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.

Population-based study of the prevalence and management of self-reported high pain scores in patients with non-resected pancreatic adenocarcinoma.

BACKGROUND: Pain is a common debilitating symptom in pancreatic adenocarcinoma. This cohort study examined the use of, and factors associated with, pain-directed interventions for a high pain score in patients with non-curable pancreatic adenocarcinoma. METHODS: Administrative databases were linked and patients with non-resected pancreatic adenocarcinoma diagnosed between 2010 and 2016, who reported one or more Edmonton Symptom Assessment System (ESAS) score, were identified. A high pain score was defined as an ESAS score of at least 4. Outcomes were pain-directed interventions: opiates (in patients aged 65 years or more with universal drug coverage), nerve block and radiation therapy for a high pain score. Reduction in pain score of at least 1 point after pain-directed intervention was also evaluated. Modified Poisson regression was used to examine factors associated with pain-directed intervention. RESULTS: Among 2623 patients with a median age of 67 years, 1223 (46·6 per cent) were women, and 1621 (61·8 per cent) reported a high pain score at a median of 38 days after diagnosis. Of those with a high pain score, 75·6 per cent (688 of 910) received opiates, 13·5 per cent (219 of 1621) radiation and 1·2 per cent (19 of 1621) nerve block. The pain score decreased in 62·1 per cent of patients after administration of opiates, 73·4 per cent after radiation and all patients after nerve block. In multivariable analysis, no patient factor (age, sex, co-morbidity burden, rurality, income quintile) was associated with receipt of non-opiate pain-directed intervention for a high pain score. In patients aged at least 65 years, advanced age was associated with lower odds of opiate use. CONCLUSION: Opiates are the most common pain-directed intervention for non-curable pancreatic adenocarcinoma, whereas radiation therapy and nerve blocks are seldom used. The lack of association between pain-directed interventions and patient factors points toward practice-driven patterns.

ANTECEDENTES: El dolor es un síntoma debilitante frecuente en el adenocarcinoma de páncreas. Este estudio de cohortes examinó el uso de las intervenciones dirigidas para el tratamiento del dolor y los factores asociados a las mismas en pacientes con adenocarcinoma pancreático incurable que presentaban puntuaciones altas de dolor. MÉTODOS: Se revisaron las bases de datos administrativas y se identificaron los pacientes con adenocarcinoma pancreático no resecado diagnosticados entre 2010-2016 con puntuaciones > 1 del Sistema de Evaluación de Síntomas de Edmonton (Edmonton Symptom Assessment System, ESAS). La puntuación alta de dolor se definió como ESAS > 4. Los resultados evaluados fueron las intervenciones dirigidas contra el dolor: opiáceos (en pacientes mayores de 65 años con cobertura universal de medicamentos), bloqueo nervioso y radioterapia en el caso de puntuación alta del dolor. También se evaluó la reducción en la puntuación del dolor (> 1 punto) después de la intervención dirigida contra el dolor. Los factores asociados a la intervención contra el dolor se analizaron mediante una regresión de Poisson modificada. RESULTADOS: De los 2.623 pacientes con una mediana de edad de 67 años, 1.223 (46,6%) eran mujeres, y 1.621 (61.8%) presentaron una puntuación alta de dolor con una mediana de 38 días desde el momento del diagnóstico. De aquellos con puntuación alta de dolor, el 75,6% recibió opiáceos (n = 688/910), el 13,5% radiación (n = 219/1.621) y el 1,2% bloqueo nervioso (n = 19/1.621). La puntuación del dolor disminuyó en el 62,2% después del tratamiento con los opiáceos, en el 73,8% después de la radiación y en el 100% después del bloqueo nervioso. En el análisis multivariable, ningún factor relacionado con el paciente (edad, sexo, comorbilidades, vivir en una zona rural, quintil de ingresos) se asoció con una intervención dirigida contra dolor sin opiáceos en los casos de puntuación alta del dolor. En pacientes mayores de 65 años, la edad avanzada se asoció con menor probabilidad de uso de opiáceos. CONCLUSIÓN: Mientras que los opiáceos son la intervención dirigida contra dolor más común para el adenocarcinoma pancreático no resecable, la radioterapia y el bloqueo nervioso rara vez se usan. La falta de asociación de las intervenciones dirigidas contra el dolor con los factores del paciente apunta hacia el uso de patrones terapéuticos basados ​​en la práctica clínica.

Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial.

BACKGROUND: Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS: Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS: Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS: Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.

Cryoprecipitate transfusion: assessing appropriateness and dosing in trauma.

BACKGROUND: Originally developed for patients with congenital factor VIII deficiency, cryoprecipitate is currently largely used for acquired hypofibrinogenemia in the context of bleeding. However, scant evidence supports this indication and cryoprecipitate is commonly used outside guidelines. In trauma, the appropriate cryoprecipitate dose and its impact on plasma fibrinogen levels are unclear. OBJECTIVES: The aims were to evaluate (i) the appropriateness of cryoprecipitate transfusion in trauma and (ii) the plasma fibrinogen response to cryoprecipitate transfusion during massive transfusion in trauma. METHODS: Retrospective review (January 1998-June 2008) of indications, dose and plasma fibrinogen response to cryoprecipitate transfusion at a large teaching hospital. A fibrinogen of <1.0 g L(-1) within 2 and 6 h of transfusion was used for evaluating appropriateness. RESULTS: Ten thousand five hundred and forty cryoprecipitate units were transfused in 1004 patients. Thirty-seven percent and 31% were used in cardiac surgery and trauma, respectively. In 394 events in trauma, 238 (60%) and 259 (66%) were considered appropriate using the 2- and 6-h cut-off criteria, respectively. In patients who did not receive plasma components 2 h prior to cryoprecipitate, a dose of 8.7 (± 1.7) units caused a mean increase in fibrinogen levels of 0.55 (± 0.24) g L(-1), or 0.06 g L(-1) per unit. CONCLUSIONS: In our hospital, where transfusion guidelines are overseen by transfusion medicine specialists and technologists, and policies for rapid blood component and laboratory turnaround times exist, it is possible to achieve high rates of appropriateness for cryoprecipitate transfusion in trauma. The current recommended dose causes a modest increase in fibrinogen levels (0.55 g L(-1) ).

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.

Compliance with Evidence-Based Guidelines in Acute Pancreatitis: an Audit of Practices in University of Toronto Hospitals.

Despite existing evidence-based practice guidelines for the management of acute pancreatitis, clinical compliance with recommendations is poor. We conducted a retrospective review of 248 patients admitted between 2010 and 2012 with acute pancreatitis at eight University of Toronto affiliated hospitals. We included all patients admitted to ICU (52) and 25 ward patients from each site (196). Management was compared with the most current evidence used in the Best Practice in General Surgery Management of Acute Pancreatitis Guideline. Fifty-six patients (22.6 %) had only serum lipase tested for biochemical diagnosis. Admission ultrasound was performed in 174 (70.2 %) patients, with 69 (27.8 %) undergoing ultrasound and CT. Of non-ICU patients, 158 (80.6 %) were maintained nil per os, and only 18 (34.6 %) ICU patients received enteral nutrition, commencing an average 7.5 days post-admission. Fifty (25.5 %) non-ICU patients and 25 (48.1 %) ICU patients received prophylactic antibiotics. Only 24 patients (22.6 %) with gallstone pancreatitis underwent index admission cholecystectomy. ERCP with sphincterotomy was under-utilized among patients with biliary obstruction (16 [31 %]) and candidates for prophylactic sphincterotomy (18 [22 %]). Discrepancies exist between the most current evidence and clinical practice within the University of Toronto hospitals. A guideline, knowledge translation strategy, and assessment of barriers to clinical uptake are required to change current clinical practice.

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.

Compliance with a massive transfusion protocol (MTP) impacts patient outcome.

BACKGROUND: About 5% of civilian trauma requires massive transfusion. Protocolized resuscitation with blood products to achieve high plasma:RBC ratio has been advocated to improve survival. Our objectives were to measure compliance to our institutional MTP, to identify quality assurance activities that could improve protocol compliance and to determine if protocol compliance was related to patient outcome. METHODS: The investigators determined 13 compliance criteria based upon our institutional protocol. We measured compliance in 72 consecutive MTP activations between January 2010 and September 2011 at a Level I trauma centre. Data elements were retrospectively retrieved from blood bank, trauma registry and clinical records. Patients were stratified into three groups based on compliance level, and mortality differences were compared. RESULTS: Average compliance for the cohort (n=72) was 66%. The most common cause of non-compliance was failure to send a complete haemorrhage panel from the trauma bay (96%). Failure to monitoring blood work every 30min occurred in 89% of cases. Delay in activation and deactivation occurred in 50% and 50% respectively. Non-compliance to protocol-based administration of blood products happened in 47%. The cohort was stratified into three groups based on compliance, A: <60%, B: 60-80% and C: >80% (low, moderate and high compliance groups). There was no statistical significance with regard to median age, median ISS, ED SBP, ED GCS and AIS of the head/spine, chest and abdomen. The mortality rates in each group were 62%, 50% and 10% in the low, moderate and high compliance groups respectively. Mortality differences were compared using adjusted logistic regression. The OR for mortality between Groups A and B=1.1 [95% CI 0.258-4.687 (P=0.899)] while the OR for mortality between Groups C and B=0.02 [95% CI <0.001-0.855 (P=0.041)]. CONCLUSIONS: Measures should be directed towards provider and system factors to improve compliance. In this study, there was an association between survival and higher level of compliance.

The gut in critical illness: evidence from human studies.

Data from a large number of published human studies support the hypothesis that the gastrointestinal tract of the critically ill patient is an important factor in ICU morbidity and mortality. Changes in proximal gut flora in the critically ill patient predict nosocomial infection with the same organism, while gut-directed therapeutic measures clearly reduce rates of nosocomial infection and may have an impact on mortality Modulation of the systemic inflammatory response through gut derived measures has been no more successful than modulation of that response through more conventional systemic forms of mediator-directed therapy. But if the gastrointestinal tract is an important factor in nosocomial ICU-acquired infection, the bigger unanswered question is, to what extent does infection per se alter outcome in critical illness? Current articulations of the gut hypothesis challenge long-held and probably outmoded views of host-microbial interactions. The challenge to replace them is no less compelling and no less treacherous than it was in the era of Metchnikoff, Lane, or their ancient forebears.

N-acetyl cysteine attenuates acute lung injury in the rat.

The development of the adult respiratory distress syndrome (ARDS) in the critically ill patient is associated with a significant morbidity and mortality. The pulmonary dysfunction in ARDS is largely secondary to neutrophil-mediated oxidant injury. The purpose of these studies is to examine the effect of the antioxidant N-acetyl cysteine (NAC) on a rodent model of lung injury. We postulated that NAC might attenuate lung injury following intratracheal challenge with endotoxin (lipopolysaccharide; LPS). Male Sprague-Dawley rats were administered NAC systemically either before or after intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary leakage of 125I-labeled albumin, pulmonary myeloperoxidase content, bronchoalveolar lavage fluid cell counts, pulmonary lipid peroxidation and histology. NAC administration significantly attenuated the LPS-induced increases in lung permeability (LPS: .24 +/- .08 vs. LPS + NAC: .12 +/- .03, p < .05) and reduced the LPS-dependent increase in lipid peroxidation. However, total and differential bronchoalveolar lavage cell counts and myeloperoxidase content were not affected by NAC pretreatment. Although neutrophil influx was unaffected, neutrophil activation as assessed by surface CD11b expression and chemiluminescence was significantly down-regulated by NAC. Importantly, NAC administration up to 2 h after endotoxin challenge was still able to significantly ameliorate LPS-induced lung injury. Our data suggests that the attenuation of acute lung injury by NAC in our rodent model is related to free radical scavenging and inhibition of the neutrophil oxidative burst, rather than by an effect on inflammatory cell migration. These results suggest novel approaches for therapeutic interventions in acute lung injury.

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.

Intestinal epithelial cells down-regulate macrophage tumor necrosis factor-alpha secretion: a mechanism for immune homeostasis in the gut-associated lymphoid tissue.

BACKGROUND: The gut lumen contains more than 10(6) organisms per gram of luminal contents. The mechanisms that limit the response of macrophages in the lamina propria to these microbial antigens are unknown, although an intrinsic defect in this mechanism may contribute to the development of inflammatory bowel disease. Intestinal epithelial cells (IEC) may play an important role in mediating tonic down-regulation of local immune cell activation. The purpose of this study was to discern whether IEC might modulate macrophage activation in response to a variety of microbial stimuli. METHODS: Thioglycollate-elicited murine peritoneal macrophages were activated by endotoxin, zymosan, Escherichia coli, and Candida albicans in the presence or absence of IEC from the rat intestinal epithelial cell line IEC-6. Macrophage tumor necrosis factor-alpha (TNF-alpha) secretion was determined by enzyme-linked immunosorbent assay. RESULTS: Lipopolysaccharide or zymosan-activated macrophages in coculture with IEC secreted significantly less TNF-alpha than macrophages cultured alone. The inhibitory effect of the IEC was dependent on their activation by lipopolysaccharide. Interleukin-1 alpha production was not affected. IEC-mediated suppression of macrophage TNF-alpha secretion was reversed by indomethacin but not by neutralizing antibody to TGF-beta. CONCLUSIONS: Lipopolysaccharide-activated IEC down-regulate macrophage TNF-alpha secretion in response to microbial stimuli through a prostanoid-mediated mechanism. IEC may mediate tonic down-regulation of immune cell activation in the gut-associated lymphoid tissue and may thereby regulate local and systemic inflammatory responses.

Thiol-mediated redox regulation of neutrophil apoptosis.

BACKGROUND: Intracellular glutathione, an endogenous antioxidant, protects cellular function against oxidative stress. Because oxidative stress has been implicated in neutrophil apoptosis, we hypothesized that reduced thiol levels may induce apoptosis through an alteration in cellular redox state. METHODS: Human polymorphonuclear leukocytes (PMNs), were incubated with medium or with increasing concentrations of the reduced glutathione (GSH)-depleting agents diethylmaleate and diamide and buthionine sulfoximine, an inhibitor of GSH synthesis. Apoptosis was assessed by means of flow cytometry with propidium iodide DNA staining and confirmed morphologically. GSH was measured colorimetrically, and tyrosine phosphorylation was assessed by means of immunoblotting. RESULTS: Diethylmaleate and diamide induced a dose-dependent reduction in GSH and a corresponding increase in PMN apoptosis. This effect could be reversed with N-acetylcysteine, suggesting that diethylmaleate induces apoptosis through the depletion of GSH. The antioxidant pyrolidine dithiocarbamate had no effect. Because oxidants can mediate intracellular signaling via tyrosine phosphorylation, we therefore evaluated the effects of the tyrosine kinase inhibition on diethylmaleate-induced PMN apoptosis. Both genistein and herbimycin A reduced diethylmaleate-induced apoptosis and tyrosine phosphorylation. CONCLUSIONS: Sulfhydryl oxidation by diethylmaleate alone induces apoptosis, providing evidence of a redox-sensitive, thiol-mediated pathway of apoptosis. Furthermore, tyrosine phosphorylation appears to play an important role in this process. Because apoptosis is a critical mechanism regulating PMN survival in vivo, manipulation of PMN intracellular thiols may represents a novel therapeutic target for the regulation of cellular function.

Diethylmaleate attenuates endotoxin-induced lung injury.

BACKGROUND: Alterations in the cellular redox state play a critical role in cell signaling and cell activation, suggesting that administration of sulfhydryl-reactive agents may have important modulatory effects on the inflammatory response. We postulated that intracellular thiol depletion may attenuate the pulmonary inflammatory response after intratracheal administration of endotoxin (LPS) and that this attenuation would supersede the reduction in antioxidant defenses associated with depletion of the endogenous antioxidant, glutathione. METHODS: Sprague Dawley rats were administered diethylmaleate (6 mmol/kg intraperitoneally), a rapidly acting glutathione-depleting agent, followed by intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary flux of 125-I albumin and expressed as a permeability index. RESULTS: Administration of diethylmaleate reduced lung glutathione levels from 1310 +/- 114 to 185 +/- 48 nmol/gm. This was associated with a reduction in the permeability index after LPS treatment (LPS, 0.22 +/- 0.03 versus LPS + diethylmaleate, 0.03 +/- 0.01). Bronchoalveolar lavage fluid polymorphonuclear neutrophil counts were markedly reduced in animals pretreated with diethylmaleate (LPS, 90.5 +/- 24 x 10(6) versus LPS + diethylmaleate, 1.9 +/- 0.4 x 10(6)). Peripheral blood polymorphonuclear neutrophils isolated from animals treated with diethylmaleate had equivalent chemotactic responses to n-formyl-methionyl-leucyl-phenylalanine and normal up-regulation of CD11b as determined by flow cytometry. Levels of bronchoalveolar lavage fluid tumor necrosis factor-alpha were unaffected. CONCLUSIONS: Diethylmaleate attenuates LPS-induced lung injury through a reduction in lung polymorphonuclear neutrophil sequestration. Normal peripheral blood neutrophil chemotactic responses and CD11b expression suggest that thiol depletion might mediate this effect through inhibition of endothelial cell adhesion molecule activity.

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.

Nosocomial infection in the surgical intensive care unit.

The critically ill surgical patient is at high risk for the development of ICU-acquired infection. Normal mucosal defenses are breached by surgical incisions or by intravascular devices, urinary catheters, and endotracheal tubes. The integrity of the gastrointestinal epithelium is compromised by the lack of enteral nutrition and episodes of hypoperfusion, resulting in translocation of normal or disturbed enteric flora. The indigenous microbial flora, an important component of normal host defenses against invasive infection, is disrupted through the use of broad-spectrum antibiotics or by poorly understood influences associated with critical illness. Systemic immunity is altered, and multiple abnormalities of specific and nonspecific immune function can be documented. Infections acquired within the ICU are commonly caused by endogenous organisms of low intrinsic pathogenicity, and the contribution of these infections to ICU outcome is controversial. Diagnosis is established by directed investigations, focusing on surgical sites and invasive devices. Therapy is primarily physical (drainage of infected collections or removal of contaminated devices), and antimicrobial therapy should employ narrow-spectrum agents guided by the results of Gram stain and culture. The prevention of ICU-acquired infection is based on timely and definitive surgical therapy, judicious use of invasive devices and antibiotics, and early enteral feeding. Infection-control measures aimed at endogenous reservoirs show some preliminary promise for certain subsets of patients, but remain, at present, experimental.

Exudative neutrophils show impaired pH regulation compared with circulating neutrophils.

OBJECTIVE: To investigate the effects of neutrophil (PMN) transmigration into inflammatory sites on cytosolic pH (pHi) regulation. DESIGN: Exudative PMNs were obtained by bronchoalveolar lavage from rats sustaining endotoxin-induced lung injury. Circulating PMNs were purified with density-gradient centrifugation. Cytosolic pH was measured with single-cell fluorescence imaging using the pH-sensitive dye biscarboxyethyl-carboxyfluorescein. RESULTS: Exudative PMNs showed impaired pHi recovery from an induced acid load compared with circulating PMNs. Under conditions of extracellular acidosis, exudative PMNs showed impaired pHi homeostasis and produced decreased superoxide compared with circulating cells. Inhibition of the sodium-proton exchanger attenuated the differences in pHi recovery, suggesting a mechanism underlying the pHi regulatory dysfunction. All cells had comparable adenosine triphosphate levels and superoxide production at physiologic extracellular pH. CONCLUSION: Impaired pHi regulation of exudative cells may mediate cellular dysfunction and impaired resolution of infection at inflammatory sites.

Glutathione depletion prevents lipopolysaccharide-induced local skin inflammation.

BACKGROUND: We have previously shown that the thiol-oxidizing agent diethyl maleate prevents lipopolysaccharide (LPS)-induced up-regulation of endothelial cell intercellular adhesion molecule-1 (ICAM-1) in vitro. OBJECTIVE: To determine the effect of glutathione depletion on the development of local skin inflammation in vivo, a model known to be dependent on ICAM-1. DESIGN: Swiss Webster mice were injected with intradermal LPS (30 micrograms) or isotonic saline solution. INTERVENTION: Mice were pretreated for 1 hour with intraperitoneal diethyl maleate (6 mmol/kg) or corn oil vehicle. MAIN OUTCOME MEASURES: Injection sites were harvested after 12 and 24 hours and evaluated for changes in vascular permeability and histological characteristics. To determine the mechanism underlying our findings, we evaluated skin ICAM-1 immunohistochemistry, levels of ICAM-1 protein and messenger RNA (mRNA), and neutrophil CD11b expression at the 24-hour point. RESULTS: Diethyl maleate significantly decreased the skin permeability index in a dose-dependent fashion at 24 hours but not at 12 hours. Skin histological examination under light microscopy showed a marked LPS-induced neutrophil infiltration at 24 hours, which was inhibited with diethyl maleate pretreatment. Immunohistochemical examination showed that diethyl maleate reduced ICAM-1 expression. In keeping with the hypothesized mechanism, diethyl maleate attenuated the LPS-induced up-regulation of ICAM-1 mRNA by 44%. Diethyl maleate also slightly but insignificantly reduced CD11b expression in vivo. CONCLUSIONS: Diethyl maleate markedly attenuates LPS-induced dermal inflammation, primarily through a reduction in ICAM-1 protein and mRNA expression. These data suggest that manipulation of the intracellular redox state may have a beneficial role in neutrophil-mediated inflammation.

Prevention of endotoxin-induced mortality by antitissue factor immunization.

BACKGROUND: Microvascular thrombosis with intravascular fibrin deposition is a characteristic pathologic alteration during endotoxic shock. This effect is predominantly mediated by expression of the cellular procoagulant tissue factor by endothelial cells and cells of monocyte or macrophage lineage, resulting in acceleration of the coagulation cascade and fibrin deposition. OBJECTIVE: To determine whether modulation of this response by treatment with an antitissue factor antibody might have beneficial effects. DESIGN: A polyclonal antibody to murine tissue factor was prepared by injecting rabbits with a synthesized peptide sequence of murine tissue factor. To determine the activity of the antibody, elicited murine peritoneal macrophages were treated for 4 hours with 10-micrograms/mL lipopolysaccharide (LPS), and procoagulant activity was determined via a clotting assay (milliunits of activity per 10(6) macrophages). RESULTS: The tissue factor antibody abrogated LPS-induced macrophage procoagulant activity, confirming activity of the antibody (macrophages, 236 +/- 28 mU/10(6) macrophages; macrophages/LPS, 3801 +/- 190* mU/10(6) macrophages; macrophages/LPS/alpha-tissue factor, 753 +/- 92* mU/10(6) macrophages; n = 3; the asterisk indicates P < .05 by an analysis of variance). Additionally, antibody-protein affinity was confirmed by Western blot analysis. Having determined the activity of the antibody in vitro, we tested its efficacy in vivo in a lethal endotoxemia model. Mice were immunized with 200 microL of antiserum intraperitoneally 2 hours before injection with 250 micrograms of LPS intraperitoneally and 24 hours later. Control animals received 200 microL of saline solution. All animals initially exhibited lethargy and piloerection, characteristic of the predicted response to LPS. However, immunized animals had a significantly (P < .05) reduced mortality compared with control animals. Fibrinogen levels were significantly (P < .05) higher in the immunized mice, suggesting decreased consumption of coagulation factors, a finding consistent with an antitissue factor effect. Further, plasma tumor necrosis factor levels 90 minutes after LPS injection were similar in both groups, suggesting normal induction of the cytokine cascade. CONCLUSIONS: Modulation of microvascular fibrin deposition by abrogating tissue factor-mediated coagulation significantly (P < .05) improved survival in this model without attenuating the initiation of the cytokine cascade. These findings suggest a pathogenic role for coagulation in the induction of acute organ injury during sepsis.