RESUMEN
OBJECTIVES: Radioactive marking can be a valuable extension to minimally invasive surgery. The technique has been clinically applied in procedures involving sentinel lymph nodes, parathyroidectomy as well as interventions in thoracic surgery. Improvements in equipment and techniques allow one to improve the limits. Pulmonary nodules are frequently surgically removed for diagnostic or therapeutic reasons; here video-assisted thoracoscopic surgery (VATS) is the preferred technique. VATS might be impossible with nodules that are small or located deep in the lung. In this study, we examined the clinical application and safety of employing the newly developed handheld single photon emission tomography (handheld SPECT) device in combination with CT-guided radioactive marking of pulmonary nodules. METHODS: In this pilot study, 10 subjects requiring surgical resection of a pulmonary nodule were included. The technique involved CT-guided marking of the target nodule with a 20-G needle, with subsequent injection of 25-30 MBq (effective: 7-14 MBq) Tc-99m MAA (Macro Albumin Aggregate). Quality control was made with conventional SPECT-CT to confirm the correct localization and exclude possible complications related to the puncture procedure. VATS was subsequently carried out using the handheld SPECT to localize the radioactivity intraoperatively and therefore the target nodule. A 3D virtual image was superimposed on the intraoperative visual image for surgical guidance. RESULTS: In 9 of the 10 subjects, the radioactive application was successfully placed directly in or in the immediate vicinity of the target nodule. The average size of the involved nodules was 9 mm (range 4-15). All successfully marked nodules were subsequently completely excised (R0) using VATS. The procedure was well tolerated. An asymptomatic clinically insignificant pneumothorax occurred in 5 subjects. Two subjects were found to have non-significant discrete haemorrhage in the infiltration canal of the needle. In a single subject, the radioactive marking was unsuccessful because the radioactivity spread into the pleural space. CONCLUSIONS: In our series of 10 patients, it was demonstrated that using handheld SPECT in conjunction with VATS to remove radioactively marked pulmonary nodules is feasible. The combination of proven surgical techniques with a novel localization device (handheld SPECT) allowed successful VATS excision of pulmonary nodules which, due to their localization and small size, would typically have required thoracotomy. REGISTRATION: ClinicalTrials.gov, NCT02050724, Public 01/29/214, Joachim Müller.
Asunto(s)
Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Cirugía Torácica Asistida por Video/instrumentación , Tomografía Computarizada de Emisión de Fotón Único/instrumentación , Tomografía Computarizada por Rayos X/instrumentación , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Radiofármacos , Compuestos de Sulfhidrilo , Agregado de Albúmina Marcado con Tecnecio Tc 99mRESUMEN
BACKGROUND: Aortic occlusion causes ischemia/reperfusion injury, kidney and spinal cord being the most vulnerable organs. Erythropoietin improved ischemia/reperfusion injury in rodents, which, however, better tolerate ischemia/reperfusion than larger species. Therefore, we investigated whether erythropoietin attenuates porcine aortic occlusion ischemia/reperfusion injury. MATERIALS AND METHODS: Before occluding the aorta for 45 mins by inflating intravascular balloons, we randomly infused either erythropoietin (n = 8; 300 IU/kg each over 30 mins before and during the first 4 hrs of reperfusion) or vehicle (n = 6). During aortic occlusion, mean arterial pressure was maintained at 80% to 120% of baseline by esmolol, nitroglycerine, and adenosine 5'-triphosphate. During reperfusion, noradrenaline was titrated to keep mean arterial pressure >80% of baseline. Kidney perfusion and function were assessed by fractional Na-excretion, p-aminohippuric acid and creatinine clearance, spinal cord function by lower extremity reflexes and motor evoked potentials. Blood isoprostane levels as well as blood and tissue catalase and superoxide dismutase activities allowed evaluation of oxidative stress. After 8 hrs of reperfusion, kidney and spinal cord specimens were taken for histology (hematoxylin-eosin, Nissl staining) and immunohistochemistry (TUNEL assay for apoptosis). RESULTS: Parameters of oxidative stress and antioxidative activity were comparable. Erythropoietin reduced the noradrenaline requirements to achieve the hemodynamic targets and may improve kidney function despite similar organ blood flow, histology, and TUNEL staining. Neuronal damage and apoptosis was attenuated in the thoracic spinal cord segments without improvement of its function. CONCLUSION: During porcine aortic occlusion-induced ischemia/reperfusion erythropoietin improved kidney function and spinal cord integrity. The lacking effect on spinal cord function was most likely the result of the pronounced neuronal damage associated with the longlasting ischemia.
Asunto(s)
Arteriopatías Oclusivas/prevención & control , Oclusión con Balón/efectos adversos , Eritropoyetina/uso terapéutico , Potenciales Evocados Motores/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/prevención & control , Animales , Arteriopatías Oclusivas/etiología , Arteriopatías Oclusivas/fisiopatología , Modelos Animales de Enfermedad , Eritropoyetina/farmacología , Femenino , Pruebas de Función Renal , Masculino , Daño por Reperfusión/etiología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/prevención & control , PorcinosRESUMEN
OBJECTIVE: It is well-established that poly(ADP)ribose-polymerase (PARP) assumes major importance during ischemic brain damage, and the selective PARP-1 inhibitor PJ34 reduced spinal cord damage in murine aortic occlusion-induced ischemia/reperfusion injury. We investigated the effect of the PARP-1 inhibitor INO1001 on aortic-occlusion-related porcine spinal cord injury. DESIGN AND SETTING: Prospective, randomized, controlled experimental study in an animal laboratory. PATIENTS AND PARTICIPANTS: Ten anesthetized, mechanically ventilated, and instrumented pigs. INTERVENTIONS: Animals underwent 45 min of thoracic aortic cross-clamping after receiving vehicle (n=5) or intravenous INO1001 (n=5, total dose 4 mg/kg administered both before clamping and during reperfusion). During reperfusion continuous intravenous norepinephrine was incrementally adjusted to maintain blood pressure at or above 80% of the preclamping level. Plasma INO1001 levels were analyzed by HPLC. After 4[Symbol: see text]h of reperfusion spinal cord biopsy samples were analyzed for neuronal damage (hematoxyline-eosine and Nissl staining), expression of the cyclin-dependent kinase inhibitor genes p21 and p27 (immunohistochemistry), and apoptosis (terminal deoxynucleotidyl transferase mediated nick end labeling assay). MEASUREMENTS AND RESULTS: Plasma INO1001 levels were 0.8-2.3 and 0.30-0.76 mM before and after clamping, respectively. While 3-5% of the spinal cord neurons were irreversibly damaged in the INO1001 animals, the neuronal cell injury was three times higher in the control group. Neither p21 and p27 expression nor apoptosis showed any intergroup difference. CONCLUSIONS: The selective PARP-1 inhibitor INO1001 markedly reduced aortic occlusion-induced spinal cord injury. Given the close correlation reported in the literature between morphological damage and impaired spinal cord function, INO1001 may improve spinal cord recovery after thoracic aortic cross-clamping.
Asunto(s)
Indoles/uso terapéutico , Traumatismos de la Médula Espinal/prevención & control , Equilibrio Ácido-Base , Animales , Femenino , Indoles/sangre , Masculino , Daño por Reperfusión Miocárdica/etiología , Cuerpos de Nissl/patología , Intercambio Gaseoso Pulmonar , Respiración Artificial , Traumatismos de la Médula Espinal/patología , PorcinosRESUMEN
OBJECTIVE: We previously reported in healthy volunteers that a cantaloupe melon extract chemically combined with wheat gliadin (melon extract/gliadin) and containing SOD, catalase and residual glutathione peroxidase (GPx), protected against DNA strand-break damage induced by hyperbaric oxygen (HBO), a well-established model of DNA damage resulting from oxidative stress. Aortic cross-clamping is a typical example of ischemia/reperfusion injury-related oxidative stress, and therefore we investigated whether this melon extract/gliadin would also reduce DNA damage after aortic cross-clamping and reperfusion. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Animal laboratory. PATIENTS AND PARTICIPANTS: 18 anesthetized, mechanically ventilated and instrumented pigs. INTERVENTIONS: After 14 days of oral administration of 1250 mg of the melon extract/gliadin (n=9) or vehicle (n=9), animals underwent 30 min of thoracic aortic cross-clamping and 4 h of reperfusion. MEASUREMENTS AND RESULTS: Before clamping, immediately before declamping, and at 2 and 4 h of reperfusion, we measured blood isoprostane (immunoassay) and malondialdehyde concentrations (fluorimetric thiobarbituric acid test), SOD, catalase and GPx activities (spectrophotometric kits), NO formation (nitrate+nitrite; chemoluminescence), DNA damage in whole blood samples and isolated lymphocytes exposed to hyperbaric oxygen (comet assay). Organ function was also evaluated. Kidney and spinal cord specimen were analysed for apoptosis (TUNEL assay). The melon extract/gliadin blunted the DNA damage, reduced spinal cord apoptosis and attenuated NO release, however, without any effect on lipid peroxidation and organ function. CONCLUSIONS: Pre-treatment with the oral melon extract/gliadin may be a therapeutic option to reduce oxidative cell injury affiliated with aortic cross-clamping.
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Apoptosis , Daño del ADN , Gliadina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Ensayo Cometa , Cucumis melo , Femenino , Oxigenoterapia Hiperbárica/efectos adversos , Etiquetado Corte-Fin in Situ , Masculino , Daño por Reperfusión/etiología , PorcinosRESUMEN
Inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) improved hemodynamics and organ function in various shock models induced by sepsis or ischemia/reperfusion. PARP-1, however, is also referred to play a pivotal role for the maintenance of genomic integrity. Therefore, we investigated the effect of the PARP-1 blocker INO-1001 on hemodynamics, kidney function, and DNA damage and repair during porcine thoracic aortic cross-clamping. The animals underwent 45 min of aortic cross-clamping after receiving vehicle (n=9) or i.v. INO-1001 (n=9; total dose, 4 mg.kg, administered both before clamping and during reperfusion), data were recorded before clamping, before declamping, and 2 and 4 h after declamping. During reperfusion, continuous i.v. norepinephrine was incrementally adjusted to maintain blood pressure greater than or equal to 80% of the pre-clamping level. The plasma INO-1001 levels analyzed with high-pressure liquid chromatography were 1 to 1.4 micromol/L and 0.4 to 0.6 micromol/L before and after clamping, respectively. Although INO-1001-treated animals required less norepinephrine support, kidney function was comparable in the 2 groups. There was no intergroup difference either in the time course of DNA damage and repair (comet assay) as assessed both in vivo in whole blood before surgery, before clamping, before declamping, 2 h after declamping, and ex vivo in isolated lymphocytes (Ficoll gradient) sampled immediately before clamping and analyzed before, immediately, and 1 and 2 h after exposure to 4 bar 100% O2 for 2 h. There was no difference either in the expression of the cyclin-dependent kinase inhibitor gene, p27, in the kidney (immunohistochemistry). The reduced norepinephrine requirements during reperfusion suggest a positive inotropic effect of INO-1001, as demonstrated by other authors. In our model, INO-1001 proved to be safe with respect to DNA repair.
Asunto(s)
Aorta Torácica/enzimología , Reparación del ADN/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Indoles/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Daño por Reperfusión/enzimología , Animales , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Indoles/farmacocinética , Riñón/enzimología , Norepinefrina/administración & dosificación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Porcinos , Vasoconstrictores/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate the hemodynamic and metabolic effects of the peroxisome proliferator-activated receptor (PPAR)-gamma ligand and nuclear-factor (NF)-kappa B inhibitor 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2) during long-term, hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: 19 anesthetized, mechanically ventilated and instrumented pigs. INTERVENTIONS: At 12 h of continuous intravenous endotoxin and hydroxyethylstarch to keep mean arterial pressure (MAP)>60 mmHg, swine randomly received vehicle (control group, n=10) or 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2 group, n=9; 1 microg kg(-1) min(-1) loading dose during 1 h; thereafter,0.25 microg kg(-1) min(-1) for 11 h). MEASUREMENTS AND RESULTS: Hemodynamic, metabolic and organ function parameters were assessed together with parameters of nitric oxide production and oxidative stress. 15d-PGJ2 prevented the endotoxin-induced progressive hypotension, due to a positive inotropic effect, which resulted in a significantly higher blood pressure during the treatment phase and prevented the rise in hepatic vein alanine-aminotransferase activity. It did not affect, however, any other parameter of organ function nor of nitric oxide production, proinflammatory cytokine release or lipid peroxidation (8-isoprostane). CONCLUSIONS: 15d-PGJ2 stabilized systemic hemodynamics, due to improved myocardial performance, and resulted in an only transient effect on alanine-aminotransferase activity, without further beneficial effect on endotoxin-induced metabolic and organ function derangements. Low tissue 15d-PGJ2 concentrations and/or the delayed drug administration may explain these findings.
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Endotoxemia/fisiopatología , Factores Inmunológicos/farmacología , Prostaglandina D2/análogos & derivados , Porcinos , Animales , Ciclopentanos , Europa (Continente) , Hipotensión/prevención & control , Factores Inmunológicos/administración & dosificación , Estrés Oxidativo , Estudios Prospectivos , Prostaglandina D2/administración & dosificación , Prostaglandina D2/farmacología , Prostaglandinas/metabolismo , Distribución Aleatoria , Respiración ArtificialRESUMEN
OBJECTIVE: To investigate the systemic, pulmonary, and hepatosplanchnic hemodynamic and metabolic effects of delayed treatment with ethyl pyruvate in a long-term porcine model of hyperdynamic endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Anesthetized, mechanically ventilated, and instrumented pigs. INTERVENTIONS: After 12 hrs of continuous infusion of lipopolysaccharide and hydroxyethyl starch to keep mean arterial pressure >60 mm Hg, swine randomly received placebo (Ringer's solution; control group, n = 11) or ethyl pyruvate in lactated Ringer's solution (n = 8; 0.03 g.kg(-1) loading dose over 10 mins, thereafter 0.03 g.kg(-1)hr(-1) for 12 hrs). MEASUREMENTS AND MAIN RESULTS: Whereas mean arterial pressure significantly decreased in control animals, mean arterial pressure was maintained at the baseline level in pigs treated with ethyl pyruvate. Global oxygen uptake was comparable, so that the trend toward a higher oxygen transport and the significantly higher mixed venous hemoglobin oxygen saturation resulted in a significantly lower oxygen extraction in the ethyl pyruvate group. Ethyl pyruvate reduced intrapulmonary venous admixture and resulted in significantly greater Pa(O2)/F(IO2) ratios. Despite comparable urine production in the two groups during the first 18 hrs of endotoxemia, ethyl pyruvate significantly increased diuresis during the last 6 hrs of the study. Lipopolysaccharide-induced systemic and regional venous metabolic acidosis was significantly ameliorated by ethyl pyruvate. Endotoxemia increased both blood nitrate + nitrite and isoprostane concentrations, and ethyl pyruvate attenuated the response of these markers of nitric oxide production and lipid peroxidation. CONCLUSIONS: Ethyl pyruvate infusion resulted in improved hemodynamic stability and ameliorated acid-base derangements induced by chronic endotoxemia in pigs. Reduced oxidative stress and an decreased nitric oxide release probably contributed to these effects.
Asunto(s)
Endotoxemia/tratamiento farmacológico , Endotoxemia/fisiopatología , Hemodinámica/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Circulación Hepática/efectos de los fármacos , Piruvatos/uso terapéutico , Circulación Esplácnica/efectos de los fármacos , Acidosis/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Diuresis/efectos de los fármacos , Endotoxemia/sangre , Endotoxemia/inducido químicamente , Lipopolisacáridos/administración & dosificación , Nitratos/sangre , Nitritos/sangre , Oxígeno/sangre , Consumo de Oxígeno/efectos de los fármacos , Estudios Prospectivos , Circulación Pulmonar/efectos de los fármacos , Piruvatos/administración & dosificación , Distribución Aleatoria , Respiración Artificial , Resucitación , PorcinosRESUMEN
OBJECTIVE: To investigate whether the vasopressin analog terlipressin might induce hepatosplanchnic ischemia during long-term, hyperdynamic, volume-resuscitated porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Eighteen pigs were divided into two groups receiving either endotoxin alone (control group, n = 10) or endotoxin and terlipressin (n = 8). INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and instrumented and received a continuous intravenous infusion of Escherichia coli endotoxin. Animals were resuscitated with hydroxyethyl starch targeted to maintain mean arterial pressure >60 mm Hg. Twelve hours after the start of the endotoxin infusion, terlipressin (5-15 microg.kg.hr titrated to maintain mean arterial pressure at preendotoxin levels) or its vehicle was administered for 12 hrs. MEASUREMENTS AND MAIN RESULTS: Terlipressin increased mean arterial pressure and systemic vascular resistances, which was affiliated with a decrease in cardiac output and global oxygen consumption. Terlipressin restored the hepatic artery buffer response, which led to an increase in hepatic artery flow, ultimately resulting in well-maintained liver oxygen delivery, oxygen uptake, and all other variables of regional metabolism and organ function. Terlipressin markedly attenuated the hepatosplanchnic venous acidosis but was associated with pronounced hyperlactatemia. CONCLUSIONS: During long-term hyperdynamic porcine endotoxemia, the well-known vasoconstrictor properties of terlipressin blunted the progressive decrease in mean arterial pressure without any detrimental effect on hepatosplanchnic perfusion, oxygen exchange, and metabolism. The marked terlipressin-induced hyperlactatemia did not originate from the hepatosplanchnic organs but from extrasplanchnic tissues, possibly muscle and skin.