned media (CM) showed multiple potent chemoattractants. Pretreating PMN with mtFPs to mimic injury potently reduced net migration towards CM and this net effect was mostly reversed by an FPR1 antagonist. Using an established mouse model of injury-dependent lung infection, we then showed simple instillation of exogenous unstimulated human neutrophils into the airway resulted in bacterial clearance from the lung. Conclusion Injury-derived mtFPs suppress global PMN localization into complex chemotactic environments like infected alveoli. Transplantation of naive exogenous human neutrophils into the airway circumvents that pathologic process and prevents development of post-traumatic pneumonia without injury noted to the recipients.

OBJECTIVES Sepsis and sterile both release "danger signals' that induce the systemic inflammatory response syndrome (SIRS). So differentiating infection from SIRS can be challenging. Precision diagnostic assays could limit unnecessary antibiotic use, improving outcomes. METHODS After surveying human leukocyte cytokine production responses to sterile damage-associated molecular patterns (DAMPs), bacterial pathogen-associated molecular patterns, and bacteria we created a multiplex assay for 31 cytokines. We then studied plasma from patients with bacteremia, septic shock, "severe sepsis," or trauma (ISS ≥15 with circulating DAMPs) as well as controls. Infections were adjudicated based on post-hospitalization review. Plasma was studied in infection and injury using univariate and multivariate means to determine how such multiplex assays could best distinguish infective from noninfective SIRS. RESULTS Infected patients had high plasma interleukin (IL)-6, IL-1α, and triggering receptor expressed on myeloid cells-1 (TREM-1) compared to controls [false discovery rates (FDR)

This is a recommended management algorithm from the Western Trauma Association addressing the management of adult patients with abdominal stab wounds. Because there is a paucity of published prospective randomized clinical trials that have generated Class I data, these recommendations are based primarily on published observational studies and expert opinion of Western Trauma Association members. The algorithm and accompanying comments represent a safe and sensible approach that can be followed at most trauma centers. We recognize that there will be patient, personnel, institutional, and situational factors that may warrant or require deviation from the recommended algorithm. We encourage institutions to use this as a guideline to develop their own local protocols.

In all multicellular organisms, immediate host responses to both sterile and infective threat are initiated by very primitive systems now grouped together under the general term 'danger responses'. Danger signals are generated when primitive 'pattern recognition receptors' (PRR) encounter activating 'alarmins'. These molecular species may be of pathogenic infective origin (pathogen-associated molecular patterns) or of sterile endogenous origin (danger-associated molecular patterns). There are many sterile and infective alarmins and there is considerable overlap in their ability to activate PRR, but in all cases the end result is inflammation. It is the overlap between sterile and infective signals acting via a relatively limited number of PRR that generally underlies the great clinical similarity we see between sterile and infective systemic inflammatory responses. Mitochondria (MT) are evolutionarily derived from bacteria, and thus they sit at the crossroads between sterile and infective danger signal pathways. Many of the molecular species in mitochondria are alarmins, and so the release of MT from injured cells results in a wide variety of inflammatory events. This paper discusses the known participation of MT in inflammation and reviews what is known about how the major.

Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF [1].We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1-2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF).Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p=0.008 and five-fold increase days 1-2, p=0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA (p=0.037 vs.2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1-2 (p=0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state.Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.

BACKGROUNDNosocomial pneumonias are common in trauma patients and so interventions to prevent and treat nosocomial pneumonia may improve outcomes. Our prior work strongly suggests that tissue injury predisposes to infections like nosocomial pneumonia because mitochondrial debris originating from inj

Background Postoperative pneumonia is a major cause of morbidity and mortality following cardiac surgery. The inflammatory response to cardiac surgery has been widely studied, but specific mechanisms for postoperative pneumonia have not been determined. Tranexamic acid is renowned for its effect on bleeding but can also modulate inflammatory processes. Cardiac surgery is known to release mitochondrial DAMPs (mtDAMPs) and is linked to postoperative inflammation and atrial fibrillation. We speculated that mtDAMPs might be related to postoperative pneumonia and that this might be modulated by tranexamic acid. Methods Forty-one (41) patients from the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial were studied. Levels of mitochondrial DNA, matrix metallopeptidase 9 (MMP-9) and neutrophil elastase (NE) were determined in plasma preoperatively, at 24 and 72 hours post-surgery and correlated with clinical outcome. Results mtDNA was significantly elevated postoperatively in the placebo and tranexamic acid (TXA) groups. Neutrophil elastase increased immediately postoperatively and at 24 hours. MMP-9 was elevated in the placebo group early postoperatively and in the TXA group at the immediate postoperative time point and after 24 hours. Six (6) of the 41 (14.6%) patients subsequently developed pneumonia. mtDNA levels were significantly increased at the early postoperative period and the 24-hour time point in patients with pneumonia. Conclusions Cardiac surgery releases mtDNA, increases MMP-9 and NE and this was not influenced by TXA. Inflammation postoperatively might be linked to pneumonia since mtDNA was further elevated in these patients. Due to the low number of individuals developing pneumonia, further studies are warranted to clearly identify whether TXA impacts on the inflammatory response in postoperative pneumonia.

Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point in vivo would reduce the severity of organ injury in this model. Conclusions: We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.

Trauma is the sixth leading cause of death worldwide, and is a serious public health problem with major social and economic costs. Local injury initiates an inflammatory cascade leading to local inflammation. More extensive injury can lead to systemic inflammation. Simultaneously though, immune-suppression develops and enhances the risk of infection in severely injured patients (1). Thus trauma patients are at high risk of infection both because physical barriers to tissue inoculation are disrupted and because of impaired host defense against bacterial inoculation (2,3) Thus infection is a leading cause of death after trauma. (2) Blunt chest trauma is common and is an important contributor to 10% to 30% of adult trauma deaths. (4) Chest trauma is commonly accompanied by injury to other organ systems. Abdominal trauma is frequently associated with chest trauma, and is an important factor affecting mortality. (5) Pneumonia is the most common infection complicating chest trauma and is highly related to mortality. (6) Furthermore, pneumonia is the most common infectious complication in multiple trauma patients as a whole with an incidence reaching 30% after severe trauma. (7) Despite the critical association between chest trauma and chest infections in the trauma population, no basic biologic mechanisms have been advanced to explain the association of injury with pneumonia or the high morbidity and mortality of pneumonia after major trauma. Rather, associated findings like ‘splinting’ and ‘failure to breathe deeply’ have been causally implicated without rigorous scientific support. Our previous studies have shown that cellular disruption by trauma releases mitochondrial debris (MTD) into the circulation that is rich in damage associated molecular patterns (DAMPs). These mitochondrial DAMPs show evolutionarily conserved similarities to bacterial Pathogen Associated Molecular Patterns (PAMPs). Thus they can initiate inflammation by signaling through innate immune pathways that create a sepsis-like state. (8–10) Sepsis however, does not necessarily lead directly to lung injury. (11) Another important phenomena we have observed is that is that MTD released by injured tissues attracts neutrophils. This is mediated at least in part by formyl peptides (FP) that act on formyl peptide receptors like FPR1. (10,12) Formyl peptides are typical of bacteria, but are also found in mitochondria. In addition to being neutrophil chemoattractants FP activate mononuclear cells releasing further chemokines and lipid chemoattractants. (13) We hypothesized that MTD released by injured tissue could suppress pulmonary immune responses by diverting neutrophils from the lung and or altering PMN function, thus potentially leaving the lung susceptible to infection

Trauma remains the main cause of death for both civilians and those in uniform. Trauma-associated coagulopathy is a complex process involving inflammation, coagulation, and platelet dysfunction. It is unknown whether activation of complement, which occurs invariably in trauma patients, is involved in the expression of trauma-associated coagulopathy. We designed a prospective study in which we enrolled 40 trauma patients and 30 healthy donors upon arrival to the emergency department of BIDMC. Platelets from healthy individuals were incubated with sera from trauma patients and their responsiveness to a thrombin receptor-activating peptide was measured using aggregometry. Complement deposition on platelets from trauma patients was measured by flow cytometry. Normal platelets displayed hypoactivity after incubation with trauma sera even though exposure to trauma sera resulted in increased agonist-induced calcium flux. Depletion of complement from sera further blocked activation of hypoactive platelets. Conversely, complement activation increased aggregation of platelets. Platelets from trauma patients were found to have significantly higher amounts of C3a and C4d on their surface compared with platelets from controls. Depletion of complement (C4d, C3a) reversed the ability of trauma sera to augment agonist-induced calcium flux in donor platelets. Our data indicate that complement enhances platelet aggregation. Despite its complement content, trauma sera render platelets hypoactive and complement depletion further blocks activation of hypoactive platelets. The defect in platelet activation induced by trauma sera is distal to receptor activation since agonist-induced Ca2+ flux is elevated in the presence of trauma sera owing to complement deposition.

Elderly falls are associated with long hospital stays, major morbidity, and mortality. We sought to examine the fate of patients ≥75 years of age admitted after falls.We reviewed all fall admissions in 2008. Causes, comorbidities, injuries, procedures, mortality, readmission, and costs were analyzed.Seven hundred eight patients ≥75 years old were admitted after a fall, with 89% being simple falls. Short-term mortality was 6%. Male sex, atrial fibrillation, acute myocardial infarction, congestive heart failure (CHF), intracranial hemorrhage, hospital-acquired pneumonia, trigger events, Clostridium difficile, and intubation were predictors of death (P.05). Thirty-day readmission occurred in 14%; CHF, craniotomy, and acute renal failure were predictive. The median cost of hospitalization was $11,000 with cardiac disease, anemia, major orthopedic and neurosurgical procedures, pneumonia, and intubation as predictive.Simple falls in the elderly have high morbidity, mortality, and costs. Methodologies for prevention are warranted and should be studied intensively.

Medical technology has benefited many types of patients, but trauma care has arguably benefited more from technologic development than almost any other field.A literature review to identify key technological advances in the care of trauma patients was performed.The advances in trauma care are in great measure due to the integration of many different systems. Medical technology impacts care in the field at the site of the trauma, in the transport to trauma facilities, and care at the trauma center itself. Once at the hospital, technology has impacted care in the trauma bay, intensive care units, the operating room, and in postoperative and long-term care settings. The integration of advancements, however, needs to be examined in a careful systematic fashion to insure that patients will actually derive benefit.

Atrial fibrillation prophylaxis with warfarin and strong antiplatelet agent use in cardiovascular diseases has increased the incidence of anticoagulation in the elderly. We studied traumatic intracranial hemorrhage (TICH) in patients ≥55 years of age on anticoagulation and antiplatelet agents in a stable population.We used a Level 1 Trauma Center registry study comparing TICH in patients on anticoagulation drugs during the index periods 1999 to 2000 (T1) and 2007 to 2008 (T2).A total of 526 TICH patients were seen in T1 and T2 (age, 77.6 vs 77.5 years; not significant [NS]), with the rate doubling from 6.2% to 12.3% of all trauma activations (P.01). There was no increase in atrial fibrillation, warfarin use, or CHADS(2) scores in atrial fibrillation patients on anticoagulation therapy. TICH in patients taking antiplatelet agents increased 5-fold (2.2 % vs 10.3%; P .01). Overall TICH mortality rate was the same (12.4% vs 12.2%, NS). TICH mortality among patients on therapeutic warfarin was greater in T1 (26%; P.05), but mortality was similar to TICH in patients not on anticoagulants in T2 (19% vs 12.2%, NS), suggesting treatment improved. Prevalence and mortality of TICH in patients on antiplatelet agents were similar to TICH in patients on warfarin.TICH in patients on anticoagulants is epidemic in patients ≥55 years of age. Despite national trends, our well-served population has not seen an increase in warfarin use for atrial fibrillation. Instead, use of antiplatelet agents has increased and is associated with an increased incidence of TICH.

Organ failure is a common cause of morbidity and mortality in patients sustaining major trauma, and hence, the pathophysiology of trauma-induced organ injury and dysfunction has been an important line of research.1 Based on these trauma studies, it is clear that shock-induced changes and trauma-induced changes in neutrophil activation are involved in the pathogenesis of the adult respiratory distress syndrome and contribute to the development of the multiple organ dysfunction syndrome.1 Likewise, recent work suggests that impaired red blood cell (RBC) deformability, which occurs in sepsis, after trauma, and during shock states,2–4 contributes to the development of multiple organ dysfunction syndrome by impairing tissue microvascular blood flow.5 Consequently, understanding the factors that modulate the magnitude and extent of neutrophil activation and RBC deformability might provide important insights into ways to limit post-trauma organ dysfunction.1 Because gender and sex hormones have been shown to modulate the development of organ injury as well as the immune system in preclinical models of trauma-hemorrhagic shock (T/HS)6–10 and in some but not all clinical studies,11 we have been interested in investigating the effects of gender and sex hormones on T/HS-induced changes in neutrophil and RBC function. Our earlier studies documented that neutrophil activation12 and RBC rigidification13 were reduced in female as opposed to male rats subjected to T/HS and that estrogen played a protective role in these studies. Because the beneficial effects of estrogen (17β-estradiol) seem to occur through high-affinity estrogen receptors (ER), the major goal of this study was to investigate the relative role that each of the two principal ERs (ER-α and -β) played in protecting against trauma-shock-induced RBC dysfunction, as measured by RBC deformability and neutrophil activation. To accomplish this goal, we administered either the ER-α agonist propyl pyrazole triol (PPT) or the ER-β agonist diarylpropiolnitrile (DPN) to ovariectomized (OVX) rats. These agents were chosen as PPT has a 410-fold higher binding affinity preference for ER-α over ER-β,14 whereas DPN exhibits a 70-fold higher binding affinity to ER-β than ER-α.15

Background: The development of coagulopathy associated with trauma is a complex process that involves a combination of many factors. It is important to be able to model experimental trauma-related coagulopathy to explore preventative and therapeutic strategies, and numerous models of traumatic coagulopathy have been explored. This systematic review assessed the primary question What are relevant experimental models with which to study early traumatic coagulopathy? and secondary questions on mechanisms. Methods: The author group reviewed 695 abstracts that resulted in 36 articles being fully reviewed by the group. The group identified 12 key studies (grade A) addressing the primary question. A further 10 articles were thought to be relevant but less important (grade B). Eight articles were considered worthwhile publications but not as relevant to the query (grade C), and six articles were considered not relevant after detailed review (grade D). Results: This structured literature review demonstrated a lack of relevant models for human traumatic coagulopathy. We identify challenges in modeling traumatic coagulopathy and limitations to current experimental models and include a proposal for features of an ideal model of traumatic coagulopathy, but recognize that this involves major challenges. Conclusions: Models of traumatic coagulopathy need to more closely resemble human physiology and real-life conditions if they are to influence clinical practice.

Background: Central venous catheter placement is a common procedure in the intensive care unit. However, these devices are not without complications. We describe the first reported case of descending necrotizing mediastinitis secondary to central venous catheterization without evidence of associated vascular perforation. Methods: Case report and literature review. Results: A 24-year-old man developed descending necrotizing mediastinitis after exploratory laparotomy for a gunshot wound. A central venous catheter was presumed to be the source because blood, intraoperative, and catheter tip cultures grew the same Klebsiella organism, and there was no evidence of venous perforation at the initial operation. Conclusions: Prompt recognition, adequate operative drainage, and appropriate antibiotics remain the best treatment for descending necrotizing mediastinitis.

Post-injury multiple organ failure results from an inappropriate, overwhelming immune response to injury. During trauma and hemorrhagic shock (T/HS), mesenteric ischemia causes gut mucosal breakdown with disruption of the intestinal barrier. It has been proposed that this releases the gut microbiota systemically via post-shock mesenteric lymph, engendering infectious complications. Despite extensive investigation, no clear evidence has been presented for gut bacterial translocation after resuscitation from T/HS. However, such previous studies were limited by available technologies. More sensitive methods, such as quantitative polymerase chain reaction (PCR), have since emerged for detection of bacterial presence and danger-associated molecular patterns (DAMPs). Quantitative PCR was applied to post-shock mesenteric lymph (PSML) derived from a rat model of T/HS. No bacterial presence was detected in a series of 12 samples, whereas multiple lymph samples showed presence of DAMPs after T/HS. Thus, we confirmed that bacterial translocation does not exist in PSML following resuscitation from T/HS-associated mesenteric ischemia. However, T/HS does increase the presence of mitochondrial DAMPs in PSML. These results support our current position that PSML elaborates remote organ injury by multiple inflammatory mechanisms, including lipid-mediated pro-inflammatory stimuli, and by contribution from gut-derived DAMPS.

INTRODUCTIONde Garengeot's hernia is very rare. Richter's hernia is responsible for 10% of acute strangulated hernias.PRESENTATION OF CASEA 91-year-old woman with three days of abdominal distention was found on computed tomogram to have an incarcerated femoral hernia. Operation revealed a de Garengeot's hernia combined with a Richter's hernia of small bowel. Primary repair was performed along with appendectomy.DISCUSSIONWe discuss these rare hernias, not previously reported in combination, and options for management.CONCLUSIONCombined de Garengeot's and Richter's hernias are rare, represent a significant diagnostic challenge, and should be repaired urgently to prevent ischemic bowel, or limit contamination if ischemia is already present. Use of computed tomography will likely lead to increased pre-operative diagnosis of this rare entity.

Na+/H+exchangers (NHEs) are integral transmembrane proteins found in all mammalian cells. There is substantial evidence indicating that NHEs regulate inflammatory processes. Because intestinal epithelial cells express a variety of NHEs, we tested the possibility that NHEs are also involved in regulation of the epithelial cell inflammatory response. In addition, since the epithelial inflammatory response is an important contributor to mucosal inflammation in inflammatory bowel disease (IBD), we examined the role of NHEs in the modulation of disease activity in a mouse model of IBD. In human gut epithelial cells, NHE inhibition using a variety of agents, including amiloride, 5-( N-methyl- N-isobutyl)amiloride, 5-( N-ethyl- N-isopropyl)- amiloride, harmaline, clonidine, and cimetidine, suppressed interleukin-8 (IL-8) production. The inhibitory effect of NHE inhibition on IL-8 was associated with a decrease in IL-8 mRNA accumulation. NHE inhibition suppressed both activation of the p42/p44 mitogen-activated protein kinase and nuclear factor-κB. Finally, NHE inhibition ameliorated the course of IBD in dextran sulfate-treated mice. Our data demonstrate that inhibition of NHEs may be an approach worthy of pursuing for the treatment of IBD.

Our objective was to test the hypotheses that small volume hypertonic saline (HTS) resuscitation protects against trauma-hemorrhagic shock (T/HS)-induced intestinal and lung injury better than standard volume resuscitation with Ringer's lactate (RL), and that the degree of lung injury correlates with the degree of gut injury after therapy. Male Sprague-Dawley rats were subjected to laparotomy (trauma) and 90 min of T/HS or sham shock (T/SS), and were then resuscitated with RL or 7.5% NaCl solution at an equivalent sodium load. Intestinal and lung injury was assessed at 3 and 24 h after resuscitation. Lung permeability, pulmonary myeloperoxidase (MPO) levels, and the bronchoalveolar lavage fluid (BALF) protein to plasma protein ratio were increased after T/HS, but were significantly lower in HTS-resuscitated than RL-treated rats. The incidence of bacterial translocation (BT) was not different between the groups, but the magnitude of BT after T/HS was less after HTS than RL resuscitation. Barrier function of intestinal segments was impaired only in the T/HS rats resuscitated with RL and histological analysis demonstrated fewer injured villi in the T/HS rats resuscitated with HTS than RL. Linear regression analysis revealed direct correlations between the percent of injured villi, increased lung permeability, and pulmonary neutrophil sequestration. Resuscitation with HTS ameliorated T/HS-induced gut and lung injury seen with RL resuscitation. These results, together with the direct correlation found between gut and lung injury, suggest that lung injury after T/HS may be mediated by gut injury.

The modulation of polymorphonuclear neutrophil (PMN) function by injury is unpredictable, and can predispose either to hyperimmune states (adult respiratory distress syndrome [ARDS], multiple organ failure) or to immune dysfunction, infection, and sepsis. Such outcomes have been related to excess production of the CXC chemokine interleukin (IL)-8, but PMN responses to IL-8 are mediated by both the relatively stable and IL-8 specific CXC receptor 1 (CXCR1) and the labile, promiscuous CXCR2. We hypothesized that progression to septic and multiple organ failure outcomes could be related to early differences in PMN CXC receptor status.PMNs were isolated 12 +/- 3 hours after injury from 15 major trauma patients (Injury Severity Score of 34 +/- 2, 11 men and 4 women, age 36 +/- 4 years) who survived at least 7 days. Volunteer normal PMNs (n = 6 donors) were studied for comparison. Cells were stimulated either with the CXCR2 specific agent growth-related oncogene-alpha, or with IL-8, which stimulates CXCR1 and CXRR2. Receptor response was assessed as the mobilization of cell calcium. The development of ARDS, sepsis, and pneumonia was assessed according to standardized criteria. Day 1 receptor activity in the clinical groups was then compared by analysis of variance with Tukey's or t tests as appropriate.In patients that were otherwise comparable, CXCR2 responses were markedly diminished in the PMNs of patients who went on to sepsis and pneumonia, but were elevated in PMNs from the patients who went on to ARDS. CXCR1 responses were modestly lower in trauma patients than volunteers, but showed no significant variations among the various clinical outcome groups.The activity of PMN CXCR2 receptors soon after injury may be reflected in the later clinical sequelae of PMN activity. High CXCR2 activity may correlate with PMN hyperfunction and outcomes such as ARDS, whereas the loss of CXCR2 function in inflammatory environments may impair PMN functions in a manner that predisposes to pneumonia or sepsis. Early responses of PMN CXC receptors to injury may influence the clinical course of trauma patients.

Background: Activated neutrophils have been shown to play a pivotal role in resuscitation injury after traumatic hemorrhagic shock. Blocking the adhesion of neutrophils with a recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) may reduce resuscitation injury but increase the risk of infection. This was a dose-finding phase II study to determine safety, pharmacokinetics, pharmacodynamics, and clinical outcome parameters for additional studies. Methods: This was a prospective, placebo-controlled, randomized (3:1), double-blind phase II trial enrolling 116 blunt and penetrating trauma patients from 14 trauma centers over a 9-month period. Patients with hypotension (blood pressure ≤90 mm Hg) from hemorrhagic shock were given a single intravenous dose of rhuMAb CD18 or placebo. The three doses tested were 0.5, 1, and 2 mg/kg. The drug was administered within 4 hours of the hypotensive episode and no later than 6 hours from time of injury. Exclusion criteria included head injury resulting in Glasgow Coma Scale score less than 8 or a history of cardiopulmonary resuscitation in the trauma center. An independent Drug Safety and Monitoring Review Board periodically reviewed unblinded data for safety issues and to give approval for dose escalation. Results: Minor and major infection rates in rhuMAb CD18 groups were comparable to placebo. There was no evidence of antibody formation against rhuMAb CD18. Linear PK was observed within the dose range studied. Duration of neutrophil binding was dose-dependent, with 2 mg/kg resulting in greater than 90% neutrophil CD18 receptor saturation for approximately 48 hours. The mortality was 6.7% (2 of 30) in the placebo group, 4.8% (1 of 21) in the 0.5-mg/kg group, 8.5% (4 of 47) in the 1-mg/kg group, and 0% (0 of 18) in the 2-mg/kg group. The study was not powered for efficacy, and none of the efficacy variables demonstrated statistical significance. Favorable trends were seen in the 2-mg/kg group as compared with placebo in median intensive care unit length of stay (5 vs. 9 days) and median time on ventilator (34 vs. 72 hours). Conclusions: A single 2-mg/kg dose of rhuMAb CD18 maintains greater than 90% saturation of neutrophil CD18 receptors for approximately 48 hours in patients with traumatic hemorrhagic shock undergoing resuscitation. There was no trend toward increased infection. A larger trial is needed to demonstrate the clinical efficacy of rhuMAb CD18, perhaps using more reliable endpoints.

Background: Trauma and adult respiratory distress syndrome (ARDS) are associated with increased CXC chemokine (CXC) activity. CXCs such as interleukin (IL)-8 activate polymorphonuclear neutrophils (PMNs) in the lung by means of calcium signals ([Ca2+]i). We studied CXC effects on PMN [Ca2+]i in ARDS and trauma. Methods: Isolated PMNs were loaded with Fura-2 dye. Normal PMNs were incubated in ARDS plasma or volunteer plasma, with or without blocking antibodies to IL-8, growth-related oncogene alpha (GRO-α), or both (n = 6 pairs), and then stimulated with 1 to 10 nmol/L IL-8. PMNs from trauma patients or volunteers (n = 10 pairs) were stimulated with GRO-α, or with sequential GRO-α/IL-8. [Ca2+]i was measured with spectrofluorometry. Results: [Ca2+]i responses to IL-8 were higher after being incubated in ARDS plasma than in volunteer plasma (251 ± 33 vs 218 ± 33 nmol/L, P = .03). Blockade of GRO-α or IL-8 reversed ARDS plasma effects. After GRO-α/IL-8, PMNs from trauma patients demonstrated more Ca2+ store release than did PMNs from volunteers (235 ± 13 vs 170 ± 10 nmol/L, P < .01). Conversely, PMNs from trauma patients lost receptor-operated Ca2+ influx to GRO-α. Conclusions: In traumatic ARDS, plasma CXCs prime PMNs for higher [Ca2+]i flux, making PMN activation more likely. IL-8 and GRO-α interact to modulate these PMN [Ca2+]i responses. (Surgery 1999;126:208-15.)

Laparoscopy is a nearly century-old technique that has experienced a resurgence of interest from surgeons since the development of technology that has broadened its applications. Although laparoscopy has been used to evaluate patients with possible abdominal trauma, its use for this purpose is limited by the availability of other diagnostic procedures that may be more suitable for particular circumstances and are more accurate for certain injuries. Laparoscopy is contraindicated in patients who are hypovolemic or hemodynamically unstable and should not be performed in patients with clear indications for celiotomy. It may not be appropriate for patients with cardiac dysfunction, nor for those with significant head injuries who are at risk for intracranial hypertension. Its best applications may be in stable patients with stab wounds or those with tangential gunshot wounds of the abdomen. The likelihood of missing hollow visceral injuries depends upon the indications for conversion to celiotomy. If peritoneal violation or the presence of a small amount of blood in the peritoneal cavity is used as an indication for celiotomy, then the missed injury rate will be low but the unnecessary celiotomy rate will be diminished only slightly compared with a policy of mandatory celiotomy. Excessive enthusiasm for laparoscopy in trauma might result in its use when other diagnostic measures or simple observation are more appropriate. The desire to perform a procedure can be compelling, especially in circumstances in which the general surgeon would not operate upon a patient but simply provide postoperative care after other surgeons have operated. The use of laparoscopy for these purposes can only be condemned, as it increases the costs and risks of care without improving the outcome. The role of laparoscopy in trauma is evolving, and further research into its diagnostic role and therapeutic applications is clearly needed.

Injury has been hypothesized to cause inflammation through systemic release of lipopolysaccharide and pro-inflammatory cytokines, but this has proved difficult to demonstrate in humans. We looked for evidence of an inflammatory pattern of cytokine gene expression by peripheral blood mononuclear cells (PBM) in six polytraumatized patients (ISS = 25 +/- 8) upon ER admission, and in six matched healthy controls. PBM tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-4, IL-6, IL-10, and interferon (IFN)-gamma message was assessed by semi-quantitative reverse-transcription polymerase chain reaction. No increase in expression of any of the pro-inflammatory cytokines (tumor necrosis factor-alpha, IL-1 beta, or IL-6) was found after trauma, and IFN-gamma tended to decrease. Of the immunosuppressive cytokines, IL-10 expression increased 5-fold (p < .05) but no change in IL-4 was discerned. This pattern is fundamentally different from the cytokine expression patterns expected with sepsis or exposure to lipopolysaccharide. These findings are inconsistent with the occurrence of systemic endotoxemia and subsequent global immunocyte activation early after trauma.

Lactate is a biomarker for hypoperfusion and subsequent resuscitation in trauma. It is also a predictor of mortality, but few studies have correlated lactate levels with relevant morbidities after trauma.A retrospective review was performed of severely injured trauma patients entered into the Trauma Registry of the German Society for Trauma Surgery (TR-DGU) between 2002 and 2008. Adults requiring intensive care were categorized into two groups: lactate and no lactate. The lactate group had three subgroups: normal, elevated, and high lactate. Mean multiple organ failure (MOF) rates and composite endpoint of time (days) to complete organ failure resolution (CTCOFR) for 14 and 21 days and ventilator-free days (VFD) were compared, as well as other endpoints.We analyzed 2,949 patients, of which 1,199 had lactate measurements. The percentage of patients with MOF increased in each higher lactate subgroup (p 0.001), as did the mean CTCOFR14 and CTCOFR21 scores (p 0.001 and 0.001, respectively). Conversely, the mean VFD decreased in each higher lactate subgroup (p 0.001). Thus, patients in the elevated and high lactate subgroups had greater MOF rates; required more days, on average, to resolve organ failure; and required more days of ventilator support than patients in the normal lactate subgroup.Elevated blood lactate levels from trauma were closely correlated with worse outcomes. Thus, lactate shows promise as a biomarker for resuscitation as well as a predictor of mortality. Furthermore, this study supports its use in critical care trials as an outcome measure.

Systemic inflammatory response syndrome (SIRS) is a fundamental host response common to bacterial infection and sterile tissue injury. Systemic inflammatory response syndrome can cause organ dysfunction and death, but its mechanisms are incompletely understood. Moreover, SIRS can progress to organ failure or death despite being sterile or after control of the inciting infection. Biomarkers discriminating between sepsis, sterile SIRS, and postinfective SIRS would therefore help direct care. Circulating mitochondrial DNA (mtDNA) is a damage-associated molecular pattern reflecting cellular injury. Circulating bacterial 16S DNA (bDNA) is a pathogen-associated pattern (PAMP) reflecting ongoing infection. We developed quantitative polymerase chain reaction assays to quantify these markers, and predicting their plasma levels might help distinguish sterile injury from infection. To study these events in primates, we assayed banked serum from Papio baboons that had undergone a brief challenge of intravenous Bacillus anthracis delta Sterne (modified to remove toxins) followed by antibiotics (anthrax) that causes organ failure and death. To investigate the progression of sepsis to "severe" sepsis and death, we studied animals where anthrax was pretreated with drotrecogin alfa (activated protein C), which attenuates sepsis in baboons. We also contrasted lethal anthrax bacteremia against nonlethal E. coli bacteremia and against sterile tissue injury from Shiga-like toxin 1. Bacterial DNA and mtDNA levels in timed samples were correlated with blood culture results and assays of organ function. Sterile injury by Shiga-like toxin 1 increased mtDNA, but bDNA was undetectable: consistent with the absence of infection. The bacterial challenges caused parallel early bDNA and mtDNA increases, but bDNA detected pathogens even after bacteria were undetectable by culture. Sublethal E. coli challenge only caused transient rises in mtDNA consistent with a self-limited injury. In lethal anthrax challenge (n = 4), bDNA increased transiently, but mtDNA levels remained elevated until death, consistent with persistent septic tissue damage after bacterial clearance. Critically, activated protein C pretreatment (n = 4) allowed mtDNA levels to decay after bacterial clearance with sparing of organ function and survival. In summary, host tissue injury correlates with mtDNA whether infective or sterile. Mitochondrial DNA and bDNA polymerase chain reactions can quantify tissue injury incurred by septic or sterile mechanisms and suggest the source of SIRS of unknown origin.

Background: Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. Methods: We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 μg/kg initially; 100 μg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma "bundles" with formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. Results: Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10.8% vs. 27.5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11.0% (rFVIIa) versus 10.7% (placebo) (p = 0.93, blunt) and 18.2% (rFVIIa) versus 13.2% (placebo) (p = 0.40, penetrating). Blunt trauma rFVIIa patients received (mean ± SD) 7.8 ± 10.6 RBC units and 19.0 ± 27.1 total allogeneic units through 48 hours, and placebo patients received 9.1 ± 11.3 RBC units (p = 0.04) and 23.5 ± 28.0 total allogeneic units (p = 0.04). Thrombotic adverse events were similar across study cohorts. Conclusions: rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.

Background: Bleeding is one of the leading causes of preventable death after traumatic injury. Trauma-associated coagulopathy complicates the control of bleeding. The published approaches on the management of this coagulopathy differ significantly. Methods: A qualitative international survey of clinical practice among senior physicians responsible for the treatment of patients with multiple injuries (Injury Severity Score greater than 16) was conducted to document common practices, highlight the variabilities, and profile the rationale behind existing clinical practices around the world. Results: Survey results are based on 80 (32%) completed returns, representing 25 countries with 93% of respondents employed by trauma centers and a mean of 20 years clinical experience. There are regional differences in the clinical specialty of physicians responsible for trauma management decisions. Blood loss, temperature, pH, platelets, prothrombin time/INR/activated partial thromboplastin time, and overall clinical assessment, were the most common criteria used to assess coagulopathy. Forty-five percent of respondents claimed to fol- low a massive transfusion protocol in their institution, 19% reported inconsistent protocol use and 34% do not use a protocol. The management of hypothermia, acidosis, blood products, and adjuvant therapy showed regional as well as institutional variability, and surprisingly few massive transfusion protocols specifically address these issues. Conclusions: The results of this survey may serve to draw attention to the need for a common definition of coagulopathy and standardized clinical protocols to ensure optimal patient care.

Background: Bleeding is the most frequent cause of preventable death after severe injury. Coagulopathy associated with severe injury complicates the control of bleeding and is associated with increased morbidity and mortality in trauma patients. The causes and mechanisms are multiple and yet to be clearly defined. Methods: Articles addressing the causes and consequences of trauma-associated coagulopathy were identified and reviewed. Clinical situations in which the various mechanistic causes are important were sought along with quantitative estimates of their importance. Results: Coagulopathy associated with traumatic injury is the result of multiple independent but interacting mechanisms. Early coagulopathy is driven by shock and requires thrombin generation from tissue injury as an initiator. Initiation of coagulation occurs with activation of anticoagulant and fibrinolytic pathways. This Acute Coagulopathy of Trauma-Shock is altered by subsequent events and medical therapies, in particular acidemia, hypothermia, and dilution. There is significant interplay between all mechanisms. Conclusions: There is limited understanding of the mechanisms by which tissue trauma, shock, and inflammation initiate trauma coagulopathy. Acute Coagulopathy of Trauma-Shock should be considered distinct from disseminated intravascular coagulation as described in other conditions. Rapid diagnosis and directed interventions are important areas for future research.

We tested the hypothesis that the female intestine is more resistant to gut I/R injury than the male intestine by comparing the effects of the isolated pure gut I/R superior mesenteric artery occlusion (SMAO) model on gut morphology and whether SMAO-induced distant organ injury (lung, bone marrow [BM], neutrophils, and red blood cells [RBCs]) would differ between male and proestrus female rats. At 6 or 24 h after SMAO or sham SMAO, gut injury, lung permeability, pulmonary neutrophil sequestration, RBC deformability, and BM RBC and white blood cell progenitor growth were measured, as was the ability of the plasma from these rats to activate naive rat neutrophils. At both 6 and 24 h after SMAO, the female rats had significantly less intestinal injury and reduced gut-induced lung injury, BM suppression, RBC dysfunction, and neutrophil activation than male rats subjected to SMAO. These results indicate that the resistance of proestrus female rats to gut injury and gut-induced distant organ injury is greater than that observed in male rats.

Background Patients with minimal head injury (MHI) and intracranial bleed (ICB) detected on cranial computed tomography (CT) scan routinely undergo a repeat cranial CT within 24 hours after injury to assess for progression of intracranial injuries. While this is clearly beneficial in patients with a deteriorating neurologic status, it is of questionable value in patients with a normal neurologic examination. The goal of this study was to prospectively assess the value of a repeat cranial CT in patients with a MHI and an ICB who have a normal neurologic examination. Methods A prospective analysis of all adult patients admitted to a Level I trauma center after blunt trauma causing a MHI (defined as the loss of consciousness or posttraumatic amnesia with a Glasgow Coma Scale (GCS) score of greater or equal to 13) and an ICB on the initial cranial CT during a 12-month period (July 2002 through July 2003) was performed. All patients with MHI were prospectively evaluated and followed until discharge. Data collected included demographics, neurologic examination and findings on the initial and repeat cranial CT scan. Outcome data included neurologic deterioration, neurosurgical intervention, and Glasgow Outcome Scale (GOS) on discharge. Results In all, 161 consecutive patients with MHI and a positive cranial CT scan were identified. The initial cranial CT lead to a neurosurgical intervention (1 craniotomy, 4 intracranial pressure monitors) in 4% of cases. The remaining 130 patients who met inclusion criteria, underwent a repeat cranial CT scan within 24 hours postadmission. Ninety nine (76%) patients had a normal neurologic examination at the time of their repeat cranial CT. After the repeat cranial CT none required immediate neurosurgical intervention or had delayed neurologic deterioration related to their head injury. Fifteen patients underwent additional neuroradiologic studies but none showed further progression of their ICB or lead to a change in management. One patient died from non-traumatic brain injury related causes and of the remaining 26 patients, 98% had an overall favorable GOS score (> 3) on discharge. In this group of patients with MHI and ICB, the negative predictive value of a normal neurologic examination was 100%. Conclusions Repeat cranial CT, in patients with a MHI and a normal neurologic examination, resulted in no change in management or neurosurgical intervention and is therefore not indicated. A multicenter prospective study would further validate these conclusions, reduce unnecessary CT scans, and likely improve our current standard of care in these patients.

Background: Because the ischemic gut may produce factors that initiate systemic inflammation, we tested the hypothesis that factors released from the gut into the mesenteric lymphatics increase neutrophil (PMN) adhesion molecule expression after trauma and shock. Methods: At 1 and 4 hours after hemorrhagic shock (30 mm Hg x 90 minutes) plus trauma (laparotomy) (T/HS) or sham-shock (T/SS), with or without mesenteric lymph duct ligation, PMN CDllb and CD18 expression was assessed in male rats. In additional rats, mesenteric lymph samples were tested for their ability to increase PMN CDllb expression in vitro. Lastly, at 4 hours after T/SS or T/HS with or without lymph duct ligation, pulmonary PMN sequestration was measured. Results: Compared with T/SS rats, T/HS was associated with up-regulation of PMN CD11b and CD18 expression, which was largely prevented by ligation of the mesenteric lymph duct (p < 0.01). Lymph duct ligation also prevented T/HS-induced pulmonary leukocyte sequestration (p < 0.01). In addition, mesenteric lymph from rats subjected to T/HS but not T/SS increased CD11b expression (p < 0.01). Conclusion: Factors produced or released by the postischemic intestine and carried in the mesenteric lymph appear responsible for PMN activation and pulmonary PMN sequestration after an episode of T/HS.

Background Patients with minimal head injury (MHI) and a cranial computed axial tomography (CAT) scan positive for the presence of intracranial injury routinely undergo a repeat CAT scan within 24 hours after injury. The value of this repeat cranial CAT scan is unclear in those patients who are neurologically normal or improving. Methods A retrospective analysis of all adult patients admitted to a level-1 trauma center with MHI and a positive cranial CAT scan during a 32-month period was performed. The need for neurosurgical intervention after repeat CAT scan in patients with a persistently normal or improved neurological examination was recorded. Results One hundred fifty-one patients had a persistently normal or improved neurological examination, but none of these patients required neurosurgical intervention after the repeat cranial CAT scan. Conclusions A persistently normal or improving neurological examination in a patient with MHI appears to exclude the need for neurosurgical intervention and thus a repeat cranial CAT scan.

The literature supports the concept that autopsies are useful in uncovering missed injuries or undiagnosed conditions that contribute to death after injury, especially late deaths that take place in the intensive care unit. Review of autopsies are also used as part of the trauma quality assurance (QA) process, and autopsy rates are queried by the American College of Surgeons Committee on Trauma in their reviews. Our hypothesis was that autopsies add little useful clinical or diagnostic information compared with QA peer review analysis in a mature trauma program.Autopsies for all mortalities at a Level I trauma center between January 1998 and October 1999 were reviewed. The autopsies were reviewed in a "blinded" fashion such that each review occurred before examination of the chart, the trauma registry, and the findings of the trauma QA peer review. Findings from all sources were compared and examined for Goldman type errors (I-IV).Two hundred sixty-three mortalities were identified, with 216 autopsies reviewed. One hundred two (39%) mortalities were considered dead on arrival to the trauma center by QA review, with no management errors identified (group 1) (Immediate Death group). Sixty-one patients survived more than 48 hours after injury (group 2). One hundred sixty-one (61%) patients were admitted to the hospital. Ninety-nine patients died within 48 hours (Early Death group) and 62 died between 2 and 143 days (Late Death group). There were no Goldman type I errors (major diagnostic discrepancies that might have influenced mortality) identified in either group. Autopsy data did uncover one potentially technical error in a death that was considered nonpreventable on peer review analysis.We conclude that autopsy information for either group appeared to add little useful information to the QA peer review of deaths in a mature trauma program. This was true even in cases where the final QA determination was held pending the results of the autopsy. Autopsy rates may not be a useful parameter in evaluating a trauma QA program.

That granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor modulate the suppression of apoptosis (Ao) of normal neutrophils incubated in the plasma of patients with postraumatic acute respiratory distress syndrome (ARDS).Experimental study using cultured human neutrophils.University hospital, level I trauma center.Plasma was obtained from 14 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 22). All samples were drawn within 24 hours after injury. Plasma was also taken from up to 21 healthy control subjects. These volunteers were also used as sources of polymorphonuclear leukocytes (PMNs).(1) Effect of early, fulminant ARDS and normal plasma on spontaneous Ao and GM-CSF receptor expression in PMNs in vitro. (2) Effect of ligation of either GM-CSF or its receptor with a neutralizing monoclonal antibody (mAb) on PMN Ao in ARDS and normal plasma. (3) Correlation of extracellular GM-CSF concentration with rate of PMN Ao. (4) Levels of GM-CSF in ARDS and normal plasma and in culture supernatant of normal PMNs incubated in early, fulminant ARDS and normal plasma.Plasma from patients with ARDS enhanced PMN viability at 24 hours (data are given as mean +/- SEM) 52% +/- 3% control vs 60% +/- 3% ARDS, P.05). Binding of the GM-CSF receptor with a neutralizing mAb significantly reduced PMN viability in ARDS plasma, but not in normal plasma (60% +/- 3% ARDS vs 53% +/- 3% ARDS + mAb, P.05). Ligation of GM-CSF with mAb had no significant effect on PMN viability in either plasma. Only 1% of PMNs expressed detectable levels of the GM-CSF receptor when incubated for 24 hours in either ARDS or normal plasma. The GM-CSF levels were undetectable (7 pg/mL) in both ARDS and normal plasma and in culture supernatants taken after 24 hours of incubation in both plasma types. Levels of GM-CSF ranging from 0 to 50000 pg/mL had no effect on PMN Ao in plasma-free medium.The antiapoptotic effect of ARDS plasma appears to be mediated by the GM-CSF receptor. This effect occurs at both low levels of plasma GM-CSF and surface expression of its PMN receptor. Ligation of GM-CSF had no effect of PMN Ao, suggesting that Ao is triggered by Fc portion-mediated receptor cross-linking. These results provide the theoretical basis for alphaGM-CSF receptor mAb therapy as a novel modality of treatment for ARDS.

Introduction: The preferred chest tube (CT) removal algorithm has not yet been established. The purpose of this study was to determine which technique, water seal or suction, allowed for shorter CT duration. In addition, the recurrent pneumothorax (PTX) rate, the need for CT reinsertion, and the total number of chest x-ray films (CXR) were determined. Methods: Prospective randomized trial of 205 trauma patients, older than 15 years of age, requiring tube thoracostomy for blunt and penetrating trauma. Patients requiring mechanical ventilation more than 24 hours were excluded from the study. Informed consent was obtained from all patients. Chest tubes were randomized for removal when output was less than 150 mL/24 hours, CXR revealed no significant PTX, and no air leak was present. Patients in the water seal group were disconnected from low wall suction and a CXR was obtained 6 to 8 hours later. Chest tubes in the no water seal group were disconnected from wall suction and pulled immediately. All tubes were removed by using standard protocol with patients at maximal inspiratory effort. A follow-up CXR was obtained after removal. Results: Of the 205 patients, 93 patients (45%) were randomized to the water seal group and 112 patients (54%) to the no water seal group. Four patients in the water seal group developed a PTX before CT removal and were considered treatment failures. After CT removal, repeat PTX was seen in 13 patients in the water seal group and in 9 patients in the no water seal group. However, seven patients in the no water seal group required CT reinsertion compared with one in the water seal group (p < 0.05). Average number of CXR in the water seal group was 6.5 compared with 5.5 radiographs in the no water seal group. There was no difference in chest tube duration or hospital length of stay between groups for either all patients or only those patients with isolated chest injuries. Patients who required another CT had a hospital length of stay twice that of patients who did not. Conclusions: It is possible that patients in the no water seal group did not have sufficient time for a possible PTX to evolve, which resulted in a larger and more significant PTX requiring another CT. Although there was no difference in chest tube duration between the no water seal and water seal groups, a short trial of water seal appears to allow occult air leaks to become clinically apparent and reduces the need for another CT.

Background: Trauma is believed to activate immunocytes but paradoxically also increases the risk of intraperitoneal infection. Objective: To investigate these events by evaluating changes in the cytokine control networks of human peritoneal macrophages (PMo) early after trauma. Design: Case-control study comparing cytokine messenger RNA (mRNA) expression by PMo from patients with extra-abdominal trauma with that of both peripheral blood mononuclear cells (PBM) and PMo obtained from healthy individuals. Setting: Level I trauma center and basic science laboratory in a university hospital center. Patients: Six patients with polytrauma (Injury Severity Score, ≥15) with clinically negative diagnostic peritoneal lavages performed on routine indications at admission to the emergency department and six healthy age- and sex-matched individuals undergoing inguinal herniorrhaphy under local anesthesia. Interventions: Peritoneal macrophages were isolated from diagnostic peritoneal lavages in trauma patients. Identical lavages were performed through the hernia sac in the control group. Measurements: Cellular RNA was assayed for tumor necrosis factor α (TNF-α), interleukin-1β, IL-6, and IL-10 message by semiquantitative reverse-transcription polymerase chain reaction. Results: Normal PMo expressed high levels of TNF-α mRNA relative to PBM, but expression of the other proinflammatory cytokines was equivalent to that of PBM. Peritoneal macrophage expression of TNF-α mRNA was markedly (64-fold) decreased after trauma ( P P =.03). Conclusions: Human PMo constitutively show high levels of TNF-α message expression, and this is down-regulated by polytrauma. This might constitute a functionally "primed" state. If so, TNF-α down-regulation might contribute to functional PMo suppression after systemic injury. (Arch Surg. 1995;130:1186-1192)

Trauma is a major cause of death worldwide, with some 30% of deaths associated with hemorrhage. Rapid control of bleeding in such patients is thus an essential aspect of trauma care. Recombinant human factor VIIa is sometimes used off-label in massively bleeding patients and has been demonstrated in two randomized trials to significantly reduce the need for blood transfusions. Whether this translates into improved outcomes has not been determined, most notably because mortality appears to be much lower than in the past as a result of improved general care of trauma patients. In this setting it may be increasingly difficult to demonstrate that any intervention can influence survival since the number of patients needed for sufficient power is so high and the duration needed for recruitment of the patients too long. In the present commentary, we reflect on how we can move forward in the management of severely bleeding trauma patients in the current environment. © 2011 BioMed Central Ltd., Editorial, SCOPUS: no.j, info:eu-repo/semantics/published

Methods: Sprague-Dawley rats were divided into 3 groups: unmanipulated controls (C), shock (SH), or shock with lymph ligation (SLL). Shocked animals (MAP 5 30mmHg for 90 min) underwent laparotomy 6 mesenteric lymph ligation. Rats were resuscitated with shed blood and fluid. Groups were sacrificed at 3 hours and BM mononuclear cells were cultured for myeloid (CFU-GM) and erythroid (CFU-E) progenitors, and immature progenitors (cobblestone area forming cells, CAFC). We also determined the effects of plasma from C, SH or SLL rats on CFU-GM and CFU-E by culturing BM cells from normal rats with plasma (2% v/v).

Background: Patients with major fracture/soft-tissue injuries are at risk for adult respiratory distress syndrome after secondary infection. Fracture fluids (FF) are rich in neutrophil (PMN) -specific chemokines such as interleukin-8. PMN respond to both interleukin-8 and bacterial stimuli with calcium ([Ca 2+ ] i ) fluxes, which can initiate respiratory burst (RB). We hypothesize that small amounts of FF entering the circulation could exaggerate PMN [Ca 2+ ] i and RB responses, potentially increasing the risk of adult respiratory distress syndrome. Methods: FF were obtained from 10 patients at open fixation of the femur 2 to 5 days postinjury. Volunteer PMN were isolated and loaded with fura dye. PMN were preincubated either in 30% autologous plasma (AP)/70% buffer, or in 5% FF/25% AP/70% buffer. Cells were resuspended in buffer with 1,2,3-dihydrorhodamine and stimulated with low-dose n-formylmethionyl-leucyl-phenylalanine (fMLP). [Ca 2+ ] i was assayed by fura fluorescence at 505 nm after excitation at 340/380 nm. RB was assessed by 1,2,3-dihydrorhodamine fluorescence at 530 nm after 488 nm excitation. Results: PMN basal [Ca 2+ ] i was higher after FF incubation than AP incubation (94 ± 12 vs. 61 ± 9 nmol/L, p = 0.0002). Peak [Ca 2+ ] i response to fMLP was 475 ± 47 nmol/L after FF but only 356 ± 22 nmol/L after AP (p = 0.01). Two hundred seconds after fMLP, [Ca 2+ ] i remained higher after FF (172 ± 17 vs. 145 ± 9 nmol/L, p = 0.04). Basal RB was slightly higher after FF than AP (13.4 ± 0.3 vs. 11.3 ± 0.3 units, p = 0.051) as was the maximal rate of extracellular oxidant release (1.10 ± 0.17 vs. 0.76 ± 0.16 units/s, p = 0.004) and total oxidant production (42.5 ± 0.8 vs. 31.7 ± 0.8 units, p = 0.006). Conclusion: Small amounts of FF in plasma can exaggerate PMN [Ca 2+ ] i flux and RB responses to subsequent bacterial stimuli. These findings are consistent with the hypothesis that release of FF into the circulation primes PMN and, thus, may predispose to adult respiratory distress syndrome. Such PMN priming events might have important implications for both the operative and medical management of patients with major fractures.

To evaluate the role of interleukin 8 (IL-8) in the regulation of neutrophil (PMN) apoptosis in normal plasma and plasma from patients with early, fulminant acute respiratory distress syndrome (ARDS).Experimental study using cultured human PMNs.University hospital, level I trauma center.Plasma was obtained from 6 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 26). All samples were drawn within 24 hours after injury. Plasma was also taken from 13 healthy control subjects. These controls were also used as sources of PMNs.Effect of early, fulminant ARDS and normal plasma on spontaneous apoptosis, CD16, and CD11-b expression in PMNs in vitro; levels of IL-8 in plasma; correlation of extracellular IL-8 concentration with rate of PMN apoptosis; and effect of IL-8 blockade on PMN apoptosis, CD16, and CD11-b expression in ARDS and normal plasma.Plasma from patients with early, fulminant ARDS inhibited spontaneous PMN apoptosis at 24 hours (35%+/-5% vs 54%+/-5%; P=.01). Neither CD16 nor CD1l-b differed significantly between the 2 groups. The mean plasma level of IL-8 in patients with early, fulminant ARDS was 359+/-161 pg/mL vs 3.0+/-0.4 pg/mL in healthy controls (P.05). Interleukin 8 inhibited apoptosis in plasma-free medium at low doses (1-50 pg/mL) but had no significant effect at higher doses (100-5000 pg/mL) (P.05). Interleukin 8 blockade with monoclonal antibody suppressed apoptosis in normal plasma (28%+/-5% with monoclonal antibody vs 51%+/-5% without monoclonal antibody; P=.008) but not in plasma from patients with early, fulminant ARDS (29%+/-5% with monoclonal antibody vs 34%+/-6% without monoclonal antibody; P=.67). It had no effect on CD16 or CD11-b expression in either plasma.Plasma from patients with early, fulminant ARDS contains soluble factors that inhibit PMN apoptosis in vitro. Low levels of IL-8 inhibit PMN apoptosis in normal plasma. Although plasma levels of IL-8 are markedly elevated in early, fulminant ARDS, IL-8 is not directly responsible for the antiapoptotic effect of plasma from patients with early, fulminant ARDS.