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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.

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.

Surgical site infections (SSIs) are important sources of morbidity, prolonged hospital stays, and readmissions, so they have become a major economic burden. We hypothesized that surgical wound assessment by sonography (SWATS) used at the bedside would detect wound fluid collections and that the presence of such collections would predict SSI better than standard clinical examination. If so, SWATS might be used to indicate early intervention that could prevent SSI morbidity.A prospective, single-institution observational study was conducted on adult inpatients following open abdominal surgery for trauma, gastrointestinal pathology, or biliary pathology at high risk (5%) for SSI using traditional wound classifications. After informed consent was obtained, SWATS was performed using a smartphone-based ultrasound system on postoperative Day 2 to 4 and again before discharge or at postoperative Day 30, whichever came first. Primary treating physicians delivered standard wound care and were blinded to SWATS. SSI was diagnosed if treatment was implemented for suspected or documented wound infection by the treating physician. Results were analyzed by χ test and two-sample pooled variance t test where appropriate, with significance set at p0.05.Forty-nine patients were studied. Nineteen patients had peri-incisional fluid collections found by SWATS. Eight of these patients went on to develop an SSI. SSI was significantly associated with the presence of fluid collections on SWATS (p = 0.009). SWATS had a sensitivity of 72.7% (0.43-0.92), a specificity of 71.1% (0.62-0.77), a positive predictive value of 42.1% (0.25-0.53), and a negative predictive value of 90.0% (0.79-0.97).SWATS has a high negative predictive value that may allow it be an effective screening tool for developing SSI in high-risk surgical wounds. SWATS has the potential to be a useful and cost-effective adjunct to the clinician by objectively suggesting need for early therapy. Further study with larger sample sizes and randomized, SWATS-based interventions are required to validate this small study and determine its place in clinical care.Diagnostic study, level IV.

Background: Phlegmonous gastritis is a rare and highly lethal primary bacterial infection of the stomach. The pathogenesis of this disease is understood poorly and no detailed description of its associated findings on computed tomography has been reported. Methods: Case report and literature review. Case Report: The authors describe an 84-year-old male with phlegmonous gastritis presenting as an abdominal catastrophe with portal venous pneumatosis observed on computed tomography. Conclusion: The association of portal venous air and related computed tomographic findings suggesting compromise of the gastric wall should be regarded with suspicion, and the possibility of phlegmonous gastritis should be entertained. Broad-spectrum antibiotic coverage should be instituted. Gram stain of the tissues of the stomach wall may help direct antibiotic therapy toward streptococcal infections as opposed to polymicrobial processes.

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.

Muscle wasting in various catabolic conditions is at least in part regulated by glucocorticoids. Increased calcium levels have been reported in atrophying muscle. Mechanisms regulating calcium homeostasis in muscle wasting, in particular the role of glucocorticoids, are poorly understood. Here we tested the hypothesis that glucocorticoids increase intracellular calcium concentrations in skeletal muscle and stimulate store-operated calcium entry (SOCE) and that these effects of glucocorticoids may at least in part be responsible for glucocorticoid-induced protein degradation. Treatment of cultured myotubes with dexamethasone, a frequently used in vitro model of muscle wasting, resulted in increased intracellular calcium concentrations determined by fura-2 AM fluorescence measurements. When SOCE was measured by using calcium “add-back” to muscle cells after depletion of intracellular calcium stores, results showed that SOCE was increased 15–25% by dexamethasone and that this response to dexamethasone was inhibited by the store-operated calcium channel blocker BTP2. Dexamethasone treatment stimulated the activity of calcium-independent phospholipase A2(iPLA2), and dexamethasone-induced increase in SOCE was reduced by the iPLA2inhibitor bromoenol lactone (BEL). In additional experiments, treatment of myotubes with the store-operated calcium channel inhibitor gadolinium ion or BEL reduced dexamethasone-induced increase in protein degradation. Taken together, the results suggest that glucocorticoids increase calcium concentrations in myocytes and stimulate iPLA2-dependent SOCE and that glucocorticoid-induced muscle protein degradation may at least in part be regulated by increased iPLA2activity, SOCE, and cellular calcium levels.

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.

Bone marrow (BM) dysfunction after trauma and hemorrhagic shock (T/HS) results in a decrease in clonogenic growth of BM progenitors through a plasma-mediated process. Although sex hormones have been shown to modulate some end-organ injury after shock, post-T/HS BM dysfunction has only been studied in male animals. Therefore, the present study examines the effects of sex hormones on post-T/HS BM dysfunction by measuring clonogenic growth of BM progenitors in castrated male rats and in ovariectomized and proestrus female rats.Laboratory experiment.University surgical research laboratory.Castrated and noncastrated male and ovariectomized and proestrus female Sprague-Dawley rats.All rats were subjected to either T/HS or sham shock with laparotomy (n = 3-5 per group). At 3 hrs after resuscitation, the rats were killed and plasma and BM mononuclear cells from bilateral femurs were harvested.BM mononuclear cells were cultured for erythroid burst-forming unit and granulocyte-macrophage colony-forming unit colonies to assess the extent of progenitor BM dysfunction. BM from noncastrated male rats subjected to T/HS demonstrated a significant decrease in granulocyte-macrophage colony-forming unit and erythroid burst-forming unit colony formation compared with BM of all the sham shock groups and with the castrated male and both female rat groups subjected to T/HS. In addition, plasma from noncastrated shocked male rats incubated in vitro with BM cells from unmanipulated male rats caused a significant suppression of BM granulocyte-macrophage colony-forming unit and erythroid burst-forming unit colonies compared with plasma from castrated rats subjected to either sham shock with laparotomy or T/HS.The profound BM dysfunction observed in noncastrated male rats after T/HS is not observed in proestrus female rats and castrated male rats. In addition, the in vitro plasma-mediated BM suppression present in male rats after T/HS is also lost in castrated male rats. Sex hormones seem to play a significant role in BM dysfunction after T/HS.

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.

Background: Prolonged courses of broad-spectrum antibiotics are often cited as the standard of care for prevention of infective complications of open fractures. The origins of these recommendations are obscure, however, and multi-drug-resistant systemic infections attributable to antibiotic overuse are common life-threatening problems in current intensive care unit practice. Objective: To review systematically the effects of prophylactic antibiotic administration on the incidence of infections complicating open fractures. Data Sources: Computerized bibliographic search of published research and citation review of relevant articles. Study Selection: All published clinical trials claiming to evaluate, or cited elsewhere as being authoritative regarding, the role of antibiotics in open fracture management were identified and then evaluated according to published guidelines for evidence-based medicine. Only small studies (

Bone marrow (BM) suppression occurs following trauma/hemorrhagic shock (T/HS) in experimental animals as well as following severe injury in humans. Although the pathophysiology of BM suppression remains poorly understood, mesenteric lymph is thought to play an important role in T/HS-induced BM suppression; however, the direct effect of mesenteric lymph on BM in vitro has never been studied. In addition, recent studies in rats have also shown that female and castrated male rats are protected against T/HS-induced BM failure. We therefore hypothesized that mesenteric lymph is a source of factor(s) causing direct BM suppression and that the effects of mesenteric lymph are gender dependent. To test this hypothesis, we subjected noncastrated (NC) and castrated (C) male and proestrus female rats to T/HS or trauma sham shock (T/SS). Mesenteric lymph collected 3 h postshock was plated (4% v/v) with BM cells collected from unmanipulated male or female rats for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) colony growth. The T/HS lymph collected from NC-male rats but not from female rats caused a 50% inhibition of CFU-GM and BFU-E colony growth compared with cells cultured without lymph (P < 0.05 versus all other groups (ANOVA + Tukey). T/HS lymph collected from C-male rats also caused no significant inhibition of CFU-GM and BFU-E colony growth compared with cells cultured without lymph. Female and male BM progenitor cells had a similar response to mesenteric lymph from all groups tested. These results show that mesenteric lymph from NC-male rats suppresses CFU-GM and BFU-E progenitor growth in vitro, whereas the lymph from C-male and female rats did not. The effects of mesenteric lymph were the same regardless of whether the target BM was from male or female rats. The results therefore indicate that BM failure in male rats is directly mediated by factors present within the mesenteric lymph that appear to be modulated by castration, and protection against BM failure in female rats occurs at a systemic rather than a local level. Further studies are needed to elucidate potential therapeutic effects of lymph manipulation in hematopoiesis after injury.

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.

Background: Unexpected immuno-modulatory effects of colloids and crystalloids prompted an investigation of albumin's ability to prevent bone marrow (BM) suppression following trauma/hemorrhagic shock (T/HS: laparotomy + MAP 30 for 90 mins). Methods: In vitro: Normal rat BM was plated for granulocyte-macrophage (CFU-GM) and erythrocyte colony forming units (BFU-E) with 2% v/v plasma from sham (T/SS) or T/HS rats and albumin (2-8 mg/mL). In vivo: Male rats (n = 4/group) were subjected to T/SS or T/HS and resuscitated with shed blood and twice the volume as Lactated Ringer's (LR) or blood and 1, 2, or 3 mL of albumin (50 mg/mL). Bone marrow harvested 3 hours post-resuscitation was plated for CFU-GM and BFU-E. Results: In vitro: T/HS plasma decreased both CFU-GM and BFU-E growth as compared with T/SS, whereas increasing doses of albumin showed dose-dependent improvement in progenitor growth (p < 0.05). In vivo: The suppression of BM red and white cell progenitor growth seen in T/HS+LR rats as compared with T/SS was fully prevented by as little as 1 mL of albumin (p < 0.05). Conclusions: Small doses of albumin fully restore CFU-GM and BFU-E to sham values. We postulate that the binding of circulating toxic factors by albumin may play a role in this prevention of T/HS-induced BM suppression.

G protein-coupled chemoattractants recruit neutrophils (PMN) to sites of injury and infection. The leukotrienes (LT) and CXC chemokines (CXC) and their receptors (BLT1/BLT2 and CXCR1/CXCR2) are all known to play roles in these responses. Each system has been studied separately in vitro, but in vivo they act concurrently, and the clinical interactions between the two systems are unstudied. We prospectively studied calcium mobilization and chemotactic responses to LTB4 in PMN from major trauma patients. The responses of the high affinity BLT1 receptor were suppressed at the 3-day postinjury time point, but recovered by 1 wk. Trauma patients had transient elevations of plasma LT and CXC levels. Functional deficits identical with those in trauma PMN were reproduced in vitro by exposing healthy PMN to CXCs at the elevated plasma concentrations found. Functional responses to LTB4 were suppressed by cross-talk with CXC and BLT2 receptors that desensitize BLT1. Since the suppression of intracellular calcium mobilization was prominent, we also studied the role of suppressed cell calcium mobilization in the defective chemotactic responses to LTB4. We noted that PMN chemotaxis to LTB4 showed far more dependence on store-operated calcium entry than on the release of cellular calcium stores, and that store-operated calcium responses to BLT1 activation were markedly inhibited during the same time period as was chemotaxis. The intermittent release of inflammatory mediators after injury can blunt PMN responses to LTs by suppressing BLT1 as well as downstream calcium entry. Diminished LT receptor activity due to cross-talk with CXC receptors can inhibit PMN recruitment to infective sites. This may predispose injured patients to septic complications.

Objective: Concern for thoracolumbar spine (TLS) injuries after major trauma mandates immobilization pending radiographic evaluation. Current protocols use standard posteroanterior and lateral radiographs of the thoracolumbar spine (XR/TLS), but many patients also undergo abdominal or thoracic computed tomographic (CT) scanning. We sought to evaluate whether helical truncal CT scanning performed to evaluate visceral trauma images the spine as well as dedicated XR/TLS. Methods: We prospectively studied 222 consecutive patients sustaining high-risk trauma requiring TLS screening because of clinical findings or altered mentation. The chest, abdomen, and pelvis were imaged with one intravenous contrast infusion. All patients had CT scan of the chest, abdomen, and pelvis (CT/CAP) and XR/TLS. Initial radiologic diagnoses were compared with the discharge diagnosis of acute fractures confirmed by thin-cut CT scan and/or clinical examination of the patient when alert. Results: Of 222 patients studied, 215 were fully evaluated. Thirty-six (17%) had acute TLS fractures. The accuracy of CT/CAP for TLS fractures was 99% (95% confidence interval [CI], 96-100%). The accuracy of XR/TLS was 87% (95% CI, 82-92%). Sensitivity, specificity, and positive and negative predictive values were better for CT/CAP than for XR/ TLS. CT/CAP found acute fractures XR/ TLS missed, and correctly classified old fractures XR/TLS read as "possibly" acute. The total XR/TLS misclassification rate was 12.6% (95% Cl, 8.4-19%); for CT/CAP it was 1.4% (95% CI, 0.3-3.3%). No fractures were missed by CT/CAP. No unstable fracture was missed by either technique. Conclusion: CT/CAP diagnoses TLS fractures more accurately than XR/TLS. Neither misses unstable fractures, but CT scanning finds small fractures that benefit by treatment and identifies chronic disease better. CT screening is far faster and shortens time to removal of spine precautions. CT scan-based diagnosis does not result in greater radiation exposure and improves resource use. Screening the TLS on truncal helical CT scanning performed for the evaluation of visceral injuries is more accurate than TLS imaging by standard radiography. CT/CAP should replace plain radiographs in high-risk trauma patients who require screening.

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 aim of this study is to assess the associations between the timing of secondary definitive fracture surgery on inflammatory changes and outcome in the patient with multiple injuries. The study population consists of a series of patients with multiple injuries who were managed using a strategy of primary temporary skeletal stabilization followed by delayed definitive fracture fixation.In a prospective cohort study performed at a Level I trauma center, the patients' injuries and operative details as well as immune markers and clinical outcomes were studied. The patients were split into an early secondary surgery group (group ESS, surgery at days 2-4) and a late secondary surgery group (group LSS, surgery at days 5-8). During the posttraumatic course, inflammatory markers (interleukin [IL]-6, tumor necrosis factor-alpha) were determined on a daily basis. Perioperatively, these markers were additionally evaluated at 30 minutes, 7 hours, and 24 hours after initiation of surgery.Secondary surgery on days 2 to 4 was associated with a higher incidence of postoperative organ dysfunction (n = 33 [46.5%]) than secondary surgery on days 5 to 8 (n = 9 [15.7%], p = 0.01). A significant association between the combination of initial IL-6 values500 pg/dL plus surgery on days 2 to 4 and the development of multiple organ failure (r = 0.96, p0.001) occurred. A correlation between the initial IL-6 values500 pg/dL and surgery on days 5 to 8 (r = 0.57, p0.07) could not be found. IL-6 also demonstrated a predictive value for the development of multiple organ failure: IL-6500 pg/dL in group ESS, r = 0.96, p0.001; IL-6500 pg/dL in group LSS, r = 0.57, p0.07.According to our data, no distinct clinical advantage in carrying out secondary definitive fracture fixation early could be determined. In contrast, in patients who demonstrated initial IL-6 values above 500 pg/dL, it may be advantageous to delay the interval between primary temporary fracture stabilization and secondary definitive fracture fixation for more than 4 days. In patients with blunt multiple injuries undergoing primary temporary fixation of major fractures, the timing of secondary definitive surgery should be carefully selected, because it may act as a second hit phenomenon and cause a deterioration of the clinical status.

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.)

Trauma has a high rate of recurrence, suggesting that some people are more injury-prone than others. This study was performed to evaluate some of the psychological and social factors that might influence the likelihood of traumatic injury.A case-control study was conducted to evaluate the relationship between selected psychosocial factors and traumatic injury. At a Level I trauma center, victims of intentional trauma (excluding attempted suicide), victims of nonintentional trauma, and patients undergoing elective surgery were interviewed by a person blinded to the purposes of the study. They were given an intelligence test and underwent a structured interview, yielding psychiatric diagnostic categories established in the third edition of the Diagnostic and Statistical Manual of Mental Disorders, Revised (DSM-III-R).Trauma patients were younger than elective surgery patients (p0.01) and were more likely to be men (p0.01). Victims of intentional injury had a higher probability of alcohol use (p0.01) and admitted illicit drug use (p0.001) than either nonintentional injury victims or elective surgery patients. Victims of intentional injury were more likely to be unemployed than those in the other two groups (p0.02), whereas elective surgery patients were more likely to be retired (p0.05) or to be disabled (p0.0001). The average intelligence score was slightly above the median in the nonintentional trauma group and in the control group (55th percentile and 54th percentile, respectively), compared with a mean intelligence score equivalent to the 35th percentile in the victims of intentional trauma (p0.001). Thirty percent of elective surgery patients met diagnostic criteria for at least one category of psychopathology, compared with 50% of nonintentional trauma patients, and 63% of intentional trauma patients (p0.01, trauma vs. elective surgery). Logistic regression analysis identified six variables that were independently associated with an increased tendency to be a victim of trauma: younger age, lower intelligence, antisocial personality, mental retardation, depression, and low income.Victims of trauma, both nonintentional, and especially intentional, have a high incidence of psychopathology. Victims of intentional trauma have significantly lower intelligence scores than either nonintentional injury or elective surgery patients. The high incidence of unemployment, alcohol abuse, and illicit drug use in victims of intentional injury might provide several opportunities for trauma prevention programs. Underlying psychological disorders will have to be addressed to reduce the likelihood of becoming a victim of trauma.

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.

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.

Safety data on recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsværd, Denmark) in actively hemorrhaging trauma patients are limited. We present detailed safety data from a large multicenter, randomized, placebo-controlled phase III study (the CONTROL trial).Data from 560 patients were analyzed. Subjects were monitored for adverse events (AEs) after rFVIIa or placebo administration. Incidences, timing, and presence of risk factors were reported by site investigators, supported by external study monitors and overseen by an independent Data Monitoring Committee.There were no differences in overall mortality, organ system failure, or AEs, serious AEs, or medical events of special interest. Arterial and venous thromboembolic (TE) events and their risk factors were similar in both groups. The greatest risk factor for TE events was a chest injury requiring mechanical ventilation3 days (86%). There were four site investigator-reported myocardial infarctions in the rFVIIa group of which only one met diagnostic criteria preestablished by the Data Monitoring Committee. There were no reported myocardial infarctions in the placebo group. Troponins were increased in 30% of all patients. The rate of acute respiratory distress syndrome was lower in the rFVIIa (3.0%) than in the placebo (7.2%) group (p = 0.022).This represents the largest placebo-controlled dataset of rFVIIa use in trauma patients to date. In this prospective study of critically bleeding trauma patients, rFVIIa use was associated with an imbalance of investigator-reported Acute myocardial infarction/non-ST segment elevation myocardial infarction (AMI/NSTEMI), but was not associated with an increased risk for other AEs, including TE complications.

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.

Background Historically, thoracolumbar spine transverse process fractures (TVPFx) found on "plain films" of the spine were occasionally associated with occult, mechanically significant vertebral fractures. Thus, "log-roll precautions" have been used pending formal spine evaluation and further imaging. As integrated helical computed tomography (CT) scans of the torso have become routine screening tools in high-energy trauma, TVPFx have been diagnosed with far greater frequency. Yet, where no associated spine injuries are found initially, such isolated TVPFx appear to be benign. Methods We retrospectively reviewed the diagnosis and management of TVPFx in a large Level I trauma center in the period between 2002 and 2005. Of 314 patients with TVPFx who survived more than 48 hours, 17% had fractures of the weight-bearing columns of the thoracolumbar spine noted on the same CT scan and were excluded from study. The management and outcome of the remaining "isolated" TVPFx were assessed by review of trauma registry and charted data. Results The 248 patients included sustained 2.3 +/- 1.5 (SD) TVPFx. They spent 29 hours +/- 32 hours on log-roll precautions while being evaluated by spine consultants and "cleared" before initiating physical therapy. Despite this prolonged immobilization and substantial further investigation, none of the patients with TVPFx judged to be isolated on the basis of screening truncal CT scan proved to have a missed injury of a major vertebral element on further study. Conclusions Isolated thoracolumbar TVPFx are found frequently when helical CT scan is used to screen the torso after high-energy injury. TVPFx are usually multiple. They can be markers for visceral injuries, and in this study, 17% were associated with "significant" fractures. TVPFx require careful pain management and benefit by early mobilization. Yet, where no other vertebral fracture is seen on an adequate screening CT scan, investigation may reasonably end. Further imaging and consultations with spine services waste scarce resources, and lead to prolonged log-roll precautions, which delay mobilization and are potentially deleterious to overall patient care.

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.

Recent literature indicates that females are more resistant to shock-, trauma-, and sepsis-induced immune dysfunction and organ injury than are males. Consequently, using trauma-hemorrhagic shock (T/HS) and burn models, we tested whether the neutrophil response to trauma occurred in a sexually dimorphic fashion and, if so, the role of sex hormones. Neutrophil activation, as reflected by CD11b expression and respiratory burst activity, was increased to a greater extent in male rats than in female rats after T/HS or burn injury. Testosterone appeared to potentiate neutrophil activation, because castration reduced neutrophil activation, whereas ovariectomy had little effect. Mechanistically, this sexually dimorphic neutrophil response appeared to be due to both cellular and humoral factors. Evidence for a cellular difference between male and female neutrophils is based on the observation that naive female neutrophils were more resistant to activation by burn or T/HS plasma and lymph than naive male neutrophils and that this resistance varied over the estrus cycle. Additionally, the humoral environment was more neutrophil activating in male rats, because burn and T/HS plasma and lymph from male rats activated naive male neutrophils to a greater extent than comparable samples from females. Last, on the basis of in vitro experiments examining the effects of estrogen on calcium signaling, it appears that estrogen limits trauma-induced neutrophil activation, at least in part, by limiting the entry of calcium into the cell via store-operated calcium entry mechanisms. In conclusion, there is a striking sexual dimorphism in neutrophil responses after trauma, and these changes reflect both cellular resistance to activation as well as a less activating humoral environment.

We examined the effects of 4-chloro-m-cresol (4-CmC, a potent and specific activator of ryanodine receptors) on Ca(2+)-release/influx and respiratory burst in freshly isolated human PMN as well as HL60 cells. 4-CmC induces Ca(2+) store-depletion in a dose-dependent manner at concentrations between 400muM and 3mM, however no dose-dependent effect on Ca(2+)-influx was found. 4-CmC depleted Ca(2+) stores that were shared with the GPC agonists such as fMLP and PAF, and therefore 4-CmC presumably depletes Ca(2+) from ER. Since the authentic ligand for RyR is cyclic ADP-ribose (cADPR), we assessed the functional relevance of RyR in PMN by studying the presence and function of membrane-bound ADP-ribosyl cyclase (CD38) in PMN. First, expression of CD38 was confirmed by RT-PCR using cDNA from HL60 cells. Second, PMN from trauma patients showed significantly enhanced CD38 expression than those from healthy volunteers. In addition, although no chemotaxis effect was detected by 4-CmC, it stimulated respiratory burst in PMN in a dose-dependent manner. Our findings suggest that RyRs exist in human PMN and that RyR pathway may play an active role in inflammatory PMN calcium signaling. 8-Br-cADPR and cyclic 3-deaza-ADP did not have inhibitory effects either on 4-CmC-induced Ca(2+) store-depletion or on respiratory burst, on the other hand, PLC inhibitor, U73122, completely attenuated both 4-CmC-induced Ca(2+) store-depletion and respiratory burst. Although it has been used as a specific activator of RyR, 4-CmC has non-specific effects which cause Ca(2+) store-depletion and respiratory burst at least in human PMN.

OBJECTIVE Since albumin has the ability to detoxify, we assessed whether low-dose albumin could protect against trauma/hemorrhagic shock (T/HS)-induced endothelial cell, lung, gut, and red blood cell (RBC) injury in vivo and endothelial cell injury in vitro. SUMMARY BACKGROUND DATA T/HS cause ischemic insult to the gut, resulting in the release of biologically active factors into the mesenteric lymph, which then cause injury to multiple distant organs. METHODS In vitro experiments tested the ability of albumin to reduce the cytotoxicity of mesenteric lymph from male rats subjected to T/HS (laparotomy + MAP 30 mm Hg for 90 minutes) for human umbilical vein endothelial cell (HUVEC). In subsequent in vivo experiments, the ability of albumin given as part of the resuscitation regimen to protect against T/HS-induced injury was tested by comparing the magnitude of injury in T/HS rats receiving human albumin (shed blood + 0.12, 0.24, or 0.36 g/kg) or lactated Ringer's solution (shed blood + 2 x volume of shed blood as LR) with that observed in rats subjected to trauma/sham shock. Rats were killed after a 3-hour recovery period and had lung permeability evaluated by bronchoalveolar lavage and myeloperoxidase assays, intestinal microvillous injury by histology, and RBC deformability using ektacytometry. RESULTS Both bovine and human albumin prevented T/HS lymph-induced HUVEC cytotoxicity in vitro, even when added 30 minutes after the lymph (viability 15 +/- 4% to 88 +/- 3%, P < 0.01). In vivo RBC deformability was better preserved by blood plus albumin than blood plus lactated Ringer's solution (P < 0.01). Likewise, albumin administration reduced T/HS-induced lung permeability and neutrophil sequestration in a dose-dependent fashion, with 0.36 g/kg of albumin effecting total lung protection (P < 0.01). In contrast, albumin treatment did not prevent T/HS-induced gut injury. CONCLUSIONS Low-dose albumin protects against gut lymph-induced lung, HUVEC, and RBC injury by neutralizing T/HS lymph toxicity.

Objective We have previously documented that gut-derived lymph from rats subjected to trauma plus hemorrhagic shock (T/HS) is injurious to vascular endothelial cells and activates neutrophils (PMNs), two key events in postshock organ injury. Because T/HS leads to gut injury, intestinal bacterial overgrowth, and the loss of gut barrier function, the relative role of gut injury as opposed to intestinal bacterial overgrowth per se in the pathogenesis of biologically active intestinal lymph is unclear. We therefore studied whether mesenteric lymph can injure endothelial cells and/or active PMNs in an intestinal bacterial overgrowth model where there is no gut injury (monoassociation). Methods Bacterial overgrowth was established in male rats by treating the animals with 4 days of oral antibiotics followed by administration of a nonpathogenic, streptomycin-resistant strain of Escherichia coli C25. Mesenteric lymph was then collected from rats with normal flora and from E. coli C25 monoassociated rats. Its effects were tested on human umbilical vein endothelial cells (HUVECs) and human PMNs. As an additional control, lymph was collected from antibiotic-decontaminated rats that received antibiotics but were not colonized with E. coli C25. Results As compared with medium, normal flora intestinal lymph, antibiotic-decontaminated lymph, or portal plasma from the monoassociated rats, mesenteric lymph from the monoassociated rats killed HUVECs and increased the permeability of a HUVEC monolayer. In contrast to the effects on HUVECs, lymph from the monoassociated rats did not increase PMN CD11b expression or prime PMNs for an augmented respiratory burst, as compared with lymph from the rats with normal flora or from antibiotic-decontaminated rats. The effects of lymph from the monoassociated rats was not caused by bacteria, because these lymph samples were sterile. Conclusion These results indicate that disruption of the normal intestinal microflora resulting in bacterial overgrowth with enteric bacilli may participate in the production of mesenteric lymph that is injurious to endothelial cells in shock, but this mechanism does not appear to be significantly involved in the activation of PMNs.

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.

There is evidence suggesting that the ischemic gut is a major source of factors that lead to neutrophil activation, and that neutrophil activation can be reduced by hypertonic saline resuscitation. Thus, we tested whether trauma-hemorrhagic shock-induced neutrophil activation can be reduced by hypertonic saline resuscitation, as well as whether hypertonic saline reduces the ability of mesenteric lymph from shocked animals to activate neutrophils. Male Sprague-Dawley rats subjected to trauma (laparotomy), plus 90 min of shock [mean arterial pressure (MAP) MAP = 30 mmHg] or sham shock were resuscitated with Ringer's lactate or 7.5% hypertonic saline at an equivalent sodium load. Whole blood samples were collected before shock as well as at 1 and 2 h after the end of the shock period for neutrophil CD11b and CD18 expression measurements. In a second set of experiments, mesenteric lymph samples collected from rats subjected to trauma plus hemorrhagic shock (T/HS) or trauma plus sham-shock (T/SS) and resuscitated with Ringer's lactate or hypertonic saline were tested for their ability to modulate PMN CD11b, CD18, or L-selectin expression, as well as prime PMN for an augmented respiratory burst. To avoid confounding results due to interspecies differences, while at the same time looking at potential human responses, both naive rat and human PMN were tested. Both CD11b and CD18 expression were increased in PMN harvested from rats subjected to T/HS and resuscitated with Ringer's lactate solution, but not in T/HS rats resuscitated with hypertonic saline. These results indicate that PMN activation is increased to a greater extent in Ringer's lactate-resuscitated than hypertonic saline-resuscitated animals. Likewise, mesenteric lymph from the T/HS rats resuscitated with Ringer's lactate increased naive rat and human PMN CD11b and CD18 expression to a greater extent than did T/HS lymph from the hypertonic saline-treated rats. Additionally, T/HS lymph from the Ringer's lactate- but not the hypertonic saline-treated rats induced PMN L-selectin shedding. Lastly, T/HS lymph from the Ringer's lactate-treated rats induced the greatest PMN respiratory burst. These results indicate that resuscitation from T/HS with hypertonic saline is associated with less PMN activation than resuscitation with Ringer's lactate, and that factors produced or released by the postischemic intestine and carried in the mesenteric lymph contribute to neutrophil activation after an episode of T/HS.

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.

Objective: To determine whether hemorrhagic shock-induced bone marrow failure is mediated by the gut through the production of toxic mesenteric lymph and whether shock-induced bone marrow failure could be prevented by division of the mesenteric lymphatics. Design: Prospective, controlled study. Setting: University surgical research laboratory. Subjects: Male Sprague-Dawley rats. Interventions: Rats were divided into five groups: unmanipulated controls (n = 12), hemorrhagic shock with laparotomy (n = 8), hemorrhagic shock with mesenteric lymph duct ligation (n = 10), sham shock with laparotomy (n = 6), and sham shock with mesenteric lymph duct ligation (n = 7). At either 3 or 6 hrs after resuscitation, bone marrow was obtained for determination of early (cobblestone forming cells) and late (granulocyte-macrophage colony forming unit and erythroid burst forming unit) hematopoietic progenitor cell growth. Parallel cultures were plated with plasma (1% and 2% v/v) from all groups to determine the effect of lymphatic ligation on hematopoiesis. Measurements and Main Results: Bone marrow cellularity, cobblestone forming cells, granulocyte-macrophage colony forming unit, and erythroid burst forming unit growth in rats subjected to hemorrhagic with lymph duct ligation were similar to those observed in sham-treated animals and significantly greater than in rats subjected to shock and laparotomy without lymphatic duct ligation. Plasma from rats subjected to shock without lymph ligation was inhibitory to hematopoietic progenitor cell growth. In contrast, this shock-induced inhibition was not observed with plasma obtained from shocked rats that underwent mesenteric lymph ligation. Conclusions: Hemorrhagic shock suppresses bone marrow hematopoiesis as measured by a decrease in early and late progenitor cell growth. This suppression appears mediated through mesenteric lymph as the effect is abrogated by mesenteric lymph duct ligation. These data clearly demonstrate a link between the gut and bone marrow failure after hemorrhagic shock.

Bone marrow (BM) dysfunction has been shown to occur in experimental animal models of hemorrhagic shock, hypoxia, soft tissue injury, and thermal injury. 1–5 Whether a similar alteration in BM function occurs in humans after injury is less clear and has been not well studied. Moore et al 6 showed that there was a marked rise in circulating granulocyte-macrophage colony-forming units (CFU-GM) in patients for up to 10 days after blunt torso trauma. Coincident with the release of immature progenitors into the periphery was the fact that peripheral mononuclear cells from trauma patients produced reduced levels of colony-stimulating activity in response to lipopolysaccharide compared with controls. The degree of BM failure also appeared to correlate with the degree of injury. Persistent anemia has long been documented in intensive care unit patients. 7 This anemia has been examined after thermal injury, 8 and most recently Iversen et al 9 reported a decrease in bone marrow erythroid burst-forming units (BFU-E) in patients after spinal cord injury. Successful hematopoiesis is a complex regulated process in which pluripotential stem cells proliferate and differentiate to generate all necessary mature blood cells. 10 The process of immune and red blood cell formation requires the interaction between BM progenitor and stem cells with their microenvironment, which includes BM stromal cells, extracellular matrix proteins, and other soluble factors. 11–13 BM stroma has previously been reported to influence hematopoiesis by the elaboration of regulatory cytokines, 14 as well as to regulate progenitor cell growth and differentiation through direct cell–cell contact. 15,16 Thus, BM stroma is central in both the maintenance and the regulation of hematopoiesis. Consequently, any disruption of BM hematopoiesis after injury is likely to be at least partly mediated through the interaction of BM stroma with hematopoietic progenitor cells. Trauma results in the migration of inflammatory cells to the site of injury, and a multitude of cytokines and chemokines have been documented to be secreted into both the local tissue environment and systemic circulation. 17–20 Many of these cytokines and wound fluids have been shown to have an effect on immune cells. For example, Hauser et al 21 showed that fluid surrounding the sites of fracture in trauma patients contained high levels of interleukin (IL)-6 and IL-8. Plasma obtained from rats subjected to hemorrhagic shock has been shown to inhibit CFU-GM formation from BM cells. 2 The hypothesis of these experiments is that plasma obtained from patients after severe injury would inhibit hematopoiesis in both red blood cell (as measured by BFU-E) and white blood cell (as measured by CFU-GM) lineages, and that this inhibition would be mediated through plasma’s interaction with the BM stroma.