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OBJECTIVES: Basic science studies of ureteral physiology and pathophysiology are commonly performed on animal ureters due to several limitations associated with human ureteral sampling. In this work we question whether animal ureters are good replicas of human ureteral behavior for pharmacological studies. MATERIALS AND METHODS: Ureteral rings from human, porcine and ovine ureters underwent the same organ bath protocol. After stimulation with KCl, ureters were subjected to different doses of vardenafil. Basic contractility and ureteral response to vardenafil were analyzed. RESULTS: A different pattern of basic contractility was evidenced between species. Vardenafil administration induced a dose-dependent reduction in KCl-induced amplitude increase in human ureters and a dose-dependent reduction in autonomic contractile rhythm of porcine and ovine ureters. Although animal ureters could predict the relaxant response of human samples to vardenafil, its effect would have been overestimated using only animal models. CONCLUSIONS: Human ureteral investigations cannot entirely be replaced by existing animal models since results of the latter will vary significantly according to the tested pharmaceutical agent.
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Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Ureter/efeitos dos fármacos , Dicloridrato de Vardenafila/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Masculino , Músculo Liso/fisiologia , Ovinos , Suínos , Ureter/fisiologiaRESUMO
The full metallic double-J ureteral stent (MS) was introduced as a method for providing long-term drainage in malignant ureteral obstruction. Experimental evaluation of the MS revealed that its mechanical features allow efficient drainage in difficult cases, which could not be managed by the insertion of a standard polymeric double-J stent. Clinical experience with the MS showed controversial results. Careful patient selection results in efficient long-term management of malignant ureteral obstruction. The use of the MS should also be considered in selected benign cases. Major complications are uncommon and the minor complications should not hinder its use. Experience in pediatric patients is limited and warrants additional study. The cost-effectiveness of the MS seems to be appropriate for long-term treatment. Further investigation with comparative clinical trials would document the outcome more extensively and establish the indications as well as the selection criteria for the MS.
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OBJECTIVE: We evaluated reconstructive and oncological laparoendoscopic single-site surgery (LESS) combined with mini-laparoscopic instruments as standard equipment. PATIENTS AND METHODS: 30 patients underwent reconstructive and oncological LESS: mini-laparoscopic-assisted LESS pyeloplasty (LESS-P, n = 18), mini-laparoscopic-assisted LESS partial nephrectomy (LESS-PN, n = 7) or mini-laparoscopic-assisted LESS radical prostatectomy (LESS-RP, n = 5). Perioperative data were prospectively collected. RESULTS: The 18 LESS-P cases had operative times ranging between 120 and 180 min (average 147.9 min). Estimated blood loss ranged between 100 and 300 ml (average 202.1 ml). Two patients required additional management for failed reconstruction. LESS-PN was performed in 7 patients with tumor size ranging between 2.5 and 3.8 cm (average 2.7 cm). Average operative time and blood loss were 155 (140-180) min and 321.4 (250-550) ml, respectively. Renal artery clamping took place in 1 case. LESS-RP was performed in 5 patients; average operative time was 156 (140-180) min and average blood loss 196 (100-400) ml. Functional and oncological outcome was directly comparable to laparoscopic radical prostatectomy. CONCLUSION: The combination of LESS and mini-laparoscopic instrumentation as routine equipment of reconstructive LESS reveals a different perspective for 'scarless' urologic surgery.
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Endoscopia/métodos , Laparoscopia/métodos , Procedimentos Cirúrgicos Urológicos , Adulto , Cicatriz , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Duração da Cirurgia , Período Pós-Operatório , Prostatectomia/métodos , Procedimentos de Cirurgia Plástica , Artéria Renal/cirurgia , Robótica , Cirurgia Assistida por Computador , Resultado do Tratamento , Adulto JovemRESUMO
Drugeluting metal stents (DESs) have been extensively used in coronary and vascular disease. This type of stents has been proven to provide significantly lower restenosis rates due to the reduction of neo-intimal hyperplasia in comparison to the traditionally used bare metal stents (BMSs). The latter stents have been evaluated for more than a decade in urological practice in an attempt to provide permanent relief of urethral or ureteral obstruction. Although the initial results were promising, long-term experience revealed significant complications, which are mainly attributed to stent-related hyperplastic reaction compromising stent patency. The favorable experience of vascular DESs led to the application of DESs in both the urethra and ureter of animal models. These experimental results demonstrated a reduction of hyperplastic reaction of DESs in comparison to BMSs. Nevertheless, clinical data are currently not available. Considering the fact that DESs are under continuous development, the use of DESs in urology holds promise for the future and seems to be an intriguing field.
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OBJECTIVE: To evaluate the mid-term effects of haemostatic sealant application during tubeless percutaneous nephrolithotomy (PCNL) on renal drainage and histology in an in vivo porcine study. MATERIALS AND METHODS: Bilateral percutaneous access was established in 28 porcine renal units. At the end of the procedure, a type 1 absorbable fish origin collagen powder, a human fibrinogen- and thrombin-coated sponge or a cross-linked gelatin granule/topical thrombin matrix were randomly placed on the nephrostomy tracts. Four nephrostomy accesses were left intact and served as controls. No percutaneous tube, ureteric stent or bladder catheter was left in place postoperatively. Computed tomography urography on postoperative days 1, 15, 30 and 40 was used to access renal drainage. On postoperative day 40, all animals were killed and both kidneys from each animal were harvested for histological evaluation. RESULTS: Evidence of risk for drainage occlusion after sealant application was found. The use of haemostatic sealants was associated with significant histological lesions in the renal parenchyma, regardless of which sealant was used. No sealant was identified as superior to the others. Nephrostomy tracts that were left without sealant application (control group) were associated with no morbidity and fewer histopathological changes. CONCLUSIONS: Based on these experimental results, the safety of the application of haemostatic sealants in tubeless PCNL should be reassessed, focusing not only on the potential of such materials to occlude urinary drainage but also on their effect on renal histology. Further investigation is considered necessary.
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Colágeno/uso terapêutico , Fibrinogênio/uso terapêutico , Esponja de Gelatina Absorvível/uso terapêutico , Hemostáticos/uso terapêutico , Rim/patologia , Rim/fisiologia , Nefrostomia Percutânea/métodos , Tampões de Gaze Cirúrgicos , Trombina/uso terapêutico , Adesivos Teciduais/uso terapêutico , Animais , Drenagem , Combinação de Medicamentos , Feminino , SuínosRESUMO
PURPOSE: Barbed self-retaining sutures (SRS) have been introduced as an advance in suture technology, facilitating reconstructive laparoscopic surgery. We present the experience of three centers performing laparoscopic pyeloplasty with the use of SRS. METHODS: Preoperative, intraoperative and follow-up data were collected for 6 patients undergoing pyeloplasty using the Quill SRS (Angiotech, Vancouver, CAN) in three centers. Standard laparoscopic pyeloplasty technique was used and a knot-less continuous anastomosis between the spatulated ureter and the renal pelvis was created. RESULTS: Knot-less uretero-pelvic anastomosis creation was feasible in all six cases. Peri-operative data were similar to standard pyeloplasty using conventional suture materials. A very high stricture recurrence rate (5/6 patients) was noted during follow-up. Further endourologic and open interventions were needed to address the recurrence of the strictures. CONCLUSIONS: Knotless intracorporeal laparoscopic suturing using SRS for the reconstruction of UPJ during laparoscopic pyeloplasty is associated with high rates of stricture recurrence at least in the initial cases of each surgeon. Until further investigations elucidate the cause of treatment failure, SRS should not be recommended for upper urinary tract reconstruction.
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Anastomose Cirúrgica/métodos , Pelve Renal/cirurgia , Laparoscopia/métodos , Procedimentos de Cirurgia Plástica/métodos , Suturas/efeitos adversos , Ureter/cirurgia , Adulto , Constrição Patológica/epidemiologia , Constrição Patológica/cirurgia , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Stents , Resultado do Tratamento , Obstrução Ureteral/epidemiologia , Obstrução Ureteral/cirurgiaRESUMO
PURPOSE: To evaluate the effect of vardenafil on renal function after renal ischemia-reperfusion (IR) injury (IRI) in a rat model. MATERIALS AND METHODS: Seventy-one Wistar rats were divided into 7 groups including (1) a vehicle-treated group, (2) a vehicle pretreated-IR group, (3-6) vardenafil pretreated-IR groups in doses of 0.02, 0.2, 2 and 20 µg/kg, respectively, (7) a group of IR followed by treatment with 2 µg/kg of vardenafil. Vardenafil or vehicle solution was administered one hour before unilateral nephrectomy and the induction of 45 min of ischemia on the contralateral kidney by clamping of renal pedicle. Four hours of reperfusion were allowed after renal ischemia. Studied parameters were serum creatinine, fractional excretion of sodium (FENa), and histological evaluation of renal specimens. In addition, renal tissue cGMP levels, ERK1/2 phosphorylation as well as renal function by renal scintigraphy were also evaluated. RESULTS: Administration of vardenafil before the induction of ischemia resulted in a significant reduction in creatinine and FENa levels as well as in less histological lesions observed in treated kidneys in comparison with the vehicle-treated group. The underlying mechanism of cytoprotection was cGMP depended and involved the phosphorylation of ERK proteins. Renal scintigraphy confirmed that PDE5 inhibition attenuates renal IRI. CONCLUSIONS: Vardenafil attenuates renal IRI. Based on similar results from relevant studies on other PDE-5 inhibitors in renal and cardiac IRI, it can be assumed that all PDE-5 inhibitors share a common mechanism of cytoprotection.
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Imidazóis/uso terapêutico , Precondicionamento Isquêmico/métodos , Rim/irrigação sanguínea , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , GMP Cíclico/fisiologia , Imidazóis/farmacologia , Rim/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Modelos Animais , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Triazinas/farmacologia , Triazinas/uso terapêutico , Dicloridrato de VardenafilaRESUMO
Laparoscopic surgery of the upper urinary tract has reduced the morbidity related to large abdominal incisions and has resulted in significant advantages over open surgery. Nevertheless, the pursuit for even more minimally invasive alternatives to laparoscopy has led to the concept of scarless surgery and the approach of laparoendoscopic single-site surgery (LESS). LESS is currently a feasible approach for the majority of kidney surgical procedures, and there is intense debate regarding its efficiency and advantages. In the present review of the literature, the current status of upper urinary LESS and its advantages and disadvantages, as well the technological and technical evolution, are presented.
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Previsões , Nefropatias/cirurgia , Laparoscópios , Laparoscopia/tendências , Nefrectomia/tendências , Desenho de Equipamento , Humanos , Laparoscopia/métodos , Nefrectomia/métodos , Reprodutibilidade dos Testes , Robótica/tendênciasRESUMO
Laparoendoscopic single-site surgery (LESS) represents the next step of laparoscopic surgery and a major advancement towards scarless surgery. LESS radical nephrectomy is an evolving technique based on technological advancement of laparoscopic instruments as well as the refinement of existing techniques.The current report describes LESS nephrectomy technique, presents the experience with the technique in a series of 42 patients and reviews current literature in the field of LESS nephrectomy.
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Endoscopia/métodos , Laparoscopia/métodos , Cirurgia Endoscópica por Orifício Natural/métodos , Nefrectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Colo/fisiologia , Endoscopia/instrumentação , Feminino , Humanos , Laparoscopia/instrumentação , Masculino , Pessoa de Meia-Idade , Cirurgia Endoscópica por Orifício Natural/instrumentação , Nefrectomia/instrumentação , Cuidados Pós-Operatórios , Ensaios Clínicos Controlados Aleatórios como Assunto , Ureter/fisiologiaRESUMO
BACKGROUND: To compare blood pressure (BP) values in the lying and sitting positions, and the effect of orthostatism when moving from each of these positions to the upright position in a geriatric population with various frailty levels. METHODS: In two sub-studies, we included a total of 157 consecutive patients, aged 75+ admitted to the Geriatric Department of Nancy University Hospital. BP and heart rate were sequentially measured three times in 1-min intervals each in lying, sitting and upright positions (Protocol#1, n = 107) or lying and upright positions (Protocol#2, n = 50) with an automatic validated Blood Pressure device. Patients were classified into two increasing frailty status (FS) categories: Low/Moderate (L/M-FS, n = 98) and High (H-FS, n = 59). RESULTS: BP levels were similar in the lying and sitting positions (Protocol#1, SBP 141 ± 22 mmHg vs. 142 ± 21 mmHg, respectively, and DBP 72 ± 12 mmHg vs. 72 ± 12 mmHg, respectively) in both frailty groups. In the H-FS, orthostatic drop of SBP was more pronounced from the lying (22.1 ± 5.8 mmHg, Protocol#2) as compared to the sitting to upright position (9.4 ± 1.9 mmHg, Protocol#1) (p < 0.008), and the same trend was observed for DBP. No such differences were observed in the L-M/FS frailty individuals. CONCLUSIONS: Orthostatic BP changes are more pronounced in the frailest patients when going from lying to the upright position than from the sitting to the upright position. Consequently, in these individuals, lying and sitting BP measurements cannot be interchangeable baseline positions to investigate orthostatic BP effects, and therefore, precise patient positioning should be specified when referring to "baseline BP measurements".
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Fragilidade , Postura Sentada , Idoso , Humanos , Pressão Sanguínea , Idoso Fragilizado , Fragilidade/diagnóstico , PosturaRESUMO
BACKGROUND: Duration of post-vaccination protection against COVID-19 in nursing home (NH) residents is a critical issue. The objective of this study was to estimate the duration of the IgG(S) response to the mRNA BNT162b2 vaccine in NH residents with (COV-Yes) or without (COV-No) history of SARS-CoV-2 infection. METHODS: A 574 COV-Yes and COV-No NH residents were included in 2 cohorts: Main (n = 115, median age 87 years) or Confirmatory (n = 459, median age 89 years). IgG(S) quantification was carried out at three different time points following the BNT162b2 vaccine: three (1st) and seven (2nd) months after the 2nd dose, and 1 month after the 3rd dose (3rd quantification) in the Main cohort, and twice (2nd and 3rd) in the Confirmatory cohort. The seroneutralization capacity according to COVID-19 history was also measured in a subgroup of patients. RESULTS: Neutralization capacity was strongly correlated with IgG(S) levels (R2 :76%) without any difference between COV-Yes and COV-No groups for the same levels of IgG(S). After the 2nd dose, duration of the assumed robust protection (IgG(S) >264 BAU/ml) was two-fold higher in the COV-Yes vs. COV-No group: 12.60 (10.69-14.44) versus 5.76 (3.91-8.64) months, with this advantage mainly due to the higher IgG(S) titers after the 2nd dose and secondary to a slower decay over time. After the 3rd dose, duration of robust protection was estimated at 11.87 (9.88-14.87) (COV-Yes) and 8.95 (6.85-11.04) (COV-No) months. These results were similar in both cohorts. CONCLUSIONS AND RELEVANCE: In old subjects living in NH, history of SARS-CoV-2 infection provides a clear advantage in the magnitude and duration of high IgG(S) titers following the 2nd dose. Importantly, the 3rd dose induces a much more pronounced IgG(S) response than the 2nd dose in COV-No subjects, the effect of which should be able to ensure a prolonged protection against severe forms of COVID-19 in these subjects.
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COVID-19 , Vacinas , Idoso de 80 Anos ou mais , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Humanos , Imunoglobulina G , Casas de Saúde , RNA Mensageiro , SARS-CoV-2RESUMO
Geriatric Medicine (GM) holds a crucial role in promoting health and managing the complex medical, cognitive, social, and psychological issues of older people. However, basic principles of GM, essential for optimizing the care of older people, are commonly unknown or undermined, especially in countries where GM is still under development. This narrative review aims at providing insights into the role of GM to non-geriatrician readers and summarizing the main aspects of the added value of a geriatric approach across the spectrum of healthcare. Health practitioners of all specialties are frequently encountered with clinical conditions, common in older patients (such as cancer, hypertension, delirium, major neurocognitive and mental health disorders, malnutrition, and peri-operative complications), which could be more appropriately managed under the light of the approach of GM. The role of allied health professionals with specialized knowledge and skills in dealing with older people's issues is essential, and a multidisciplinary team is required for the delivery of optimal care in response to the needs and aspirations of older people. Thus, countries should assure the educational background of all health care providers and the specialized health and social care services required to meet the demands of a rapidly aging society.
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UNLABELLED: Objectives should be describe a modular training scheme (MTS) which aims to provide training in percutaneous nephrolithotripsy (PCNL) and ensure the safety of the patients. SUBJECTS AND METHODS: Two trainees with no experience in PCNL attended the MTS under the supervision of an experienced mentor. The MTS included five modules, comprising an initial animal laboratory course (using pigs), to acquire basic skills (Module 1), and Modules 2-5 included making the puncture, tract dilatation, single-stone and large-stone management in clinical cases, respectively. Each participant progressed from one module to the next under constant mentoring and evaluation by the mentor. When the trainees completed the MTS they proceeded to perform 60 PCNL procedures independently while the mentor performed 25 for comparison purposes. A global rating scale was used for the objective evaluation of the trainees. Peri-operative variables were recorded and statistically compared as appropriate. Statistical significance was defined as P < 0.05. RESULTS: One pig and 16 patients, and two pigs and 22 patients, were necessary to complete the MTS by each subject. There were no significant differences among the characteristics of the independently performed operations. The duration of surgery and fluoroscopy achieved a plateau similar to those of the mentor after ≈ 30 patients. The decrease in haemoglobin level, stone-free and complication rates in the patients were similar among the two trainees and the mentor. The complication rate of the trainees and the mentor never exceeded 13.3%. CONCLUSION: The MTS successfully combined animal and stepwise clinical training based on a standardised technique and objective evaluation.
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AIM OF THE STUDY: In this work, surgical technique followed by two academic departments on laparoscopic simple prostatectomy (LSP) of large prostatic adenomas is being described. MATERIALS AND METHODS: The initial cumulative experience from 11 patients with lower urinary tract symptoms of benign prostatic hyperplasia origin subjected to LSP is being presented. RESULTS: All cases had prostatic adenomas greater than 80 ml. Mean operation time was 99.5 min (values from 70 to 150 min) and mean blood loss was 205 ml (values from 100 to 300 ml). Blood transfusion was deemed necessary in one case. Bladder catheter was removed successfully on postoperative day 5 in all cases. No significant postoperative complication was noted. At a 3 months follow-up a significant decrease in International Prostate Symptom Score (IPSS) was evident in all patients (mean IPSS 27.7 vs. 15.3 preoperative vs. postoperative accordingly). CONCLUSIONS: According to our data and similarly to the rest of the LSP literature, laparoscopic excision of voluminous prostatic adenomas is a feasible and safe procedure. Nevertheless, further investigation including a larger number of patients and long-term follow-up is deemed necessary before making definite conclusions regarding the approach.
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OBJECTIVE: To evaluate the development of natural orifice transluminal endoscopic surgery (NOTES) transvaginal nephrectomy and present the initial experience. METHODS: Thirty-eight female patients were submitted to hybrid NOTES transvaginal nephrectomy for tumor (n=23) and nonfunctioning renal unit (n=15) in 2 academic medical centers. Patients underwent surgery from July 2010 to June 2012 and none of them were candidates for partial nephrectomy (clinical stage T1b or higher). The procedure was performed by the use of multi-instrument ports or flexible cannulas inserted through umbilical and vaginal incisions. A 30° lens extra-long camera and combinations of conventional laparoscopic and prebent instruments were used. Specially designed extra-long, prebent straight instruments were found to be particularly useful for transvaginal manipulations. Prospective data regarding patient demographics, intraoperative and postoperative course of the patients, and pathology results were collected. RESULTS: Average tumor diameter was 6 cm (range, 4.9-7.5 cm). Average operative time was 114.1 minutes (range, 90-190 minutes). Estimated blood loss ranged between 50 and 150 mL (average, 80 mL). Intraoperatively, 2 bladder perforations occurred and were treated by suturing. Postoperatively, 2 patients suffered from fever of unknown origin and 2 patients required transfusions due to bleeding. Average hospital stay was 3.3 days (range, 3-5 days). Positive surgical margins were not detected. CONCLUSION: Hybrid NOTES transvaginal nephrectomy is a feasible and safe alternative to standard laparoscopic nephrectomy in selected patients. Difficulties arising from limitations in current instrumentation have been addressed by the use of specially designed instruments. Further clinical studies are required to ascertain this approaches' place among nephrectomy techniques.
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Cirurgia Endoscópica por Orifício Natural , Nefrectomia/métodos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , VaginaRESUMO
Local intralumenal administration of substances with beneficial effects over the ureter appears to be a very attractive route for the administration of drugs to the urinary system, avoiding systemic adverse reactions associated with per os administration. This work investigates whether vardenafil is a good candidate for local intralumenal ureteral administration. More precisely, we examined the effect of vardenafil on human ureter contractility and on the viability of cultured human urothelial cells (hUC) and bladder smooth muscle cells (hBSMC). Our study revealed that vardenafil induced a dose-depended relaxation of isolated human ureteral tissue. In addition, growth and cell viability of cultured hBSMC and hUC remained unaltered after vardenafil application. Based on the above, this selective phosphodiesterase type 5 inhibitor can be considered as a promising pharmacologic agent for local intralumenal administration in clinical conditions in which ureteral dilation might be beneficial.
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Imidazóis/administração & dosagem , Contração Muscular/efeitos dos fármacos , Piperazinas/administração & dosagem , Ureter/efeitos dos fármacos , Doenças Urológicas/tratamento farmacológico , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Humanos , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , Sulfonas/administração & dosagem , Triazinas/administração & dosagem , Ureter/patologia , Ureter/fisiopatologia , Doenças Urológicas/patologia , Doenças Urológicas/fisiopatologia , Dicloridrato de VardenafilaRESUMO
PURPOSES: This study examines whether inherent patient-related risk factors (age, gender) modify the effect of laparoscopic cholecystectomy (LC) upon the coagulation and fibrinolysis cascades. METHODS: This observational study included 119 low-risk for deep vein thrombosis (DVT) patients undergoing elective LC, without thromboprophylaxis. Pre-operatively and 24 h post-operatively we measured PT-INR, aPTT, FDP, d-dimer, and fibrinogen. Color Doppler scan of the lower extremity was performed the 1st post-operative day. Differences before and after surgery were analyzed with respect to risk factors. RESULTS: No clinically or ultrasound evident DVT was observed. INR (1.04 ± 0.06 vs. 1.12 ± 0.11, p < 0.0001), d-dimer (0.38 ± 0.36 vs. 0.9 ± 0.64, p < 0.0001), plasma fibrinogen (380.8 ± 74.9 vs. 403.8 ± 78.8, p = 0.0001) and FDP positivity exhibited statistically significant increase after surgery. The levels of aPTT did not exhibit any significant change. Concerning d-dimer, older age was associated with higher pre-operative concentrations; older patients accordingly exhibited more intense increase in d-dimer and FDP positivity after surgery. Male sex was associated with higher PT-INR and aPTT before surgery, as well as with more pronounced increase in PT- INR postoperatively; similarly, older age was associated only with higher PT-INR before surgery. CONCLUSIONS: Despite no DVT, significant increase in PT-INR, d-dimer, FDP and fibrinogen appeared after LC. This may be attributed to surgical trauma and pneumoperitoneum effects on the portal vein flow. Elderly subjects and males seem particularly vulnerable, demonstrating more sizeable changes.