RESUMEN
OBJECTIVE: Over 67,000 individuals died in the United States due to drug overdose in 2018; the majority of these deaths were secondary to opioid ingestion. Our aim was to determine surgeon perceptions on opioid abuse, the adequacy of perioperative and graduate medical education, and the role surgeons may play. We also aimed to investigate any differences in attending and resident surgeon attitudes. DESIGN: Anonymous online survey assessing surgeons' opioid counseling practices, prescribing patterns, and perceptions on opioid abuse, adequacy of education about opioid abuse, and the role physicians play. SETTING: Two Accreditation Council for Graduate Medical Education accredited general surgery programs at a university-based tertiary hospital and a community hospital in the Midwest. PARTICIPANTS: Attending and resident physicians within the Departments of Surgery participated anonymously. RESULTS: Attending surgeons were more likely than residents to discuss posoperative opioids with patients (62% vs. 33%; p < 0.05), discuss the potential of opioid abuse (31% vs. 6%; p < 0.05), and check state-specific prescription monitoring programs (15% vs. 0%; p < 0.05). Surgeons and trainees feel that surgeons have contributed to the opioid epidemic (76% attending vs. 88% resident). Overall, attending and resident surgeons disagree that there is adequate formal education (66% vs. 66%) but adequate informal education (48% vs. 61%) on opioid prescribing. However, when attending physicians were broken down into those who have practiced ≤5 years vs. those with >5 years experience, those with ≤5 years experience were more confident in recognizing opioid abuse (61% vs. 34%) and fewer young faculty disagreed that there is adequate formalized education on opioid prescribing (45% vs. 84%). CONCLUSION AND RELEVANCE: Patient education should be improved upon in the preoperative setting and should be treated as an important component of preoperative discussions. Formalized opioid education should also be undertaken in graduate surgical education to help guide appropriate opioid use by resident and attending physicians.
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Internado y Residencia , Cirujanos , Analgésicos Opioides/uso terapéutico , Prescripciones de Medicamentos , Humanos , Epidemia de Opioides , Manejo del Dolor , Dolor Postoperatorio/tratamiento farmacológico , Pautas de la Práctica en Medicina , Estados UnidosRESUMEN
BACKGROUND: The impact of recent preoperative opioid exposure on outcomes of colorectal surgery is unclear. Our aim was to evaluate the impact of preoperative opioid use on outcomes and opioid prescribing patterns after colorectal surgery. METHODS: We performed a retrospective review of all patients undergoing elective resection at a single institution from 2015 to 2017. Primary outcomes included in-hospital narcotic use and cost. Secondary outcomes included postoperative surgical outcomes and discharge prescribing patterns. RESULTS: A total of 390 patients underwent elective colorectal surgery, of whom 63 (16%) had a recent history of preoperative opioid use. Opioid users had similar age, sex, American Society of Anesthesiologists score, and operative indication compared with opioid-naïve patients (P > .05 for each). Postoperatively, the 30-day readmission rate was greater among opioid users (18% vs 9%, P = .03). Opioid users had greater total narcotic use (218 morphine milligram equivalents vs 111 morphine milligram equivalents, P = .04) and direct costs ($11,165 vs $8,911, P < .01). These patients were also more likely to require an opioid prescription on discharge (90% vs 68%, P < .01) and an opioid refill within 30 days (54% vs 21%, P < .01). CONCLUSION: Recent preoperative opioid exposure among colorectal surgery patients was associated with increased opioid consumption and costs. Moreover, unadjusted analysis was pertinent for more readmissions after surgery among preoperative opioid users. This work underscores the negative impact of preoperative, chronic opioid use on surgical outcomes and highlights the need for developing protocols to minimize perioperative narcotics.
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Analgésicos Opioides/administración & dosificación , Neoplasias Colorrectales/cirugía , Cirugía Colorrectal/métodos , Procedimientos Quirúrgicos Electivos/métodos , Tiempo de Internación/economía , Dolor Postoperatorio/tratamiento farmacológico , Anciano , Analgésicos Opioides/economía , Estudios de Cohortes , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Cirugía Colorrectal/mortalidad , Análisis Costo-Beneficio , Procedimientos Quirúrgicos Electivos/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/fisiopatología , Periodo Preoperatorio , Pronóstico , Puntaje de Propensión , Estudios Retrospectivos , Medición de Riesgo , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
BACKGROUND: While previous studies have demonstrated short-term efficacy of laparoscopic sleeve gastrectomy in candidates awaiting renal transplantation, the combination of morbid obesity and end-stage renal disease presents unique challenges to perioperative care. We demonstrate how increasing experience and the development of postoperative care guidelines can improve outcomes in this high-risk population. METHODS: Single-center medical records were reviewed for renal transplantation candidates undergoing laparoscopic sleeve gastrectomy between 2011 and 2015 by a single surgeon. Postoperative care protocols were established and continually refined throughout the study period, including a multidisciplinary approach to inpatient management and hospital discharge planning. The first 100 laparoscopic sleeve gastrectomy patients were included and divided into 4 equal cohorts based on case sequence. RESULTS: Compared with the first 25 patients undergoing laparoscopic sleeve gastrectomy, the last 25 patients had shorter operative times (97.8 ± 27.9 min vs 124.2 ± 33.6 min), lower estimated blood loss (6.6 ± 20.8 mL vs 34.0 ± 38.1 mL), and shorter hospital duration of stay (1.7 ± 2.1 days vs 2.9 ± 0.7 days) (P < .01 each). Readmission rates, complications, and 1-year mortality did not differ significantly. CONCLUSION: Increasing experience and the development of clinical care guidelines in this high-risk population is associated with reduced health care resource utilization and improved perioperative outcomes.
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Gastrectomía , Fallo Renal Crónico/complicaciones , Obesidad Mórbida/cirugía , Adulto , Pérdida de Sangre Quirúrgica , Femenino , Humanos , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Tiempo de Internación , Masculino , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Tempo Operativo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.
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Exosomas/metabolismo , Hepatocitos/metabolismo , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Daño por Reperfusión/metabolismo , Animales , Proliferación Celular , Ceramidasas/metabolismo , Lisofosfolípidos/biosíntesis , Masculino , Ratones , Ratones Noqueados , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8B/genética , Daño por Reperfusión/patología , Esfingomielina Fosfodiesterasa/metabolismo , Esfingosina/análogos & derivados , Esfingosina/biosíntesis , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Proteínas rab27 de Unión a GTPRESUMEN
BACKGROUND & AIMS: Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. METHODS: Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. RESULTS: Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. CONCLUSIONS: Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease.
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Exosomas/fisiología , Regeneración Hepática , Lisofosfolípidos/fisiología , Esfingosina/análogos & derivados , Animales , Proliferación Celular , Hepatocitos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Esfingosina/fisiologíaRESUMEN
BACKGROUND: Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy. METHODS: Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration. RESULTS: We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC), was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration. CONCLUSIONS: Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.
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Hepatocitos/fisiología , Regeneración Hepática , Receptores de Interleucina-8B/fisiología , Animales , Proliferación Celular , Quimiocina CXCL2/farmacología , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Daño por Reperfusión/metabolismoRESUMEN
Sphingolipids are not only essential components of cellular membranes but also function as intracellular and extracellular mediators that regulate important physiological cellular processes including cell survival, proliferation, apoptosis, differentiation, migration and immune responses. The liver possesses the unique ability to regenerate after injury in a complex manner that involves numerous mediators, including sphingolipids such as ceramide and sphingosine 1-phosphate. Here we present the current understanding of the involvement of the sphingolipid pathway and the role this pathway plays in regulating liver injury, repair and regeneration. The regulation of sphingolipids and their enzymes may have a great impact in the development of novel therapeutic modalities for a variety of liver injuries and diseases.
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Hepatopatías/metabolismo , Hígado/lesiones , Hígado/metabolismo , Esfingolípidos/metabolismo , Animales , Ceramidas/metabolismo , Humanos , Regeneración Hepática/fisiología , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismoRESUMEN
The role of stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptor CXC chemokine receptor-4 (CXCR4) in ischemic liver injury and recovery has not been studied. Some reports suggest that this chemokine may aid in liver regeneration, but others suggest that it may be profibrotic through its activation of hepatic stellate cells. In this study we sought to elucidate the role of SDF-1 and its receptor CXCR4 during liver injury, recovery, and regeneration after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. CXCR4 was expressed constitutively in the liver, and hepatic levels of SDF-1 peaked 8 h after reperfusion but remained significantly increased for 96 h. Treatment of mice with the CXCR4 antagonist AMD3100 or agonist SDF-1 had no effect on acute liver injury assessed 8 h after I/R. However, treatment with AMD3100 increased hepatocyte proliferation after 72 and 96 h of reperfusion and reduced the amount of liver necrosis. In contrast, treatment with SDF-1 significantly decreased hepatocyte proliferation. These effects appeared to be dependent on the presence of liver injury, as AMD3100 and SDF-1 had no effect on hepatocyte proliferation or liver mass in mice undergoing 70% partial hepatectomy. The data suggest that signaling through CXCR4 is detrimental to liver recovery and regeneration after I/R and that clinical therapy with a CXCR4 antagonist may improve hepatic recovery following acute liver injury.
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Proliferación Celular , Quimiocina CXCL12/metabolismo , Hepatocitos/metabolismo , Hepatopatías/metabolismo , Regeneración Hepática , Hígado/metabolismo , Receptores CXCR4/metabolismo , Daño por Reperfusión/metabolismo , Transducción de Señal , Traslado Adoptivo , Animales , Bencilaminas , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CXCL12/farmacología , Ciclamas , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/inmunología , Hepatocitos/patología , Compuestos Heterocíclicos/farmacología , Antígenos Comunes de Leucocito/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/trasplante , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Hepatopatías/tratamiento farmacológico , Hepatopatías/inmunología , Hepatopatías/patología , Regeneración Hepática/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Receptores CXCR4/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
AIM: Liver fibrosis occurs as a result of several chronic liver diseases and leads to portal hypertension, cirrhosis and liver failure, often requiring liver transplantation. Activated hepatic stellate cells (HSC) are known to contribute to liver fibrosis, but currently there are no effective therapies for the treatment of established liver fibrosis. Activation of the acidic sphingomyelinase (ASM) has been shown to be involved in HSC activation. In the present study we investigated whether treatment with the ASM inhibitor, amitriptyline (TCA), could prevent and/or reverse fibrosis induced in mice by carbon tetrachloride (CCl4 ). METHODS: Mice were treated with CCl4 for 8 weeks to induce fibrosis. Concurrently, mice received drinking water with or without 180 mg/L TCA. RESULTS: Mice receiving TCA in the water had decreased hepatic collagen deposition and reduced liver mRNA expression of the fibrogenic mediators, transforming growth factor (TGF)-ß1, tissue inhibitor of matrix metalloproteinase-1, collagen and tumor necrosis factor-α. TCA treatment also reduced HSC activation determined by α-smooth muscle actin staining. In a separate set of experiments, mice were treated with CCl4 for 5 weeks prior to treatment with TCA, to test whether TCA had any effect on established fibrosis. Remarkably, in mice with established fibrosis, treatment with TCA significantly reduced collagen deposition, HSC activation, and prevented portal hypertension and improved hepatic architecture. Treatment of isolated HSCâ in vitro with TCA completely inhibited TGF-ß1-induced collagen expression and platelet-derived growth factor-ß-ß-induced proliferation. CONCLUSION: The data suggest that ASM is a critical signaling component in HSC for the development of liver fibrosis and represents an important therapeutic target.
RESUMEN
BACKGROUND: Hepatic ischemia-reperfusion (I/R) is a well-studied model of liver injury and has demonstrated a biphasic injury followed by recovery and regeneration. Microparticles (MPs) are a developing field of study and these small membrane bound vesicles have been shown to have effector function in other physiologic and pathologic states. This study was designed to quantify the levels of MPs from various cell origins-platelets, neutrophils, and endolethial cells-following hepatic ischemia-reperfusion injury. METHODS: A murine model was used with mice undergoing 90 minutes of partial hepatic ischemia followed by various times of reperfusion. Following reperfusion, plasma samples were taken and MPs of various cell origins were labeled and levels were measured using flow cytometry. Additionally, cell specific MPs were further assessed by Annexin V, which stains for the presence of phosphatidylserine, a cell surface marker linked to apoptosis. Statistical analysis was performed using one-way analysis of variance with subsequent Student-Newman-Keuls test with data presented as the mean and standard error of the mean. RESULTS: MPs from varying sources show an increase in circulating levels following hepatic I/R injury. However, the timing of the appearance of different MP subtypes differs for each cell type. Platelet and neutrophil-derived MP levels demonstrated an acute elevation following injury whereas endothelial-derived MP levels demonstrated a delayed elevation. CONCLUSION: This is the first study to characterize circulating levels of cell-specific MPs after hepatic I/R injury and suggests that MPs derived from platelets and neutrophils serve as markers of inflammatory injury and may be active participants in this process. In contrast, MPs derived from endothelial cells increase after the injury response during the reparative phase and may be important in angiogenesis that occurs in the regenerating liver.