Antonio Compañ

Brain edema and inflammatory activation in bile duct ligated rats with diet‐induced hyperammonemia: A model of hepatic encephalopathy in cirrhosis

Studies of the pathogenesis of hepatic encephalopathy are hampered by the lack of a satisfactory animal model. We examined the neurological features of rats after bile duct ligation fed a hyperammonemic diet (BDL+HD). Six groups were studied: sham, sham pair‐fed, hyperammonemic, bile duct ligation (BDL), BDL pair fed, and BDL+HD. The BDL+HD rats were made hyperammonemic via an ammonia‐containing diet that began 2 weeks after operation. One week later, the animals were sacrificed. BDL+HD rats displayed an increased level of cerebral ammonia and neuroanatomical characteristics of hepatic encephalopathy (HE), including the presence of type II Alzheimer astrocytes. Both BDL and BDL+HD rats showed activation of the inflammatory system. BDL+HD rats showed an increased amount of brain glutamine, a decreased amount of brain myo‐inositol, and a significant increase in the level of brain water. In coordination tests, BDL+HD rats showed severe impairment of motor activity and performance as opposed to BDL rats, whose results seemed only mildly affected. In conclusion, the BDL+HD rats displayed similar neuroanatomical and neurochemical characteristics to human HE in liver cirrhosis. Brain edema and inflammatory activation can be detected under these circumstances. (HEPATOLOGY 2006;43:1257–1266.)

Brain cholinergic impairment in liver failure

The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (∼30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (∼20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (∼50–60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density gradient fractionation and western blotting analysis. In conclusion, this study is the first direct evidence of a cholinergic imbalance in the brain as a consequence of liver failure and points to the possible role of the cholinergic system in the pathogenesis of hepatic encephalopathy.

Changes in liver and plasma acetylcholinesterase in rats with cirrhosis induced by bile duct ligation

Classical studies of cholinesterase activity during liver dysfunction have focused on butyrylcholinesterase (BuChE), whereas acetylcholinesterase (AChE) has not received much attention. In the current study, liver and plasma AChE levels were investigated in rats with cirrhosis induced after 3 weeks of bile duct ligation (BDL). BDL rats showed a pronounced decrease in liver AChE levels (∼50%) compared with sham‐operated (non‐ligated, NL) controls; whereas liver BuChE appeared unaffected. A selective loss of tetrameric (G4) AChE was detected in BDL rats, an effect also observed in rats with carbon tetrachloride‐induced cirrhosis. In accordance, SDS‐PAGE analysis showed that the major 55‐kd immunoreactive AChE band was decreased in BDL as compared with NL. A 65‐kd band, attributed in part to inactive AChE, was increased as became the most abundant AChE subunit in BDL liver. The overall decrease in AChE activity in BDL liver was not accompanied by a reduction of AChE transcripts. The loss of G4 was also reflected by changes observed in AChE glycosylation pattern attributable to different liver AChE forms being differentially glycosylated. BDL affects AChE levels in both hepatocytes and Kupffer cells; however, altered AChE expression was mainly reflected in an alteration in hepatocyte AChE pattern. Plasma from BDL rats had approximately 45% lower AChE activity than controls, displaying decreased G4 levels and altered lectin‐binding patterns. In conclusion, the liver is an important source of serum AChE; altered AChE levels may be a useful biomarker for liver cirrhosis. (HEPATOLOGY 2006;43:444–453.)

Animal models in the study of episodic hepatic encephalopathy in cirrhosis.

The availability of an animal model is crucial in studying the pathophysiological mechanisms of disease and to test possible therapies. Now, there are several models for the study of liver diseases, but there still remains a lack of a satisfactory animal model of chronic liver disease with hepatic encephalopathy (HE) and abnormalities in nitrogen metabolism, as seen in humans. In rats, two models of chronic HE are widely used: rats after portacaval anastomosis (PCA) and rats with chronic hyperammonemia. The first one mimics the situation induced in cirrhosis by collateral circulation, and has the problem of the absence of hepatocellular injury. The model of hyperammonemia is useful to study the effect of ammonia as a brain toxic substance, but also lacks liver failure. Bile-duct ligation has been used to induce cirrhosis and could also be a model of HE, probably with the addition of a precipitant factor. An ideal model of HE in chronic liver disease must have liver cirrhosis and a precipitant factor of HE; it must also show neuropathological characteristic findings of HE, neurochemical alterations in the main pathways impaired in these complications of cirrhosis, and low-grade brain edema.

Bile duct ligation plus hyperammonemia in rats reproduces the alterations in the modulation of soluble guanylate cyclase by nitric oxide in brain of cirrhotic patients

Modulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) is altered in brain from cirrhotic patients. The aim of this work was to assess whether an animal model of cirrhosis, bile duct ligation, alone or combined with diet-induced hyperammonemia for 7-10 days reproduces the alterations in NO modulation of sGC found in brains from cirrhotic patients. sGC activity was measured under basal conditions and in the presence of NO in cerebellum and cerebral cortex of the following groups of rats: controls, bile duct ligation without or with hyperammonemia and hyperammonemia without bile duct ligation. In cerebellum activation of sGC by NO was significantly lower in bile duct ligated rats with (12 +/- five-fold) or without (14 +/- six-fold) hyperammonemia than in control rats (23 +/- seven-fold). In cerebral cortex activation of sGC by NO was higher in rats with bile duct ligation with hyperammonemia (124 +/- 30-fold) but not without hyperammonemia (59 +/- 15-fold) than in control rats (66 +/- 11-fold). The combination of bile duct ligation and hyperammonemia reproduces the alterations in the modulation of soluble guanylate cyclase by NO found in cerebral cortex and cerebellum of cirrhotic patients while bile duct ligation or hyperammonemia alone reproduces the effects in cerebellum but not in cerebral cortex.

Uso inadecuado de la hospitalización en cirugía general. Magnitud, factores asociados y causas

OBJECTIVE To determine the proportion of inappropriate days of hospitalization in the general surgery wards of three university hospitals, its causes, and associated factors. MATERIAL AND METHOD We concurrently reviewed 596 days of hospitalisation during a 1-week period in 2000, using the Appropriateness Evaluation Protocol (AEP). The association among inappropriate days of hospital stay and independent variables was evaluated using bivariable and multivariable methods. Finally, the causes for inappropriate hospitalization use were analyzed. RESULTS The percentage of inappropriate days was 17.6%, with no significant differences among the hospitals (21.5%, 12.5% and 17.5%). Inappropriate days were associated with the weekend (odds ratio [OR] = 2.1, scheduled admissions (OR = 2.9), hospital stay of more than 1 week (OR:2.3), the last third of the hospital stay (OR: 3.7), and inappropriate admission (OR: 2.1). The main causes of inappropriate hospital stays were organizational problems in the hospital or in the clinical management of discharge. CONCLUSIONS Inappropriate days of hospitalization represent a considerable percentage of hospitalization in surgery wards. The main reasons for inappropriate days are problems with surgical and discharge planning and factors that depend on the organization of the surgery departments and other related departments in the hospital.

Effectiveness of a physician-oriented feedback intervention on inappropriate hospital stays

Objective: To evaluate the effectiveness of a combined intervention to reduce inappropriate hospital stays. Design: Quasi-experimental pre-test/post-test with a non-equivalent control group. Setting: Three teaching hospitals in the National Health System in Alicante, Spain. Study participants: Intervention group (2 Surgical Units with 1451 hospital stays) and control group (1 Surgical Unit with 1268 hospital stays). Intervention: Structured oral presentation followed by direct feedback to surgeons about their own percentages of inappropriate stays and daily evaluation of appropriateness by the surgeons during their rounds. Main outcome measures: Reduction in the percentage of inappropriate stays identified by the Appropriateness Evaluation Protocol during the intervention period compared to the basal period. Results: The intervention group reduced its percentage of inappropriate stays from 14.3% to 7.9% (absolute reduction: –6.40; 95% CI –10.7 to –2.14; relative reduction: 44.8%), while no changes occurred in the control group. The reduction was in the number of inappropriate stays attributable to the patients’ medical management that went from 12.7% to 5.8% (absolute reduction: –6.92; 95% CI –10.90 to –2.92), while no significant changes occurred in inappropriate stays due to other causes. Conclusions: A combined intervention of feedback and physician participation in appropriateness evaluations is effective in reducing the percentage of inappropriate hospital stays, particularly those attributable to conservative medical patterns at discharge.

Efectos adversos en cirugía mayor ambulatoria

Resumen Objetivo Determinar la incidencia de efectos adversos y de pacientes con efectos adversos en cirugia mayor ambulatoria y compararla con la incidencia encontrada en los servicios de cirugia general incluidos en el estudio ENEAS. Material y metodo Estudio de cohortes historicas. El ambito del estudio fue la unidad de cirugia mayor ambulatoria de un hospital universitario. Se incluyo a todos los pacientes atendidos en el servicio de cirugia general durante el ano 2005. Resultados La incidencia de pacientes con efectos adversos relacionados directamente con la asistencia sanitaria fue del 3% (intervalo de confianza del 95%, 0,9-5). De los 8 efectos adversos detectados, 5 se consideraron leves, 3 moderados y ninguno grave. Todos los moderados se consideraron inevitables y de los leves tan solo uno era evitable. Entre los efectos adversos, 6 tuvieron relacion con un procedimiento, uno con infeccion nosocomial y otro con otras causas. Tres cuartas partes de los efectos adversos tuvieron como consecuencia un incremento de la estancia y en una cuarta parte el efecto adverso condiciono el ingreso. Conclusiones La incidencia de efectos adversos relacionados con la asistencia sanitaria en los hospitales espanoles es similar a la de los estudios realizados en paises americanos y europeos con similar metodologia. Se considera que el area quirurgica es de alto riesgo para desencadenarlos; sin embargo, la cirugia mayor ambulatoria reduce su incidencia. Por lo tanto, ademas de mejorar la eficiencia tecnica de los servicios clinicos, es mas segura para los pacientes.

Es necesaria la profilaxis antibiótica en la cirugía protésica de la hernia inguinal

Resumen Introduccion Clasicamente, se ha indicado la profilaxis antibiotica en la cirugia limpia cuando se instaure material protesico. Una de las intervenciones mas habituales de este tipo es la herniorrafia inguinal. Debido a los bajos indices de infeccion de herida y al reducido tamano del material protesico implantado, existen dudas razonables sobre la utilidad de la profilaxis antibiotica en esta intervencion. Por eso, hemos realizado un estudio para conocer si la presencia o ausencia de profilaxis antibiotica modifica la tasa de infecciones de la herniorrafia inguinal con protesis. Pacientes y metodo Estudio de intervencion sin asignacion aleatoria ni cegamiento, en pacientes intervenidos de herniorrafia inguinal con protesis en el Servicio de Cirugia General del Hospital Clinico Universitario Sant Joan de Alicante. El estudio se realizo entre los anos 1998 y 2002, ambos incluidos. Los criterios de exclusion fueron: pacientes inmunodeprimidos y/o con hernia inguinal bilateral. Los pacientes fueron divididos en dos grupos: un grupo sometido a profilaxis antibiotica preoperatoria (PAP), consistente en 1,5 g de cefuroxima i.v. en la induccion anestesica y otro grupo de pacientes sin profilaxis. Se estandarizo la tecnica quirurgica. La infeccion de herida se definio segun los criterios de los CDC (Centers for Disease Control). Los pacientes fueron seguidos a la semana, al mes y al ano de la intervencion quirurgica. Analisis estadistico Se analizo la incidencia acumulada (IA) de infeccion de herida quirurgica, junto con su intervalo de confianza (IC), en cada uno de los grupos y si la diferencia era significativa entre los dos grupos. Tambien se calculo el NNT (numero de individuos tratados necesario para que se observe un efecto beneficioso). Resultados El estudio incluyo a un total de 425 pacientes (408 varones y 17 mujeres), 358 de ellos aquejados de hernia primaria y 67 de hernia recidivada, con unas edades medianas de 59 y 63 anos, respectivamente. Se realizo profilaxis antibiotica en el 48,6% de los pacientes con hernia inguinal primaria y en el 49,2% de las hernias recidivadas. Sufrieron complicaciones 45 pacientes intervenidos de hernia inguinal primaria (12,5% de este grupo y 10,6% de toda la serie), frente a ocho del grupo de hernias recidivadas (11,9% de este grupo y 1,9% de toda la serie). Se documentaron dos infecciones de herida quirurgica (0,47%), ambas en pacientes intervenidos por hernia primaria, una en el grupo de PAP y otra en el grupo sin PAP. Entre los 207 pacientes con PAP el riesgo de infeccion fue del 0,48% (IC del 95%, 0,46- 1,42%), y para los 218 que no la realizaron fue del 0,45% (IC del 95%, 0,43-1,33%), sin que la diferencia alcanzara significacion estadistica. Tampoco hubo diferencias en la incidencia de aparicion de otras complicaciones distintas de la infeccion de localizacion quirurgica. El numero necesario de pacientes (NNT) intervenidos de hernia inguinal que deben recibir quimioprofilaxis antibiotica perioperatoria para observar un efecto beneficioso con la aplicacion de PAP, es decir, la ausencia de infeccion en un paciente, fue de 3.333 pacientes. Conclusion Dada la presencia de una minima cantidad de “cuerpo extrano” con la protesis habitual de una herniorrafia, es poco probable la presencia de infecciones, sobre todo cuando la protesis esta mallada y multiperforada. Por ello, parece que se puede prescindir sistematicamente de la profilaxis antibiotica en las intervenciones de herniorrafia con protesis sin que se incremente significativamente el riesgo de infeccion de la herida quirurgica ni las complicaciones locales derivadas de su ausencia, limitando su uso unicamente a pacientes con factores de riesgo.