Search

Objective: To formulate management guidelines for blunt vertebral arterial injury (BVI)., Summary Background Data: Compared with carotid arterial injuries, BVIs have been considered innocuous. Although screening for BVI has been advocated, particularly in patients with cervical spine injuries, the appropriate therapy of lesions is controversial., Methods: In 1996 an aggressive arteriographic screening protocol for blunt cerebrovascular injuries was initiated. A prospective database of all screened patients has been maintained. Analysis of injury mechanisms and patterns, BVI grades, treatment, and outcomes was performed., Results: Thirty-eight patients (0.53% of blunt trauma admissions) were diagnosed with 47 BVIs during a 3.5-year period. Motor vehicle crash was the most common mechanism, and associated injuries were common. Cervical spine injuries were present in 71% of patients, but there was no predilection for cervical vertebral level or fracture pattern. The incidence of posterior circulation stroke was 24%, and the BVI-attributable death rate was 8%. Stroke incidence and neurologic outcome were independent of BVI injury grade. In patients treated with systemic heparin, fewer overall had a poor neurologic outcome, and fewer had a poor outcome after stroke. Trends associated with heparin therapy included fewer injuries progressing to a higher injury grade, fewer patients in whom stroke developed, and fewer patients deteriorating neurologically from diagnosis to discharge., Conclusions: Blunt vertebral arterial injuries are more common than previously reported. Screening patients based on injury mechanisms and patterns will diagnose asymptomatic injuries, allowing the institution of therapy before stroke. Systemic anticoagulation appears to be effective therapy: it is associated with improved neurologic outcome in patients with and without stroke, and it appears to prevent progression to a higher injury grade, stroke, and deterioration in neurologic status.

Purpose: Breast radiotherapy (BrRT) often includes a "boost" to the lumpectomy bed. Selection of an appropriate electron energy and field size is based upon the dimensions and location of the surgical cavity. This study was performed to confirm our impression that ultrasound (US) inadequately defines the volume at risk compared to radiographic evaluation of surgical clips placed within the operative bed at the time of lumpectomy. METHODS AND MATERIALS Twenty-nine women treated with BrRT at our institution between 1996-1998 were prospectively identified as having surgical clips within the lumpectomy cavity. These patients underwent both US evaluation and radiographic evaluation of the clips to independently define two sets of transverse (T), longitudinal (L), and depth (D) measurements for each cavity. Volumes (V) were calculated for each method, assuming the cavity to be a box (V = T x L x D). Twenty-one women began BrRT following a median postoperative interval of 6 weeks (Group A), and 8 after 24 weeks (Group B) due to delivery of systemic therapy., Results: Dimensions derived by US were smaller than the clip method in 22/29 of T, 25/29 of L, and 23/29 of D, or 80% of all linear measurements. A paired t-test demonstrated the difference between the methods to be statistically significant: T: p = 0.0004; L: p = 0.0001; D: p = 0.0004; and V: p = 0.0001. This underestimation by US did not fit any predictable pattern. Although the mean difference between methods (clips - US) was only 1.3, 1.9, and 1.1 cm for T, L, and D, respectively, differences ranged up to 5. 7, 9.2, and 5.5 cm for T, L, and D. The bias toward underestimation of V by US was significantly greater for Group B than Group A (p = 0. 03)., Conclusions: US significantly underestimates all three dimensions of the lumpectomy cavity and hence the volume at risk compared to radiographic evaluation of surgical clips. Breast-conserving surgery should include placement of clips at the margins of the lumpectomy cavity (superior, inferior, medial, lateral, and posterior) to aid in radiotherapy treatment planning. US should not be utilized to guide the design of the boost field as it will result in inappropriate selection of lower electron energies and smaller field sizes (geographical miss), particularly among patients who receive chemotherapy prior to breast radiotherapy.

Background: The Injury Severity Score (ISS) has been observed consistently to be a robust predictor of postinjury multiple organ failure (MOF). However, the ISS fails to account for multiple injuries to the same body region. Recently, the "new" ISS (NISS) has been proposed to address this shortcoming. Preliminary studies suggest the NISS is superior to the ISS in predicting trauma mortality. Our purpose was to determine whether the NISS is a better predictor of postinjury MOF than the ISS., Methods: A total of 558 patients admitted to our Level I trauma center with ISS > 15, age > 15 years, and survival > 48 hours were prospectively identified; 101 (18%) developed postinjury MOF. Data characterizing postinjury MOF were collected, and the NISS was calculated retrospectively. The ISS and NISS were compared as univariate predictors of MOF. Multivariate analysis was used to determine whether substitution of NISS for ISS resulted in a superior predictive model., Results: In 295 patients (53%), the NISS was greater than the ISS. This subgroup of patients experienced a greater frequency of MOF (26.7% vs. 8.3%, p < 0.0001), a higher mortality (12.8% vs. 4.9%, p < 0.001), and a higher early transfusion requirement (6.7 U vs. 3.6 U, p < 0.0001) compared with the group in which NISS equaled ISS. Moreover, the NISS yielded better separation between patients with and without MOF reflected by the greater difference in median NISS scores compared with ISS scores. The multivariate predictive model, including NISS, showed a better goodness of fit compared with the same model that included ISS., Conclusions: The NISS is superior to the ISS in the prediction of postinjury MOF. This measure of tissue injury severity should replace the ISS in trauma research.

Background: The sequelae of blunt injury to the carotid arteries are unusual, but pseudoaneurysms causing subsequent strokes are devastating. The utility of treatment of these pseudoaneurysms was examined., Methods: All patients at a Level I trauma center with previously documented traumatic risk factors were assessed for blunt injury to the carotid arteries and, when a pseudoaneurysm was present, a self-expanding metallic stent was placed across the lesion and the patient placed on anticoagulation. Follow-up arteriograms were obtained in 2 months and every 6 months thereafter., Results: Fourteen patients (7 men, 7 women) with an average age of 27 years, an Injury Severity Score of 38, had formed pseudoaneurysms in 16 extracranial internal carotid arteries. These were stented with metallic endoprostheses. No strokes occurred after the placement of the stents. Mean follow-up period has been 2.5 years., Conclusions: Use of metallic endoprostheses is an effective method to treat this potentially devastating injury. However, longer follow-up and more patients studied are needed to further examine this promising treatment.

Background: The potential to modulate the inflammatory response has renewed interest in hypertonic saline (HTS) resuscitation of injured patients. However, the effect of the timing of HTS treatment with respect to polymorphonuclear neutrophil (PMN) priming and activation remains unexplored. We hypothesized that HTS attenuation of PMN functions requires HTS exposure before priming and activation., Methods: Isolated PMN were incubated in HTS (180 mM Na+) before L-alpha-phosphatidylcholine, beta-acetyl-gamma-O-alkyl (PAF)/N-formylmethionyl-leucyl-phenylalanine (fMLP) priming/activation, after priming, or after priming/activation. Superoxide production was measured by the reduction cytochrome c, elastase release by cleavage of AAPV-pNA, and beta2-integrin expression by flow cytometry., Results: HTS before priming or activation decreased beta2-integrin expression, superoxide production, and elastase release. In contrast, HTS after priming/activation augmented superoxide production and elastase release., Conclusion: The timing of HTS is a key variable in the attenuation of PMN cytotoxic functions. Maximal attenuation of cytotoxicity is achieved before priming, whereas HTS exposure after activation augments cytotoxicity.

Introduction: Prone ventilation improves oxygenation in selected patients with acute respiratory distress syndrome (ARDS). However, prone positioning of critically ill patients with multiple invasive lines and tubes is potentially dangerous. Trauma patients, in particular, may require special consideration because of skeletal fixation devices or prior operative procedures. Our objective was to critically evaluate our experience with prone positioning in patients with severe postinjury ARDS., Methods: Injured patients admitted to our Level I trauma center who developed ARDS were prospectively identified. Serial lung injury severity and pulmonary mechanical data, as well as complications of prone ventilation were recorded., Results: During the 12-month period ending August of 1998, nine patients with postinjury ARDS were treated with prone ventilation because of hypoxemia refractory to other ventilatory strategies. All patients suffered blunt trauma. Their mean age was 29 +/- 4.5 years; seven patients were men. The average Injury Severity Score was 26 +/- 5; and, at the time of prone positioning, the mean Lung Injury Score was 3.5. The mean PaO2/FIO2 ratio increased from 75 +/- 7 to 147 +/- 27 with prone ventilation (p < 0.05, paired t test); and in six patients, the FIO2 could be decreased. Four major complications occurred (44%). One patient experienced a midline abdominal wound dehiscence. Severe facial or upper chest wall pressure necrosis developed in two patients, despite extensive padding and careful attention to skin care. The fourth patient sustained a cardiac arrest immediately after prone positioning., Conclusion: Prone ventilation in postinjury patients with ARDS may improve oxygenation but has the potential for significant complications. Careful consideration is required before prone positioning in this subset of patients.

Packed red blood cell (PRBC) transfusion has been invoked previously with immunosuppression and increased infections, but it has now been demonstrated that stored PRBCs (>14 days) can prime PMNs and provoke multiple organ failure. Recently, the role of PMNs in the genesis of MOF has been extended to their release of inflammatory cytokines, notably IL-1, IL-8, TNFalpha, and secretory phospholipase A2 (sPLA2). We hypothesize that stored PRBCs can act as a second event via stimulating the release of inflammatory cytokines from PMNs. Isolated human PMNs were incubated for 24 h in RPMI with either 20% fresh plasma or plasma from 42 day old PRBC (day of outdate) and release of IL-8, IL-1beta, TNFalpha, and sPLA2 were measured. Plasma from stored PRBCs contained small amounts of IL-8, sPLA2, and TNFalpha (102.1 +/-5.6 pg/ml, 87.6+/-6.0 pg/ml and 9.7+/-.7 pg/ml). Levels of IL-1beta were below detection (<1 pg/ml). Day 42 PRBC plasma stimulated significant PMN release of both IL-8 and sPLA2 as compared to both control and day 0 plasma (*P < .05), but PRBC plasma did not stimulate PMN release of either IL-1beta or TNFalpha. Transfused blood is emerging as an inflammatory agent that is capable of producing PMN priming. In this study we have demonstrated that PRBC plasma selectively activates PMNs to release both IL-8 and sPLA2. Thus, transfusion of PRBCs may represent a preventable inflammatory insult via modification of both blood banking and transfusion practices.

Objective: Neutrophil (PMN) priming after hemorrhagic shock is predictive of the subsequent development of multiple organ failure, but the mechanism remains unknown. Recently, we and others have demonstrated that mesenteric lymph from shock animals resuscitated with lactated Ringer's solution (LR) is not only a potent PMN priming agent but also causes lung injury. Work by others has shown that resuscitation with hypertonic saline (HTS) protects animals from lung injury after hemorrhagic shock. Therefore, we hypothesize that resuscitation with HTS will abolish PMN priming by postshock mesenteric lymph., Methods: After mesenteric lymph duct catheterization, male rats underwent hemorrhagic shock (mean arterial pressure of 40 mm Hg for 90 minutes) and resuscitation with shed blood plus either LR (2x volume of shed blood) or 4 mL/kg of 7% HTS (isonatremic). Priming for superoxide by PMN was measured after fMLP (1 microM) activation., Results: Shock significantly decreased mesenteric lymph flow from preshock levels in both groups. LR resuscitation produced significantly more mesenteric lymph than HTS resuscitation. Mesenteric lymph from LR animals primed PMN for superoxide production, whereas, HTS eliminated this priming., Conclusion: HTS not only decreases postshock mesenteric lymph production, it eliminates PMN priming by mesenteric lymph, suggesting a mechanism for the beneficial effects of HTS resuscitation.

Background: The recognition that early diagnosis and intervention, prior to ischemic neurologic injury, has the potential to improve outcome following blunt cerebrovascular injuries (BCVI), led to a policy of aggressive screening for these injuries. The resultant epidemic of BCVI has created a dilemma, as widespread screening is impractical. We sought to identify independent predictors of BCVI, to focus resources., Methods: Cerebral arteriography was performed based on signs or symptoms of BCVI, or in asymptomatic patients with high-risk mechanisms (hyperextension, hyperflexion, direct blow) or injury patterns. Logistic regression analysis identified independent predictors., Results: A total of 249 patients underwent arteriography; 85 (34%) had injuries. Independent predictors of carotid arterial injury were Glasgow coma score < or =6, petrous bone fracture, diffuse axonal brain injury, and LeFort II or III fracture. Having one of these factors in the setting of a high-risk mechanism was associated with 41% risk of injury. Of patients with cervical spine fracture, 39% had vertebral arterial injury., Conclusions: Patients sustaining high-risk injury mechanisms or patterns should be screened for BCVI. In the face of limited resources, screening efforts should be focused on those with high-risk predictors.

Background: Breast conservation therapy (BCT) offers equivalent survival to modified radical mastectomy in patients with early-stage (I and IIa) breast cancer, but is utilized in less than 50% of eligible patients. While patient demographics have been linked to BCT rates, we suspected that physician influence was a major factor. The purpose of this study was to compare BCT at three affiliated centers staffed by similarly trained surgeons yet serving widely disparate populations, in order to assess the importance of physician influence on the utilization of BCT., Methods: Tumor registry data were reviewed from 1993 through 1997 at affiliated city/county (CH), university (UH), and private hospitals (PH). Data were analyzed for clinical stage, treatment, and age of patient., Results: The utilization of BCT for stage I and IIa breast cancer is similar at the three hospitals: 45% of patients at CH, 55% of patient at UH, and 57% of patients at PH (P>0.05). Rates of BCT were similar across all patient age groups at all sites., Conclusions: Similar BCT utilization rates can be achieved despite widely disparate patient populations. The three affiliated hospitals are staffed by surgeons with similar training, and all offer a multidisciplinary approach to breast cancer care. This suggests that physician influence may override patients' socioeconomic issues in providing optimal breast cancer therapy.

Background: Soluble tumor necrosis factor receptor (sTNFr) and interleukin-1 receptor antagonist (IL-1ra) have been identified as endogenous inhibitors of TNF-alpha and IL-1beta. While TNF-alpha and IL-1beta levels are not systematically elevated in postinjury patients who developed multiorgan failure (MOF), their involvement at the tissue level has been suggested. Our study hypothesis was that levels of sTNFr-I and IL-1ra would discriminate patients at risk for postinjury MOF., Methods: Serial plasma levels of sTNFr and IL-1ra were measured in 29 trauma patients at high risk for postinjury MOF., Results: sTNFr-I levels were higher in MOF compared with non-MOF patients at 12, 84, and 132 hours postinjury. MOF patients also had higher IL-1ra values 36, 60, 84, and 132 hours postinjury., Conclusions: Anti-inflammatory mechanisms are activated after trauma. Since increased levels of sTNFr and IL-1ra correlate with postinjury MOF, they may contribute to our understanding of the pathogenesis as well as prediction of outcome. High levels of antagonists to TNF-alpha and IL-1beta suggest tissue level involvement of these cytokines in postinjury hyperinflammation.

Background: Blunt carotid arterial injuries (BCI) have the potential for devastating outcomes. A paucity of literature and the absence of a formal BCI grading scale have been major impediments to the formulation of sound practice guidelines. We reviewed our experience with 109 BCI and developed a grading scale with prognostic and therapeutic implications., Methods: Patients admitted to a Level I trauma center were evaluated with cerebral arteriography if they exhibited signs or symptoms of BCI or met criteria for screening. Patients with BCI were treated with heparin unless they had contraindications, and follow-up arteriography was performed at 7 to 10 days. Endovascular stents were deployed selectively. A prospective database was used to track the patients., Results: A total of 76 patients were diagnosed with 109 BCI. Two-thirds of mild intimal injuries (grade I) healed, regardless of therapy. Dissections or hematomas with luminal stenosis (grade II) progressed, despite heparin therapy in 70% of cases. Only 8% of pseudoaneurysms (grade III) healed with heparin, but 89% resolved after endovascular stent placement. Occlusions (grade IV) did not recanalize in the early postinjury period. Grade V injuries (transections) were lethal and refractory to intervention. Stroke risk increased with injury grade. Severe head injuries (Glasgow Coma Scale score < or =6) were found in 46% of patients and confounded evaluation of neurologic outcomes., Conclusion: This BCI grading scale has prognostic and therapeutic implications. Nonoperative treatment options for grade I BCI should be evaluated in prospective, randomized trials. Accessible grade II, III, IV, and V lesions should be surgically repaired. Inaccessible grade II, III, and IV injuries should be treated with systemic anticoagulation. Endovascular techniques may be the only recourse in high grade V injuries and warrant controlled evaluation in the treatment of grade III BCI.

Background: Accumulating clinical and epidemiological evidence suggests significant gender differences in the incidence of and outcome following major infection. In a rodent model of hemorrhagic shock, investigators have shown that males manifest depressed cell-mediated immunity that is reversed by castration or pharmacologic testosterone receptor blockade. Female rats, in contrast, show enhanced immune function that is reduced to male levels by testosterone administration. This sexual dimorphism is believed responsible for the improved outcome in female mice following septic challenge., Hypothesis: Male gender is a risk factor for major infections following severe injury., Design: Five-year prospective cohort study ending October 1998., Setting: Urban level I regional trauma center., Patients and Methods: A total of 545 trauma patients older than 15 years with an Injury Severity Score greater than 15 and survival more than 48 hours were prospectively identified and studied. Collected data included age, injury mechanism, and Injury Severity Score. Major infections, defined as pneumonia, abdominal and pelvic abscess, wound infection requiring operative debridement, and meningitis, were tabulated. The occurrence of major infections in males and females was compared using multiple logistic regression analysis., Main Outcome Measure: Postinjury major infectious complications., Results: Of the 545 patients, 135 (24.8%) were female and 410 (75.2%) were male. Major infections occurred in 219 (40.2%) patients. Logistic regression confirmed that male gender is an independent risk factor for major infections (P=.04) after controlling for age and Injury Severity Score. Males had a 58% greater risk of developing a major infection (odds ratio, 1.58; 95% confidence interval, 1.01-2.48)., Conclusions: Male gender is associated with a dramatically increased risk of major infections following trauma. This effect is most significant following injuries of moderate severity (Injury Severity Score 16-25) and persists in all age groups.

Background: Postinjury multiple organ failure (MOF) is the result of a dysregulated systemic inflammatory response in which primed neutrophils (PMNs) are sequestered in tissues, vulnerable to activation through secondary insults. Apoptosis is critical to the normal clearance of these sequestered PMNs. Conversely, dysfunctional apoptosis prolongs the PMN functional life span, potentially exacerbating PMN-mediated tissue injury and the development of MOF. We hypothesized that severe trauma, in addition to priming PMNs, provokes dysfunctional PMN apoptosis., Methods: Neutrophils were harvested daily from 12 severely injured patients at high risk for MOF, cultured for 24 hours, and assessed for apoptosis with use of acridine orange-ethidium bromide staining and fluorescence microscopy. Priming for elastase release was measured in freshly isolated patient PMNs. Plasma from patients was assessed for its ability to delay apoptosis of normal PMNs., Results: Four patients (33%) had MOF. Neutrophil apoptosis was profoundly delayed in severely injured patients throughout the 5-day study period. Priming for elastase release was augmented concomitantly. Patients' plasma delayed apoptosis of normal PMNs., Conclusion: In patients at high risk for postinjury MOF, PMNs are not only primed for cytotoxicity but also resist apoptosis. The dysfunctional apoptosis is attributed, at least in part, to a plasma-borne mediator. The net effect may facilitate hyperinflammatory organ injury.

On the basis of our experience and the available literature, we submit that aggressive screening for BCI based on injury patterns is warranted. However, several important clinical issues remain unresolved. The precise injury patterns and relative cerebrovascular risks remain to be defined. Furthermore, the optimal diagnostic screening test remains to be identified, with consideration of the relative risk-benefit profile. Finally, we must determine the best methods for the treatment of BCI. Although the definitive study has yet to be completed, the use of heparin was associated with a trend toward improved outcomes in symptomatic patients. In addition, no asymptomatic patient experienced the development of new neurologic deficits during heparin therapy. Therefore we believe that the early institution of heparin therapy is indicated. The role of endovascular stenting, however, remains unclear.

Unlabelled: Postinjury neutrophil (PMN) dysfunction is a well recognized event that may be responsible for increased infections. PMN cytokine production is an important component of their bactericidal capacity. When PMNs are stimulated, inhibitory factor kappaB (IkappaB) is degraded, allowing nuclear factor kappaB (NFkappaB) to translocate to the nucleus and promotes genes for the transcription of the interleukin-8 (IL-8) and tumor necrosis factor (TNF) genes. We hypothesize that similar to their late postinjury depressed superoxide production, postinjury PMNs manifest suppressed cytokine production, which is mediated by stabilization of IkappaB levels., Methods: Twelve severely injured patients with an injury severity score (ISS) of 24 (+/-4.6) were studied as well as 10 elective surgical patients as a control. PMNs were isolated and incubated for 24 h in RPMI. PMNs were stimulated with lipopolysaccharide (LPS; 100 ng) or PAF (200 nm) and fMLP (1 microM) and release of IL-8, TNF, and interleukin-1 receptor antagonist (IL-1ra) were measured. Postinjury PMNs were also stimulated with LPS (100 ng), and IkappaB breakdown was measured at 0, 30, and 60 min using gel electrophoresis., Results: Postinjury PMNs displayed a significant suppression of both IL-8 and TNF on postinjury Days 1-3, while the release of IL-1ra was preserved throughout the entire study period. In contrast, elective surgical patients demonstrated no decrease in IL-8 or TNF. Furthermore, IkappaB levels were preserved in the postinjury PMNs as compared with normal control PMNs., Conclusion: Postinjury PMNs have a suppressed release of both IL-8 and TNF following injury that did not occur in elective surgical patients. Furthermore, the NFkappaB/IkappaB-independent IL-1ra did not show suppression of release. In addition, stabilization of IkappaB following severe injury leads to decreased PMN IL-8 and TNF production. This genetic reprogramming may help explain PMN dysfunction and subsequent infections seen in severely injured patients.

Background: Postinjury neutrophil (PMN) priming identifies the injured patient at risk for the subsequent development of multiple organ failure (MOF). PMN priming has previously been shown to cause enhanced release of proteases and superoxide. PMNs, however, are a rich source of proinflammatory cytokines, such as interleukin (IL)-8 and tumor necrosis factor (TNF), which have been implicated in the development of MOF. PMNs also make IL-1ra, which is an anti-inflammatory cytokine that inhibits IL-1. It is our hypothesis that postinjury PMNs are primed for increased stimulated release of the proinflammatory cytokines IL-8 and TNF but not the anti-inflammatory cytokine IL-1ra., Methods: Twelve trauma patients with a mean Injury Severity Score of 24 (+/-4.6) and 10 elective surgical patients were studied. Postinjury PMNs were isolated from blood obtained at presentation (within 2 hours after injury) and 24 hours after trauma. PMNs from elective surgical patients were obtained preoperatively, immediately postoperatively, and at 24 hours. The PMNs were stimulated with platelet-activating factor (200 nM)/N-formyl-methionyl-leucyl-phenylalanine (1 micromol/L) or lipopolysaccharide (100 ng/mL) incubated for 24 hours in RPMI-1640, and release of IL-8, TNF, and IL-1ra were measured., Results: Postinjury PMNs were primed for both platelet-activating factor/N-formyl-methionyl-leucyl-phenylalanine-stimulated and lipopolysaccharide-stimulated IL-8 and TNF release at 2 hours after injury (fourfold increase of IL-8 release and fivefold increase of TNF release), whereas elective surgical patients demonstrated no priming. In contrast, postinjury patients were not primed for increased release of the counterinflammatory cytokine IL-1ra, suggesting a specific postinjury up-regulation of IL-8 and TNF., Conclusion: After injury, PMNs are primed for proinflammatory cytokine release in addition to superoxide and elastase. This augmented release of IL-8 and TNF may be involved in the subsequent development of organ dysfunction and ultimately MOF.

The fundamental objective of staged laparotomy is to accomplish definitive operative management in a calculated, stepwise fashion based on the patient's physiologic tolerance. This important concept has emerged from collective experience with massive acute abdominal injuries but clearly extends to elective operative procedures and surgical challenges in other torso compartments. Whereas the inability to achieve hemostasis is due most frequently to a recalcitrant coagulopathy following trauma, other scenarios include inaccessible venous injuries, coexisting extraperitoneal life-threatening injuries, uncertain viability of abdominal contents, and the inability to reapproximate abdominal fascia due to reperfusion-induced visceral edema. There are five critical decision-making phases of staged laparotomy: I, patient selection; II, intraoperative reassessment; III, physiologic restoration in the surgical intensive care unit; IV, return to the operating room for definitive procedures; and V, abdominal wall reconstruction. The abdominal compartment syndrome (ACS) is a common, often insidious complication of staged laparotomy. In fact, during phases II and III there is often a delicate balance between effective pressure tamponade of capillary bleeding and the untoward effects of the ACS. During phases IV and V a frequent dilemma is how to enclose the abdominal contents to reduce protein loss and facilitate patient mobilization.

Major abdominal vascular injuries are associated with significant morbidity and mortality. They present a formidable challenge to the most experienced surgeon. Most commonly the result of penetrating trauma, hemorrhagic shock is the usual presentation, and diagnostic maneuvers are unnecessary. Conversely, a high index of suspicion is critical in diagnosing occult injuries. This article reviews the cause, diagnosis, and treatment of major abdominal vascular injuries, with an emphasis on exposures and techniques of repair. In addition, the concepts of repair versus ligation, staged laparotomy, and the abdominal compartment syndrome are discussed.

Objective: To determine the benefit of screening for blunt carotid arterial injuries (BCI) in patients who are asymptomatic., Summary Background Data: Blunt carotid arterial injuries have the potential for devastating complications. Published studies report 23% to 28% mortality rates, with 48% to 58% of survivors having permanent severe neurologic deficits. Most patients have neurologic deficits when the injury is diagnosed. The authors hypothesized that screening patients who are asymptomatic and instituting early therapy would improve neurologic outcome., Methods: The Trauma Registry of the author's Level I Trauma Center identified patients with BCI from 1990 through 1997. Beginning in August 1996, the authors implemented a screening for BCI. Arteriography was used for diagnosis. Patients without specific contraindications were anticoagulated. Endovascular stents were deployed in the setting of pseudoaneurysms., Results: Thirty-seven patients with BCI were identified among 15,331 blunt-trauma victims (0.24%). During the screening period, 25 patients were diagnosed with BCI among 2902 admissions (0.86%); 13 (52%) were asymptomatic. Overall, eight patients died, and seven of the survivors had permanent severe neurologic deficits. Excluding those dying of massive brain injury and patients admitted with coma and brain injury, mortality associated with BCI was 15%, with severe neurologic morbidity in 16% of survivors. The patients who were asymptomatic at diagnosis had a better neurologic outcome than those who were symptomatic. Symptomatic patients who were anticoagulated showed a trend toward greater neurologic improvement at the time of discharge than those who were not anticoagulated., Conclusions: Screening allows the identification of asymptomatic BCI and thereby facilitates early systemic anticoagulation, which is associated with improved neurologic outcome. The role of endovascular stents in the treatment of blunt traumatic pseudoaneurysms remains to be defined.

Interaction of the beta2-integrin complex on the polymorphonuclear neutrophil (PMN) with intercellular adhesion molecule-1 (ICAM-1) has been implicated in PMN-mediated cytotoxicity. This study examined interaction of the CD11a, CD11b, and CD18 subunits of the beta2-integrin with ICAM-1, transfected into Chinese hamster ovarian (CHO) cells to avoid effects of other adhesion molecules. Incubation of quiescent PMNs with wild-type and ICAM-1-transfected CHO cells produced nominal cell lysis. Similarly, when phorbol myristate acetate (PMA)-activated PMNs were incubated with wild-type CHO cells, minimal cytotoxicity was produced. However, when ICAM-1-transfected CHO cells were incubated with PMA-activated PMNs, 40% cell lysis occurred. Blockade with a monoclonal antibody (MAb) to ICAM-1 or MAbs to CD11a, CD11b, or CD18 reduced PMN-mediated cytotoxicity to baseline. To examine the role of adhesion in cytotoxicity, we studied beta2-integrin-mediated PMN adhesion to ICAM-1-transfected CHO cells and found that MAbs for CD11a, CD11b, and CD18 all abrogated PMN cytotoxicity despite disparate effects on adhesion. To assess the role of CD18, beta2-integrin subunits were cross-linked, and CD18 alone mediated protease release. Moreover, ICAM-1 was immunoprecipitated from transfected CHO cells and incubated with PMNs. This soluble ICAM-1 provoked elastase release, similar to PMA, which could be inhibited by MAbs to CD18 but not MAbs to other beta2-integrin subunits. In addition, coincubation with protease inhibitors eglin C and AAPVCK reduced PMN-mediated cytotoxicity to control levels. Finally, ICAM-1-transfected CHO cells were exposed to activated PMNs from a patient with chronic granulomatous disease that caused significant cell lysis, equivalent to that of PMNs from normal donors. Collectively, these data suggest that ICAM-1 provokes PMN-mediated cytotoxicity via CD18-mediated protease release.

Background: Interleukin-6 (IL-6) appears to be a reliable marker of disease severity in critically ill patients at risk for inflammatory organ injury such as ARDS and MOF. Debate continues, however, as to whether this pleiotropic cytokine acts principally as a proinflammatory or counterregulatory mediator. Because the polymorphonuclear leukocyte (PMN) is a central effector of inflammatory injury, defining the effects of IL-6 on mechanisms of PMN cytotoxicity may be revealing. Previous investigations of PMN release of reactive oxygen species demonstrate that IL-6 in concert with other mediators may augment cytotoxicity. We hypothesized that IL-6 alone increases PMN cytotoxic potential through selective enhancement of elastase release., Materials and Methods: Isolated human PMNs were incubated with IL-6 in the physiologic range observed in critically ill patients (0.1 to 100 ng/ml) for 10 to 30 min. Selected cells were then activated with fMLP (1 microM). Elastase release was measured by specific cleavage of AAPV-pNA and compared to untreated cells and cells activated with formyl-Met-Leu-Phe (fMLP; 1 microM) alone. To determine if changes in elastase release might be due to IL-6 induced generation of PAF, WEB 2347 (50 microM) was preincubated with selected cells for 20 min. Surface expression of beta 2 integrins was measured by flow cytometry after incubating with labeled antibodies to CD11b and CD18., Results: IL-6 alone at 100 ng/ml augmented basal elastase release by 116 +/- 41% within 10 min. Doses as low as 0.1 ng/ml stimulated elastase release when the incubation time was increased to 30 min. After 30 min of incubation, IL-6 at all doses examined augmented the elastase release of fMLP-activated cells (increases of 33 to 45%). WEB 2347 preincubation did not block augmentation of elastase release by IL-6 at 10 ng/ml. IL-6 had no effect on surface expression of beta 2 integrins at 10 ng/ml., Conclusions: IL-6 alone enhances both basal and fMLP-stimulated elastase release by PMNs. This proinflammatory action on PMNs may help explain the observed correlation between circulating IL-6 levels and inflammatory organ injury.

Background: Selective surgical exploration of penetrating neck wounds is now the standard of care, but the safety and cost effectiveness of selective diagnostic testing remains controversial. We herein review our 18-year prospective evaluation of a progressively selective approach., Patients and Methods: Since 1979, 312 patients sustained penetrating trauma to the anterior neck; 75% were stabbed and 24% were shot. Zone I was penetrated in 13%, zone II in 67%, and zone III in 20%., Results: In all, 105 (34%) of the patients had early exploration (16% were nontherapeutic). Of the 207 (66%) observed, 1 (0.5%) required delayed exploration. Length of stay was 8.0 days following exploration, 5.1 days following negative exploration, and 1.5 days following observation. In the last 6 years, 40% have had adjunctive testing: 69% of zone I, 15% of zone II, and 50% of zone III injuries., Conclusion: Selective management of penetrating neck injuries is safe and does not mandate routine diagnostic testing for asymptomatic patients with injuries in zones II and III.

Our basic laboratory work has identified the postischemic gut as a source of platelet-activating factor (PAF), which primes circulating neutrophils for the production of reactive oxygen metabolites (ROMs) leading to distant organ injury. Circulating PAF-acetylhydrolase (PAF-AH) hydrolyzes PAF to lyso-PAF. Recently, ROMs have been shown to rapidly and irreversibly inactivate human PAF-AH. Consequently, our study hypothesis was that reduced levels of PAF-AH in severely injured patients would be associated with the development of multiple organ failure (MOF). Over a 16 mo period, 26 patients at known risk for MOF (Injury Severity Score (ISS) > or = 25 or an ISS > 15 with > or = 6 U of blood transfused within the first 6 h) had blood sampled on postinjury days 0, 1, 2, 3, and 5. PAF-AH activity was assessed by measuring the percentage of 3H-labeled PAF hydrolyzed. MOF was defined by a standard score. The mean age of the 26 study patients was 34 +/- 2 yr; 19 (73%) were male. The injury mechanism was blunt in 18 (69%), and the mean ISS was 31 +/- 2. Eight patients (31%) developed MOF. In the MOF patients, plasma PAF-AH activity was significantly lower on the day of injury and remained depressed throughout the ensuing 5 days compared with the non-MOF patients. Reduced PAF-AH activity is associated with the development of postinjury MOF. With the recent molecular cloning of human plasma PAF-AH, repleting this circulating, anti-inflammatory enzyme may represent useful therapy for these high risk patients.

Background: Interleukin-6 (IL-6), interleukin-8 (IL-8), and adhesion molecules have been implicated as mediators in neutrophil (PMN) and endothelial cell (EC) interactions leading to postinjury multiple organ failure (MOF). Our hypothesis was that circulating levels of IL-6, IL-8, and soluble intercellular adhesion molecule-1 (sICAM-1) would discriminate patients at risk for postinjury MOF., Methods: Serial plasma levels of IL-6, IL-8, and sICAM-1 were measured in 27 high-risk trauma patients., Results: The IL-6 and IL-8 levels were significantly elevated in MOF patients compared with non-MOF patients at 12 and 36 hours postinjury. The IL-6 level was also elevated at 84 and 132 hours, and IL-8 at 84 hours. The sICAM-1 level did not become elevated in MOF patients until 132 hours postinjury., Conclusion: Interleukin-6 and IL-8 are elevated early after trauma and discriminate patients who will develop MOF. Late elevation of sICAM-1 likely results from PMN cytotoxicity leading to EC injury or inflammation.

Objective: The effects of interleukin (IL)-6 in the injured patient are examined in an attempt to clarify the potential pathophysiologic role of IL-6 in the response to injury., Summary Background Data: Interleukin-6 is an integral cytokine mediator of the acute phase response to injury and infection. However, prolonged and excessive elevations of circulating IL-6 levels in patients after trauma, burns, and elective surgery have been associated with complications and mortality. The mechanistic role of IL-6 in mediating these effects is unclear., Methods: A review of current literature is performed to summarize the origins, mechanisms of action, and biologic effects of IL-6 and to characterize the IL-6 response to injury., Results: Interleukin-6 is a multifunctional cytokine expressed by a variety of cells after a multitude of stimuli, under complex regulatory control mechanisms. The IL-6 response to injury is uniquely consistent and related to the magnitude of the insult. Moreover, the early postinjury IL-6 response correlates with complications as well as mortality., Conclusions: Interleukin-6 appears to play an active role in the postinjury immune response, making it an attractive therapeutic target in attempts to control hyperinflammatory provoked organ injury.

Background: Elevated levels of soluble intercellular adhesion molecule-1 (sICAM-1) correlate with the development of postinjury multiple organ failure. Soluble ICAM-1 secretion is known to be induced in endothelial cells and monocytes by diverse inflammatory stimuli. We have found that incubation of quiescent polymorphonuclear leukocytes (PMNs) with sICAM-1 elicits elastase release and, more recently, that cross-linking CD18 receptors on PMNs also produces elastase release. Consequently, our study hypothesis was that sICAM-1 provokes PMN elastase release through its interaction with CD18., Methods: To obtain sICAM-1, Chinese hamster ovarian cells transfected with human ICAM-1 were lysed and centrifuged at 150,000 g for 1 hour; the supernatant was passed over an ICAM-1 affinity column, eluted with 0.1 mmol/L glycine HCl, and concentrated with dialysis filter. Human PMNs (2.5 x 10(5)) were saturated with specific monoclonal antibodies for the beta 2 subunits (CD11a, CD11b, CD18) or nonspecific monoclonal antibodies for 30 minutes on ice before a 1-hour incubation with sICAM-1 (75 ng/ml) at 37 degrees C. Elastase activity was measured by the cleavage of n-methoxysuccinyl-A-A-P-V-p-nitroanilide., Results: Neutrophil incubation with sICAM-1 resulted in 19.2% +/- 2.8% of total PMN elastase, compared with 2.4% +/- 0.5% in the controls. Blockade of CD18 abrogated sICAM-1 provoked elastase release with monoclonal antibodies to CD18 (TS1/18, 31H8) resulting in 4.3% +/- 1.0% and 5.5% +/- 1.4% elastase release, respectively. Blockade of CD11a, CD11b, and nonspecific antibody controls had no effect on sICAM-1 induced elastase release., Conclusions: In vitro, sICAM-1 provokes PMN elastase release through CD18. This may represent a mechanism by which elevated levels of circulating sICAM-1, released from local injury sites, provoke distal organ dysfunction.

Elevated levels of soluble intercellular adhesion molecule-1 have been shown predictive of post-injury multiple organ failure. We hypothesized that sICAM-1 augments distant organ injury via its affect on the PMN and; thus, have examined neutrophil elastase and superoxide production in response to sICAM-1. To obtain soluble ICAM-1, Chinese Hamster Ovarian (CHO) cells were transfected with human ICAM-1 (cDNA vector CD1.8), lysed and centrifuged at 150,000g for 1 hr; supernatant was passed over an ICAM-1 affinity gradient, eluted with 0.1 mM glycine x HCl, and concentrated using an Amicon Spin-X filter. PMNs were incubated for 1 hr with sICAM-1 at 37 degrees C. Quiescent and PMA-activated PMNs served as negative and positive controls respectively. Elastase activity was measured by the cleavage of methoxy-succinyl-alalyl-alalyl-prolyl-valyl-p-nitroanilide. Superoxide production was determined by superoxide dismutase inhibitive ferricytochrome C reduction over a 5-60 min incubation. PMN incubation with sICAM-1 provoked marked increase in elastase release 10.43 +/- 2.90 (10(-6) U/hr) compared to control 1.64 +/- 0.57, and was equivalent to PMA-activated PMN elastase release 11.60 +/- 1.50 (10(-6) U/hr). In contrast, sICAM-1 alone did not promote spontaneous PMN superoxide production beyond buffer treated PMNs (0.25 +/- 0.09 nmole/2.5 x 10(5) PMN/min). In sum, sICAM-1 stimulates PMN elastase release in vitro. Clinically, this may represent a mechanism by which sICAM-1 participates in the genesis of post-injury multiple organ failure.

Nitric oxide (NO.) has proven effective in improving oxygenation and reducing pulmonary hypertension in the acute respiratory distress syndrome (ARDS), but the precise mechanism remains unclear. NO. has been shown to reduce leukocyte-endothelial adhesion, attenuate neutrophil (PMN) sequestration, and protect endothelium from an inflammatory insult. Intercellular adhesion molecule (ICAM)-1 is a pivotal regulator of PMN-endothelial adhesion and, thus, a critical mediator of PMN cytotoxicity. Consequently, we hypothesized that NO. suppresses ICAM-1 expression on endothelium. Human umbilical vein endothelial cells (HUVEC) were cultured. The NO. donor 3-morpholinosidnonimine (SIN-1) (0.1-10 microM) was incubated with HUVEC for 4 hr. In separate experiments, HUVEC were incubated with bacterial lipopolysaccharide (LPS) (100 ng/ml) alone or following SIN-1 pretreatment. ICAM-1 expression on HUVEC was measured by flow cytometric analysis. SIN-1 (1 and 10 microM) reduced the expression of ICAM-1 on resting HUVEC by 58 and 47%, respectively. LPS upregulated ICAM-1 expression; however, this was not affected by SIN-1 pretreatment. We conclude that NO. reduces constitutive endothelial expression of ICAM-1, but does not prevent LPS-stimulated upregulation of ICAM-1 expression. Downregulation of ICAM-1 may be a mechanism whereby NO. protects resting endothelium (distant organ bed) from circulating primed or activated PMNs, but may not be as effective at a primary inflammatory site.

Interleukin-6 (IL-6) is an integral mediator of the acute phase response to injury and infection; an exaggerated IL-6 response has been associated with adverse clinical events. The precise role of IL-6 is unclear, but it appears capable of modulating the functional repertoire of mature neutrophils (PMNs). Our previous work demonstrated that IL-6 -stimulated PMNs are primed by lower concentrations of platelet-activating factor (PAF) than nonstimulated PMNs. Recently, we have found that IL-6 suppresses PMN apoptosis via a PAF-like mechanism. We hypothesized that IL-6 stimulates PMNs to produce PAF. PMNs isolated from healthy human donors were incubated with IL-6 (0.1-100 ng/ml) at 37 degrees C. Lipid production was measured by use of thin-layer chromatography, and PAF quantitated with a scintillation proximity assay. IL-6 (1 and 10 ng/ml) stimulated PMNs to produce increase quantities of PAF. PAF production was associated with an increase in PMN cytosolic calcium. These data may provide mechanistic insight into IL-6 regulation of PMN-mediated cytotoxicity and the role of PAF in mediating IL-6 effects on PMNs.

Background: Interleukin (IL)-6, an integral mediator of the physiologic acute phase response to injury, has been associated with adverse postinjury complications when present in excessive concentrations. The precise role of IL-6 is unclear, but may involve exacerbation of polymorphonuclear neutrophil leukocytes (PMN)-mediated hyperinflammation. We have shown that IL-6 delays PMN apoptosis, thereby inhibiting the resolution of inflammation. More recently we have found that IL-6 stimulates PMNs to generate platelet-activating factor (PAF). Given the evidence for PAF involvement in postinjury hyperinflammation, we hypothesized that IL-6 delayed apoptosis via a mechanism involving PAF., Methods: PMNs were isolated from healthy human donors using plasma-Percoll gradients and were cultured in enriched RPMI 1640 media at 2 x 10(7) PMNs/mL for 24 hours (37 degrees C, 5% CO2). Subgroups were treated with IL-6 (0.1-10 ng/mL) or PAF (0.1-10 ng/mL) or pretreated with the PAF receptor antagonist WEB 2170 (20 microM) before IL-6 or PAF. Morphologic assessment and quantitation of apoptosis was performed with acridine orange/ethidium bromide stain., Results: Both IL-6 and PAF suppressed PMN apoptosis. Pretreating PMNs with WEB 2170 abrogated the effects IL-6 as well as PAF., Conclusion: Interleukin-6 delays PMN apoptosis via a mechanism involving PAF. These observations may help elucidate the mechanisms of IL-6 and PAF in mediating postinjury hyperinflammation and secondary organ dysfunction, ultimately leading to effective therapeutic targets in patients at risk for multiple organ failure.

Background: Neutrophil (PMN) apoptosis promotes the phagocytosis of PMNs without inciting an inflammatory response or local cytotoxic effect. This is important in the normal resolution of inflammatory processes and the control of tissue injury. Conversely, a delay in PMN apoptosis may facilitate PMN-mediated organ dysfunction by extending PMN functional integrity at an inflammatory site. Elevated circulating and tissue levels of interleukin-6 (IL-6) have been associated with postinjury organ dysfunction, and IL-6 appears to augment PMN cytotoxic functions. Therefore, we hypothesized that IL-6 delays PMN apoptosis, thereby enhancing PMN-mediated cytotoxicity., Methods: Neutrophils isolated from healthy human donors were incubated for 24 hours in enriched RPMI 1640 cell culture medium at 37 degrees C in 5% carbon dioxide. Subgroups were incubated with IL-6, heat-denatured IL-6, or buffer alone. Apoptosis was assessed morphologically using acridine orange-ethidium bromide stain, and biochemically by DNA gel electrophoresis. Functional capacity of PMNs was assessed by superoxide generation after activation with phorbol myristate acetate or platelet-activating factor plus formyl-methionyl-leucyl-phenylalanine., Results: Treatment with IL-6 resulted in a greater population of surviving (nonapopototic) PMNs after 24 hours. In addition, the IL-6-treated population produced more superoxide after 24 hours than did the untreated or heat-denature IL-6-treated groups, after either activating stimulus., Conclusions: Interleukin-6 delays PMN apoptosis, resulting in a larger population of surviving PMNs with a greater collective capacity for superoxide production. This could potentially facilitate PMN-mediated tissue injury and may be a mechanism whereby IL-6 contributes to organ dysfunction.

Background: Late acute respiratory distress syndrome (ARDS), characterized by progressive pulmonary interstitial fibroproliferation, is associated with mortality > 80%. Although previous large prospective trials failed to show a benefit of steroids in early ARDS, recent small reports describe improved survival in patients with late ARDS. Recognizing the pathogenetic differences between early and late ARDS, we employed steroid therapy in patients with refractory late ARDS., Patients and Methods: Over a 5-year period, we treated 6 patients who were dying of isolated refractory ARDS with methylprednisolone sodium succinate (1 to 2 mg/kg every 6 hours). Ventilatory parameters and lung injury scores were serially recorded, and steroids were weaned based on clinical response., Results: Steroids were instituted after 16 days of advanced mechanical ventilatory support. By day 7 of steroid therapy, there was clinically significant improvement in PaO2/FiO2 ratios (84 to 172) and lung injury scores (3.6 to 2.9); 5 patients (83%) survived., Conclusions: Steroid therapy appears to be effective in patients with refractory late ARDS. Prospective trials are needed to define the indications, timing of intervention, dose and duration, and precautions of steroid therapy.

Apoptosis of polymorphonuclear leukocytes (PMNs) is a critical step in the resolution of tissue inflammation. PMN apoptosis has been studied extensively in vitro, and diverse inflammatory mediators have been shown to modulate the process. The reported effects of interleukin-6 (IL-6) on PMN apoptosis are inconsistent; however, analysis of published studies reveals at least one discriminating factor--the use of varied concentrations of PMNs in the experimental design. Consequently, we hypothesized that the in vitro effects of IL-6 on PMN apoptosis varied with the concentration of PMNs in culture. PMNs isolated from healthy human donors were cultured at concentrations from 1 to 20 x 10(6)/mL, and incubated with IL-6 doses from 1 to 100 ng/mL. PMNs cultured at 1-5 x 10(6)/mL were unaffected by IL-6; in contrast, IL-6 inhibited apoptosis in PMNs cultured at 10-20 x 10(6)/mL, compared with untreated similarly concentrated PMNs. These data suggest caution in interpreting in vitro studies of apoptosis; on the other hand, appropriately designed experiments may help elucidate the regulation of apoptosis in vivo.

Laboratory studies suggest that the postischaemic gut serves as a priming bed for circulating neutrophils that provoke multiple organ failure. Platelet-activating factor, generated by phospholipase A2, appears to be active in priming neutrophils in the gut. Interleukin-6 also appears to be elaborated by the postischaemic gut, but may be even more important in distant organs via promoting neutrophil-mediated organ dysfunction.

Background: Interaction of the CD11/CD18 complex on polymorphonuclear neutrophils (PMNs) and intercellular adhesion molecule (ICAM)-1 on endothelium is a critical event in PMN-mediated tissue injury. In addition, increased expression of ICAM-1 on type I pneumocytes has been identified in a variety of pulmonary disorders associated with PMN-induced inflammation. We hypothesized that ICAM-1 up-regulation is sufficient to promote cytotoxicity via activated PMNs., Methods: The complementary DNA for human ICAM-1 was transfected into Chinese hamster ovarian (CHO) cells, which do not inherently express this adhesion receptor, by using the expression vector CD1.8. Fluorescence-activated cell sorter analysis revealed 62% CHO cell surface expression of ICAM-1. Wild type and transfected CHO cells were labeled with chromium 51 and exposed to quiescent or activated (1 mumol/L phorbol myristate acetate) PMNs for 4 hours. Subsets were pretreated with a monoclonal antibody to ICAM-1. PMN cytotoxicity was determined by specific percent 51Cr release., Results: Incubation of quiescent PMNs with wild type and transfected CHO cells produced nominal cell lysis, 0.5% +/- 0.3% and 0.2% +/- 0.2%, respectively. Activated PMNs produced 13.6% +/- 3.2% versus 1.4% +/- 0.7% cell lysis, comparing transfected with wild type CHO cells, and 0.5% +/- 0.2% cell lysis after pretreatment with a monoclonal antibody to ICAM-1, p < 0.01., Conclusions: ICAM-1 up-regulation is sufficient to promote cytotoxicity via activated PMNs. This may represent a potential target for attenuating PMN-mediated injury to endothelial and other cell lines, including parenchyma.

Interleukin-8 (IL-8) has been associated with a variety of hyperinflammatory states and adverse clinical events. Circulating IL-8 levels correlate with the severity of tissue trauma, and excessive elevations of IL-8 are associated with postinjury adult respiratory distress syndrome and multiple organ failure. While IL-8 is a potent neutrophil (PMN) chemoattractant and activator and enhances PMN transendothelial migration, it also acts to inhibit PMN adhesion to stimulated endothelial cells (ECs). We hypothesized that IL-8 could interact directly with ECs to increase permeability independent of PMNs. Human umbilical vein ECs (HUVECs) were cultured on collagen-coated micropore filters, and integrity of the EC monolayer measured by albumin flux across the filter. Cytochalasin D was used as a positive control. IL-8 induced increased permeability at a concentration of 1000 ng/mL. This effect was abrogated by preincubation of HUVECs with a protein synthesis inhibitor (cycloheximide). These data suggest a role for IL-8 in promoting endothelial leak independent of PMNs, via a mechanism involving protein synthesis.

Our in vivo model of mesenteric ischemia/reperfusion (I/R) has shown that the gut serves as a priming bed for neutrophils (PMN). Activation of phospholipase A2 (PLA2) during ischemia temporally precedes PMN sequestration in the gut and the appearance of primed PMN in the portal circulation. Therefore, we hypothesized that reperfused gut secretes platelet activating factor (PAF) via PLA2 activation that is responsible for increased PMN chemotaxis and priming for superoxide (O2-) generation. Sprague-Dawley rats underwent gut ischemia/reperfusion (45 min SMA occlusion/2 hr reperfusion) or sham laparotomy. Distal ileum was harvested, rinsed with bacteriostatic saline/neomycin, and incubated for 1 hr at 37 degrees C in RPMI 1640 and the cell-free supernatant was collected. Normal human PMNs, isolated by plasma-Percoll gradients, were pretreated with or without a PAF receptor antagonist (WEB 2170). Chemotaxis toward gut supernatant was then measured by the agarose method. Additionally, PMNs were preincubated with or without WEB 2170 and their O2- release in response to 1 microM FMLP was measured by the Vmax of SOD-inhibitable cytochrome c reduction. Reperfused gut produced a chemotactic index of 2.1 +/- 0.1 compared to 0.2 +/- 0.9 following sham laparotomy (P < 0.05); this was reduced to 0.4 +/- 0.9 with PAF receptor blockade. Similarly, gut I/R supernatant primed PMNs for O2- (P < 0.05) compared to laparotomy, and this effect was abrogated by a PAF antagonist. These data suggest that reperfused gut can elaborate PAF which chemoattracts and primes PMNs for O2- generation.

Our trauma research center program entitled, "Trauma Primes Cells" is based on the fundamental hypothesis that prior exposure to multiple, sequential, sublethal cellular insults primes constructive or destructive pathways of cellular responses of subsequent injury. A major objective is to design therapy that will reduce the incidence of multiple organ failure. Although a number of inflammatory cascades have been incriminated in the pathogenesis of multiple organ failure (MOF), diffuse PMN-mediated tissue injury remains an attractive unifying concept. We have developed a sequential insult rodent model in which the priming event consisted of superior mesenteric arterial (SMA) clamping for 45 minutes followed by 6 hours of reperfusion. Following this priming event, activation was induced with a low dose of endotoxin (2.5 mg/kg). We believe that these studies support our hypothesis: mesenteric ischemic/reperfusion primes circulating PMNs. When these have been activated they can then be provoked by endotoxin to provoke distant organ injury. Primed PMNs are released from the postischemic mesenteric bed and enter the systemic circulation. They subsequently sequester in the pulmonary vascular bed where they are relatively harmless until they are activated by low dose endotoxin. These activated PMNs then migrate across the endothelium cell and release reactive oxygen metabolites.

Background: Myocardial contusion is commonly diagnosed following blunt chest trauma, and has potentially lethal complications. Cost-effective case management in patients with suspected myocardial contusion is confounded by the low incidence of complications and the lack of a reliable test to predict them. The clinical usefulness of elevated cardiac enzyme levels is controversial., Methods: We analyzed a 4-year experience of 359 patients with high-risk blunt chest trauma who were assessed using an established practice guideline. Our multivariate statistical model evaluated all of the early risk factors included in the guideline, specifically focusing on cardiac enzyme levels., Results: Myocardial contusion was diagnosed in 30% of patients, and complications (dysrhythmias and cardiogenic shock) occurred in 5%. In no case was cardiac enzyme elevation the sole predictor of a complication. The cost of routine cardiac enzyme assay was substantial., Conclusion: Cardiac enzyme determinations have no useful role in the evaluation of patients with suspected myocardial contusion. They should be eliminated from current practice guidelines.

Background: Polymorphonuclear neutrophil (PMN) priming appears to be an important event in the pathogenesis of hyperinflammatory states, resulting in adult respiratory distress syndrome or multiple organ failure. Interleukin-6 (IL-6) is an integral mediator of the acute stress response to injury and infection, but excessive and prolonged systemic levels have been associated with morbidity and mortality following trauma, burns, and elective surgery. We hypothesized that IL-6 primed PMNs for exaggerated cytotoxicity. However, we have been unable to directly prime PMNs for superoxide release with IL-6., Objective: To determine whether IL-6 acted in concert with another inflammatory mediator (platelet-activating factor [PAF]) to prime PMNs., Methods: Polymorphonuclear neutrophils isolated from healthy human donors were incubated for varying times with IL-6 (0.01 to 100 ng/mL), PAF (0.01 to 100 ng/mL), or a combination of IL-6 and PAF. Superoxide production was then measured with and without the addition of the PMN-activating formylpeptide formyl-methionyleucylphenylalanine., Results: Over the range of times (5 to 90 minutes) and doses tested, IL-6 did not prime PMNs, while PAF primed PMNs in a dose- and time-dependent manner. Interleukin 6 (10 ng/mL) combined with a nonpriming concentration of PAF (0.1 ng/mL) primed PMNs for superoxide production over a range of incubation times., Conclusion: The inflammatory mediators IL-6 and PAF act synergistically to prime PMNs in vitro. This observation may begin to elucidate the mechanistic role of IL-6 in pathologic clinical states.