Aplicación de protocolos ERAS (Enhanced Recovery After Surgery) en pacientes cistectomizados: el camino hacia la estandarización. Una revisión sistemática / Implementation of ERAS (Enhanced Recovery After Surgery) protocols for radical cystectomy patients: The pathway to standardization. A systematic review

CONTEXTO: El desarrollo de protocolos ERAS (Enhanced Recovery After Surgery) en pacientes sometidos a cirugía mayor ha aportado beneficios perioperatorios en diversas disciplinas. En urología, su principal aplicación se centra en pacientes sometidos a cistectomía radical. OBJETIVO: Revisión sistemática de la literatura disponible de protocolos ERAS aplicados a pacientes intervenidos de cistectomía radical, tanto a nivel de resultados perioperatorios como en el análisis de su implementación. Adquisición de la evidencia: Se realizó búsqueda bibliográfica en base de datos electrónicas Pubmed, Embase, Cochrane y Scopus, utilizando los términos «Cystectomy», «Enhanced Recovery After Surgery» y «Fast-Track». Se seleccionaron estudios aleatorizados y no aleatorizados que comparasen la implementación de un protocolo ERAS en pacientes sometidos a cistectomía radical frente a un protocolo tradicional. Síntesis de la evidencia: Se identificaron 869 artículos; 25 fueron seleccionados para el análisis final: 22 estudios no aleatorizados y 3 aleatorizados. No se detectaron diferencias en cuanto a características demográficas entre los distintos estudios. Se identificaron diferencias estadísticamente significativas a favor del protocolo ERAS en tiempo de estancia hospitalaria, tasa de complicaciones mayores, tiempo a primera deambulación y recuperación intestinal. En el análisis de protocolos se detectó una alta variabilidad, tanto en número de ítems como en método de implementación. CONCLUSIONES: El carácter multidisciplinar y el número de ítems de los protocolos ERAS conlleva una alta heterogeneidad en su implementación. Se requieren más estudios aleatorizados, estandarización a la hora de reportar y analizar resultados, así como un análisis sistemático de la adherencia posterior para aumentar la comparabilidad entre grupos

CONTEXT: The development of ERAS (Enhanced Recovery After Surgery) protocols in patients undergoing major surgery has brought perioperative benefits in several disciplines. Its main application in urology is focused on patients undergoing radical cystectomy. OBJECTIVE: Systematic review of the available literature on ERAS protocols applied to patients undergoing radical cystectomy in terms of perioperative outcomes as well in the analysis of their implementation. Evidence acquisition: A bibliographic search was conducted in the electronic databases PubMed, Embase, Cochrane and Scopus, using the terms «Cystectomy», «Enhanced Recovery After Surgery» and «Fast-Track». Randomized and non-randomized studies that compared the implementation of an ERAS protocol versus a traditional protocol in patients undergoing radical cystectomy were selected. Evidence synthesis: 869 articles were identified; 25 were selected for final analysis: 22 non-randomized and 3 randomized studies. No differences were observed in terms of demographic characteristics between studies. Statistically significant differences were identified in favor of the ERAS protocol: length of hospital stay, major complication rate, time to first ambulation and return of bowel function. In the analysis of protocols, a high variability was detected in the number of items and in the implementation method. CONCLUSIONS: The multidisciplinary nature and the number of items of the ERAS protocols imply a high heterogeneity in their implementation. Further randomized studies, standardized reporting and analyzing results, as well as a systematic analysis of subsequent adherence are required to increase comparability between groups

Implementation of ERAS (Enhanced Recovery After Surgery) protocols for radical cystectomy patients: The pathway to standardization. A systematic review. / Aplicación de protocolos ERAS (Enhanced Recovery After Surgery) en pacientes cistectomizados: el camino hacia la estandarización. Una revisión sistemática.

CONTEXT: The development of ERAS (Enhanced Recovery After Surgery) protocols in patients undergoing major surgery has brought perioperative benefits in several disciplines. Its main application in urology is focused on patients undergoing radical cystectomy. OBJECTIVE: Systematic review of the available literature on ERAS protocols applied to patients undergoing radical cystectomy in terms of perioperative outcomes as well in the analysis of their implementation. EVIDENCE ACQUISITION: A bibliographic search was conducted in the electronic databases PubMed, Embase, Cochrane and Scopus, using the terms «Cystectomy¼, «Enhanced Recovery After Surgery¼ and «Fast-Track¼. Randomized and non-randomized studies that compared the implementation of an ERAS protocol versus a traditional protocol in patients undergoing radical cystectomy were selected. EVIDENCE SYNTHESIS: 869 articles were identified; 25 were selected for final analysis: 22 non-randomized and 3 randomized studies. No differences were observed in terms of demographic characteristics between studies. Statistically significant differences were identified in favor of the ERAS protocol: length of hospital stay, major complication rate, time to first ambulation and return of bowel function. In the analysis of protocols, a high variability was detected in the number of items and in the implementation method. CONCLUSIONS: The multidisciplinary nature and the number of items of the ERAS protocols imply a high heterogeneity in their implementation. Further randomized studies, standardized reporting and analyzing results, as well as a systematic analysis of subsequent adherence are required to increase comparability between groups.

Interstitial lung disease in systemic sclerosis: data from the spanish scleroderma study group.

OBJECTIVES: To evaluate the clinical characteristics of patients with interstitial lung disease (ILD) in the setting of a large cohort of systemic sclerosis (SSc) patients, and to analyse the differences according to the SSc subtype (following the modification of classification criteria of the American College of Rheumatology for SSc proposed by LeRoy and Medsger), factors are associated with moderate-to-severe impairment of lung function, as well as mortality and causes of death. METHODS: A descriptive study was performed, using the available data from the Spanish Scleroderma Study Group. RESULTS: Twenty-one referral centers participated in the registry. By April 2014, 1374 patients with SSc had been enrolled, and 595 of whom (43%) had ILD: 316 (53%) with limited cutaneous SSc (lcSSc), 240 (40%) with diffuse cutaneous SSc (dcSSc), and 39 (7%) with SSc sine scleroderma (ssSSc). ILD in the lcSSc and the ssSSc subsets tended to develop later, and showed a less impaired forced vital capacity (FVC) and a ground glass pattern on high-resolution computed tomography (HRCT) less frequently, compared with the dcSSc subset. Factors related to an FVC < 70% of predicted in the multivariate analysis were: dcSSc, positivity to anti-topoisomerase I antibodies, a ground glass pattern on HCRT, an active nailfold capillaroscopy pattern, lower DLco, older age at symptoms onset, and longer time between symptoms onset and ILD diagnosis. Finally, SSc-associated mortality and ILD-related mortality were highest in dcSSc patients, whereas that related to pulmonary arterial hypertension was highest in those with lcSSc-associated ILD. CONCLUSIONS: Our study indicates that ILD constitutes a remarkable complication of SSc with significant morbidity and mortality, which should be borne in mind in all three subgroups (lcSSc, dcSSc, and ssSSc).

Multimodality scoring of chondral injuries in the equine fetlock joint ex vivo.

OBJECTIVE: We investigate the potential of a prototype multimodality arthroscope, combining ultrasound, optical coherence tomography (OCT) and arthroscopic indentation device, for assessing cartilage lesions, and compare the reliability of this approach with conventional arthroscopic scoring ex vivo. DESIGN: Areas of interest (AIs, N = 43) were selected from equine fetlock joints (N = 5). Blind-coded AIs were independently scored by two equine surgeons employing International Cartilage Repair Society (ICRS) scoring system via conventional arthroscope and multimodality arthroscope, in which high-frequency ultrasound and OCT catheters were attached to an arthroscopic indentation device. In addition, cartilage stiffness was measured with the indentation device, and lesions in OCT images scored using custom-made automated software. Measurements and scorings were performed twice in two separate rounds. Finally, the scores were compared to histological ICRS scores. RESULTS: OCT and arthroscopic examinations showed the highest average agreements (55.2%) between the scoring by surgeons and histology scores, whereas ultrasound had the lowest (50.6%). Average intraobserver agreements of surgeons and interobserver agreements between rounds were, respectively, for conventional arthroscope (68.6%, 69.8%), ultrasound (68.6%, 68.6%), OCT (65.1%, 61.7%) and automated software (65.1%, 59.3%). CONCLUSIONS: OCT imaging supplemented with the automated software provided the most reliable lesion scoring. However, limited penetration depth of light limits the clinical potential of OCT in assessing human cartilage thickness; thus, the combination of OCT and ultrasound could be optimal for reliable diagnostics. Present findings suggest imaging and quantitatively analyzing the entire articular surface to eliminate surgeon-related variation in the selection of the most severe lesion to be scored.

Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation.

Endocrine disruptors (ED) are environmental pollutants that mimic endogenous hormonal signals. Exposure to EDs during fetal and early life is a public health concern because these are periods characterized by high cellular plasticity that influence the physiology and development of disease later in life. Phthalates are plasticizers used in the industry to manufacture polyvinyl chloride products and several consumer products. Di(2-ethylhexyl) phthalate (DEHP) is one of the most produced plasticizers; it is ubiquitously found contaminating the environment, and has been shown to be an ED. Human exposure to phthalates starts during fetal development and continues after birth through contact of the newborn with the environment and contaminated food sources. We used a rat model in which pregnant dams are gavaged with DEHP from gestational day 14 until birth to study the long-term effects of DEHP. This window of fetal exposure results in decreased circulating testosterone and aldosterone levels in adult male offspring and estradiol in the female. The observed steroid changes are likely of an epigenetic origin as DEHP is rapidly cleared after birth. Here, we review the long-term effects of fetal exposure to DEHP with a focus on the molecular and epigenetic changes, including DNA methylation, which may mediate long-term endocrine dysfunction.

Histological findings in equine testes one year after standing laparoscopic peritoneal flap hernioplasty.

In order to know reproduction-related complications due to standing laparoscopic peritoneal flap hernioplasty, histological characteristics of the testicles from five stallions one year after surgery were compared with seven testicles from four healthy stallions. Moreover, the daily sperm output (DSO) was determined before (T0) and one year after surgery (T12). DSO did not show significant differences between T0 and T12. The diameter of the seminiferous tubules was significantly decreased in the samples from the hernioplasty group. The percentage of tubules with full spermatogenesis was smaller in the hernioplasty group, but the difference was not significant. It can be concluded that standing laparoscopic peritoneal flap hernioplasty produced mild histological changes in the testicular parenchyma, epididymis and pampiniform plexus after one year follow-up.

Development of a technique for standing hand-assisted laparoscopic splenectomy in five horses.

OBJECTIVES: To develop an experimental standing hand-assisted laparoscopic splenectomy (HALS) technique, report the associated peri-operative complications and document the short-term surgical outcomes. METHODS AND RESULTS: Five healthy 300-470 kg horses that underwent standing HALS. Spleens of different weights (2.25-7.0 kg) were removed using this technique. The main complication during surgery was difficulty sectioning the gastrosplenic ligament. The postoperative complications included adhesions of the colon to the nephrosplenic ligament stump and incisional discharge in two horses. CONCLUSIONS: Standing HALS is a feasible experimental procedure for medium-sized horses, which avoids rib excision and general anaesthesia, but requires further development.

Identification of hot spots of DNA methylation in the adult male adrenal in response to in utero exposure to the ubiquitous endocrine disruptor plasticizer di-(2-ethylhexyl) phthalate.

Exposure to environmental toxicants during fetal development alters gene expression and promotes disease later in life. Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer widely used for the manufacturing of consumer products. Exposure to DEHP has been associated with obesity, asthma, and low T levels. In utero exposure of pregnant dams to DEHP from gestational day 14 until birth resulted in reduced levels of serum T and aldosterone in the adult male offspring. Because DEHP is rapidly cleared from the body, the effects observed in the adult are likely epigenetic in origin. Under the same experimental conditions, we used reduced-representation bisulfite sequencing to assess changes in DNA methylation. We identified hot spots of DNA methylation changes primarily within CpG islands followed by shelf regions of the genome known to control regional gene expression. We also identified epigenomic areas responsive to exposure to environmental levels of DEHP and found the chromosomal region that houses genes controlling immune responsiveness to be a primary target of DEHP. These data suggest that DEHP phthalate exposure early in life induces epigenetic changes that may be linked to altered gene expression and function in the adult.

In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring.

BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used to increase the flexibility of polyvinyl chloride. DEHP and its active metabolite mono-(2-ethylhexyl) phthalate are detected in many biological fluids during fetal and postnatal life. In rodent models, in utero DEHP exposure has been shown to alter sexual organ development, decrease testosterone and aldosterone production, increase body and epididymal adipose tissue weight, and raise serum lipids and glucose levels in male offspring. OBJECTIVES: The objective of this study is to characterize the effects of in utero DEHP exposure on adipose tissue development and function in male offspring. METHODS: Sprague-Dawley pregnant dams were gavaged 1, 20, 50 or 300 mg DEHP per kg per day from gestational day 14 until birth. RESULTS: Global gene expression analyses of postnatal day 60 male offspring that were exposed in utero to 300 mg DEHP per kg per day revealed increased expression of immune response and inflammation markers, and increased expression of differentiation pathway genes in the epididymal whole-adipose tissue and isolated stromal vascular fraction. C-reactive protein and tumor necrosis factor (TNF) serum levels were increased in the 300 mg DEHP in utero-exposed offspring. TNF levels in adipose tissue homogenates were increased in the 50 and 300 mg DEHP in utero-exposed offspring. Immunofluorescence studies revealed focal macrophage infiltration in whole-adipose tissue confirmed by increased CD163 tissue content. CONCLUSIONS: In utero DEHP exposure promotes local adipose tissue inflammation and chronic low-grade systemic inflammation. Moreover, evidence is presented, suggesting that DEHP increases the differentiation capacity of the pre-adipocytes of male offspring without affecting total body weight.

In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate induces long-term changes in gene expression in the adult male adrenal gland.

The plasticizer di-(2-ethylhexyl) phthalate (DEHP) is used to add flexibility to polyvinylchloride polymers and as a component of numerous consumer and medical products. DEHP and its metabolites have been detected in amniotic fluid and umbilical cord blood, suggesting fetal exposure. In the present study, we used an in utero exposure model in which pregnant rat dams were exposed to 1- to 300-mg DEHP/kg·d from gestational day 14 until birth. We previously reported that this window of exposure to environmentally relevant doses of DEHP resulted in reduced levels of serum testosterone and aldosterone in adult male offspring and that the effects on aldosterone were sustained in elderly rats and resulted in decreased blood pressure. Here, we characterized the long-term effects of in utero DEHP exposure by performing global gene expression analysis of prepubertal (postnatal d 21) and adult (postnatal d 60) adrenal glands. We found that the peroxisome proliferator-activated receptor and lipid metabolism pathways were affected by DEHP exposure. Expression of 2 other DEHP targets, hormone-sensitive lipase and phosphoenolpyruvate carboxykinase 1 (Pck1), correlated with reduced aldosterone levels and may account for the inhibitory effect of DEHP on adrenal steroid formation. The angiotensin II and potassium pathways were up-regulated in response to DEHP. In addition, the potassium intermediate/small conductance calcium-activated channel Kcnn2 and 2-pore-domain potassium channel Knck5 were identified as DEHP targets. Based on this gene expression analysis, we measured fatty acid-binding protein 4 and phosphoenolpyruvate carboxykinase 1 in sera from control and DEHP-exposed rats and identified both proteins as putative serum biomarkers of in utero DEHP exposure. These results shed light on molecular targets that mediate DEHP long-term effects and, in doing so, provide means by which to assess past DEHP exposure.

Fetal origin of endocrine dysfunction in the adult: the phthalate model.

Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer with endocrine disrupting properties that is found ubiquitously in the environment as well as in human amniotic fluid, umbilical cord blood, human milk, semen, and saliva. It is used in the industry to add flexibility to polyvinyl chloride-derived plastics and its wide spread use and presence has resulted in constant human exposure through fetal development and postnatal life. Epidemiological studies have suggested an association between phthalate exposures and human reproductive effects in infant and adult populations. The effects of fetal exposure to phthalates on the male reproductive system were unequivocally shown on animal models, principally rodents, in which short term deleterious reproductive effects are well established. By contrast, information on the long term effects of DEHP in utero exposure on gonadal function are scarce, while its potential effects on other organs are just starting to emerge. The present review focuses on these novel findings, which suggest that DEHP exerts more complex and broader disruptive effects on the endocrine system and metabolism than previously thought. This article is part of a Special Issue entitled "CSR 2013".

Maternal in utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate affects the blood pressure of adult male offspring.

Di-(2-ethylhexyl) phthalate (DEHP) is used industrially to add flexibility to polyvinyl chloride (PVC) polymers and is ubiquitously found in the environment, with evidence of prenatal, perinatal and early infant exposure in humans. In utero exposure to DEHP decreases circulating testosterone levels in the adult rat. In addition, DEHP reduces the expression of the angiotensin II receptors in the adrenal gland, resulting in decreased circulating aldosterone levels. The latter may have important effects on water and electrolyte balance as well as systemic arterial blood pressure. Therefore, we determined the effects of in utero exposure to DEHP on systemic arterial blood pressure in the young (2month-old) and older (6.5month-old) adult rats. Sprague-Dawley pregnant dams were exposed from gestational day 14 until birth to 300mg DEHP/kg/day. Blood pressure, heart rate, and activity data were collected using an intra-aortal transmitter in the male offspring at postnatal day (PND) 60 and PND200. A low (0.01%) and high-salt (8%) diet was used to challenge the animals at PND200. In utero exposure to DEHP resulted in reduced activity at PND60. At PND200, systolic and diastolic systemic arterial pressures as well as activity were reduced in response to DEHP exposure. This is the first evidence showing that in utero exposure to DEHP has cardiovascular and behavioral effects in the adult male offspring.

Intra and postoperative assessment of re-sterilised Ligasure Atlas for orchidectomies in horses: clinical study.

Horses (n=35) underwent orchidectomy in a single institution with a re-sterilised LSA as sole means of haemostasis. During the surgery, the gross quality of the seal, the stickiness of the forceps to the tissues, bleeding/oozing from the stump and the need for a subsequent application in already severed spermatic cord were assessed for haemostasis quality. After surgery, physical parameters (appearance of the mucous membranes, quality of the peripheral pulse, heart rate, respiratory rate, rectal temperature and blood dripping from the incisions), haematology or packed cell volume and total protein were monitored to assess signs of bleeding or any other condition. For cleanliness and asepsis assessment, signs of surgical infection were recorded. Complications during surgery were mild degree of sticking of the LSA forceps to the tissues and dulling of the blade. There was no need to reapply LSA a second time except in one horse. This means a haemostasis complication rate of 2.85 per cent of the horses. No postoperative bleeding was detected. Only two horses with fever had associated signs of surgical site infection. This means an infection rate of 5.71 per cent of the horses.

Peritoneal concentrations of transforming growth factor beta in horses with colic.

REASONS FOR PERFORMING THE STUDY: In man, peritoneal transforming growth factor beta (TGF-beta) is associated with peritoneal diseases and subsequent adhesion formation. No studies on plasma and peritoneal TGF-beta concentrations in horses with colic are available. OBJECTIVES: 1) To determine both plasma and peritoneal TGF-beta(1) and TGF-beta(3) concentrations in horses with different types of colic (not previously subjected to abdominal surgery); 2) to compare these concentrations according to the type of peritoneal fluid (transudate, modified transudate and exudate); and 3) to compare and correlate plasma and peritoneal concentrations of TGF-beta(1) and TGF-beta(3) and the types of peritoneal fluid according to the colic group and outcome. METHODS: Peritoneal fluid and plasma samples from 78 horses with colic and 8 healthy horses were obtained. Patients were classified according to diagnosis (obstructions, enteritis, ischaemic disorders and peritonitis), peritoneal fluid analysis (transudate, modified transudate and exudate), and outcome (survivors and nonsurvivors). Plasma and peritoneal TGF-beta(1) and TGF-beta(3) concentrations were determined by ELISA. Data were analysed by parametric and nonparametric tests. P< or =0.05 was considered as statistically significant. RESULTS: Concentrations of peritoneal fluid TGF-beta(1) were significantly (P = 0.01) higher in horses with peritonitis in comparison with all other colic groups and controls. Horses with ischaemic lesions had significantly (P = 0.01) higher concentrations of peritoneal TGF-beta(1) in comparison with controls and the group of horses with obstructions. Peritoneal TGF-beta(1) concentration also was significantly (P = 0.01) higher in exudates in comparison with transudates. Peritoneal TGF-beta(1) and TGF-beta(3) concentrations and plasma TGF-beta(1) concentration were significantly increased in nonsurvivors compared to survivors (P = 0.001, P = 0.004 and P = 0.05, respectively). CONCLUSIONS: Peritoneal TGF-beta(1) concentration was higher in horses with severe gastrointestinal diseases (ischaemic intestinal lesions and peritonitis), in horses with an altered peritoneal fluid (exudate), and in nonsurvivors. POTENTIAL RELEVANCE: Peritoneal TGF-beta concentration increases in horses with severe gastrointestinal disease as an anti-inflammatory response.

Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo.

The Translocator Protein (TSPO), previously known as the peripheral-type benzodiazepine receptor, is a ubiquitous drug- and cholesterol-binding protein that is up regulated in several types of cancer cells. TSPO drug ligands (e.g., diazepam) induce or inhibit tumor cell proliferation, depending on the dose and tissue origin. We have previously shown that TSPO is expressed in Ehrlich tumor cells and that diazepam increases proliferation of these cells in vitro. Here, we investigated the in vivo effects of diazepam on Ehrlich tumor growth and the role of TSPO in mediating this process. Oral administration of diazepam to mice (3.0mg/kg/day for 7 days) produced plasma and ascitic fluid drug concentrations of 83.83 and 54.12 nM, respectively. Diazepam increased Ehrlich tumor growth, likely due to its ability to increase tumor cell proliferation and Reactive Oxygen Species production. Radioligand binding assays and nucleotide sequencing revealed that Ehrlich tumor cell TSPO had the same pharmacological and biochemical properties as TSPO described in other tumor cells. The estimated K(d) for PK 11195 in Ehrlich tumor cells was 0.44 nM and 8.70 nM (low and high binding site, respectively). Structurally diverse TSPO drug ligands with exclusive affinity for TSPO (i.e., 4-chlordiazepam, Ro5-4864, and isoquinoline-carboxamide PK 11195) also increased Ehrlich tumor growth. However, clonazepam, a GABA(A)-specific ligand with no affinity for TSPO, failed to do so. Taken together, these data suggest that diazepam induces in vivo Ehrlich tumor growth in a TSPO-dependent manner.

In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis.

In utero exposure to di-(2-ethylhexyl) phthalate (DEHP) has been shown to result in decreased androgen formation by fetal and adult rat testes. In the fetus, decreased androgen is accompanied by the reduced expression of steroidogenic enzymes. The mechanism by which in utero exposure results in reduced androgen formation in the adult, however, is unknown. We hypothesized that deregulation of the nuclear steroid receptors might explain the effects of in utero DEHP exposure on adult testosterone production. To test this hypothesis, pregnant Sprague Dawley dams were gavaged with 100-950 mg DEHP per kilogram per day from gestational d 14-19, and testes were collected at gestational d 20 and postnatal days (PND) 3, 21, and 60. Among the nuclear receptors studied, the mineralocorticoid receptor (MR) mRNA and protein levels were reduced in PND60 interstitial Leydig cells, accompanied by reduced mRNA expression of MR-regulated genes. Methylation-sensitive PCR showed effects on the nuclear receptor subfamilies NR3A and -3C, but only MR was affected at PND60. Pyrosequencing of two CpG islands within the MR gene promoter revealed a loss of methylation in DEHP-treated animals that was correlated with reduced MR. Because MR activation is known to stimulate Leydig cell testosterone formation, and MR inhibition to be repressive, our results are consistent with the hypothesis that in utero exposure to DEHP leads to MR dysfunction and thus to depressed testosterone production in the adult. We suggest that decreased MR, possibly epigenetically mediated, is a novel mechanism by which phthalates may affect diverse functions later in life.