Influence of postoperative complications on long-term outcome after oncologic lung resection surgery. Substudy of a randomized control trial.

Lung resection surgery (LRS) causes an intense local and systemic inflammatory response. There is a relationship between inflammation and postoperative complications (POCs). Also, it has been proposed that the inflammation and complications related with the surgery may promote the recurrence of cancer and therefore deterioration of survival. We investigated the association between inflammatory biomarkers, severity of POCs and long-term outcome in patients who were discharged after LRS. This is a prospective substudy of a randomized control trial. We established three groups based in the presence of POCs evaluated by Clavien-Dindo (C-D) classification: Patients with no postoperative complications (No-POCs group) (C-D = 0), patients who developed light POCs (L-POCs group) (C-D = I-II), and major POCs (M-POCs group) (C-D = III, IV, or V). Kaplan-Meier curves and Cox regression model were created to compare survival and oncologic recurrence in those groups. Patients who developed POCs (light or major) had an increase in some inflammatory biomarkers (TNF-α, IL-6, IL-7, IL-8) compared with No-POCs group. This pro-inflammatory status plays a fundamental role in the appearance of POCs and therefore in a shorter life expectancy. Individuals in the M-POCs group had a higher risk of death (HR = 3.59, 95% CI 1.69 to 7.63) compared to individuals in the No-POCs group (p = 0.001). Patients of L-POCs group showed better survival than M-POCs group (HR = 2.16, 95% CI 1.00 to 4.65, p = 0.049). Besides, M-POCs patients had higher risk of recurrence in the first 2 years, when compared with L-POCs (p = 0,008) or with No-POCs (p = 0.002). In patients who are discharged after undergoing oncologic LRS, there is an association between POCs occurrence and long term outcome. Oncologist should pay special attention in patients who develop POCs after LRS.

Role of surgical manipulation in lung inflammatory response in a model of lung resection surgery.

OBJECTIVES: Lung resection surgery with one-lung ventilation leads to an inflammatory response. Surgical manipulation can play a key role in this response. Sevoflurane, a commonly used volatile anaesthetic, has a proven anti-inflammatory effect. Our main goal was to evaluate the segregated effect of surgical manipulation during lung resection surgery and the protective role of sevoflurane with regard to this response. METHODS: Fifteen pigs underwent left thoracotomy for caudal lobectomy under general anaesthesia. The animals were divided into 3 groups: control, sevoflurane and sham. The animals in the sham group underwent left thoracotomy and one-lung ventilation over 120 min, without lobectomy. The animals in the sevoflurane group received anaesthetic maintenance with sevoflurane. The animals in the sham group and the control group received propofol during the procedure. Lung biopsies were collected before the procedure (left caudal lobe) and 24 h later (right mediastinal lobe and left upper lobe). The samples were stored to measure levels of inflammatory markers (IL-1, TNF-α and ICAM-1), apoptotic mediators (BAD, BAX, BCL-2 and Caspase-3), Syndecan-1, MicroRNAs 182, 145 and lung oedema. RESULTS: Surgical manipulation increased the expression of inflammation (IL-1, TNF-α and ICAM-1) and proapoptotic mediators (BAX, BAD and Caspase-3). It also caused degradation of endothelial glycocalyx (Syndecan-1) and pulmonary oedema. Administration of sevoflurane reduced the elevation of inflammatory markers, degradation of glycocalyx and pulmonary oedema observed in the control group. CONCLUSIONS: Surgical manipulation of the collapsed lung could increase the expression of inflammation and proapoptotic mediators and cause tissue damage in the form of pulmonary oedema. Sevoflurane could attenuate this molecular response and pulmonary oedema.

Procedimiento de autotrasplante pulmonar en el cerdo como modelo experimental para el estudio del síndrome de isquemia-reperfusión / Experimental Swine Lung Autotransplant Model to Study Lung Ischemia-Reperfusion Injury

Introducción: El daño pulmonar agudo por isquemia reperfusión (IR) ha sido estudiado fundamentalmenteen modelos experimentales y clínicos con IR fría. Son limitados los estudios que profundizan en lasalteraciones bioquímicas durante la IR normotérmica (caliente). El objetivo del este trabajo es presentarun modelo de autotrasplante pulmonar en cerdo para el estudio de las fases más precoces del síndromede IR normotérmica pulmonar.Animales y métodos: Seis cerdos de la raza Large-White fueron sometidos a neumonectomía izquierda,lobectomía craneal ex situ, reimplantación del lóbulo caudal y reperfusión del mismo durante 30 min.Durante el procedimiento se analizaron diferentes parámetros para identificar cambios hemodinámicos,gasométricos y bioquímicos en el modelo. El estudio estadístico se realizó con pruebas no paramétricas.Resultados: Tras la isquemia, se observó en tejido pulmonar un aumento significativo (p < 0,05) de metabolitosde peroxidación lipídica, de citoquinas y quemoquinas proinflamatorias (TNF- , IL-1 y MCP-1),de actividad leucocitaria (mieloperoxidasa o MPO), de actividad óxido nítrico sintasa inducible y de laproteína quinasaMAPKp38, mientras que se observóundescenso de actividad tisular de las formas constitutivasde NOS y de monóxido de carbono sérico. Estas alteraciones se mantuvieron o acentuaron durantela reperfusión, donde se observó también una mayor actividad tisular hemo-oxigenasa constitutiva.Conclusiones: Se presenta un procedimiento experimental de IR normotérmica pulmonar describiendo enprofundidad cambios hemodinámicos, gasométricos y bioquímicos. Tanto el modelocomolos parámetrosanalizados podrían ser útiles en el estudio de nuevas terapias moduladoras del da˜no pulmonar agudo ensituaciones clínicas de IR normotérmica(AU)

Introduction: Ischemia-reperfusion (IR) lung injury has been investigated extensively on clinical andexperimental models of cold ischemia. However, relatively few studies examine the detailed biochemicalchanges occurring during normothermic (warm) IR.The objective of this work was to establish an experimental lung autotransplant model to be carried outon pigs in order to study the early stages of normothermic lung IR.Animals y methods: Six Large-White pigs underwent a lung autotransplant which entailed left pneumonectomy,ex situ cranial lobectomy, caudal lobe reimplantation and its reperfusion for 30 min. Throughoutthe procedure, several parameters were measured in order to identify hemodynamic, gasometric andbiochemical changes. Non-parametric statistical analyses were used to compare differences between periods. Results: After ischemia, a significant increase (P < 0.05) in lipid peroxidation metabolites, proinflammatorycytokines and chemokines (TNF- , IL-1 y MCP-1), neutrophil activation, inducible nitric oxide synthaseactivity and protein-kinase MAPK p38 levels were observed in lung tissue. However, constitutive nitricoxide synthase activity in lung tissue and carbon monoxide plasma levels were decrease. The same heldtrue throughout the reperfusion period, when an increase in the constitutive heme-oxygenase activitywas also shown.Conclusions: An experimental model of normothermic lung IR injury is presented and detailed changes inhemodynamic, gasometric and biochemical parameters are shown. Both the model and the studied parametersmay be clinically useful in future investigations testing new therapies to prevent normothermicIR induced lung injury(AU)

Experimental Swine lung autotransplant model to study lung ischemia-reperfusion injury.

INTRODUCTION: Ischemia-reperfusion (IR) lung injury has been investigated extensively on clinical and experimental models of cold ischemia. However, relatively few studies examine the detailed biochemical changes occurring during normothermic (warm) IR. The objective of this work was to establish an experimental lung autotransplant model to be carried out on pigs in order to study the early stages of normothermic lung IR. ANIMALS Y METHODS: Six Large-White pigs underwent a lung autotransplant which entailed left pneumonectomy, ex situ cranial lobectomy, caudal lobe reimplantation and its reperfusion for 30 min. Throughout the procedure, several parameters were measured in order to identify hemodynamic, gasometric and biochemical changes. Non-parametric statistical analyses were used to compare differences between periods. RESULTS: After ischemia, a significant increase (P < 0.05) in lipid peroxidation metabolites, proinflammatory cytokines and chemokines (TNF-α, IL-1ß y MCP-1), neutrophil activation, inducible nitric oxide synthase activity and protein-kinase MAPK p38 levels were observed in lung tissue. However, constitutive nitric oxide synthase activity in lung tissue and carbon monoxide plasma levels were decrease. The same held true throughout the reperfusion period, when an increase in the constitutive heme-oxygenase activity was also shown. CONCLUSIONS: An experimental model of normothermic lung IR injury is presented and detailed changes in hemodynamic, gasometric and biochemical parameters are shown. Both the model and the studied parameters may be clinically useful in future investigations testing new therapies to prevent normothermic IR induced lung injury.