RESUMO
Recurrent colorectal carcinoma constitutes a major health care problem, with 90,000 patients diagnosed annually with metastatic disease. Recent advances have offered treatment to selected patients with liver, lung, and intra-abdominal metastases. Resection of liver secondary tumors improves 5-year survival from 0% to approximately 30% and offers the only possibility for cure. As experience mounts, hepatic surgery can be performed with quite acceptable morbidity and mortality. Adjuvant therapies are being developed that may improve results with surgery alone. Cryoablation is a new technique that appears to effectively eradicate liver tumors, but its role remains to be defined. In patients with unresectable disease, the benefit of hepatic artery infusion of chemotherapy is unproven. Resection of pulmonary metastases significantly improves survival in patients with solitary nodules. Consistent data regarding the benefit of pulmonary metastatectomy in patients with multiple nodules are not available. Combined cytoreductive surgery and intraperitoneal hyperthermic chemotherapy is being investigated as a treatment for peritoneal carcinomatosis from colorectal cancer. Although selected patients may benefit, this combined treatment modality appears to be less effective in patients with colorectal cancer than with other types of cancer.
Assuntos
Neoplasias Abdominais/secundário , Neoplasias Abdominais/terapia , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Terapia Combinada , Hepatectomia/métodos , Humanos , PrognósticoRESUMO
OBJECTIVE: To evaluate the hypothesis that splanchnic ischemia and mucosal hypoxia are responsible for lipopolysaccharide-induced intramucosal acidosis in pigs. DESIGN: Prospective, randomized, unblinded study. SETTING: Surgical research laboratory at a large, university-affiliated medical center. SUBJECTS: Anesthetized, mechanically ventilated swine. INTERVENTIONS: Pigs were infused with lactated Ringer's solution (12 mL/kg/hr) and, starting at 30 mins, 25-mL boluses of dextran-70 (maximum 15 mL/kg/hr) to maintain cardiac output at 90% to 110% of the baseline value for each pig. Ileal mucosal hydrogen ion concentration was measured tonometrically. A segment of distal ileum was exteriorized, opened, and placed on a platform to permit measurement of mucosal PO2, using an array of Clark-type microelectrodes and a computerized data acquisition and analysis system. Mucosal perfusion was measured using laser-Doppler flowmetry. The control group (n = 4) received no further interventions. Pigs in the lipopolysaccharide group (n = 6) were infused with 150 micrograms/kg of Escherichia coli lipopolysaccharide over 60 mins. To assess the effect of mucosal acidosis on mucosal PO2 in nonendotoxemic animals, intramucosal hydrogen ion concentration, mucosal PO2, and mucosal perfusion were measured in pigs rendered hypercarbic through deliberate hypoventilation (hypercarbia group; n = 4). MEASUREMENTS AND MAIN RESULTS: Infusion of lipopolysaccharide resulted in a significant increase in intramucosal hydrogen ion concentration. However, in the lipopolysaccharide group, mucosal perfusion did not change significantly and mucosal PO2 increased significantly. In the hypercarbia group, hypercarbia was associated with significant increases in both intramucosal hydrogen ion concentration and mucosal PO2. CONCLUSIONS: Mucosal hypoxia is not responsible for lipopolysaccharide-induced mucosal acidosis in this normodynamic pig model of septic shock. A rightward shift of the oxyhemoglobin dissociation curve (the Bohr effect) can explain the increase in mucosal oxygenation observed in endotoxemic pigs.
Assuntos
Acidose/etiologia , Modelos Animais de Doenças , Endotoxinas/sangue , Hipóxia/complicações , Doenças do Íleo/etiologia , Mucosa Intestinal/metabolismo , Choque Séptico/etiologia , Toxemia/complicações , Acidose/metabolismo , Animais , Escherichia coli , Concentração de Íons de Hidrogênio , Hipóxia/metabolismo , Doenças do Íleo/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Consumo de Oxigênio , Pressão Parcial , Estudos Prospectivos , Distribuição Aleatória , Choque Séptico/metabolismo , Suínos , Toxemia/metabolismoRESUMO
BACKGROUND: Cationic antimicrobial protein of 18 kd (CAP18) is a neutrophil-derived peptide that binds lipopolysaccharide (LPS) with high affinity. We hypothesized that CAP18(106-137), a novel synthetic 32-amino acid C-terminal fragment of CAP18, would neutralize the physiologic derangements induced by LPS in anesthetized swine. METHODS: Pigs were randomly allocated into three groups. Those in the LPS group (n = 6) were infused with LPS (3 micrograms/kg/hr for 4 hours). Pigs in the LPS/CAP18 group (n = 6) were challenged with LPS (3 micrograms/kg/hr for 4 hours) and also treated with CAP18(106-137) (4 mg/kg/hr for 4 hours). Pigs in the RL group (n = 4) received neither LPS nor CAP18(106-137). RESULTS: Treatment with CAP18(106-137) blocked LPS-induced increases in plasma levels of 6-keto-prostaglandin F1 alpha and tumor necrosis factor-alpha and prevented LPS-induced changes in cardiac output, arterial PO2, phagocyte activation, and peripheral leukocyte count. Changes in circulating concentrations of thromboxane B2, mean pulmonary artery pressure, and dynamic pulmonary compliance were attenuated in the LPS/CAP18 group. CONCLUSIONS: Treatment with CAP18(106-137) neutralizes many of the deleterious effects of LPS in pigs.
Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos , Proteínas de Transporte/farmacologia , Endotoxinas/antagonistas & inibidores , Escherichia coli , Lipopolissacarídeos/antagonistas & inibidores , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Antibacterianos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Proteínas de Transporte/administração & dosagem , Catelicidinas , Modelos Animais de Doenças , Endotoxinas/sangue , Contagem de Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/sangue , Complacência Pulmonar/efeitos dos fármacos , Masculino , Proteínas Opsonizantes/efeitos dos fármacos , Oxigênio/sangue , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Suínos , Tromboxano B2/sangue , Fator de Necrose Tumoral alfa/análiseRESUMO
The role of leukotriene B4 (LTB4) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB4-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB4 but had a much smaller effect on opsonin receptor upregulation induced by platelet-activating factor. In pigs treatment with LY-306669 prevented leukopenia induced by injection of authentic LTB4 but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxane-A2 mimetic. In a second study, pigs received an intravenous priming dose of lipopolysaccharide (LPS) at time (t) = -18 h and were randomized to receive 1) no further treatment (n = 5), 2) LPS (250 micrograms/kg over 1 h beginning at t = 0 h) and LY-306669 (10 mg/kg bolus and 3 mg.kg-1.h-1 infusion beginning at t = -15 min) (n = 7), or 3) LPS and vehicle (n = 6). Treatment with LY-306669 significantly ameliorated LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data suggest that LTB4 is an important mediator of pulmonary dysfunction and transendothelial migration of neutrophils in LPS-induced acute lung injury.
Assuntos
Endotoxinas/sangue , Leucotrieno B4/fisiologia , Pneumopatias/etiologia , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Hemodinâmica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Fenóis/farmacologia , Receptores do Leucotrieno B4/antagonistas & inibidores , Suínos , Tetrazóis/farmacologia , Tromboxano B2/sangueRESUMO
BACKGROUND: Cardiovascular responses to the adrenergic stimulation are depressed in clinical and experimental endotoxemia. However, the effect of Escherichia coli endotoxemia on coronary microvascular beta-adrenergic function remains to be determined. The purpose of the present study was to test the hypothesis that endotoxemia impairs the beta-adrenoceptor- and adenosine 3'5'-cyclic monophosphate-mediated relaxation in the porcine coronary microcirculation. METHODS: Coronary arterioles (80 to 170 microns internal diameter) were isolated from pigs 3 hours after intravenous administration of E. coli endotoxin (150 micrograms/kg, over 1 hour, n = 8) or Ringer's lactate (control, n = 8). Arterioles were studied in vitro in a pressurized, partially contracted, no-flow state by videomicroscopy. RESULTS: Precontracted (30% to 50% of baseline diameter with acetylcholine) control coronary arterioles dilated in response to either the nonselective beta-adrenoceptor agonist, isoproterenol, the Gs-protein activator, sodium fluoride, or the adenylate cyclase activator, forskolin. After 3 hours of endotoxemia, the relaxation responses to isoproterenol and sodium fluoride were significantly reduced, but the relaxation response to forskolin was preserved. The beta 2-adrenoceptor blocker, ICI-118, 551, markedly reduced the relaxation of control microvessels induced by isoproterenol, whereas the beta 1-adrenoceptor blocker, atenolol, caused only a slight reduction in isoproterenol-induced relaxation. CONCLUSIONS: beta 2-Adrenoceptors appear to predominate over beta 1-adrenoceptors in the coronary microcirculation. E. coli endotoxemia impairs beta 2-adrenoceptor-mediated relaxation in the porcine coronary microcirculation, apparently because of changes proximal to adenylate cyclase in the signal transduction pathway.
Assuntos
Vasos Coronários/efeitos dos fármacos , Escherichia coli/patogenicidade , Lipopolissacarídeos/toxicidade , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Animais , Colforsina/farmacologia , Vasos Coronários/fisiologia , Hemodinâmica/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Microcirculação/efeitos dos fármacos , Receptores Adrenérgicos beta 2/fisiologia , SuínosRESUMO
Bactericidal/permeability-increasing protein (BPI), a cationic protein isolated from human neutrophils, binds lipopolysaccharide (LPS), kills gram-negative bacteria, and neutralizes many of the effects of LPS in vitro and in vivo. We hypothesized that a recombinant 23-kDa NH2-terminal fragment of BPI (BPI23) would reduce acute lung injury in endotoxemic pigs. At -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 4); 2) LPS (250 micrograms/kg over 50 min) and BPI23 (3-mg/kg bolus and 3 mg/kg over 60 min) (n = 6); or 3) LPS and thaumatin, a cationic protein devoid of LPS neutralizing activity that has a molecular mass and isoelectric point that are similar to that of BPI23 (n = 7). BPI23 treatment significantly ameliorated LPS-induced hypoxemia, functional upregulation of opsonin receptors on circulating phagocytes, and alveolitis but had no effect on the elaboration of tumor necrosis factor-alpha or thromboxane A2. The salutory effects of BPI23 on acute lung injury in endotoxemic pigs may be mediated, at least in part, by inhibition of direct activation of phagocytes by LPS.
Assuntos
Antibacterianos/uso terapêutico , Proteínas Sanguíneas/uso terapêutico , Pneumopatias/fisiopatologia , Proteínas de Membrana , Toxemia/fisiopatologia , Animais , Peptídeos Catiônicos Antimicrobianos , Gasometria , Pressão Sanguínea/fisiologia , Líquido da Lavagem Broncoalveolar/citologia , Eicosanoides/biossíntese , Escherichia coli/metabolismo , Lipopolissacarídeos , Complacência Pulmonar/fisiologia , Pneumopatias/induzido quimicamente , Pneumopatias/tratamento farmacológico , Masculino , Proteínas Opsonizantes/metabolismo , Peroxidase/metabolismo , Fagocitose , Suínos , Toxemia/tratamento farmacológicoRESUMO
In order to examine the effects of Escherichia coli endotoxemia on coronary and pulmonary microvascular responses to serotonin (5-HT) and ADP, arterioles (80-190 micros diameter) were isolated from pigs 3 h after administration of E. coli endotoxin (150 micrograms/kg, intravenously over 1 h, n = 8) or Ringer's lactate (control, n = 8). Arterioles were studied in vitro in a pressurized, partially contracted, no-flow state with video-microscopy. Precontracted (30-50% of baseline diameter) control coronary arterioles dilated in responses to either 5-HT (24 +/- 2%) or ADP (89 +/- 2%). These relaxations were partially inhibited by indomethacin, but were markedly reduced with nitric oxide synthase inhibition. After 3 h of endotoxemia, 5-HT caused contraction of coronary arterioles which was inhibited with indomethacin. In the presence of indomethacin, coronary vessels from endotoxic pigs relaxed slightly, but significantly, more to 5-HT than did control vessels exposed to indomethacin. In contrast, the relaxation response to ADP was unchanged following endotoxemia. Precontracted (15-30% of baseline diameter) pulmonary arterioles dilated in response to 5-HT (13 +/- 1%) or ADP (67 +/- 3%). Following 3 h of endotoxemia, the pulmonary arteriolar relaxation induced by 5-HT was reduced, whereas the response to ADP was not altered. In both coronary and pulmonary arterioles, relaxation induced by the endothelium-independent vasodilator, sodium nitroprusside, was unaffected by endotoxemia. Thus, coronary and pulmonary microvascular relaxation response to ADP are minimally affected by 3 h of endotoxemia, but relaxation responses to 5-HT are significantly reduced or converted to contractile responses.
Assuntos
Plaquetas/fisiologia , Circulação Coronária/fisiologia , Endotoxinas/toxicidade , Circulação Pulmonar/fisiologia , Toxemia/fisiopatologia , Difosfato de Adenosina/farmacologia , Difosfato de Adenosina/fisiologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Circulação Coronária/efeitos dos fármacos , Escherichia coli , Técnicas In Vitro , Masculino , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Serotonina/farmacologia , Serotonina/fisiologia , Suínos , Toxemia/sangue , Toxemia/etiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Administration of lipopolysaccharide (LPS) to experimental animals leads to diminished mesenteric perfusion, increased ileal mucosal [H+] , and increased gut epithelial permeability to hydrophilic solutes. We sought to determine whether these phenomena are causally related. Experiments were performed in anesthetized pigs. Permeability was assessed by measuring the plasma-to-lumen clearance of fluorescein isothiocyanate dextran (4,000 Da; FD-4) by a segment of ileum perfused with Ringer lactate solution. Mucosal perfusion (Qmuc) and [H4+] were estimated using laser-Doppler flowmetry and tonometry, respectively. In an initial series of experiments, we showed that mucosal permeability was linearly correlated with mucosal [H+] in animals subjected to graded degrees of mechanically induced mesenteric ischemia (n = 14, R2 = 0.58, P < 0.002) or injected with graded doses of LPS (n = 11, R2 = 0.93, P < 0.0001). In a second series of experiments, we induced mucosal acidosis in normal pigs by mechanical ventilation with either a hypoxic (n = 7) or a hypercapnic (n = 5) gas mixture. In both groups, ileal mucosal permeability to FD-4 increased significantly (P < 0.05), although transmesenteric release of lactate increased significantly only in the hypoxic group. Qmuc was unchanged in both groups. These data suggest that mucosal acidosis, even in the absence of tissue ischemia or hypoxia, increases intestinal permeability to a macromolecular hydrophilic solute. Tissue acidosis may be an important factor contributing to LPS-induced gut mucosal hyperpermeability.
Assuntos
Acidose/metabolismo , Endotoxinas/farmacologia , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Animais , Artérias , Dextranos , Fluoresceína-5-Isotiocianato/análogos & derivados , Gases/sangue , Hemodinâmica/efeitos dos fármacos , Hidrogênio/sangue , Lactatos/sangue , Ácido Láctico , Masculino , Concentração Osmolar , Oxigênio/sangue , Permeabilidade/efeitos dos fármacos , Circulação Esplâncnica , Suínos , VeiasRESUMO
OBJECTIVE: To determine if air introduced directly into the lumen of a hollow viscus can be used instead of fluid in a Silastic balloon to estimate gastrointestinal mucosal PCO2. DESIGN: Prospective, unblinded comparison of two methods of mucosal PCO2 measurement. SETTING: Animal surgery suite at a large, university-affiliated medical center. INTERVENTIONS: Standard, commercially available, tonometric catheters were positioned in the ileum (n = 4) or the stomach and ileum (n = 12) of anesthetized, immature Yorkshire swine. Using gas-tight purse-string sutures, plastic cannulas were inserted into the lumen of the stomach (n = 12) and the lumen of a 10-cm isolated segment of ileum (n = 16). Data were collected after equilibration periods of 30 or 60 mins. Before each equilibration period, the "air tonometers" (i.e., the lumens of the stomach and/or the isolated ileal segment) were lavaged with 200 mL (stomach) or 20 mL (ileum) of air. In group 1 (n = 4) and group 2 (n = 3), graded degrees of mesenteric hypoperfusion were achieved by mechanical mesenteric occlusion or pericardial tamponade, respectively. In group 3 (n = 8), graded degrees of respiratory acidosis were induced. At various intervals, PCO2 was determined simultaneously in arterial blood, gastric air, saline from the gastric tonometric balloon, ileal air, and saline from the ileal tonometric balloon. MEASUREMENTS AND MAIN RESULTS: In pigs with ischemia created by mesenteric vascular occlusion (group 1), there was a moderate correlation between PCO2 values in air samples from the ileal lumen and samples of saline from the standard tonometer (r2 = .61, p < .001). In pigs with mesenteric ischemia secondary to pericardial tamponade (group 2), air and saline tonometry were well-correlated in the stomach (r2 = .71, p < .001) and ileum (r2 = .83, p < .001). In pigs with normal mesenteric perfusion (group 3) and PaCO2 > 40 torr (5.3 kPa), PaCO2 correlated with ileal mucosal PCO2, determined using air (r2 = .93, p < .001) or saline (r2 = .91, p < .001) tonometry, or gastric mucosal PCO2, determined using air (r2 = 1.00, p < .001) or saline (r2 = .97, p < .001) tonometry. Values obtained by air tonometry were highly correlated with values obtained using standard saline tonometry in the stomach (r2 = .98, p < .001; bias = -5 +/- 5 torr [-0.65 +/- 0.65 kPa]) or ileum (r2 = .96, p < .001; bias = 1 +/- 9 torr [0.13 +/- 1.17 kPa]). CONCLUSIONS: a) Under stable hemodynamic and respiratory conditions, air tonometry (which, in theory, can be performed using a conventional nasogastric or nasoenteric feeding tube) estimates gastrointestinal mucosal PCO2 as accurately as standard saline tonometry in the stomach or ileum; b) respiratory acidosis leads to tissue hypercarbia, a phenomenon that must be considered when tonometry is used to guide therapy in the clinical setting; c) under stable, nonischemic conditions, gastric or intestinal tonometry can be used to estimate PaCO2.
Assuntos
Dióxido de Carbono/metabolismo , Íleo/irrigação sanguínea , Mucosa Intestinal/metabolismo , Isquemia/metabolismo , Manometria/métodos , Acidose/metabolismo , Animais , Concentração de Íons de Hidrogênio , Masculino , SuínosRESUMO
The simultaneous measurements of mixed venous oxygen saturation (SvO2) and right ventricular ejection fraction (RVEF) have now made it possible to precisely define and correlate the various hemodynamic changes that occur during abdominal aortic operations. Twenty-five patients undergoing infrarenal abdominal aortic aneurysm repair were examined with a pulmonary artery catheter capable of continuously measuring SvO2 and RVEF. With aortic clamping, significant reductions in cardiac index, stroke volume index, and right ventricular end-diastolic volume index (RVEDVI) were noted, while RVEF remained unchanged. Following unclamping of the aorta, a significant reduction in SvO2 occurred, accompanied by an increase in mean pulmonary artery pressure and in pulmonary vascular resistance. Despite the increase in afterload, RVEDVI and RVEF did not change after unclamping. These preliminary data suggest that right ventricular function is preserved during abdominal aortic aneurysm repair.