RESUMEN
The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.
Asunto(s)
Modelos Biológicos , Insuficiencia Multiorgánica/enzimología , Insuficiencia Multiorgánica/prevención & control , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/metabolismo , Preeclampsia/tratamiento farmacológico , Preeclampsia/metabolismo , 3',5'-GMP Cíclico Fosfodiesterasas , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Insuficiencia Multiorgánica/etiología , Óxido Nítrico/metabolismo , Placenta/efectos de los fármacos , Placenta/metabolismo , Preeclampsia/complicaciones , Embarazo , Resultado del TratamientoRESUMEN
UNLABELLED: Chong et al. examined risk factors for sudden infant death syndrome (SIDS) before and after the start of the Swedish campaign to reduce the risk of SIDS. They found that maternal smoking was the strongest risk factor for SIDS in the post-campaign compared to the pre-campaign period. CONCLUSION: After successful results of the SIDS campaigns to prevent prone sleeping, strong efforts need to be undertaken to eliminate maternal smoking during pregnancy altogether without replacing cigarette smoking with other nicotine delivery devices such as snuff, gum or patches.
Asunto(s)
Prevención del Hábito de Fumar , Muerte Súbita del Lactante/prevención & control , Humanos , Recién Nacido , Factores de Riesgo , Fumar/efectos adversos , Muerte Súbita del Lactante/etiología , Suecia/epidemiologíaRESUMEN
AIMS: To determine whether combined pre- and postnatal nicotine exposure compared with prenatal exposure alone results in more compromised postnatal hypoxia defense mechanisms and further alteration of the postnatal breathing pattern (reduced tidal volume and increased respiratory rate). METHODS: Seven lambs exposed to nicotine prenatally (pN) (approximate maternal dose: 0.5 mg/kg/d) and seven lambs exposed to nicotine pre- and postnatally (ppN) (postnatal dose: 1.6-2 mg/kg/d) were studied without sedation at an average age of 5 d and 21 d during resting (room air) conditions, during exposure to 10% O2 and during a brief exposure to 100% O2. RESULTS: Resting minute ventilation, occlusion pressure, effective impedance, heart rate and mean arterial blood pressure were similar in the two groups during wakefulness and quiet sleep. Resting tidal volume was significantly higher in ppN than in pN lambs during wakefulness (9.4 +/- 0.7 vs 7.7 +/- 1.4 ml/kg, p < 0.05) and quiet sleep (9.8 +/- 0.6 vs 7.6 +/- 1.5 ml/kg, p < 0.01) at 5 d and also at 21 d during wakefulness (7.7 +/- 1.0 vs 6.2 +/- 1.1 ml/kg, p < 0.05). The ventilatory, heart rate and blood pressure responses to hypoxia were comparable in the two groups during both activity states. Time to arousal from quiet sleep in response to hypoxia was equivalent in the two groups. The ventilatory response to hyperoxia was not significantly different in the two groups during either activity state. CONCLUSION: Continued postnatal nicotine exposure after prenatal exposure did not further compromise hypoxia defense mechanisms after birth.
Asunto(s)
Animales Recién Nacidos/fisiología , Hipoxia/fisiopatología , Nicotina/toxicidad , Efectos Tardíos de la Exposición Prenatal , Respiración/efectos de los fármacos , Fenómenos Fisiológicos Respiratorios , Animales , Peso al Nacer , Análisis de los Gases de la Sangre , Determinación de la Presión Sanguínea , Femenino , Edad Gestacional , Frecuencia Cardíaca , Modelos Animales , Nicotina/sangre , Embarazo , Ovinos , Volumen de Ventilación PulmonarRESUMEN
OBJECTIVE: To determine whether the group B streptococcal (GBS) polysaccharide exotoxin CM101, which induces a complement-activated cytokine-driven inflammatory response, is present in body fluids of infants with GBS disease. STUDY DESIGN: With a sandwich enzyme-linked immunosorbent assay, CM101 was measured in plasma, urine, and cerebrospinal fluid from newborn infants who were evaluated for possible infection and from older infants with culture-confirmed GBS disease. RESULTS: Urine from 11 newborn infants with culture-confirmed early-onset disease contained large amounts of CM101 (1.0 to 5.5 mg/48 h). Plasma concentrations were 62.6 +/- 10.5 microg/mL in these infants and were 69.0 +/- 21.2 microg/mL in 4 older infants with late-onset disease. Plasma CM101 concentrations did not correlate with indexes of illness severity, leukocyte counts, or interleukin-6 or interleukin-8 plasma concentrations. CM101 was present in cerebrospinal fluid of 5 infants with meningitis (8.4 +/- 1.6 microg/mL). CM101 was not found in control samples. CM101 isolated from urine had molecular weight and sugar composition similar to those obtained from GBS culture media, and they both elicited a comparable pathophysiologic response when infused intravenously in lambs. CONCLUSIONS: CM101 is present in infants with GBS disease, and it appears to be the same as CM101 obtained from GBS culture media.
Asunto(s)
Toxinas Bacterianas/aislamiento & purificación , Polisacáridos Bacterianos/aislamiento & purificación , Sepsis/microbiología , Infecciones Estreptocócicas/microbiología , Animales , Toxinas Bacterianas/metabolismo , Líquidos Corporales/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Lactante , Recién Nacido , Interleucina-6/sangre , Interleucina-8/sangre , Recuento de Leucocitos , Polisacáridos Bacterianos/metabolismo , Sepsis/metabolismo , Sepsis/fisiopatología , Ovinos , Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/fisiopatología , Streptococcus agalactiae/clasificación , Streptococcus agalactiae/metabolismoRESUMEN
A decreased ability to arouse from sleep in response to arterial hypoxemia may lead to severe asphyxia and has been proposed as a mechanism of sudden infant death syndrome. Based on previous observations that nicotine exposure, a major environmental risk factor for sudden infant death syndrome, may impair hypoxic defense in neonates, we hypothesized that a short-term infusion of nicotine could impair hypoxic arousal through interference with oxygen-sensing mechanisms. Seven chronically instrumented unanesthetized lambs were studied at the age of 4.6 +/- 1.3 d during normoxia and acute hypoxia (0.1 fraction of inspired oxygen) for 5 min. Ventilation, transcutaneous Hb oxygen saturation, blood pressure, heart rate, and time to arousal were compared during a control saline infusion and during a 0.5 microg x kg(-1) x min(-1) nicotine infusion. Activity states, i.e. wakefulness and quiet sleep as well as arousal, were defined by EEG, nuchal electromyogram, and electrooculogram. Each lamb acted as its own control. Arousal from quiet sleep occurred significantly later during nicotine infusion compared with control (177 +/- 93 versus 57 +/- 41 s, p < 0.01) and at a lower transcutaneous Hb oxygen saturation (60 +/- 12 versus 79 +/- 12%, p < 0.01) (paired t test). The ventilatory response to hypoxia in wakefulness was similar during both conditions but was significantly attenuated in quiet sleep during nicotine infusion (p < 0.001, 2-way ANOVA repeated-measures design). Blood pressure and heart rate responses were similar during both conditions. These results suggest that a brief nicotine exposure blunts oxygen sensitivity in young lambs, a finding of potential relevance for sudden infant death syndrome.
Asunto(s)
Nivel de Alerta/efectos de los fármacos , Hipoxia/metabolismo , Nicotina/farmacología , Animales , Animales Lactantes , Análisis de los Gases de la Sangre , Electroencefalografía , Electromiografía , Electrooculografía , Hemodinámica/efectos de los fármacos , Hiperoxia/sangre , Hipoxia/sangre , Infusiones Intravenosas , Nicotina/administración & dosificación , Nicotina/sangre , Tiempo de Reacción/efectos de los fármacos , Respiración/efectos de los fármacos , Ovinos , Sueño/efectos de los fármacosRESUMEN
Respiratory inhibition following laryngeal water administration was investigated by breath-by-breath analysis of inspiratory ventilation (VI) and central inspiratory drive (P0.1) in 15 unanesthetized lambs studied in 0.21 FIO2 (PaO2: 82-92 torr, PaCO2 41-43 torr) and in 0.1 FIO2 (Pao2 30-34 torr, PaCO2 32-33 torr). During the 30 sec period after stimulation, VI decreased significantly compared to prestimulation levels both in 0.21 FIO2 (-22, -21 and -18%) and in 0.1 FI(O2), (-16, -23 and -19%) at 5, 16 and 29 days, respectively. In contrast, P0.1 remained at prestimulation levels during normoxia in all age groups (1, 10 and 9%, NS), but decreased significantly during hypoxia (-11 and -13%, P < 0.05) at 16 and 29 days, respectively. Poststimulation apnea duration was significantly related to the decrease in VI (P < 0.001) but not to the change in P0.1. Laryngeal stimulation during hypoxemia/hypocapnia induces a prolonged decrease of central inspiratory drive in postneonatal lambs, a finding of potential significance for the mechanisms of sudden infant death syndrome.
Asunto(s)
Apnea/fisiopatología , Hipoxia/fisiopatología , Laringe/metabolismo , Ventilación Pulmonar/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Apnea/sangre , Dióxido de Carbono/sangre , Células Quimiorreceptoras/metabolismo , Hipoxia/sangre , Laringe/efectos de los fármacos , Oxígeno/sangre , Presión Parcial , Respiración Artificial , Ovinos , Procesamiento de Señales Asistido por Computador , Volumen de Ventilación Pulmonar , AguaRESUMEN
We determined if surfactant treatment effect can be enhanced by mechanical volume recruitment during surfactant administration by measuring functional residual capacity, tidal volume, the alveolar portion of tidal volume, dynamic compliance of the respiratory system, a/A ratio, and PaCO2 by measuring before and after surfactant administration to rabbits with lung injury induced by airway lavage. There was improvement in all lung function indices when surfactant was given with volume recruitment, but when surfactant was given without volume recruitment, the only index to show significant improvement was a/A ratio of oxygenation. These results support the hypothesis that mechanical recruitment of terminal airspaces from a previously unventilated compartment will enhance the effectiveness of surfactant replacement by facilitating the distribution of instilled surfactant to this compartment.
Asunto(s)
Surfactantes Pulmonares/uso terapéutico , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Capacidad Residual Funcional/efectos de los fármacos , Humanos , Recién Nacido , Rendimiento Pulmonar/efectos de los fármacos , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Conejos , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
CM101 is a bacterial polysaccharide that induces neovascular inflammation in malignant tumors. Fifteen patients with refractory malignancies received CM101 i.v. by a 15-min infusion every other day, three times in 1 week, at doses ranging from 1 unit (7.5 microgram)/kg to 5 units/kg. Serum was analyzed for anti-CM101 IgG and IgM weekly. Plasma levels of inflammatory cytokines, including tumor necrosis factor alpha, interleukin 8, interleukin 10, MIP-1alpha, and soluble E-selectin, were analyzed from -15 min to 12 h during each treatment. Dose-limiting toxicities, including grade IV dyspnea and arrhythmia, were encountered at the 5-unit/kg level. Toxicities occurred primarily within the first 12 h after therapy and included mild-to-moderate fever and chills, nausea, cough, headache, facial flushing, dyspnea, myalgias, and acute tumor-related pain. No patient developed detectable antibodies to CM101. All patients experienced marked time- and dose-dependent elevations in all cytokines studied. Three patients experienced tumor shrinkage. The results show that CM101 can be safely administered at doses that produce evidence for severe, and possibly tumor-specific, inflammation. Further study is necessary to better characterize the mechanism of action and determine the optimal dose and schedule of this new agent.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Polisacáridos Bacterianos/efectos adversos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Citocinas/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Polisacáridos Bacterianos/administración & dosificación , Pruebas CutáneasRESUMEN
A polysaccharide toxin, GBS toxin, is produced by group B Streptococcus (GBS) isolates from neonates who died of "early-onset disease". GBS toxin, named CM101 in the clinic, was hypothesized, on the basis of our previous in vivo studies, to induce inflammation in pulmonary neovasculature in neonates by cross-linking of embryonic receptors still expressed after birth and in tumor neovasculature in adults. Immunohisto chemical in vitro analysis of human biopsies showed that tumor neovasculature is indeed a binding site for CM101. In vivo studies in mice have demonstrated that CM101 induced inflammatory responses in neoplastic tumor neovasculature causing inhibition of tumor growth and tumor cell necrosis. These experimental observations warranted a phase I clinical trial for CM101 as an anti-neovascularization agent in human cancer therapy. Cancer patients received one cycle of therapy consisting of three treatments during 1 week. CM101 was administered over 15 min by i.v. infusion. Dosages of 7.5 micrograms/kg (1 U/kg), n = 3; 15 micrograms/kg (2 U/kg), n = 6; 24.75 micrograms/kg (3.3 U/kg), n = 3; and 37.5 micrograms/kg (5 U/kg), n = 3 were used. Enzyme-linked immunosorbent sandwich assays (ELISA) of the patients sera showed a marked elevation of soluble E-selectin with a peak concentration observed at 8-12 h after each CM101 infusion. The average baseline value for soluble E-selectin prior to the first treatment was 97.3 +/- 23.4 ng/ml (mean +/- SEM, n = 15) and the average peak level at 8 h was 441.6 +/- 62.4 (mean +/- SEM, n = 15; P < 0.001). Subsequent treatments gave average maximum soluble E-selectin levels again at 8 h of 466.9 +/- 87.6 and 412.0 +/- 67.8 ng/ml, for treatments 2 and 3 respectively. Baseline values for treatments 2 and 3 were 192.3 +/- 26.4 and 226.4 +/- 26.1 ng/ml respectively (p < 0.01 versus treatment 1). Out of 15 patients, 5 showed tumor reduction or stabilization and were given additional cycles of therapy. CM101 induced an increase in soluble E-selectin levels, which remained elevated over baseline at the start of the following treatment cycles. The baseline remained elevated for several weeks after the final treatment, i.e., P < 0.01 for levels before treatment 1 compared to those at week 4 after treatment. Elevated soluble E-selectin is considered proof of endothelial engagement in an inflammatory process. Our data support the contention that the inflammatory response observed in these cancer patients is targeting the tumor neovasculature and that measurement of soluble E-selectin levels in patients treated with CM101 can provide important information on the magnitude of CM101-mediated neovascular endothelial activation and tumor cell damage in cancer of endothelial origin, or cancer with a major neo-angiogenic component.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Biomarcadores de Tumor/sangre , Selectina E/sangre , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Polisacáridos Bacterianos/administración & dosificación , Polisacáridos Bacterianos/sangre , Adulto , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Selectina E/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polisacáridos Bacterianos/efectos adversosRESUMEN
To evaluate the effect of respiratory syncytial virus (RSV) infection on the response to laryngeal chemostimulation (LCS) with water, five lambs were inoculated with human RSV and three lambs were given control media at an age of 3-5 days. During RSV infection, LCS resulted in increased inhibition of minute ventilation and delayed recovery of regular breathing. Sleep further increased the response, and arousal was less likely to occur in active sleep. Two of the five infected lambs needed resuscitation after LCS when arousal was absent. Histological studies showed bronchiolitis and pneumonitis. Laryngeal tastebud morphology was unchanged at 8 days after inoculation. However, infected lambs had disrupted tastebuds 4-6 weeks after infection. Failure to arouse and to terminate reflex apnea may play a role in the pathogenesis of the sudden infant death syndrome associated with respiratory tract infection.
Asunto(s)
Apnea/etiología , Nivel de Alerta/fisiología , Laringe/fisiopatología , Reflejo Anormal/fisiología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Virus Sincitial Respiratorio Humano , Papilas Gustativas/fisiopatología , Animales , Apnea/inducido químicamente , Apnea/fisiopatología , Frecuencia Cardíaca/fisiología , Humanos , Laringe/patología , Modelos Lineales , Pulmón/patología , Ovinos , Fases del Sueño/fisiología , Papilas Gustativas/patología , Agua/efectos adversosRESUMEN
The ventilatory effects of breath-by-breath measurements of airway occlusion pressure, i.e., airway pressure determined 100 ms after initiation of inspiration (P0.1) were evaluated in seven lambs studied sequentially between 7 and 28 days after birth. P0.1 was determined by computer-aided, on-line regression analysis of the inspiratory pressure versus time (dP/dt) by means of a pneumatic occlusion valve that allowed occlusion times to vary in proportion to respiratory rate. No significant changes were found in minute ventilation, tidal volume, respiratory rate or end-tidal CO2 concentration when the valve was operating as a oneway valve (opening pressure 0.02 kPa or 0.2 cmH2O) compared to when in occlusion mode [opening pressure 0.18-0.2 kPa or 1.8-2.0 cmH2O, mean occlusion time 44 (25) ms]. The calculated P0.1 values correlated well with those obtained from manual occlusions (r = 0.87, P < 0.0001). This new technique, which detects and discards irregular or non-linear (r < 0.95) inspiratory pressure profiles, enables breath-by-breath determinations of inspiratory drive in rapidly breathing lambs with minimal impact on respiratory pattern and ventilation.
Asunto(s)
Envejecimiento/fisiología , Resistencia de las Vías Respiratorias/fisiología , Mecánica Respiratoria/fisiología , Presión del Aire , Algoritmos , Animales , Animales Recién Nacidos/fisiología , Recolección de Datos , Pruebas de Función Respiratoria , Ovinos , Tráquea/fisiologíaRESUMEN
A multiple-breath nitrogen washout system designed to measure lung volume in mechanically ventilated infants was validated by assessing three performance criteria: 1) accuracy of lung volume measurements in the presence of an endotracheal tube leak was assessed by comparing the measurements of functional residual capacity (FRC) in a mechanical lung model with and without airway leak; 2) in vivo accuracy was assessed in rabbits by comparing FRC measurements obtained by this system with measurements obtained by helium dilution; and 3) in vivo precision was assessed by analyzing measurements of FRC obtained in replicate measurements at different times in ventilator-dependent premature infants with hyaline membrane disease. The average difference between the measurements of FRC in a mechanical lung model with airway leak and without leak was 3.0 +/- 9.4% (mean +/- SD, P > 0.2), and no difference was greater than 20%. There was a significant correlation between the measurements of FRC in rabbits by nitrogen washout and by helium dilution (r = 0.93, P < 0.0001), and 65.4% of the paired measurements were within 20% of their average. The 95% limits of agreement within pairs of measurements by the two techniques ranged from -4.0 to + 6.5 mL/kg. FRC measured by helium dilution was slightly higher (1.3 +/- 2.7 mL/kg, P < 0.01) than FRC measured by nitrogen washout, and positive end-expiratory pressure was a significant predictor of this difference (P < 0.0001). The regression between the individual FRC measurements obtained in premature infants and the average of the other replicates was significant (r2 > 0.98, P < 0.0001). The coefficient of variation was 12.3%. These findings provide further validation of this multiple-breath nitrogen washout system for measuring FRC in premature infants during mechanical ventilation.
Asunto(s)
Capacidad Residual Funcional , Enfermedad de la Membrana Hialina/fisiopatología , Animales , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro/fisiología , Intubación Intratraqueal , Mediciones del Volumen Pulmonar/métodos , Masculino , Conejos , Reproducibilidad de los Resultados , Respiración ArtificialRESUMEN
Decreased ability to generate a hyperventilatory response to hypoxemia is believed to be an important mechanism in the pathophysiology of sudden infant death syndrome, and maternal smoking is a leading risk factor. To investigate whether there may be a link between these two observations, we studied five lambs at mean ages of 7, 17, and 27 d to determine the effects of an i.v. infusion of nicotine (0.5 microgram/kg/min) on ventilation when peripheral chemoreceptor activity was stimulated by hypoxia (0.1 FiO2) or briefly inhibited by hyperoxia. Ventilatory measurements were performed using a computer-aided occlusion valve device which permitted breath-by-breath determinations of inspiratory occlusion pressures (P0.1) and minute ventilation. Nicotine attenuated the early ventilatory response to hypoxia (min 1, 2, and 3 of the test) by 8, 26, and 37%, respectively, at the age of 7 d (analysis of variance overall, p < 0.05), by 23%, 23 and 37% at 17 d (p = NS) and by 40, 45, and 37% at 27 d (p < 0.05). The decrease in ventilation in response to hyperoxia during the control study without nicotine was 18, 35, and 34% at 7, 17, and 27 d, respectively. Nicotine caused a greater decrease in the response: 31, 45, and 46%, respectively, (p < 0.05 at 27 d). The paradoxical effects of nicotine, attenuation of the ventilatory response to hypoxia and augmentation of the response to hyperoxia, suggest that nicotine altered peripheral chemoreceptor oxygen sensitivity and most likely also affected central processing of the chemoreceptor input.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hiperoxia/fisiopatología , Hipoxia/fisiopatología , Nicotina/farmacología , Respiración/efectos de los fármacos , Factores de Edad , Animales , Bovinos , Impedancia Eléctrica , Pruebas de Función Respiratoria , OvinosRESUMEN
GBS toxin is a polysaccharide exotoxin produced by group B Streptococcus. This organism causes sepsis and respiratory distress in human neonates (so-called early onset disease). This disease is marked by a strong inflammatory response only in the lung, with pulmonary sequestration of granulocytes and extensive capillary endothelial damage, and occurs only during the first few days after birth. We have found that a similar inflammatory response can be induced by i.v. infusion of picomole quantities of GBS toxin in the developing vasculature of transplanted tumors in mice and can significantly retard the tumor growth. When optimum treatment with GBS toxin was started shortly after tumor implantation, a majority of tumors in the mice regressed and the mice remained tumor-free for over 5 months. Some tumors regressed in mice receiving short-term treatment with GBS toxin, but recurred after the treatment was stopped. Median survival times were extended by all regimens and all doses of GBS toxin tested. No evidence of toxicity to the vasculature of other tissues was observed. GBS toxin is being tested for cancer therapy in humans.
Asunto(s)
Adenocarcinoma/terapia , Toxinas Bacterianas/uso terapéutico , Neoplasias Pulmonares/terapia , Polisacáridos Bacterianos/uso terapéutico , Streptococcus agalactiae , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/mortalidad , Animales , Línea Celular , Inyecciones Intravenosas , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/mortalidad , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Factores de TiempoRESUMEN
To determine the influence of an altered carotid body function on the laryngeal chemoreflex (LCR) response, reflex apnea was induced by laryngeal water stimulation during normoxia or acute hypoxia in unanesthetized awake lambs in which the ventilatory response to acute hypoxia was attenuated by prolonged postnatal hypoxemia. Prolonged hypoxemia (H) was induced in seven lambs for 12 d after birth through exposure to 0.10 fraction of inspired oxygen. Five control lambs were kept in 0.21 fraction of inspired oxygen. Studies were performed repeatedly during the first 7 wk after birth. The ventilatory response to LCR stimulation, expressed as a percent decrease in minute ventilation, was tested in 0.21, 0.14, and 0.10 fraction of inspired oxygen. H after birth resulted in a markedly increased inhibition of ventilation in response to LCR stimulation and postponed the age-related decrease in LCR response. A potential failure to recover from apnea occurred only in the H lambs, and in these lambs there was a significantly greater requirement for mechanical ventilation after LCR stimulation. Acute hypoxemia preceding LCR stimulation significantly attenuated the ventilatory response in both control and H lambs, with a stronger effect in the H lambs. There was no difference between the two groups in heart rate response to LCR stimulation. Acute hypoxemia significantly augmented reflex bradycardia in the H lambs. These results show that there is a relationship between H immediately after birth--which is known to delay resetting of carotid chemoreceptors--and augmented ventilatory inhibition in response to LCR stimulation. They do not confirm the theory that acute hypoxia reinforces reflex apnea.
Asunto(s)
Apnea/etiología , Hipoxia/complicaciones , Hipoxia/fisiopatología , Laringe/fisiopatología , Reflejo/fisiología , Animales , Animales Recién Nacidos , Apnea/fisiopatología , Apnea/terapia , Dióxido de Carbono/sangre , Células Quimiorreceptoras/fisiopatología , Modelos Animales de Enfermedad , Frecuencia Cardíaca/fisiología , Concentración de Iones de Hidrógeno , Hipoxia/sangre , Oxígeno/sangre , Estimulación Física , Respiración/fisiología , Respiración Artificial , OvinosRESUMEN
The effect of prolonged hypoxemia (H) after birth on the evolution of the ventilatory response to changes in arterial partial pressure of O2 was determined in unanesthetized, awake lambs. H was induced for 12 d after birth in seven lambs through exposure to 0.10 fraction of inspired O2 (FiO2). Five control (C) lambs were kept in 0.21 FiO2. The ventilatory response (percent increase from baseline) to acute hypoxia was tested with 0.14 FiO2 and 0.10 FiO2. The tonic activity of the peripheral chemoreceptors was assessed by the transient pure oxygen inhalation test (Dejours' test). The occlusion technique was used to measure the baseline neuromuscular drive of breathing. A markedly decreased early ventilatory response to acute hypoxia persisted in the H lambs for at least 5 wk after termination of H compared with the C group. The second phase of the response was significantly lower only at 12 d (the end of H) and was thereafter comparable to that in the C lambs. The ventilatory response to hyperoxia was significantly lower in the H lambs only at the end of hypoxemia at 12 d and rapidly normalized after return to normoxia. H did not significantly affect resting neuromuscular drive. These results show that postnatal maturation of the ventilatory response to changes in arterial partial pressure of O2 can be delayed by prolonged postnatal hypoxemia. The effect on the response to hyperoxia is transient, whereas the response to acute hypoxia is affected for an extended time. This study illustrates the importance of an adequate postnatal arterial partial pressure of O2 for the development of the ventilatory response to acute hypoxia.
Asunto(s)
Hipoxia/fisiopatología , Oxígeno/sangre , Respiración/fisiología , Animales , Animales Recién Nacidos , Dióxido de Carbono/sangre , Cuerpo Carotídeo/fisiopatología , Células Quimiorreceptoras/fisiopatología , Hipoxia/sangre , Mecánica Respiratoria/fisiología , Ovinos , Volumen de Ventilación Pulmonar/fisiología , Factores de TiempoRESUMEN
To describe the physiologic effects of surfactant treatment on gas exchange in human premature infants with hyaline membrane disease, functional residual capacity (FRC), tidal volume (VT), the alveolar portion of tidal volume (VA), alveolar ventilation (VA), nitrogen clearance index, effective breath fraction calculated as VA/VT, compliance of the respiratory system, and arterial oxygen and carbon dioxide tensions were measured in 17 patients before and 0.5, 2, and 6 h after the administration of a single dose of either a synthetic surfactant (SS), Exosurf (n = 10), or a bovine surfactant (BS), Survanta (n = 7). By 2 h, treatment with either BS or SS was followed by an increase in the arterial/alveolar ratio of PO2 (a/A) and in FRC (p < 0.01 for both a/A and FRC). The a/A and FRC improved sooner (p < 0.001) and to a greater extent (p < 0.01) after BS than after SS. Compliance of the respiratory system and VT were decreased after either BS or SS at 0.5 h (p < 0.01) and remained decreased after SS at 2 h (p < 0.01). There was no significant change in VA or VA after either BS or SS. Because FRC and a/A increased without an accompanying increase in VA, VA, or compliance of the respiratory system, we believe that the immediate increase in FRC in this study was caused by stabilization of gas exchange units already being ventilated in addition to recruitment of new units.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Productos Biológicos , Alcoholes Grasos/uso terapéutico , Enfermedad de la Membrana Hialina/fisiopatología , Enfermedad de la Membrana Hialina/terapia , Recien Nacido Prematuro , Fosforilcolina , Polietilenglicoles/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Peso al Nacer , Combinación de Medicamentos , Femenino , Edad Gestacional , Humanos , Concentración de Iones de Hidrógeno , Recién Nacido , Masculino , Oxígeno/sangre , Pruebas de Función RespiratoriaRESUMEN
An animal model for intrauterine surgical treatment of myelomeningocele is described using sheep. We report the technical feasibility of endoscopic intrauterine skin graft placement over surgically induced defects, including over exposed spinal cord. These grafts exclude amniotic fluid from the underlying lesion and provide a matrix for fetal skin growth below the graft. The potential for human application is discussed.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Fetales/cirugía , Histeroscopios , Meningomielocele/cirugía , Animales , Femenino , Enfermedades Fetales/patología , Meningomielocele/patología , Embarazo , Ovinos , Piel/patología , Trasplante de Piel/patología , Cicatrización de Heridas/fisiologíaRESUMEN
A group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress ("early-onset disease") produces a polysaccharide exotoxin (GBS toxin) that, when infused in sheep, causes lung pathophysiology similar to that seen in humans. Histological studies have demonstrated that GBS toxin induces a strong inflammatory response in the lung, with pulmonary sequestration of granulocytes and extensive capillary endothelial damage. The susceptibility of humans to GBS toxin is age-dependent and limited to about 4 days after birth. It is rarely evident thereafter. This suggests that the binding of GBS toxin to the target endothelium occurs via specific components in the developing lung endothelial cells of the newborn that are later lost. We report here that GBS toxin can also bind to developing endothelium associated with neoplasia and induce an inflammatory response. GBS toxin was shown by immunohistochemistry to bind to capillary endothelium of human large-cell carcinomas. In nude mice bearing human tumor xenografts, intravenously administered GBS toxin caused tumor necrosis and hemorrhagic lesions, and substantially inhibited the rate of growth of the tumors. In BALB/c mice bearing Madison lung tumors, GBS toxin induced an inflammatory response resulting in marked changes in tumor morphology, including vasodilation, endothelial and tumor cell necrosis, invasion of lymphocytes and macrophages, and capillary thrombosis. In these tumor models, no evidence of toxicity to the vasculature of other tissues was observed. The reported pathophysiology of GBS in human neonates, the lack of disease in non-neonates colonized with GBS, and these results suggest that GBS toxin may have potential as a well tolerated agent in cancer therapy of some human tumors.
Asunto(s)
Adenocarcinoma/terapia , Toxinas Bacterianas/uso terapéutico , Neoplasias Pulmonares/terapia , Polisacáridos Bacterianos/uso terapéutico , Adenocarcinoma/irrigación sanguínea , Animales , Toxinas Bacterianas/metabolismo , Sitios de Unión , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/irrigación sanguínea , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Polisacáridos Bacterianos/metabolismo , Análisis de RegresiónRESUMEN
Cardiac-related deflections in thoracic electrical impedance have been thought to correlate sufficiently well with cardiac stroke volume to be used as the basis for a noninvasive estimation of cardiac output. To determine more precisely the physiological origin of the impedance deflection (DZ), we regarded right ventricular stroke volume (SVa) as the sum of two components: 1) that part of SVa responsible for the transient increment in pulmonary blood volume within a cardiac cycle, SVa-v and 2) the remaining part of SVa, (SVa-SVa-v). SVa-v was measured in lambs by integration of the difference between pulmonary arterial and pulmonary venous flow. SVa and its components were varied experimentally by opening and closing an aorticocaval shunt or by inflating and deflating a cuff implanted around the pulmonary artery. DZ was measured using a tetrapolar disk electrode system. Multivariate linear regression analysis revealed that SVa-v had a significant positive effect on DZ, and, at the same time, (SVa-SVa-v) had a significant negative effect on DZ. In the pulmonary artery occluder model, the positive effect of SVa-v dominated the opposing negative effect of (SVa - SVa-v) so that the net effect of SVa on DZ was positive and significant. In the aorticocaval shunt model, these effects opposed each other to the extent that there was no significant correlation between SVa and DZ. These results shed new light on the physiological origin of DZ. They also demonstrate that use of DZ to measure acute changes in cardiac output may yield misleading results. Changes or the lack of changes in thoracic electrical impedance do not necessarily reflect cardiac output status.