Search

Background We implemented expanded screening criteria for blunt cerebrovascular injuries (BCVIs) in an attempt to capture the remaining 20% of patients not historically identified with earlier protocols. We hypothesized that these expanded criteria would capture the additional 20% of BCVI patients not previously identified. Methods Screening criteria for BCVI were expanded in 2011 after identifying new injury patterns. The study population included 4 years prior (2007 to 2010; classic) and following (2011 to 2014; expanded) implementation of expanded criteria. Results BCVIs were identified in 386 patients: 150 during the classic period (2.36% incidence) and 236 in the expanded period (2.99% incidence). In the expanded period, 155 patients were imaged based on classic screening criteria, 62 on expanded criteria (21 complex skull fractures, 20 upper rib fractures, 6 mandible fractures, 2 scalp degloving, 1 great vessel injury, and 12 combination), and 19 for other injuries and symptoms. Conclusions There was a significant increase in the identification of BCVI following the adoption of expanded screening criteria, resulting in a substantial reduction of missed injuries. Expanded criteria should be adopted when screening for BCVI.

Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m2 plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival.

BACKGROUND: Life-threatening hemorrhage is a rare event in hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Epidemiologic data are lacking to predict patients at risk for hemorrhage requiring surgical consultation. We sought to identify early clinical predictors of hemorrhagic complications in patients at risk for HELLP syndrome. METHODS: Patients at risk for HELLP syndrome from 1997 to 2007 were identified retrospectively. Variables evaluated in at-risk women were maternal age, gestational history, hepatic transaminase levels, and platelet count. Multiple logistic regression analysis was used to identify independent predictors of poor maternal outcomes, which were defined as hemorrhage requiring transfusion of blood products, need for surgical intervention, hepatic rupture, and death. RESULTS: A total of 109 at-risk women were identified. Adverse outcomes included transfusions (18%), hemorrhage interventions (8%), damage control laparotomy (2.8%), and hepatic rupture (2.8%). Maternal and perinatal mortality were .9% and 3.7%, respectively. Median transfusion requirements for women with hepatic rupture were 56 U of packed red blood cells, 26 U of fresh-frozen plasma, 18 U of platelets, and 6 U of cryoprecipitate. Multiple logistic regression analysis showed previous gestations (P = .002), platelet count (P = .01), and aspartate aminotransferase level increase (P = .04) were independent predictors of life-threatening hemorrhage. Previous gestations increased the risk of adverse outcome 3-fold. CONCLUSIONS: Identifiable risk factors predictive of major hemorrhage are thrombocytopenia (< 100,000 cells/μL), increase of aspartate aminotransferase level greater than 70 IU/L, and previous gestations.

Introduction. Progressive postinjury coagulopathy has become the fundamental rationale for damage control surgery, and the decision to abort operative intervention must occur prior to overt laboratory confirmation of coagulopathy. Current coagulation testing is most commonly performed for monitoring anticoagulation therapy, the results are delayed, and the applicability of these tests in the trauma setting is questionable. Point-of-care (POC) rapid thrombelastography (r-TEG) provides real time analysis of thrombostatic function, which may allow for accurate, goal directed therapy. The test differs from standard thrombelastography (TEG) because the clotting process and subsequent analysis is accelerated by the addition of tissue factor to the whole blood sample, but is limited by the requirement that the analysis be performed within 4 min of blood draw to prevent clot formation. Consequently, citrated specimens have been proposed to obviate this time limitation. We hypothesized that the speed of r-TEG analysis following tissue factor addition to citrated blood might compromise accurate determinations compared with noncitrated whole blood. Additionally, we sought to compare the use of r-TEG with conventional coagulation tests in analysis of postinjury coagulopathy. Methods. We conducted a retrospective study of severely injured patients entered into our trauma database between January and June 2008 who were at risk for postinjury coagulopathy. Patients needed simultaneous conventional coagulation (INR, fibrinogen, platelet count) and r-TEG specimens with either fresh or citrated whole blood for inclusion in the study. κ-Statistics were used to determine the agreement between the tests in predicting hypocoagulability. McNemar's x 2 tests were used to compare theoretical blood product administration between r-TEG and conventional coagulation tests for noncitrated specimens. Therapeutic transfusion triggers were: INR ( >1.5) and r-TEG ACT ( > 125 s) for FFP administration; fibrinogen (

Background Recent guidelines do not support local wound exploration (LWE) or diagnostic peritoneal lavage (DPL) in the evaluation of patients with anterior abdominal stab wounds (AASWs), favoring computed tomography scanning or serial examinations. In patients without immediate indications for laparotomy, we hypothesized that LWE/DPL would identify patients requiring surgery while limiting unnecessary hospital admissions. Methods Patients sustaining penetrating trauma at our level I trauma center over a 3-year period were reviewed. Results During the study period, 139 patients with AASW followed our LWE/DPL algorithm. Fifty-six patients had LWE without fascial penetration: 46 were discharged immediately, 10 required admission. Fifty-eight patients had fascial penetration on LWE but negative DPL: 37 were observed for less than 24 hours, 19 were observed for more than 24 hours, and 2 patients developed peritonitis requiring exploration. Twenty-five patients had positive LWE/DPL: 13 had therapeutic laparotomy, 12 had nontherapeutic laparotomy. Conclusions Only 11% of patients with AASWs without overt indication for laparotomy require surgical care. LWE remains a valid method to exclude intra-abdominal injury and to eliminate hospitalization in more than one third of AASW patients.

Human polymerized hemoglobin (PolyHeme) is a universally compatible oxygen carrier developed for use when red blood cells are unavailable and oxygen-carrying replacement is needed to treat life-threatening anemia. This multicenter phase III trial assessed survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. Patients resuscitated with PolyHeme had outcomes comparable to those receiving the standard of care including rapid access to stored red blood cells. Although there were more adverse events in the PolyHeme group compared with control patients receiving blood, the observed safety profile is acceptable for the intended population. The benefit-to-risk ratio of PolyHeme is favorable when blood is needed but is not available or an option.

Purpose The 111 In-capromab pendetide scan (ProstaScint; Cytogen Corp., Princeton NJ) is approved by the Food and Drug Administration to evaluate increasing prostate-specific antigen (PSA) levels after radical prostatectomy. This study evaluated the role of prostate bed 111 In-capromab pendetide scan findings to predict response to salvage radiotherapy (RT). Methods and Materials Forty patients who had PSA recurrence after radical prostatectomy and a 111 In-capromab pendetide scan immediately before salvage prostate bed RT (median, 66 Gy) were identified from the Duke Prostate Center database. Patients with distant uptake of capromab pendetide or long-term androgen deprivation therapy were excluded. Median follow-up after salvage RT was 2.7 years. Patient demographic, clinical, and pathologic characteristics; PSA values; and 111 In-capromab pendetide scan results were retrospectively analyzed. A PSA failure after salvage RT was defined as PSA level greater than 0.2 ng/ml. Data were combined with other published results in a secondary pooled analysis of 106 patients. Results 111 In-Capromab pendetide findings included 20 patients with negative scan results and 20 with locally positive scan results. Two-year progression-free survival rates were 60% for patients with a negative scan result and 74% for those with a locally positive scan result ( p = 0.49). Combined analysis did not show a difference in outcome based on local 111 In-capromab pendetide scan result. Conclusion For patients without distant signal detected by using 111 In-capromab pendetide scan, patients with locally positive scan findings did not have statistically different progression-free survival than those with a negative scan result, suggesting that salvage RT may be successful in patients with either a locally positive or negative 111 In-capromab pendetide scan result.

Background Secondary abdominal compartment syndrome (SACS) is a well-recognized sequelae of massive fluid resuscitation in surgical patients, but has only anecdotally been reported in the medical patient population. The purpose of this study was to compare the clinical scenarios, physiologic indices, and outcomes of patients with SACS due to medical versus trauma etiologies. Methods Patients undergoing decompression for SACS from January 1999 to January 2006 were identified using our computerized operative records. Results During the 7-year study period, 54 patients developed SACS (41 postinjury patients and 13 medical patients). There were no significant differences in demographics, physiologic indices, or fluid resuscitation between the medical and postinjury groups: age (46.6 ± 4.7 vs 40.6 ± 2.3), bladder pressure (33.5 ± 1.1 vs 32.8 ± 1.8), peak airway pressures (45.9 ± 2.4 vs 49.3 ± 2.1), base deficit (14.6 ± 1.4 vs 13.6 ± 1.1), and fluids (18.5 ± 1.8 vs 16.0 ± 1.5 liters). Patients with a medical cause of SACS had a significantly longer time to decompression (21 ± 3.6 versus 6.5 ± 1.9 hours), significantly higher incidence of MOF (62% v 27%), and trend toward greater mortality (54% versus 34%). Conclusions Patients with diverse disease processes may develop SACS. Despite similar age and physiologic indices, the MOF and mortality rates associated with medical SACS are markedly higher. These findings highlight the need for routine monitoring in at-risk patients, prevention of pathologic intra-abdominal hypertension, and a low threshold for decompression.

Background: Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL). Patients and methods: A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m2, V 20 mg/m2, and D 15 mg/m2 for transplant-naive patients, and G 800 mg/m2, V 15 mg/m2, and D 10 mg/m2 for post-transplant patients. Results: The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively. Conclusions: GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients.

Background Aggressive screening for blunt cerebrovascular injury (BCVI) and prompt anticoagulation for documented injuries has resulted in a significant reduction in ischemic neurologic events. An association between vertebral artery injuries (VAIs) and specific cervical spine fracture patterns has been suggested; however, current screening guidelines would subject all patients with cervical spine fractures to imaging because no distinction has been made for carotid artery injuries (CAIs). We hypothesized that specific cervical spine fracture patterns that warrant screening evaluation exist, hence limiting unwarranted diagnostic imaging. Methods Patients undergoing screening for BCVI on the basis of injury patterns and mechanism have been prospectively followed at our regional trauma center since January 1996. Results During the study period from January 1996 to January 2005, there were 17,007 blunt trauma admissions. Twenty-three patients presented with symptoms of BCVI. Screening angiography was performed in 766 patients (4.5%), and diagnosed 258 (34%) patients with BCVI. One hundred twenty-five patients with BCVI had cervical spine fractures; 18 patients had isolated CAI; 84 had isolated VAI, and 23 had combined CAI and VAI. Eight patients with VAI had minor cervical fractures but underwent screening for other injury patterns. Fractures in the remaining patients with BCVI were 1 of 3 patterns. Subluxations in 56 (48%) patients, C1 to C3 cervical spine fractures in 42 (36%), or extension of the fracture through the foramen transversarium in 19 (16%). Cervical spine fractures were the sole indication for screening in 90% of the study population. Screening yield of all patients admitted with 1 of these 3 fracture patterns was 37%. Conclusions Blunt cerebrovascular injury is associated with complex cervical spine fractures that include subluxation, extension into the foramen transversarium, or upper C1 to C3 fractures. Patients sustaining such cervical fractures should undergo prompt screening.

Mesenteric lymph may provide the mechanistic link between gut ischemia and acute lung injury after hemorrhagic shock (HS). Studies have focused on the toxic mediators that develop in the post-shock mesenteric lymph (PSML). However, a complementary possibility is that there is loss of protective mediators found in pre-shock normal mesenteric lymph (NML) after HS. We hypothesize that NML protects against inflammatory insults to the pulmonary endothelium and that this effect is lost in PSML.Primary human pulmonary endothelial cells (HMVECs) were incubated with NML or PSML collected from rats subjected to HS and resuscitation and then stimulated with 20 ng/mL LPS. ICAM-1 surface expression was measured by flow cytometry. In subsequent experiments, lipoproteins were extracted from NML before incubation and LPS-induced ICAM-1 expression determined.Mean fluorescent intensity (MFI) of LPS-induced ICAM-1 in NML and PSML treated HMVECs were 10.1 +/- 2.3 versus 27.7 +/- 0.83, respectively (P0.05). This represented at 71% decrease in ICAM-1 expression by NML compared to ICAM-1 expression in LPS-induced controls (MFI: 34.6 +/- 6.9). Lipoprotein extraction from NML abolished this protective effect (MFI: 31.2 +/- 5.3 versus Control + LPS: 33.5 +/- 3.6, P0.05). Baseline ICAM-1 levels were not significantly different among control, NML, and PSML groups.Lipoproteins in NML contain anti-inflammatory properties that decrease ICAM-1 expression induced by LPS in pulmonary endothelium. Decreased protective lipoproteins after HS and resuscitation may contribute to the toxicity associated with PSML from the ischemic gut.

Background Damage-control surgery and the recognition of the abdominal compartment syndrome have improved patient outcomes but at the cost of an open abdomen. Multiple techniques have been introduced to obtain fascial closure for the open abdomen to minimize morbidity and cost of care. We performed a modification of the vacuum-assisted closure (VAC) technique that provided constant fascial tension, hypothesizing this would result in a higher rate of primary fascial closure. Methods After initial temporary closure of the abdomen after post-injury damage control or decompressive laparotomy for abdominal compartment syndrome, we began the sequential closure technique. The technique begins by covering the bowel with the multiple white sponges overlapped like patchwork, and the fascia is placed under moderate tension over the white sponges with #1-PDS sutures. Large black VAC sponges are placed on top of the white sponges and affixed with an occlusive dressing and standard suction tubing is placed. Patients are returned to the operating room for sequential fascial closure and replacement of the sponge sandwich every 2 days, with a resulting decrease in the fascial defect. Results Fourteen patients underwent sequential abdominal closure during the study period: 9 owing to damage control surgery and 5 owing to secondary abdominal compartment syndrome. Average time to closure was 7.5 ± 1.0 days (range 4–16) and average number of laparotomies to closure was 4.6 ± 0.5 (range 3–8). All patients attained primary fascial closure. Conclusion We propose a modification of the previously described vacuum-assisted closure technique that achieves 100% fascial approximation in our limited experience. Further application and refinement of this technique may eliminate the need for delayed complex and costly reconstructive abdominal wall procedures for the open abdomen.

Background Postinjury multiple organ failure (MOF) is a result of a dysfunctional inflammatory response to severe injury and shock. Acute lung injury is thought to promote further organ dysfunction by the systemic release of inflammatory mediators from injured lung tissue. Although clinical evidence supports this model, a clear understanding of the relationship between lung dysfunction and multiple organ failure has yet to be defined. We hypothesized that respiratory dysfunction is an early obligate event in the progression of postinjury MOF. Methods Data were collected prospectively on 1,344 trauma patients at risk for postinjury MOF. Inclusion criteria were age greater than 16 years, trauma intensive care unit admission, Injury Severity Score greater than 15, and survival longer than 48 hours. Isolated head injuries and head injuries with an extracranial abbreviated injury score of less than 2 were excluded. Daily physiologic and laboratory data were collected through surgical intensive care unit day 28 and clinical events were recorded thereafter until death or hospital discharge. Organ failure was characterized using the Denver MOF scale. Results Organ dysfunction was observed in 1,011 (75%) of 1,344 patients. Lung dysfunction was observed in 951 (94%) patients with 1 or more organ dysfunctions and 598 (99%) of 605 patients with 2 or more organ dysfunctions. Lung dysfunction preceded heart, liver, and kidney dysfunction by an average of 0.6 ± 0.2 days, 4.8 ± 0.2 days, and 5.5 ± 0.5 days, respectively. The severity of lung dysfunction correlated with the severity of heart, liver, and kidney dysfunction, and the number of other dysfunctional organ systems. Conclusions Postinjury respiratory dysfunction is an obligate event that precedes heart, liver, and kidney failure. The severity of other organ dysfunction is related directly to the severity of respiratory dysfunction. These data implicate lung dysfunction as central to the promotion of pathogenic inflammation and the development of postinjury MOF.

Identification of novel diagnostic or therapeutic biomarkers from human blood plasma would benefit significantly from quantitative measurements of the proteome constituents over a range of physiological conditions. Herein we describe an initial demonstration of proteome-wide quantitative analysis of human plasma. The approach utilizes post-digestion trypsin-catalyzed 16O/18O peptide labeling, two-dimensional liquid chromatography (LC)-Fourier transform ion cyclotron resonance ((FTICR) mass spectrometry, and the accurate mass and time (AMT) tag strategy to identify and quantify peptides/proteins from complex samples. A peptide accurate mass and LC-elution time AMT tag database was initially generated using tandem mass spectrometry (MS/MS) following extensive multidimensional LC separations to provide the basis for subsequent peptide identifications. The AMT tag database contains >8,000 putative identified peptides, providing 938 confident plasma protein identifications. The quantitative approach was applied without depletion for high abundant proteins for comparative analyses of plasma samples from an individual prior to and 9 h after lipopolysaccharide (LPS) administration. Accurate quantification of changes in protein abundance was demonstrated by both 1:1 labeling of control plasma and the comparison between the plasma samples following LPS administration. A total of 429 distinct plasma proteins were quantified from the comparative analyses and the protein abundances for 25 proteins, including several known inflammatory response mediators, were observed to change significantly following LPS administration.

Background Critically injured patients are susceptible to the abdominal compartment syndrome (ACS), which requires decompressive laparotomy with delayed abdominal closure. Previous work by the University of Texas Houston group showed impaired gut function after resuscitation-associated gut edema. The purpose of this study was to determine if enteral nutrition was precluded by the intra-abdominal hypertension and bowel edema of the ACS. Methods Patients developing postinjury ACS from January 1996 to August 2003 at our level-I trauma center were reviewed. Patient demographics, time to definitive abdominal closure, and institution and tolerance of enteral nutrition were evaluated. Results Thirty-seven patients developed postinjury ACS during the study period; 26 men and 11 women with a mean age of 36 ± 4 and injury severity score of 33 ± 4. Mean intra-abdominal pressure before decompression was 32 ± 3 mm Hg, and concurrent mean peak airway pressure was 50 ± 4 cm oxygen. Enteral feeding was never started in 12 patients; 4 died within 48 hours of admission, 7 required vasoactive agents until their death, and 1 developed an enterocutaneous fistula requiring parenteral nutrition. Enteral feeding was initiated in the remaining 25 patients: 13 had feeds started within 24 hours of abdominal closure; 5 were fed with open abdomens; and 7 had a delay because of vasopressors (n = 2), multiple trips to the operating room (n = 2), paralytics (n = 2), and increased intra-abdominal pressures (n = 1). Once advanced, enteral feeding was tolerated in 23 (92%) of the 25 patients with attainment of goal feeds in a mean of 3.1 ± 1 days. Conclusions Despite the bowel edema and intra-abdominal hypertension related to the ACS, early enteral feeding is feasible after definitive abdominal closure.

Background: Recent reports have described resuscitation-induced, “secondary” abdominal compartment syndrome (ACS) in trauma patients without intra-abdominal injuries. We have diagnosed secondary ACS in a variety of nontrauma as well as trauma patients. The purpose of this review is to characterize patients who develop secondary ACS. Methods: Our prospective ACS database was reviewed for cases of secondary ACS. Physiologic parameters and outcomes were recorded. Data are expressed as mean ± SEM. Results: Fourteen patients (13 male, aged 45 ± 5 years) developed ACS 11.6 ± 2.2 hours following resuscitation from shock. Eleven (79%) had required vasopressors; the worst base deficit was 14.1 ± 1.9. Resuscitation included 16.7 ± 3.0 L crystalloid and 13.3 ± 2.9 red blood cell units. Decompressive laparotomy improved intra-abdominal, systolic, and peak airway pressures, as well as urine output; however, mortality was 38% among trauma and 100% among nontrauma patients. Conclusions: Secondary ACS may be encountered by general surgeons in a variety of clinical scenarios; resuscitation from severe shock appears to be the critical factor. Early identification and abdominal decompression are essential. Unfortunately, in our experience, this is a highly lethal event.

Background: The abdominal compartment syndrome (ACS) is a recognized complication of damage control surgery (DCS). The purposes of this study were to (1) determine the effect of ACS on outcome after DCS, (2) identify patients at high risk for the development of ACS, and (3) determine whether ACS can be prevented by preemptive intravenous bag closure during DCS. Methods: Patients requiring postinjury DCS at our institution from January 1996 to June 2000 were divided into groups depending on whether or not they developed ACS. ACS was defined as an intra-abdominal pressure (IAP) greater than 20 mm Hg in association with increased airway pressure or impaired renal function. Results: ACS developed in 36% of the 77 patients who underwent DCS with a mean IAP prior to decompression of 26 ± 1 mm Hg. The ACS versus non-ACS groups were not significantly different in patient demographics, Injury Severity Score, emergency department vital signs, or intensive care unit admission indices (blood pressure, temperature, base deficit, cardiac index, lactate, international normalized ratio, partial thromboplastin time, and 24-hour fluid). The initial peak airway pressure after DCS was higher in those patients who went on to develop ACS. The development of ACS after DCS was associated with increased ICU stays, days of ventilation, complications, multiorgan failure, and mortality. Conclusions: ACS after postinjury DCS worsens outcome. With the exception of early elevation in peak airway pressure, we could not identify patients at higher risk for ACS; moreover, preemptive abdominal bag closure during initial DCS did not prevent this highly morbid complication.

Summary Background Patients with resistant diffuse aggressive non-Hodgkin's lymphoma (DA-NHL) have a poor prognosis. Studies have suggested infusional therapy may be beneficial. Patients and methods This trial used an infusional regimen called I-CHOPE in resistant patients who had previously received only bolus CHOPE or CHOP regimen. Resistance was defined as: a) primary refractory disease, b) progression on therapy, c) partial response, d) complete remission lasting less than one year. Eligibility criteria included a diagnosis of DA-NHL (IWF E-H), no prior irradiation and adequate organ function. Results Thirty-seven patients were entered and twenty-nine were eligible. Reasons for ineligibility were incorrect histology (5) and other (3). The median age was 57 years (range 29–81) with 21 males. The performance status scores were: 0 (12 patients); 1 (9 patients); 2 (8 patients). Prior therapy consisted of standard CHOP (26 patients), bolus CHOPE (2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hour continuous intravenous infusion of doxorubicin 10 mg/m2/day, vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/m2day. Cyclophospharnide 750 mg/m2 was given as an iv bolus day 6 and prednisone was given at 100 mg/day p.o. on days 1–5. G-CSF was allowed for myelosuppression. The overall response rate was 48% (CR 17%; PR 31%). Freedom from progression was 24% at six months and 8% at one year. Survival was 69% at six months and 40% at one year. In an exploratory analysis a prior CR or PR predicted response to I-CHOPE. Twelve of sixteen patients who had a CR/PR on previous therapy responded while two of thirteen who had no prior response, responded to I-CHOPE (P = 0.003). The toxicity was tolerable with grade 3–4 hematologic toxicity being leucopenia 94% and thrombocytopenia 41%. The grade 3–4 non-hematologic toxicities were infection in 28%, phlebitis in 11%, and stomatitis in 15%. Conclusions I-CHOPE can induce responses in this group of patients with a poor prognosis, but most were seen in those who had previously had a response to bolus chemotherapy.

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. (Surgery 1999;126:198-202.)

Background: Increased expression of pulmonary endothelial intercellular adhesion molecule–1 (ICAM-1) is obligatory to neutrophil adherence culminating in adult respiratory distress syndrome (ARDS). The p38 mitogen-activated protein kinases (MAPKs) have been established as crucial in leukocyte proinflammatory signaling, but their role in the endothelial cell remains ill defined. We hypothesized that p38 MAPK activity is integral to ICAM-1 up-regulation on pulmonary endothelium. Methods: Human pulmonary microvascular endothelial cells (HMVECs) were grown to confluence and pretreated with either the tyrosine phophorylation inhibitor herbimycin A (1 μmol/L) or the p38 MAPK inhibitor SB203580 (10–7 to 10–5 mol/L) for 6 hours. ICAM-1 expression was quantified by flow cytometry. Data are expressed as mean fluorescence intensity. Western blotting was used to show p38 MAPK activity after stimulation with lipopolysaccharide (LPS) or tumor necrosis factor–α (TNF-α). Results: Tyrosine phosphorylation inhibition with herbimycin A attenuated both LPS and TNF-α stimulated ICAM-1 up-regulation. Similarly, specific inhibition of p38 MAPK attenuated both LPS (10-6 to 10-5 mol/L SB203580) and TNF-α (10-7to 10-5 mol/L SB203580) stimulated expression of ICAM-1 on HMVECs. Both LPS and TNF-α induced activation of p38 in HMVECs. Conclusions: Signaling through p38 MAPKs contributes to LPS and TNF-α stimulated ICAM-1 surface expression on HMVECs. Thus p38 MAPKs appear integral to both neutrophil and endothelial cell proinflammatory signaling and may be a potential therapeutic target in the treatment of ARDS. (Surgery 1998;124:403-8.)

Background.Priming of neutrophils (PMNs) for protease release is believed to be central to the pathogenesis of PMN-mediated tissue injury observed in ARDS/MOF. Defining the intracellular signaling pathways involved with this excessive protease release may aid in establishing future therapies for ARDS. Phospholipase D (PLD) production of phosphatidic acid (PA) is thought to be pivotal in reactive oxygen species generation but its role in degranulation (i.e., protease release) remains unclear. Our hypothesis was that primed neutrophils require PLD production of PA for maximal activated release of elastase. Methods.Isolated human PMNs were incubated with a well described antagonist of PA production, ethanol (ETOH, 100–1000 mg/dL), and then primed (PAF, 200 nM) followed by activation (fMLP, 1 μM). To mimic fMLP receptor-dependent activation, PMNs were primed and then directly activated with exogenous dioctanoyl l -α-phosphatidic acid (PA8, 0.5–200 μM). To confirm the importance of PA in elastase release, PA8was given to primed–activated PMNs after ethanol pretreatment in an attempt to recover the maximal response. Elastase release was measured by the cleavage of AAPV-pNA. Results.PA blockade with ETOH attenuated PAF-primed/fMLP-activated PMN elastase release in a dose-dependent manner. Exogenous PA8reproduced maximally primed-activated PMN elastase release, and furthermore, PA8was able to restore maximal elastase release following ethanol attenuation. Conclusions.Elastase release from PAF-primed/ fMLP-activated neutrophils is dependent on PA production. Thus, PA production appears to be involved in both oxidant-dependent and independent mechanisms of neutrophil cytotoxicity and may be a potential therapeutic target in the treatment of hyperinflammatory diseases such as ARDS/MOF.

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 μM). 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 μM) alone. To determine if changes in elastase release might be due to IL-6 induced generation of PAF, WEB 2347 (50 μM) was preincubated with selected cells for 20 min. Surface expression of β 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 β 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 Resuscitative thoracotomy performed in the emergency department (EDT) continues to have clear indications in patients sustaining trauma to the torso, particularly penetrating injuries. However, adjunctive use of aortic cross-clamping during EDT for hemorrhagic shock also may be useful in the acute resuscitation of patient with nontorso injuries (NTI). We questioned the utility of EDT in patients with nontorso trauma. Methods Patients undergoing EDT have been prospectively followed since 1977 at our regional level I trauma center. Results During the 26-year study period, 959 patients underwent EDT; 27 (3%) of these patients underwent EDT for penetrating NTI. Three (11%) of these patients survived to leave the hospital, with only 1 patient sustaining mild neurologic deficit. The mechanism of injury in the survivors was stab wound to the neck (1), gunshot wound to the neck (1), and extremity vascular injury (1). All survivors of EDT for NTI underwent prehospital cardiopulmonary resuscitation and successful endotracheal intubation in the field. There were no survivors of EDT for penetrating injury to the head. Conclusions Resuscitative EDT with aortic cross-clamping is a potential adjunct in the acute resuscitation of NTI involving penetrating neck or extremity vascular injuries.

Objective: Our goal was to determine the clinical significance of size discordancy in preterm twins. Study Design: A retrospective study was performed to review outcomes of twins delivered between Jan. 1, 1988, and June 30, 1995. Maternal and neonatal records were assessed for demographic data, maternal medical history, and neonatal mortality and morbidity outcomes. Discordancy was defined as ≥20% difference in birth weight. The χ 2 analysis was performed. Results: There were 42 sets of discordant twins and 77 sets of concordant twins in the final analysis. The distribution of gestational ages in both groups was similar. We found no difference in maternal morbidity between the groups. Discordant sets had a significantly longer hospital stay ( p = 0.003) and more cases of hyperbilirubinemia ( p = 0.01), but there were no other differences in morbid outcomes. There were no differences in outcome variables between the two twins within discordant sets with respect to gender, size, birth order, growth restriction, or route of delivery. There were no stillbirths among any of the 238 infants. Of the 15 neonatal deaths, none occurred in infants delivered after 32 weeks' gestation or in infants weighing >2000 gm at birth. Infants who were small for gestational age had a higher incidence of sepsis ( p = 0.043) and longer hospital stays ( p = 0.005) compared with infants who were appropriate for gestational age. Conclusions: Size discordancy alone does not appear to be an indication for preterm delivery of twins. When results of antenatal testing are normal and growth restriction is absent, attempts should be made to achieve a gestational age >32 weeks and weight >2000 gm before delivery is considered.

All transthoracic defibrillators on the US market use nominally monophasic shock waveforms. However, biphasic waveforms have a lower defibrillation threshold than monophasic waveforms for transthoracic defibrillation of animals and for defibrillation of humans by implantable cardioverter defibrillators. The relative efficacies of Edmark monophasic and Gurvich biphasic transthoracic cardioversion waveforms (200 J into 50 omega) were compared for transthoracic cardioversion in 171 patients undergoing electrophysiologic study for evaluation of ventricular arrhythmias. Patients were randomized in a blinded fashion to receive either a monophasic or a biphasic waveform for the initial shock for conversion of induced ventricular arrhythmias (ventricular fibrillation [VF] = 53, monomorphic ventricular tachycardia [VT] = 80, polymorphic VT = 30, ventricular flutter = 8). Delivered energies for the Edmark and Gurvich waveforms were 215 +/- 11 and 171 +/- 11 J, respectively. There were no significant differences in patient characteristics, use of antiarrhythmic agents, arrhythmia cycle length, or duration of arrhythmia prior to shock for monophasic and biphasic waveform groups. The first shock for all arrhythmias was successful in 75 of 88 patients (85.2%) for the monophasic waveform compared with 81 of 83 patients (97.6%) for the biphasic waveform, p = 0.0054. The first shock for VF was successful in 22 of 28 patients (78.6%) for the monophasic waveform compared with 25 of 25 (100%) for the biphasic waveform, p = 0.0241. The Gurvich biphasic waveforms delivering a mean of 171 J were superior to Edmark monophasic waveforms delivering a mean of 215 J for transthoracic cardioversion of arrhythmias of short duration. This finding may have important implications for the development of future transthoracic defibrillators.

Acute chest syndrome complicating sickle cell anemia may progress to adult respiratory distress syndrome despite appropriate therapy. Extra-alveolar air leaks may complicate the care of these patients as conventional mechanical ventilation becomes increasingly difficult. We successfully treated a child with sickle cell anemia, acute chest syndrome, adult respiratory distress syndrome, and severe extra-alveolar air leaks using a new combined mode ventilatory approach: pressure control with high-frequency ventilation.

Background: Percutaneous tracheostomy as described by Ciaglia is accepted as a safe technique with minimal associated morbidity. Recent modification of the technique to a single-step dilator prompted us to evaluate this in the critically injured patient. Methods: A comparison of patients undergoing percutaneous tracheostomy was performed. From May 1998 to May 1999, patients underwent surgery using the sequential multidilator technique (MDT), and from July 1999 to July 2000, patients underwent surgery using the single dilation technique (SDT). Results: Ninety-three tracheostomies were performed, 49 MDT and 44 SDT. Time to tracheostomy and total ventilator days was similar between the groups. Three complications occurred. In the MDT group, 1 patient experienced delayed tracheal hemorrhage not requiring transfusion. In the SDT group, 1 patient had transient right lower lobe collapse, and another patient had unexplained extubation requiring emergent cricothyroidotomy. Conclusions: Percutaneous tracheostomy using the single-step Rhino dilator technique is technically easier than the currently accepted multidilator technique with equivalent complications.

Migration of orthopedic fixation pins into the thoracic cavity can result in perforation of pulmonary vasculature, aorta, bronchus, atrium, or ventricle. Prompt diagnosis and treatment is tantamount in preventing devastating consequences. A patient who had fixation of a right humeral fracture weeks later had intrathoracic migration of a fixation pin, found by routine postoperative radiographic examination. Because the patient was asymptomatic, we removed the pin with a thoracoscopic operation. The foreign body was retrieved successfully without intraoperative or postoperative complication.

Introduction: The lipid fraction of mesenteric lymph collected after hemorrhagic shock (HS) and reperfusion primes the neutrophil oxidative burst in vitro. Recently, we have identified the culprit agent to be a neutral lipid consistent with Leukotriene B4 (LTB4). We hypothesized that plasma LTB4 increases after HS and that diversion of mesenteric lymph (DML) abrogates this effect. Furthermore, we posited that administration of an LTB4 antagonist blocks the priming effect of mesenteric lymph on neutrophils (PMNs). Methods: Adult male Sprague-Dawley rats (325–375 g) underwent laparotomy with cannulation of the mesenteric lymphatics for lymph diversion (DML) or laparotomy without mesenteric cannulation (Sham). Additionally, DML rats had lymph collected both pre- and post-shock. All rats underwent cannulation of the femoral artery and vein. HS to a MAP of 30 mmHg for 45 minutes was achieved via venous exsanguination. Animals were resuscitated with shed blood and with 2x the shed blood volume of NS over two hours. After resuscitation, plasma was collected for LTB4 measurement by ELISA. Lymph collected in the resuscitation phase was added to isolated PMNs that were then measured for superoxide release in the presence and absence of the LTB4 receptor antagonist CP-105,696. Results: LTB4 concentration in the lymph collected from the DML group measured 281.25 ± 53.81 ng/ml pre-shock, increasing to 692.13 ± 176.91 ng/ml post-shock (p

Evans County black males had lower ischemic heart disease (IHD) prevalence, incidence, and mortality than white males. High-density lipoprotein (HDL) cholesterol was lower in IHD cases than in subjects without IHD. HDL cholesterol and apolipoprotein A-I (Apo A-I) were higher and low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and Apo C-II were lower in black than white males. Of the black-white male HDL cholesterol difference, 22% was statistically explained by Apo A-I. Controlling for Apo C-II reduced the black-white differences in total cholesterol 87%, LDL cholesterol 44%, VLDL cholesterol 83%, and total triglyceride 83%. There were negative associations between Apo A-I and age, Quetelet index, and cigarettes smoked; the association between Apo A-I and alcohol was positive. Only body mass index and race were strong correlates of Apo C-II. The ratios of Apo A-I to Apo A-II and of HDL cholesterol to Apo A-II were higher in black than white males with adjustment for age, body mass, and cigarette and alcohol consumption. Thus black-white differences in total lipids, lipoprotein lipids, and lipoprotein apoproteins were observed, indicating a relatively antiatherogenic profile in black males only partially explained by known correlates.

The prevalence and clinical associations of beta-migrating very-low-density lipoprotein (beta-very-low-density lipoprotein), an atherogenic lipoprotein associated with type III hyperlipidemia, were compared in men and women using and not using estrogen-containing hormones. Beta-very-low-density lipoprotein was more common in men, 0.54 percent or one in 185, than in women not taking hormones, 0.30 percent or one in 333, and was least common in women taking hormones, 0.04 percent or one in 2,500. Beta-very-low-density lipoprotein-positive men and women were heavier and had higher triglyceride, cholesterol, and very-low-density lipoprotein cholesterol levels compared with beta-very-low-density lipoprotein-negative subjects, but 30 percent of the men and 21 percent of the nonuser women did not have elevated triglyceride or cholesterol levels. The very-low-density lipoprotein cholesterol/total triglyceride ratio exceeded 0.30 in 55 percent and 54 percent of beta-very-low-density lipoprotein-positive men and women compared with 3.3 percent and 3.9 percent of beta-very-low-density lipoprotein-negative men and women. Ninety-three percent of the beta-very-low-density lipoprotein-positive subjects had some lipoprotein lipid abnormality and 60 percent had an abnormal glucose, liver, or renal function test result or high alcohol or dietary cholesterol intake. In conclusion, beta-migrating very-low-density lipoprotein is more common in men than in women, consistent with a protective effect of estrogen. About half of the time, beta-very-low-density lipoprotein is associated with an elevated very-low-density lipoprotein cholesterol/total triglyceride ratio, indicating that beta-very-low-density lipoprotein can be present independent of other markers of type III hyperlipidemia. Nonetheless, beta-very-low-density lipoprotein signifies abnormal lipoprotein metabolism of some kind in almost every instance, is frequently associated with treatable medical conditions, and may on pathophysiologic grounds be considered important in its own right in predicting atherosclerosis risk. Beta-very-low-density lipoprotein-associated conditions should attract medical attention.