RESUMEN
Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.
Asunto(s)
Imidazoles/uso terapéutico , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Norepinefrina/uso terapéutico , Piridinas/uso terapéutico , Choque Séptico/tratamiento farmacológico , Animales , Evaluación Preclínica de Medicamentos , Femenino , Lactatos/sangre , Microcirculación/efectos de los fármacos , Modelos Animales , Suelo de la Boca/irrigación sanguínea , Peritonitis/complicaciones , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Circulación Renal/efectos de los fármacos , Ovinos , Choque Séptico/enzimología , Choque Séptico/etiología , Choque Séptico/fisiopatología , Circulación Esplácnica/efectos de los fármacosRESUMEN
BACKGROUND: Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg). METHODS AND RESULTS: After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension. CONCLUSIONS: Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.
Asunto(s)
Benzoatos/uso terapéutico , Guanilato Ciclasa/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Vasodilatadores/uso terapéutico , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Benzoatos/farmacología , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipotensión/inducido químicamente , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Presión Esfenoidal Pulmonar/efectos de los fármacos , Guanilil Ciclasa Soluble , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/administración & dosificación , Vasodilatadores/efectos adversos , Vasodilatadores/farmacologíaRESUMEN
Clinical efficiency of If-inhibitor ivabradin (Coraxan, Servier) in 40 patients with cardiorespiratory pathology (CRP) was studied. It was shown, that use of ivabradin in dose of 5 mg two times a day leaded to significant decrease in number of angina attacks in a week, and also in time of painless myocardial ischemia, decrease in heart rate at a day and during physical exercises, increase in 6 minutes walking distance and circadian index, oxygen saturation and partial tension, decrease in average pressure in pulmonary artery, increase in ejection fraction of left ventricle. Thus, ivabradin (Coraxan, Servier) is an effective antianginal drug for CRP patients, it improves life quality and do not has an influence on external respiration function. Ivabradin in dose of 5 mg two times a day can be used for CRP patients and as alternative to beta-adrenoblockers.
Asunto(s)
Benzazepinas/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Benzazepinas/administración & dosificación , Canales Catiónicos Regulados por Nucleótidos Cíclicos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Ecocardiografía , Electrocardiografía Ambulatoria , Femenino , Estudios de Seguimiento , Humanos , Ivabradina , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/fisiopatología , Proyectos Piloto , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Presión Esfenoidal Pulmonar/efectos de los fármacos , Calidad de Vida , Volumen Sistólico/efectos de los fármacos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Calcium salts are frequently used in the treatment of calcium antagonist poisoning. Different dosing regimens have been employed. The major risk of high dose calcium therapy is iatrogenic hypercalcemia, especially in patients with diminished renal function. Repeated doses of calcium are therefore often avoided; however, inadequate use of intravenous calcium may cause treatment failure in severe calcium antagonist overdose. We report our experience of using high dose intravenous calcium chloride effectively and safely to treat severe amlodipine overdose in a patient with severe renal insufficiency.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Amlodipino/envenenamiento , Antídotos/uso terapéutico , Bloqueadores de los Canales de Calcio/envenenamiento , Calcio/uso terapéutico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/fisiopatología , Adulto , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Cateterismo de Swan-Ganz , Carbón Orgánico/uso terapéutico , Relación Dosis-Respuesta a Droga , Sobredosis de Droga , Femenino , Pruebas de Función Cardíaca , Humanos , Inyecciones Intravenosas , Presión Esfenoidal Pulmonar/efectos de los fármacos , Resultado del Tratamiento , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVES: Nitric oxide inhibits the expression of many genes involved in inflammatory diseases. Glucocorticoids inhibit similar transcription factors. We hypothesized that there may be an interaction between nitric oxide and glucocorticoids, with the potential to enhance the anti-inflammatory effect when administered simultaneously. DESIGN: Prospective, randomized, controlled study. SETTING: Animal research laboratory. SUBJECTS: A total of 45 anesthetized and mechanically ventilated pigs. INTERVENTIONS: Lung and systemic injury was induced by intravenous infusion of endotoxin (lipopolysaccharide) for 6 hrs. After 2.5 hrs, one group received 3.5 mg/kg hydrocortisone, another group inhaled nitric oxide (30 ppm), and still another group received both steroid and nitric oxide. Control groups of healthy and endotoxin-exposed piglets were also studied. MEASUREMENTS AND MAIN RESULTS: Central hemodynamics and gas exchange were measured. Detection of the glucocorticoid receptor and inflammatory markers in lung, liver, and kidney tissue were made by immunohistochemistry, and morphology was studied with light microscopy. Endotoxin infusion markedly reduced glucocorticoid receptor expression in lung, liver, and kidney and up-regulated activator protein-1 and the inflammatory markers nuclear factor-kappaB and tumor necrosis factor-alpha. When administered separately, steroids and nitric oxide had modest effect on the inflammatory response. However, nitric oxide up-regulated the glucocorticoid receptor expression. Simultaneous administration of steroids and nitric oxide attenuated the inflammatory response and almost preserved or restored normal histology of both lung and systemic organs. When the glucocorticoid receptor was blocked by a receptor antagonist (mifepristone, 600 mg) and inhaled nitric oxide was subsequently administered, no increase in the expression of the glucocorticoid receptor was seen. CONCLUSION: We suggest that up-regulation of glucocorticoid receptor expression by nitric oxide made steroid therapy more effective.
Asunto(s)
Antiinflamatorios/uso terapéutico , Óxido Nítrico/uso terapéutico , Receptores de Glucocorticoides/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/inmunología , Regulación hacia Arriba/efectos de los fármacos , Administración por Inhalación , Animales , Antiinflamatorios/inmunología , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Antagonistas de Hormonas/inmunología , Hidrocortisona/inmunología , Hidrocortisona/uso terapéutico , Inmunohistoquímica , Inflamación , Infusiones Intravenosas , Lipopolisacáridos/efectos adversos , Mifepristona/inmunología , Óxido Nítrico/inmunología , Óxido Nítrico/fisiología , Estudios Prospectivos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/ultraestructura , Síndrome de Dificultad Respiratoria/microbiología , Sepsis/patología , Sepsis/fisiopatología , PorcinosRESUMEN
OBJECTIVE: Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of acute pulmonary embolism (APE)-induced pulmonary hypertension. Here, we evaluate the effects of atorvastatin pretreatment on APE-induced pulmonary hypertension, 24-hr mortality rate, and changes in plasma and lung MMP-2 and MMP-9 activities. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Rats received atorvastatin (30 mg/kg/day orally) or tap water for 2 wks. In study 1, we examined whether atorvastatin affected APE-induced pulmonary hypertension by using a rat isolated lung perfusion model of APE. In study 2, we examined whether atorvastatin affects the survival rate after APE, which was induced by rapid intravenous injection of 14 mg/kg of a suspension of microspheres (or saline) into the tail vein. MEASUREMENTS AND MAIN RESULTS: Plasma nitrite/nitrate concentrations were measured by chemiluminescence. Pretreatment with atorvastatin was associated with 49% higher nitrite/nitrate levels compared with controls (p < .05). In study 1, whereas APE increased mean pulmonary artery pressure (MPAP) by 13.0 +/- 1.6 mm Hg in perfused lungs isolated from rats pretreated with water, pretreatment with atorvastatin attenuated by 27% the increases in MPAP after APE. In study 2, pretreatment with atorvastatin was associated with a significant increase in 24-hr survival rate after APE, which was 48% in embolized rats pretreated with water and 64% in rats pretreated with atorvastatin (p < .05). Gelatin zymography of lung and plasma MMP-2 and MMP-9 was performed. Lungs and plasma from embolized rats showed higher levels of both pro- and activated forms of MMP-9 compared with those from nonembolized animals (all p < .05). However, pretreatment with atorvastatin attenuated by 32% the increases in lung-activated MMP-9 levels after APE (p < .05). CONCLUSIONS: These results suggest that pretreatment with atorvastatin attenuates APE-induced pulmonary hypertension and increases 24-hr survival rate by mechanisms that result in attenuated increases in lung activated MMP-9 after APE.
Asunto(s)
Modelos Animales de Enfermedad , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/prevención & control , Metaloproteinasa 9 de la Matriz , Pirroles/uso terapéutico , Enfermedad Aguda , Análisis de Varianza , Animales , Atorvastatina , Evaluación Preclínica de Medicamentos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/mortalidad , Inyecciones Intravenosas , Luminiscencia , Pulmón/química , Masculino , Metaloproteinasa 2 de la Matriz/análisis , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/análisis , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Microesferas , Nitratos/sangre , Nitritos/sangre , Modelos de Riesgos Proporcionales , Embolia Pulmonar/complicaciones , Presión Esfenoidal Pulmonar/efectos de los fármacos , Pirroles/farmacología , Distribución Aleatoria , Ratas , Ratas Wistar , Tasa de SupervivenciaRESUMEN
INTRODUCTION: A decrease in alpha-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (alpha-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury. MATERIALS AND METHODS: Under deep anesthesia, sheep (33 +/- 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40 degrees C). Half of the injured group received alpha-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH2O; tidal volume = 15 ml/kg) for 48 h. RESULTS: Plasma alpha-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 +/- 6.2 ml/min, compared with 27.3 +/- 6.0 ml/min, respectively), increased the PaO2/FiO2 ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine. CONCLUSIONS: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure.
Asunto(s)
Quemaduras/prevención & control , Pulmón/efectos de los fármacos , Lesión por Inhalación de Humo/prevención & control , alfa-Tocoferol/uso terapéutico , gamma-Tocoferol/uso terapéutico , Enfermedad Aguda , Animales , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Quemaduras/metabolismo , Quemaduras/fisiopatología , Modelos Animales de Enfermedad , Agua Pulmonar Extravascular/efectos de los fármacos , Agua Pulmonar Extravascular/fisiología , Lípidos/sangre , Pulmón/fisiopatología , Lesión Pulmonar , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Intercambio Gaseoso Pulmonar/fisiología , Presión Esfenoidal Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/fisiología , Ovinos , Lesión por Inhalación de Humo/metabolismo , Lesión por Inhalación de Humo/fisiopatología , Tirosina/análogos & derivados , Tirosina/metabolismo , alfa-Tocoferol/sangre , alfa-Tocoferol/farmacocinética , gamma-Tocoferol/sangre , gamma-Tocoferol/farmacocinéticaRESUMEN
BACKGROUND: Previously, we had shown that elevation of cerebral perfusion pressure, using pressors, improved short-term outcomes after traumatic brain injury and hemorrhagic shock in swine. The current study evaluates outcomes after resuscitation with diaspirin cross-linked hemoglobin (DCLHb)--a hemoglobin-based oxygen carrier with pressor activity--in the same swine model of traumatic brain injury and hemorrhagic shock. METHODS: Anesthetized and ventilated swine received traumatic brain injury via cortical fluid percussion (6-8 atm) followed by 45% blood volume hemorrhage. One hour later, animals were randomized to either a control group (SAL) resuscitated with normal saline equal to three times shed blood volume or to one of two experimental groups resuscitated with DCLHb. The two experimental groups consisted of a low-dose group, resuscitated with 250 mL of DCLHb (Hb1), and a high-dose group, resuscitated with 500 mL of DCLHb (Hb2). Animals were observed for 210 minutes postresuscitation. Outcomes evaluated were cerebral oxygenation by measuring partial pressure and saturation of oxygen in cerebrovenous blood; cerebral function by evaluating the preservation and magnitude of cerebrovascular carbon dioxide reactivity; and brain structural damage by semiquantitatively assessing beta amyloid precursor protein positive axons. RESULTS: Postresuscitation, cerebral perfusion pressure was higher in the DCLHb groups (p < 0.05, Hb1 and Hb2 vs. SAL), and intracranial pressure was lower in the Hb2 group (p < 0.05 vs. SAL). Cerebrovenous oxygen level was similar in all groups (p > 0.05). At baseline, 5% carbon dioxide evoked a 16 +/- 1% increase in cerebrovenous oxygen saturation, indicating vasodilatation. At 210 minutes, this response was nearly absent in SAL (4 +/- 4%) (p < 0.05 vs. baseline) and Hb1 (1 +/- 5%), but was partially preserved in Hb2 (9 +/- 5%). There was no intergroup difference in beta amyloid precursor protein positive axons. Five of 20 SAL and 0 of 13 DCLHb animals developed brain death (flat electroencephalogram) (p = 0.05, SAL vs. DCLHb). Postresuscitation, DCLHb animals maintained higher mean pulmonary arterial pressure (28 +/- 1 mm Hg, SAL; 42 +/- 1 mm Hg, Hb1; 45 +/- 1 mm Hg, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL) and lower cardiac output (3.9 +/- 1.6 L/min, SAL; 2.6 +/- 0.1 L/min, Hb1; 2.7 +/- 0.1 L/min, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL). Three Hb2 animals died as a result of cardiac failure, and one SAL animal died as a result of irreversible shock. CONCLUSION: In this swine model of traumatic brain injury and hemorrhagic shock, resuscitation with DCLHb maintained a higher cerebral perfusion pressure. Low-dose DCLHb (minimal increase in oxygen carriage) failed to significantly improve short-term outcome. With high-dose DCLHb (significant improvement in oxygen carriage), intracranial pressure was lower and cerebrovascular carbon dioxide reactivity was partially preserved; however, this was at the cost of poorer cardiac performance secondary to high afterload.
Asunto(s)
Aspirina/análogos & derivados , Aspirina/uso terapéutico , Lesiones Encefálicas/tratamiento farmacológico , Modelos Animales de Enfermedad , Hemoglobinas/uso terapéutico , Presión Intracraneal/efectos de los fármacos , Choque Hemorrágico/etiología , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Animales , Aspirina/farmacología , Presión Sanguínea/efectos de los fármacos , Volumen Sanguíneo/efectos de los fármacos , Química Encefálica , Muerte Encefálica , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/fisiopatología , Dióxido de Carbono/sangre , Gasto Cardíaco/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Hemoglobinas/farmacología , Oxígeno/sangre , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Resucitación/métodos , Cloruro de Sodio/farmacología , Cloruro de Sodio/uso terapéutico , PorcinosRESUMEN
OBJECTIVE: The study investigates the effectiveness of aerosol treatment on gas exchange and pulmonary inflammatory reaction using perfluorocarbons with different molecular structure and vapor pressure. DESIGN: Experimental, prospective, randomized, controlled study. SETTING: Experimental laboratory at a university hospital. SUBJECTS: Twenty anesthetized neonatal piglets assigned to four groups. INTERVENTIONS: After establishment of lung injury by bronchoalveolar lavage, piglets either received aerosolized FC77 (n = 5), perfluorooctylbromide (n = 5), or FC43 (n = 5, 10 mL x kg(-1) x hr(-1) for 2 hrs) or intermittent mandatory ventilation (control, n = 5). Thereafter, animals were supported for another 6 hrs. MEASUREMENTS AND MAIN RESULTS: Pao2 significantly improved in the perfluorocarbon groups compared with control (p < .01). Final Pao2 (mean +/- SEM) was FC77, 406 +/- 27 mm Hg; perfluorooctylbromide, 332 +/- 32 mm Hg; FC43, 406 +/- 19 mm Hg; control, 68 +/- 8 mm Hg. Paco2 and mean pulmonary arterial pressure were lower in all perfluorocarbon groups compared with control. The ratio of terminal dynamic compliance to total compliance was significantly higher in the FC77 than in the FC43, perfluorooctylbromide, and control groups. Relative gene expression of interleukin-1beta, interleukin-8, P-selectin, E-selectin, and intercellular adhesion molecule-1 in lung tissue was determined by TaqMan real time polymerase chain reaction normalized to hypoxanthineguanine-phosphoribosyl-transferase and was shown to be reduced by all perfluorocarbons. CONCLUSIONS: Aerosol treatment with all the perfluorocarbons investigated improved gas exchange and reduced pulmonary inflammatory reaction independently from molecular structure and vapor pressure of the perfluorocarbons. Although differences in vapor pressure and molecular structure may account for varying optimal dosing strategies, several different perfluorocarbons were shown to be principally suitable for aerosol treatment.
Asunto(s)
Modelos Animales de Enfermedad , Fluorocarburos/uso terapéutico , Surfactantes Pulmonares , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Administración por Inhalación , Aerosoles , Animales , Evaluación Preclínica de Medicamentos , Selectina E/análisis , Selectina E/genética , Fluorocarburos/química , Fluorocarburos/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Hidrocarburos Bromados , Recién Nacido , Inflamación , Molécula 1 de Adhesión Intercelular/análisis , Molécula 1 de Adhesión Intercelular/genética , Interleucina-1/análisis , Interleucina-1/genética , Interleucina-8/análisis , Interleucina-8/genética , Ventilación Liquida , Rendimiento Pulmonar/efectos de los fármacos , Estructura Molecular , Selectina-P/análisis , Selectina-P/genética , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , PorcinosRESUMEN
The finely-tuned increases and decreases in the intracellular calcium levels in myocytes ultimately regulate the contraction and relaxation of the heart. Therapeutic agents can improve or interfere with this delicate balance. Calcium sensitizers enhance cardiac contraction by improving the use of calcium that is available, rather than by inundating the cell with excessive calcium, as is the case with traditional inotropes. With the sensitizing mechanism, the energy cost of contraction is maintained at a near-normal level, and the threat of arrhythmias and sudden death is low. Levosimendan is the first calcium sensitizer to become available for the treatment of patients with acute heart failure. In recent clinical studies, levosimendan increased cardiac output and stroke volume without significantly increasing oxygen demand. By its additional action as a vasodilator (via potassium channel opening), levosimendan also corrects the hemodynamic decompensation, thus lowering the pulmonary capillary wedge pressure and systemic vascular resistance. Furthermore, levosimendan increases the coronary circulation thus leading to an improved function of the stunned myocardium and lessened ischemia. Taken together, levosimendan's primary calcium-sensitizing action, along with its complementary vasodilator properties, make this new drug a highly promising agent for the treatment of patients with acute heart failure.
Asunto(s)
Canales de Calcio Tipo L/uso terapéutico , Calcio/fisiología , Cardiotónicos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Enfermedad Aguda , Gasto Cardíaco/efectos de los fármacos , Insuficiencia Cardíaca/metabolismo , Humanos , Hidrazonas/uso terapéutico , Presión Esfenoidal Pulmonar/efectos de los fármacos , Piridazinas/uso terapéutico , Simendán , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the effects of endogenous endothelins on pulmonary haemodynamics and gas exchange in oleic acid lung injury. DESIGN: Prospective experimental study in dogs. SETTING: Animal research laboratory in a university teaching hospital. SUBJECTS. Seventeen anaesthetised and ventilated mongrel dogs. INTERVENTIONS: Nine pretreated dogs received an infusion of the endothelin A and B receptor antagonist bosentan (10 mg/kg) started before oleic acid. Eight treated dogs received bosentan started 90 min after oleic acid. Cardiac index (CI) was manipulated by inflating an inferior vena caval balloon or by opening a femoral arterio-venous bypass. MEASUREMENTS AND RESULTS: Pulmonary vascular resistance was defined by measuring the gradient between mean pulmonary artery pressure (MPAP) and occluded PAP (PAOP) at five levels of CI. Intrapulmonary shunt was measured using the inert gas SF(6). Pretreatment with bosentan prevented the oleic acid-induced shift of (MPAP-PAOP)/CI plots to higher pressures, but did not affect the increase in intrapulmonary shunt. Treatment of established oleic acid lung injury with bosentan had no effect. CONCLUSIONS: Pretreatment, but not treatment, with bosentan, in the dose used, blunted the oleic acid-induced increase in pulmonary vascular resistance, suggesting that endothelins contribute to the increase in pulmonary vascular tone in the early stages of oleic acid lung injury.
Asunto(s)
Antihipertensivos/uso terapéutico , Modelos Animales de Enfermedad , Antagonistas de los Receptores de Endotelina , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Animales , Antihipertensivos/farmacología , Bosentán , Perros , Evaluación Preclínica de Medicamentos , Infusiones Intravenosas , Ácido Oléico , Estudios Prospectivos , Circulación Pulmonar/efectos de los fármacos , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/fisiología , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatología , Sulfonamidas/farmacología , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: To determine the effects of titrated arginine vasopressin (AVP) alone or in combination with norepinephrine (NE) on hemodynamics and oxygen transport in healthy and endotoxemic sheep. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six adult ewes. INTERVENTIONS: Healthy sheep received AVP as a titrated infusion, initiated with 0.6 units/hr and increased by 0.6 units/hr every 15 mins, either until mean arterial pressure was increased by 20 mm Hg vs. baseline or a maximum of 3.6 units/hr was administered. After 90 mins, AVP infusion was continued with the investigated dosage, and NE (0.2 microg x kg(-1) x min(-1)) was also infused for 90 mins. After a 24-hr period of recovery, endotoxemia was induced and maintained (Salmonella typhosa endotoxin, 10 ng x kg(-1) x min(-1)) in the same sheep for the next 19 hrs. After 16 hrs of endotoxemia, AVP and NE were administered as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamics were obtained at baseline, every 15 mins during the titration period, and 60 and 90 mins after additional NE infusion. Variables of oxygen transport were calculated before and after the titration period. In healthy and endotoxemic sheep, AVP reduced heart rate and cardiac index (p <.001) and compromised oxygen delivery (p <.001) and oxygen consumption (healthy sheep, p =.003; endotoxemic sheep, p <.001). Vasopressin infusion did not alter mean pulmonary arterial pressure but increased pulmonary vascular resistance index in both groups (p <.001). Additional infusion of NE further augmented mean arterial pressure and increased cardiac index during endotoxemia (p <.001). This was accompanied by an increase in oxygen delivery and consumption (p <.05 each). CONCLUSIONS: During ovine endotoxemia, AVP decreased cardiac index, compromised oxygen delivery, and increased pulmonary vascular resistance index. These side effects may limit its use as a sole vasopressor during sepsis. Potentially, a simultaneous infusion of AVP and NE could represent a useful therapeutic option.
Asunto(s)
Arginina Vasopresina/administración & dosificación , Modelos Animales de Enfermedad , Endotoxemia/tratamiento farmacológico , Endotoxemia/metabolismo , Hemodinámica/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Transporte Respiratorio/efectos de los fármacos , Fiebre Tifoidea/tratamiento farmacológico , Fiebre Tifoidea/metabolismo , Vasoconstrictores/administración & dosificación , Animales , Arginina Vasopresina/farmacología , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Monitoreo de Drogas , Quimioterapia Combinada , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Norepinefrina/farmacología , Norepinefrina/uso terapéutico , Estudios Prospectivos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Ovinos , Resistencia Vascular/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
The effects of electroacupuncture (EA) on the minimum alveolar concentration (MAC) and on the cardiovascular system were evaluated with dogs under isoflurane anesthesia. Eight healthy male beagles were randomly assigned to six study groups (five heads/group) with washout intervals of 7 ~ 31 days between experiments for recovery and anesthetic clearance. MAC of isoflurane and cardiovascular parameters were determined after EA at nonacupoint and and at acupoints LI-4, SP-6, ST-36 and TH-8. Electroacupuncture for 30 minutes at LI-4, SP-6, ST-36 and TH-8 acupoints lowered the MAC of isoflurane by 17.5 +/- 3.1%, 21.3 +/- 8.0%, 20.5 +/- 8.2% and 15.6 3.1%, respectively (p < 0.05). However, electrical stimulation of nonacupoint did not induce a significant change in MAC of isoflurane. In the cardiovascular system, the ST-36 group did not induce any significant change in cardiovascular parameters. In the TH-8 group, the mean and diastolic arterial pressure and the systemic vascular resistance were decreased. In the LI-4 group, cardiac output and cardiac index decreased after EA. These results indicate that EA at LI-4, SP-6 and ST-36 have advantages in isoflurane anesthesia in terms of reducing the dose of anesthetics and minimizing cardiovascular side effects.
Asunto(s)
Anestesia por Inhalación/veterinaria , Anestésicos por Inhalación/farmacocinética , Perros/metabolismo , Electroacupuntura/veterinaria , Isoflurano/farmacocinética , Alveolos Pulmonares/metabolismo , Anestesia por Inhalación/efectos adversos , Anestésicos por Inhalación/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco , Perros/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Isoflurano/farmacología , Masculino , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Resistencia Vascular/efectos de los fármacosRESUMEN
The effects of electroacupuncture (EA) on the minimum alveolar concentration (MAC) and on the cardiovascular system were evaluated with dogs under isoflurane anesthesia. Eight healthy male beagles were randomly assigned to six study groups (five heads/group) with washout intervals of 7 ~ 31 days between experiments for recovery and anesthetic clearance. MAC of isoflurane and cardiovascular parameters were determined after EA at nonacupoint and and at acupoints LI-4, SP-6, ST-36 and TH-8. Electroacupuncture for 30 minutes at LI-4, SP-6, ST-36 and TH-8 acupoints lowered the MAC of isoflurane by 17.5 +/- 3.1%, 21.3 +/- 8.0%, 20.5 +/- 8.2% and 15.6 +/- 3.1%, respectively (p < 0.05). However, electrical stimulation of nonacupoint did not induce a significant change in MAC of isoflurane. In the cardiovascular system, the ST-36 group did not induce any significant change in cardiovascular parameters. In the TH-8 group, the mean and diastolic arterial pressure and the systemic vascular resistance were decreased. In the LI-4 group, cardiac output and cardiac index decreased after EA. These results indicate that EA at LI-4, SP-6 and ST-36 have advantages in isoflurane anesthesia in terms of reducing the dose of anesthetics and minimizing cardiovascular side effects.
Asunto(s)
Animales , Masculino , Anestesia por Inhalación/efectos adversos , Anestésicos por Inhalación/farmacocinética , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco , Perros/metabolismo , Electroacupuntura/veterinaria , Frecuencia Cardíaca/efectos de los fármacos , Isoflurano/farmacocinética , Alveolos Pulmonares/metabolismo , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVES: To determine possible additive effects of combined high-dose partial liquid ventilation (PLV) and almitrine bismesylate (ALM) on pulmonary gas exchange and hemodynamics in an animal model of acute lung injury (ALI). DESIGN AND SETTING: Prospective, controlled animal study in an animal research facility of a university hospital. INTERVENTIONS: ALI was induced in 12 anesthetized and mechanically ventilated pigs by repeated wash-out of surfactant. After initiation of PLV with 30 ml/kg perfluorocarbon the animals were randomly assigned to receive either accumulating doses of ALM (0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 micrograms/kg per minute) for 30 min each (n = 6) or the solvent malic acid (n = 6). MEASUREMENT AND RESULTS: Pulmonary gas exchange and hemodynamics were measured at the end of each infusion period. Compared to ALI, PLV alone significantly increased arterial oxygen partial pressure (PaO2) and decreased venous admixture (QVA/QT) and mean pulmonary artery pressure (MPAP). Administration of ALM did not result in a further improvement in PaO2, QVA/QT or MPAP compared to PLV alone but decreased PaO2 and increased QVA/QT and MPAP when 16 micrograms/kg per min ALM was compared to PLV alone. CONCLUSIONS: In an animal model of surfactant depletion induced ALI the combined treatment of PLV and ALM induced no significant improvement in pulmonary gas exchange or hemodynamics when compared to PLV alone. Moreover, high-dose ALM significantly impaired gas exchange and pulmonary hemodynamics.
Asunto(s)
Almitrina/administración & dosificación , Modelos Animales de Enfermedad , Fluorocarburos/administración & dosificación , Hemodinámica/efectos de los fármacos , Ventilación Liquida/métodos , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Fármacos del Sistema Respiratorio/administración & dosificación , Almitrina/farmacología , Animales , Análisis de los Gases de la Sangre , Terapia Combinada , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Fluorocarburos/farmacología , Hidrocarburos Bromados , Estudios Prospectivos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Respiración Artificial , Síndrome de Dificultad Respiratoria/metabolismo , Fármacos del Sistema Respiratorio/farmacologíaRESUMEN
OBJECTIVES: To investigate effects of intravenous norepinephrine (NE) and phenylephrine (PE) on intestinal oxygen supply in an autoperfused, innervated jejunal segment. DESIGN AND SETTING: Prospective, randomized animal study in an animal research laboratory. MATERIALS AND METHODS: In 24 anesthetized and normoventilated pigs a segment of the jejunal mucosa was exposed by midline laparotomy and antimesenteric incision. Mucosal oxygen tension (PO2muc; Clark-type surface oxygen electrodes), microvascular hemoglobin oxygen saturation (HbO2, tissue reflectance spectrophotometry), and microvascular blood flow (perfusion units, PU; laser Doppler velocimetry), systemic hemodynamics, mesenteric-venous acid base and blood gas variables, and systemic acid base and blood gas variables were recorded after a resting period and at 20-min intervals during infusion of NE (0.01, 0.05, 0.1, 0.5, 1, 2 micrograms x kg-1 x min-1; n = 8) or PE (0.1, 0.5, 1, 2, 5, 10 micrograms x kg-1 x min-1; n = 8) and in controls (n = 8) without treatment. RESULTS: NE infusion led to significant tachycardia, an increase in cardiac output, and systemic oxygen delivery and consumption while PE progressively increased mean arterial pressure with only small effects on systemic blood flow. NE or PE infusion did not affect mesenteric venous oxygen tension (baseline: PE 53 +/- 5, NE, 52 +/- 4.2 mmHg), mesenteric oxygen extraction ratio (baseline: PE 0.29 +/- 0.08, NE 0.3 +/- 0.06), jejunal microvascular blood flow (baseline: PE 254 +/- 127, NE 282 +/- 72 PU), PO2muc (baseline: PE 31 +/- 9.1, NE 33 +/- 11 mmHg), and HbO2 (baseline: PE 52 +/- 9.6%, NE 58 +/- 11.6%). CONCLUSION: Despite major differences in systemic hemodynamics jejunal tissue oxygen supply is not affected by progressively increasing intravenous infusion of norepinephrine and phenylephrine.
Asunto(s)
Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Hipotensión/tratamiento farmacológico , Hipotensión/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Norepinefrina/uso terapéutico , Consumo de Oxígeno/efectos de los fármacos , Fenilefrina/uso terapéutico , Vasoconstrictores/uso terapéutico , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Hipotensión/diagnóstico , Hipotensión/fisiopatología , Mucosa Intestinal/irrigación sanguínea , Yeyuno/irrigación sanguínea , Flujometría por Láser-Doppler , Microcirculación/efectos de los fármacos , Norepinefrina/farmacología , Fenilefrina/farmacología , Estudios Prospectivos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Distribución Aleatoria , Espectrofotometría , Porcinos , Factores de Tiempo , Vasoconstrictores/farmacologíaRESUMEN
OBJECTIVE: The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Sixty-six adult rabbits of either sex. INTERVENTIONS: The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs. MEASUREMENTS AND MAIN RESULTS: Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group. CONCLUSIONS: The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.
Asunto(s)
Acetilcolina/fisiología , Acetilcolina/uso terapéutico , Endotelina-1/fisiología , Endotelina-1/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Circulación Pulmonar/efectos de los fármacos , Circulación Pulmonar/fisiología , Presión Esfenoidal Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animales , Inhibidores de la Ciclooxigenasa/farmacología , Diclofenaco/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Antagonistas de los Receptores de Endotelina , Femenino , Hipertensión Pulmonar/inducido químicamente , Técnicas In Vitro , Masculino , Péptidos Cíclicos , Conejos , Tromboxano A2/fisiología , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , VasoconstrictoresRESUMEN
OBJECTIVE: To compare the effect of different concentrations of inhaled nitric oxide and doses of nebulized prostacyclin on hypoxia-induced pulmonary hypertension in pigs. DESIGN: Prospective, controlled animal study. SETTING: Animal research facilities of an university hospital. INTERVENTIONS: After reducing the fraction of inspired oxygen (FIO(2)) from 1.0 to 0.1, two groups of five pigs each were submitted to inhalation of three concentrations of nitric oxide (5, 10 and 20 ppm) or three doses of prostacyclin (2.5, 5, 10 ng x kg(-1) x min(-1)). RESULTS: All doses of prostacyclin and concentrations of nitric oxide resulted in a decrease in mean pulmonary arterial pressure and pulmonary vascular resistance when compared to hypoxic ventilation (p < 0.001) which was independent of the dose or concentration of either drug used. While inhalation of nitric oxide caused a reduction in mean pulmonary arterial pressure back to values obtained during ventilation with FIO(2) 1.0, values achieved with prostacyclin were still significantly higher when compared to measurements prior to the initiation of hypoxic ventilation. However, direct comparison of the effect of 20 ppm nitric oxide and 10 ng x kg(-1) x min(-1) prostacyclin on mean pulmonary arterial pressure revealed no differences between the drugs. All other hemodynamic and gas exchange parameters remained stable throughout the study. CONCLUSIONS: Inhalation of clinically used concentrations of nitric oxide and doses of prostacyclin can decrease elevated pulmonary arterial pressure in an animal model of hypoxic pulmonary vasoconstriction without impairing systemic hemodynamics or gas exchange.
Asunto(s)
Antihipertensivos/administración & dosificación , Modelos Animales de Enfermedad , Epoprostenol/administración & dosificación , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Óxido Nítrico/administración & dosificación , Vasodilatadores/administración & dosificación , Enfermedad Aguda , Administración por Inhalación , Aerosoles , Animales , Antihipertensivos/farmacología , Análisis de los Gases de la Sangre , Evaluación Preclínica de Medicamentos , Monitoreo de Drogas , Epoprostenol/farmacología , Femenino , Hipertensión Pulmonar/fisiopatología , Hipoxia/sangre , Óxido Nítrico/farmacología , Estudios Prospectivos , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Respiración Artificial/métodos , Porcinos , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: The clinical course in primary pulmonary hypertension (PPH) is improved by calcium channel blocker therapy in those with a favorable hemodynamic response during a trial of high-dose oral nifedipine. Although trials of nifedipine are performed only in patients who demonstrate pulmonary vasodilator reserve to short-acting agents, this response does not predict the safety of nifedipine treatment, which can result in severe first-dose hypotension and death. STUDY OBJECTIVES: To identify echocardiographic parameters that predict first-dose nifedipine-induced hypotension in patients with PPH. METHODS: The pretrial echocardiograms of 23 consecutive PPH patients (mean age, 42.3 +/- 13 years; 77% female) undergoing evaluation of pulmonary vasodilator reserve with nifedipine were analyzed. Patients were classified as those who suffered first-dose nifedipine hypotension (group 1) and those who did not (group 2). Echocardiographic measures of chamber size and septal geometry in the two groups were compared. RESULTS: Five measures reflecting diminished left ventricular (LV) size and leftward ventricular septal bowing were found to be associated with nifedipine hypotension: LV transverse diameter in systole (LVDs; p = 0.007), LV transverse diameter in diastole (LVDd; p = 0.05), LV area in systole (LVAs; p = 0.009), LV area in diastole (LVAd; p = 0.03), the ratio of RV to LVAs (p = 0. 02), and leftward ventricular septal bowing (p = 0.01). The LV dimensions found to best predict nifedipine-induced hypotension were LVDs < 2.7 cm, LVDd < 4.0 cm, LVAs < 15.5 cm(2), and LVAd < 20.0 cm(2). CONCLUSIONS: Readily available echocardiographic parameters in patients with PPH are predictive of nifedipine-induced hypotension, and can be used to select patients in whom a trial of nifedipine should be avoided.
Asunto(s)
Bloqueadores de los Canales de Calcio/efectos adversos , Ecocardiografía , Tabiques Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Hipertensión Pulmonar/tratamiento farmacológico , Hipotensión/inducido químicamente , Nifedipino/efectos adversos , Administración Oral , Adulto , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Femenino , Tabiques Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Hipertensión Pulmonar/diagnóstico por imagen , Hipotensión/diagnóstico por imagen , Masculino , Contracción Miocárdica/efectos de los fármacos , Nifedipino/administración & dosificación , Valor Predictivo de las Pruebas , Presión Esfenoidal Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Obstrucción del Flujo Ventricular Externo/inducido químicamente , Obstrucción del Flujo Ventricular Externo/diagnóstico por imagenRESUMEN
In a subset of patients with primary pulmonary hypertension (PPH), high doses of oral calcium-channel blockers (CCB) produce a sustained clinical and haemodynamic improvement. However, significant side-effects have been reported during acute testing with CCB. Therefore, to identify accurately patients who may benefit from long-term CCB therapy, there is a need for a safe, potent and short-acting vasodilator. The aim of this study was to compare the acute response to inhaled nitric oxide (NO) and oral high doses of CCB in 33 consecutive patients with PPH. A significant acute vasodilator response was defined by a fall in both mean pulmonary artery pressure and total pulmonary resistance by >20%. Ten patients responded acutely to NO, nine of whom responded acutely to CCB, without any complications. The 23 other patients failed to respond to NO and CCB. In these nonresponders, nine serious adverse events were observed with CCB (38%). There was no clinical or baseline haemodynamic feature predicting acute vasodilator response. Long-term oral treatment with CCB was restricted to the nine acute responders and a sustained clinical and haemodynamic improvement was observed in only six patients. In primary pulmonary hypertension, the acute response rate to high doses of calcium-channel blockers is low (27%). Serious adverse reactions to high doses of calcium-channel blockers during acute testing are frequently observed in nonresponders. It is concluded that nitric oxide may be used as a screening agent for safely identifying patients with primary pulmonary hypertension who respond acutely to calcium-channel blockers and may benefit from long-term treatment with these agents.