Early operative management in patients with adhesive small bowel obstruction: population-based cost analysis.

BACKGROUND: Adhesive small bowel obstruction (aSBO) is a potentially recurrent disease. Although non-operative management is often successful, it is associated with greater risk of recurrence than operative intervention, and may have greater downstream morbidity and costs. This study aimed to compare the current standard of care, trial of non-operative management (TNOM), and early operative management (EOM) for aSBO. METHODS: Patients admitted to hospital between 2005 and 2014 in Ontario, Canada, with their first episode of aSBO were identified and propensity-matched on their likelihood to receive EOM for a cost-utility analysis using population-based administrative data. Patients were followed for 5 years to determine survival, recurrences, adverse events and inpatient costs to the healthcare system. Utility scores were attributed to aSBO-related events. Cost-utility was presented as the incremental cost-effectiveness ratio (ICER), expressed as Canadian dollars per quality-adjusted life-year (QALY). RESULTS: Some 25 150 patients were admitted for aSBO and 3174 (12·6 per cent) were managed by EOM. Patients managed by TNOM were more likely to experience recurrence of aSBO (20·9 per cent versus 13·2 per cent for EOM; P < 0·001). The lower recurrence rate associated with EOM contributed to an overall net effectiveness in terms of QALYs. The mean accumulated costs for patients managed with EOM exceeded those of TNOM ($17 951 versus $11 594 (€12 288 versus €7936) respectively; P < 0·001), but the ICER for EOM versus TNOM was $29 881 (€20 454) per QALY, suggesting cost-effectiveness. CONCLUSION: This retrospective study, based on administrative data, documented that EOM may be a cost-effective approach for patients with aSBO in terms of QALYs. Future guidelines on the management of aSBO may also consider the long-term outcomes and costs.

ANTECEDENTES: La oclusión de intestino delgado por adherencias (adhesive small bowel obstruction, aSBO) es una enfermedad potencialmente recidivante. Aunque el tratamiento no quirúrgico es a menudo eficaz, se asocia con un mayor riesgo de recidiva que la intervención quirúrgica, y puede provocar más adelante morbilidad y costes. El objetivo de este estudio fue comparar un Ensayo de Tratamiento No Quirúrgico (Trial of Non-operative Management, TNOM, el estándar actual de tratamiento) con Tratamiento Operatorio Precoz (Early Operative Management, EOM) para el tratamiento de aSBO. MÉTODOS: Pacientes ingresados en el hospital entre 2005-2014 en Ontario, Canadá con un primer episodio de aSBO fueron identificados y emparejados por puntaje de propensión respecto a la probabilidad de recibir EOM para un análisis de coste-utilidad utilizando datos administrativos de base poblacional. Los pacientes fueron seguidos durante 5 años para determinar la supervivencia, recidivas, eventos adversos, y costes de la hospitalización para el sistema de salud. Las puntuaciones de utilidad se atribuyeron a los eventos relacionados con la aSBO. El coste-utilidad se presentó como la razón costo efectividad incremental (incremental cost-effectiveness ratio, ICER) expresada como dólares por año de vida ajustado por calidad (quality-adjusted life-year, QALY). RESULTADOS: Un total de 25.150 pacientes fueron ingresados por aSBO y 3.174 (12,6%) fueron tratados con EOM. Los pacientes tratados mediante TNOM tenían más probabilidades de presentar una recidiva de la aSBO (20,9% versus 13,2%, P < 0,0001). La menor incidencia de recidivas asociada con EOM contribuyó a una eficacia neta global en términos de QALYs. Mientras que los costes medios acumulados para los pacientes tratados con EOM superaron a los de TNOM ($17,951 versus $11,594, P < 0,0001), el ICER de EOM versus TNOM fue $29,881/QALY, lo que sugiere un coste-eficacia de esta estrategia. CONCLUSIÓN: Este estudio retrospectivo basado en datos administrativos evidenció que EOM puede representar un abordaje coste-efectivo para pacientes con aSBO en términos de QALYs. Las futuras guías clínicas para el tratamiento de la aSBO pueden también considerar los resultados a largo plazo y los costes.

Population-based study of the impact of small bowel obstruction due to adhesions on short- and medium-term mortality.

BACKGROUND: Small bowel obstruction due to adhesions (aSBO) is a common indication for admission to a surgical unit. Despite the prevalence of this condition, the short- and medium-term survival of this patient population has not been well described. The purpose of this study was to measure the short- and medium-term survival of patients admitted to hospital with aSBO. METHODS: Linked administrative data were used to identify patients admitted to hospital in Ontario, Canada, for aSBO between 2005 and 2011. Patients were divided into two groups: those aged less than 65 years (younger group) and those aged 65 years and older (older group). Thirty-day, 90-day and 1-year mortality rates were estimated. One-year mortality was compared with that in the general population, adjusting for age and sex. The timing of deaths in relation to admission was assessed, as well as the proportion of patients discharged before experiencing short-term mortality. RESULTS: There were 22 197 patients admitted to hospital for aSBO for the first time in the study interval. Mean age was 64·5 years and 52·2 per cent of the patients were women. Overall, the 30-day, 90-day and 1-year mortality rates for the cohort were 5·7 (95 per cent c.i. 5·4 to 6·0), 8·7 (8·3 to 9·0) and 13·9 (13·4 to 14·3) per cent respectively. For both groups, the 1-year risk of death was significantly greater than that of the age-matched general population. The majority of deaths (62·5 per cent) occurred within 90 days of admission, with 36·4 per cent occurring after discharge from the aSBO admission. CONCLUSION: Patients admitted with aSBO have a high short-term mortality rate. Increased monitoring of patients in the early period after admission is advisable.

ANTECEDENTES: La obstrucción del intestino delgado por adherencias (adhesive small bowel obstruction, aSBO) es una indicación frecuente de ingreso en una unidad quirúrgica. A pesar de la prevalencia de esta patología, la supervivencia de estos pacientes a corto y a medio plazo no ha sido bien descrita. El objetivo de este estudio fue determinar la supervivencia a corto y a medio plazo de pacientes con aSBO ingresados en el hospital. MÉTODOS: Utilizando el enlace de datos administrativos se identificaron a los pacientes ingresados por aSBO en Ontario, Canadá, entre 2005-2011. Los pacientes se dividieron en dos subgrupos: los menores de 65 años de edad (subgrupo joven) y los de 65 años o más (subgrupo mayor). Se estimó la mortalidad a los 30 días, 90 días y a 1 año. La mortalidad a 1 año se comparó con la de la población general, ajustando por edad y sexo. Se evaluó el momento del fallecimiento respecto al ingreso, así como la proporción de pacientes que fueron dados de alta antes de fallecer a los 30 días. RESULTADOS: Durante el periodo de estudio se ingresaron en el hospital 22.197 pacientes con aSBO por primera vez. La edad media de los pacientes era de 65 años y un 52% eran mujeres. La mortalidad global de la cohorte a los 30 días, a los 90 días y a 1 año fue del 5,7% (i.c. del 95%: 5,4-6,0%), 8,3% (i.c. del 95%: 8,3-9,0%) y 13% (i.c. del 95%: 12,9-15,0%), respectivamente. Para ambos subgrupos, el riesgo de mortalidad a 1 año fue significativamente mayor que en la población general emparejada por edad. La mayoría de los fallecimientos (59%) ocurrieron durante los 90 días del ingreso, con un 36% tras el alta después del ingreso por aSBO. CONCLUSIÓN: Los pacientes ingresados por aSBO presentan una alta mortalidad a corto plazo. Se recomienda incrementar la vigilancia de estos pacientes en el periodo temprano tras el alta hospitalaria.

Hepatic fat and abdominal adiposity in early pregnancy together predict impaired glucose homeostasis in mid-pregnancy.

Hepatic fat and abdominal adiposity individually reflect insulin resistance, but their combined effect on glucose homeostasis in mid-pregnancy is unknown. A cohort of 476 pregnant women prospectively underwent sonographic assessment of hepatic fat and visceral (VAT) and total (TAT) adipose tissue at 11-14 weeks' gestation. Logistic regression was used to assess the relation between the presence of maternal hepatic fat and/or the upper quartile (Q) of either VAT or TAT and the odds of developing the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus at 24-28 weeks' gestation, based on a 75 g OGTT. Upon adjusting for maternal age, ethnicity, family history of DM and body mass index (BMI), the co-presence of hepatic fat and quartile 4 (Q4) of VAT (adjusted odds ratio (aOR) 6.5, 95% CI: 2.3-18.5) or hepatic fat and Q4 of TAT (aOR 7.8 95% CI 2.8-21.7) were each associated with the composite outcome, relative to women with neither sonographic feature. First-trimester sonographic evidence of maternal hepatic fat and abdominal adiposity may independently predict the development of impaired glucose homeostasis and GDM in mid-pregnancy.

Regionalization of services improves access to emergency vascular surgical care.

Management of vascular surgical emergencies requires rapid access to a vascular surgeon and hospital with the infrastructure necessary to manage vascular emergencies. The purpose of this study was to assess the impact of regionalization of vascular surgery services in Toronto to University Health Network (UHN) and St Michael's Hospital (SMH) on the ability of CritiCall Ontario to transfer patients with life- and limb-threatening vascular emergencies for definitive care. A retrospective review of the CritiCall Ontario database was used to assess the outcome of all calls to CritiCall regarding patients with vascular disease from April 2003 to March 2010. The number of patients with vascular emergencies referred via CritiCall and accepted in transfer by the vascular centers at UHN or SMH increased 500% between 1 April 2003-31 December 2005 and 1 January 2006-31 March 2010. Together, the vascular centers at UHN and SMH accepted 94.8% of the 1002 vascular surgery patients referred via CritiCall from other hospitals between 1 January 2006 and 31 March 2010, and 72% of these patients originated in hospitals outside of the Toronto Central Local Health Integration Network. Across Ontario, the number of physicians contacted before a patient was accepted in transfer fell from 2.9 ± 0.4 before to 1.7 ± 0.3 after the vascular centers opened. In conclusion, the vascular surgery centers at UHN and SMH have become provincial resources that enable the efficient transfer of patients with vascular surgical emergencies from across Ontario. Regionalization of services is a viable model to increase access to emergent care.

Antioxidants increase lipopolysaccharide-stimulated TNF alpha release in murine macrophages: role for altered TNF alpha mRNA stability.

Through their effects on gene activation, antioxidants have been reported to modulate cellular expression of several proinflammatory cytokines and adhesion molecules, an effect mediated by preventing translocation of the transcription factor nuclear factor-kappa B (NF-kappa B) into the nucleus. In addition, modulation of the intracellular redox state may have profound effects on cell activation and subsequent gene expression distinct from effects on NF-kappa B; these effects may account for the divergent effects of antioxidants on cytokine gene expression in various reports. In the present studies, we evaluated the effect of the antioxidant, pyrrolidine dithiocarbamate (PDTC), on murine and human myeloid cell tumor necrosis factor alpha (TNF alpha) gene and protein expression. PDTC-enhanced LPS-induced TNF alpha secretion in cells derived from a murine macrophage cell line (J774.1), as well as in primary murine peritoneal macrophages by 4-fold. The effect was both stimulus and species dependent, as TNF alpha secretion was attenuated by PDTC in human THP-1 cells and in murine cells stimulated with zymosan. Northern analysis demonstrated that these effects were evident at the level of mRNA expression. Electrophoretic mobility shift assays confirmed the down-regulatory effect of PDTC on human myeloid NF-kappa B activation, whereas in murine cells no such inhibitory effect was evident. Evaluation of TNF alpha mRNA stability in murine cells demonstrated that the potentiating effect of PDTC on TNF alpha mRNA expression was due to an increase in mRNA half-life from 37 to 93 min. Together, these data suggest that the effect of antioxidants on gene expression are both stimulus and species dependent and illustrate a novel mechanism whereby redox manipulation might modulate TNF alpha expression in vivo.

The relationship between trauma center volume and outcome.

In spite of the limited direct evidence available, increasing data support a positive volume-outcome association in trauma care. When coupled with the extensive indirect data suggesting that regions with organized systems of trauma care are associated with lower trauma-related mortality rates than regions where the number of centers and their level of commitment are unlimited and untested, there is little doubt that experience improves outcome and that volume plays a critical role in the accrual of experience. Although regionalization of trauma care has the inevitable consequence of increased prehospital transport times, particularly in rural areas remote from large trauma centers, some states have designed inclusive systems where a large number of smaller centers have been verified and designated as lower level trauma centers (i.e., level 3-5). The process of trauma center verification holds these smaller volume centers to a standard of care such that the quality of care of the trauma patient may exceed that of other, less-regulated aspects of medical or surgical care. Several reports have suggested that trauma outcomes in smaller rural level 3 centers or centers with dedicated trauma programs with appropriate, functional triage protocols are comparable to national norms, thus reflecting the importance of commitment to outcome. These data suggest that quality of care does not only follow volume, particularly when stipulations and requirements are clear regarding the process of care and ongoing quality assurance.

Timing of urgent thoracotomy for hemorrhage after trauma: a multicenter study.

HYPOTHESIS: It is possible to quantify an amount of thoracic hemorrhage, after blunt and penetrating injury, at which delay of thoracotomy is associated with increased mortality. DESIGN: A retrospective case series. SETTING: Five urban trauma centers. STUDY SELECTION: Patients undergoing urgent thoracotomy (within 48 hours of injury) for hemorrhage (excluding emergency department thoracotomy). DATA EXTRACTION: Respective registries identified patients who underwent urgent thoracotomy. Injury characteristics, initial and subsequent chest tube outputs, time before thoracotomy, and outcomes were evaluated. MAIN OUTCOME MEASURE: Death. RESULTS: One hundred fifty-seven patients (36 with blunt and 121 with penetrating injuries) underwent urgent thoracotomy for hemorrhage between January 1, 1995, and December 31, 1998. Mortality correlated with mean (+/- SD) Injury Severity Score (38 +/- 19 vs 22 +/- 12.6 for survivors; P<.01) and mechanism (24 [67%] for blunt vs 21 [17%] for penetrating injuries; P<.01). Mortality increased as total chest blood loss increased, with the risk for death at blood loss of 1500 mL being 3 times greater than at 500 mL. Blunt-injured patients waited a significantly longer time to thoracotomy than penetrating-injured patients (4.4 +/- 9.0 h vs 1.6 +/- 3.0 h; P =.02) and also had a greater total chest tube output before thoracotomy (2220 +/- 1235 mL vs 1438 +/- 747 mL; P =.001). CONCLUSIONS: The risk for death increases linearly with total chest hemorrhage after thoracic injury. Thoracotomy is indicated when total chest tube output exceeds 1500 mL within 24 hours, regardless of injury mechanism.

Payer status: the unspoken triage criterion.

BACKGROUND: The cost of uncompensated trauma care is a significant barrier to trauma system development. Trauma center designation may burden an institution with an unprofitable mix of underinsured, severely injured patients. Concerns about inadequate reimbursement may motivate interhospital transfers on the basis of insurance status rather than medical necessity, potentially undermining the effectiveness of the system. We set out to explore whether this phenomenon exists in a mature trauma system. METHODS: Trauma patients receiving definitive care at Level III or IV trauma centers were compared with patients transferred from these centers to the only Level I regional center. Insurance status was classified as either commercial or noncommercial. Logistic regression was used to determine the independent predictors of transfer after adjusting for differences in injury severity. RESULTS: Only 12% of 2,008 patients initially evaluated at Level III/IV centers were transferred to the Level I center, an indicator of the effectiveness of prehospital triage protocols in the region. The presence of specific complex injuries, younger age, male gender, and insurance status were all associated with an increased likelihood of transfer. Insurance status was an independent predictor of transfer: patients without commercial insurance were 2.4 (95% confidence interval, 1.6-3.6) times more likely to be transferred to a Level I facility than patients with commercial insurance after adjusting for differences in injury severity. CONCLUSION: Insurance status influences the decision to transfer to higher levels of care. These findings suggest that the financial burden of a trauma system may be inequitably distributed. This inequitable distribution may be necessary for trauma system sustainability and calls for the development of disproportionate reimbursement strategies to support regional referral centers.

Relationship between trauma center volume and outcomes.

CONTEXT: The premise underlying regionalization of trauma care is that larger volumes of trauma patients cared for in fewer institutions will lead to improved outcomes. However, whether a relationship exists between institutional volume and trauma outcomes remains unknown. OBJECTIVE: To evaluate the association between trauma center volume and outcomes of trauma patients. DESIGN: Retrospective cohort study. SETTING: Thirty-one academic level I or level II trauma centers across the United States participating in the University Healthsystem Consortium Trauma Benchmarking Study. PATIENTS: Consecutive patients with penetrating abdominal injury (PAI; n = 478) discharged between November 1, 1997, and July 31, 1998, or with multisystem blunt trauma (minimum of head injury and lower-extremity long-bone fractures; n = 541) discharged between June 1 and December 31, 1998. MAIN OUTCOME MEASURES: Inpatient mortality and hospital length of stay (LOS), comparing high-volume (>650 trauma admissions/y) and low-volume (

Relevance and utility of peritoneal cultures in patients with peritonitis.

BACKGROUND: The pathogenic organisms responsible for the manifestations of secondary peritonitis have been well characterized through almost 30 years of experimental and clinical studies. Enteric gram-negative organisms and anaerobes predominate, with Escherichia coli and Bacteroides fragilis, respectively, being the most frequent isolates. This flora is remarkably consistent across patients and institutions. As a result of this consistency and the availability of well-established effective empiric antimicrobial regimens, many surgeons believe that cultures of peritoneal exudates in patients with peritonitis offer no useful information and no clinical benefit. METHODS: Review of pertinent antibiotic and management trials in the management of intraabdominal infection. RESULTS: There is increasing evidence that identification of organisms resistant to the chosen empiric antibiotic regimen portends a higher likelihood of failure. What is not clear is whether postoperative changes in the regimen in accordance with sensitivity patterns of the isolates offers any clinical advantage. In most circumstances, the data provided allow for simplification of the antibiotic regimen. CONCLUSION: The potential for reducing antibiotic exposure and the value of information derived from surveillance of microbial sensitivity patterns support the routine performance of peritoneal cultures.

Effect of an older sibling and birth interval on the risk of childhood injury.

OBJECTIVE: Certain family structures have been identified as putting children at high risk for injury. To further define children at highest risk, we set out to explore the effect of an older sibling and birth interval on the risk of injury related hospital admission or death. METHODS: Data were analyzed using a case-control design. Cases and controls were identified by linking longitudinal birth data from Washington state (1989-96) to death certificate records and hospital discharge data obtained from the Washington State Comprehensive Hospital Abstract Reporting System and frequency matched in a 1:2 ratio on year of birth. Cases consisted of singleton children 6 years of age or younger who were hospitalized or died as a result of injury during the years 1989-96. Multivariate logistic regression was used to identify and adjust for confounding variables. RESULTS: There were 3145 cases and 8371 controls. The adjusted odds ratio for injury in children with an older sibling was 1.50 (95% confidence interval 1.37 to 1.65). The effect was greatest in children under 2 years of age, and in those with a birth interval of less than two years. As the number of older siblings increased, so did the risk of injury, with the highest risk in children with three or more older siblings. CONCLUSION: These data suggest that the presence of an older sibling is associated with an increased risk of injury. The risk is highest in those with very short birth intervals. Potential mechanisms for this increased risk may relate to inadequate parental supervision. Pediatricians and other care providers need to be alert to these identifiable risk factors and then direct preventive strategies, such as home visits and educational programs, toward these families.

The effect of organized systems of trauma care on motor vehicle crash mortality.

CONTEXT: Despite calls for wider national implementation of an integrated approach to trauma care, the effectiveness of this approach at a regional or state level remains unproven. OBJECTIVE: To determine whether implementation of an organized system of trauma care reduces mortality due to motor vehicle crashes. DESIGN: Cross-sectional time-series analysis of crash mortality data collected for 1979 through 1995 from the Fatality Analysis Reporting System. SETTING: All 50 US states and the District of Columbia. SUBJECTS: All front-seat passenger vehicle occupants aged 15 to 74 years. MAIN OUTCOME MEASURES: Rates of death due to motor vehicle crashes compared before and after implementation of an organized trauma care system. Estimates are based on within-state comparisons adjusted for national trends in crash mortality. RESULTS: Ten years following initial trauma system implementation, mortality due to traffic crashes began to decline; about 15 years following trauma system implementation, mortality was reduced by 8% (95% confidence interval [CI], 3%-12%) after adjusting for secular trends in crash mortality, age, and the introduction of traffic safety laws. Implementation of primary enforcement of restraint laws and laws deterring drunk driving resulted in reductions in crash mortality of 13% (95% CI, 11%-16%) and 5% (95% CI, 3%-7%), respectively, while relaxation of state speed limits increased mortality by 7% (95% CI, 3%-10%). CONCLUSIONS: Our data indicate that implementation of an organized system of trauma care reduces crash mortality. The effect does not appear for 10 years, a finding consistent with the maturation and development of trauma triage protocols, interhospital transfer agreements, organization of trauma centers, and ongoing quality assurance.

Effectiveness of state trauma systems in reducing injury-related mortality: a national evaluation.

BACKGROUND: Regional trauma systems were proposed 2 decades ago to reduce injury mortality rates. Because of the difficulties in evaluating their effectiveness and the methodologic limitations of previously published studies, the relative benefits of establishing an organized system of trauma care remains controversial. METHODS: Data on trauma systems were obtained from a survey of state emergency medical service directors, review of state statutes and a previously published trauma system inventory. Injury mortality rates were obtained from national vital statistics data, whereas motor vehicle crash (MVC) mortality rates were obtained from the Fatality Analysis Reporting System. Mortality rates were compared between states with and without trauma systems. RESULTS: As of 1995, 22 states had regional trauma systems. States with trauma systems had a 9% lower crude injury mortality rate than those without. When MVC-related mortality was evaluated separately, there was a 17% reduction in deaths. After controlling for age, state speed laws, restraint laws, and population distribution, there remained a 9% reduction in MVC-related mortality rate in states with a trauma system. CONCLUSION: These data demonstrate that a state trauma system is associated with a reduction in the risk of death caused by injury. The effect is most evident on analysis of MVC deaths.

Analysis of hypertrophic and normal scar gene expression with cDNA microarrays.

Hypertrophic scar is one form of abnormal wound healing. Previous studies have suggested that hypertrophic scar formation results from altered gene expression of extracellular matrix molecules. A broadscale evaluation of gene expression in hypertrophic scars has not been reported. To better understand abnormalities in hypertrophic scar gene expression, we compared messenger RNA expression in hypertrophic scars, normal scars, and uninjured skin with the use of complementary (c)DNA microarrays. Total RNA was extracted from freshly excised human hypertrophic scars, normal scars, or uninjured skin and reverse transcribed into cDNA with the incorporation of [33P] deoxycytidine triphosphate. The resulting radioactive cDNA probes were hybridized onto cDNA microarrays of 4000 genes. Hybridization signals were normalized and analyzed. In the comparison of tissue samples, mean intensities were calculated for each gene within each group (hypertrophic scars, normal scars, and uninjured skin). Ratios of the mean intensities of hypertrophic scars to normal scars, hypertrophic scars to uninjured skin, and normal scars to uninjured skin were generated. A ratio that was greater than 1 indicated upregulation of any particular gene and a ratio that was less than 1 indicated downregulation of any particular gene. Our data indicated that 142 genes were overexpressed and 50 genes were underexpressed in normal scars compared with uninjured skin, 107 genes were overexpressed and 71 were underexpressed in hypertrophic scars compared with uninjured skin, and 44 genes were overexpressed and 124 were underexpressed in hypertrophic scars compared with normal scars. Our analysis of collagen, growth factor, and metalloproteinase gene expression confirmed that our molecular data were consistent with published biochemical and clinical observations of normal scars and hypertrophic scars. cDNA microarray analysis provides a powerful tool for the investigation of differential gene expression in hypertrophic scar samples and either uninjured skin or normal scars. Our data validate the use of this technology for future studies on gene expression during repair processes of normal and abnormal wounds.

Redox manipulation using the thiol-oxidizing agent diethyl maleate prevents hepatocellular necrosis and apoptosis in a rodent endotoxemia model.

Manipulation of the intracellular redox state has been shown to alter cell activation pathways with resultant changes in cellular function. Previous studies have suggested that thiol oxidation, using the glutathione-depleting agent diethyl maleate (DEM), was able to inhibit endothelial cell activation. We hypothesized that this agent might exert beneficial effects following endotoxemia in the rat, a model in which transendothelial migration of neutrophils is central to the development of hepatocellular injury. Sprague-Dawley rats treated intraperitoneally with lipopolysaccharide (LPS) (200 microg/kg) plus D-galactosamine (GalN) (600 mg/kg) developed hepatocellular necrosis, as evidenced by liver enzyme release and morphological changes. Pretreatment with DEM abrogated this injury in a dose-dependent fashion. Histology revealed reduced neutrophil accumulation in both the parenchyma and sinusoids, consistent with reduced neutrophil sequestration and transendothelial migration. This effect appeared to be related to the ability of DEM to prevent LPS-induced up-regulation of both vascular cell adhesion molecule-1 (VCAM-1) mRNA and intercellular adhesion molecule-1 (ICAM-1) mRNA in the liver, as well as reducing tumor necrosis factor (TNF) mRNA expression. In addition, DEM prevented hepatocyte apoptosis following LPS treatment. The effect was reproduced when TNF was used as an inflammatory stimulus, suggesting a direct protective effect on the hepatocyte. Taken together, these studies show that redox manipulation through thiol oxidation may represent a novel approach to preventing liver necrosis and apoptosis in inflammatory conditions.

Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence.

OBJECTIVE: To determine the comparative efficacy of selective decontamination of the digestive tract in critically ill surgical and medical patients, and in selected subgroups of surgical patients with pancreatitis, major burn injury, and those undergoing major elective surgery and transplantation. DATA SOURCES: The MEDLINE database was searched from January 1966 to December 1996 using the terms "decontamination or prophylaxis," "intensive care units," and "antibiotics." The search was limited to English-language studies evaluating the efficacy of selective decontamination of the digestive tract in human subjects. STUDY SELECTION: The primary review was restricted to prospective randomized trials. DATA EXTRACTION: End points of interest included rates of nosocomial pneumonia, bacteremia, urinary tract infection, wound infection, mortality, and length of intensive care unit stay. Methodologic quality of individual studies was assessed using a previously described model. DATA SYNTHESIS: Odds ratios (ORs) together with their (95% confidence interval [Cls]) were reported and determined using the Mantel-Haenszel method. Mortality was significantly reduced with the use of selective decontamination of the digestive tract in critically ill surgical patients (OR, 0.7, 95% CI, 0.52-0.93), while no such effect was demonstrated in critically ill medical patients (OR, 0.91; 95% CI, 0.71-1.18). The greatest effect was demonstrated in studies where both the topical and systemic components of the regimen were used. Rates of pneumonia were reduced in both subsets of patients, while those of bacteremia were significantly reduced only in surgical patients. CONCLUSIONS: Selective decontamination of the digestive tract notably reduces mortality in critically ill surgical patients, while critically ill medical patients derive no such benefit. These data suggest that the use of selective decontamination of the digestive tract should be limited to those populations in whom rates of nosocomial infection are high and in whom infection contributes notably to adverse outcome.

The glutathione depleting agent diethylmaleate prolongs renal allograft survival.

INTRODUCTION: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in mediating allograft rejection through its role in cellular trafficking and as an important costimulatory signal mediating T cell activation. We have previously reported that systemic administration of the glutathione (GSH) depleting agent diethylmaleate (DEM) prevents upregulation of ICAM-1 in various inflammatory models, suggesting that this agent may offer benefit in preventing allograft rejection. Thus we evaluated the effects of DEM in a murine model of renal transplantation. METHODS: Kidneys from C57BL/6 mice were transplanted into MHC incompatible C3H mice. Donors were treated with DEM 1 h prior to sacrifice, whereas recipients received DEM 1 h following transplantation. Animals were followed until the time of death. In separate studies, renal ICAM-1 mRNA expression was evaluated by polymerase chain reaction and the CD4(+) T cell cytokine profile evaluated in a mixed lymphocyte reaction using C3H responder splenocytes and C57BL/6 stimulator cells. RESULTS: Pretreatment with DEM increased survival from 18.9 +/- 3.6 to 30.6 +/- 10 days (P < 0.05). This increase in survival was associated with a reduction in renal ICAM-1 mRNA expression. Mixed lymphocyte cultures derived from animals pretreated with DEM demonstrated a reduction in the Th1 cytokines IFN-gamma and IL-2 and an increase in the Th2 cytokines IL-4 and IL-10. CONCLUSION: Administration of DEM with consequent systemic GSH depletion significantly reduces allograft ICAM-1 expression and prolongs graft survival. Although speculative, a shift from a Th1 to a Th2 cytokine response raises the possibility that tolerance induction plays a role in prolonged allograft survival.