摘要:

Glucocorticoids promote lung cell differentiation and thus enhance surfactant synthesis in the management of neonatal respiratory distress syndrome. Because they also accelerate differentiation in other targets, glucocorticoids may compromise physiologic responses that operate through specialized fetal-neonatal mechanisms. The current study explores one such process, the capacity to maintain cardiac function during hypoxia, a critical function in light of the hypoxia associated with parturition and with neonatal respiratory distress. Pregnant rats were given 0.05, 0.2, or 0.8 mg/kg of dexamethasone on gestational d 17, 18, and 19, and the response to hypoxia was assessed in the offspring on the day after birth. Dexamethasone produced a dose-dependent impairment of survival during exposure to 5% O2(5 kPa O2) for 120 min. ECG measurements showed that death in the dexamethasone-exposed animals was preceded by multiple arrhythmias and progressive atrioventricular conduction defects, terminating in cardiac arrest. Because maintenance of neonatal cardiac conduction during hypoxia depends on adrenergic mechanisms operating through adrenomedullary catecholamine release and actions at transiently expressed α2-receptors in the immature myocardium, we examined these mechanisms in control and dexamethasone-exposed neonates. Dexamethasone caused cardiac α2-receptors to disappear prematurely, an effect that was selective for this receptor population because no comparable changes were seen in α1-receptors. Under normal circumstances, neonatal adrenomedullary responses to hypoxia operate in the absence of functional sympathoadrenal innervation, and cardiac-sympathetic innervation does not play a significant role; in a similar fashion, the dexamethasone-exposed animals did not display alterations in the functional state of sympathetic innervation of the adrenal medulla or heart at birth. Nevertheless, adrenomedullary catecholamine levels and the secretory response to hypoxia were significantly impaired by prenatal dexamethasone exposure, probably as a result of adrenal atrophy caused by the glucocorticoid. These results indicate that exposure to glucocorticoids in doses commensurate with their therapeutic actions on lung function evokes premature loss of the unique fetal-neonatal adrenergic mechanisms that are required to preserve cardiac function during hypoxia.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Congenital diaphragmatic hernia, a highly lethal condition, displays at term the pulmonary biochemical and morphologic immaturity characteristic of premature delivery. We hypothesized that antenatal glucocorticoid, now the standard treatment to prevent hyaline membrane disease in premature human beings, might correct the parameters of the pulmonary biochemical and morphologic immaturity in severe congenital diaphragmatic hernia. A total of 112 fetal rats with or without nitrofcn-induced congenital diaphragmatic hernias from 34 pregnancies were treated antenatally with either saline or dexamethasone. Antenatal dexamethasone increased the lung disaturated phosphatidylcholine content, reduced the lung glycogen concentration, reduced the saccular septal thickness, and increased the mean saccular size and volume fraction of saccules in the lungs of rats with large congenital diaphragmatic hernia in comparison with similar rats not so treated. All differences were statistically significant. Antenatal glucocorticoid therapy was efficacious in treating rats with nitrofen-induced congenital diaphragmatic hernia. This encouraging finding warrants further investigation in a large animal model with surgically created congenital diaphragmatic hernia.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In newborn rats, antenatal thyroid stimulation with thyroid-releasing hormone is associated with developmental decreases in pulmonary antioxidant enzyme activities and decreased survival rates during prolonged hyperoxic exposure, with pathologic evidence of increased O2-induced lung damage. Propylthiouracil (PTU), in addition to its antithyroid effects, reportedly has antioxidant properties. To explore possible pulmonary protective effects from both the antithyroid and antioxidant properties of PTU, we administered PTU (0.015%) in drinking water to timed-pregnant rats for the final 10 d of gestation and during lactation; control rats received untreated water. The survival rate of the PTU-treated pups when placed in more than 95% O2at birth was consistently higher at all time periods in hyperoxia from 6 d [PTU, 81 of 81 (100%); control pups, 70 of 84 (83%); p < 0.01] to 14 d [PTU, 41 of 53 (77%); control pups = 14 of 56 (25%); p < 0.01]. Further evidence of increased tolerance to more than 95% O2in PTU pups included a significant decrease in the incidence of microscopic intraalveolar edema, decreased lipid peroxidation (malondialdehyde), and a significant increase in lung tissue surfactant-related phospholipids compared with O2-exposed control pups. No differences were present in lung structural maturation, antioxidant enzyme activity response to hyperoxia, or lung tissue O2radical formation in more than 95% O2. We conclude that PTU treatment has important postnatal effects that protect newborn rats against oxidant-induced lung injury and lethality during hyperoxia, which may be related to PTU inhibition of thyroid hormone production, effect on O2metabolism, or its direct antioxidant properties.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The purpose of this study was to evaluate the relationship between changes in minute ventilation (VE) and oxygen consumption (Vo2) in response to acute hypoxia in the newborn piglet. Twenty-five (mean ± SD; age, 4.7 ± 1.1 d; weight, 1451 ± 320 g) sedated, spontaneously breathing newborn piglets were studied. VE was measured by pneumotachography, and Vo2was measured by the open-circuit technique. Measurements were performed while the animals breathed room air and repeated after 10 min of hypoxia, which was induced by breathing 10% oxygen. Although the mean VE values during hypoxia displayed a typical biphasic ventilatory response, the individual pattern of this ventilatory response to hypoxia was variable. Thirteen animals sustained VE above baseline after 10 min of hypoxia, whereas the 12 remaining animals decreased VE after 10 min of hypoxia to values below their room air baseline. The Vo2values did not differ between groups during normoxia, and a similar decrease in Vo2occurred in both groups after 10 min of hypoxia. Further-more, no correlation was observed between changes in VE and Vo2during hypoxia either in absolute values or in the percent change from room air baseline. Arterial Po2decreased similarly in both groups, but Paco2decreased significantly only in the group that sustained VE above baseline after 10 min of hypoxia. These data demonstrate that in this animal model the hypoxic ventilatory depression is not determined by the decrease in Vo2that occurs during hypoxia.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To study the effect of atrial natriuretic peptide (ANP) on vascular permeation of albumin in the fetus, ANP (167–600 ng/min) was infused into eight ovine fetuses and saline vehicle was infused into eight twin controls (gestational age 127 ± 3 d) over a 50-min period. Using two different radiolabeled albumin markers, we determined the tissue to blood isotope ratio (TBIR), an index of albumin permeation, and the albumin clearance. Although ANP had no hemodynamic effect, a marked increase in the hematocrit was observed in ANP-infused fetuses compared with initial values (0.37 ± 0.04vs0.42 ± 0.04, p < 0.005) but was unchanged in the twin fetuses receiving saline vehicle (0.35 ± 0.03versus0.35 ± 0.02). TBIR and albumin permeation were increased in combined tissues of ANP-infused fetuses compared with saline controls (TBIR: 1.49 ± 0.58versus1.29 ± 0.3, p < 0.001; albumin clearance: 1091 ± 1279versus827 ± 1464 mL/g/min, p < 0.01). In individual tissues, TBIR was significantly increased in skin (2.88 ± 0.67versus1.55 ± 0.35, p < 0.02), muscle (1.6 ± 0.27 versus 1.24 ± 0.26, p < 0.02), adrenal (1.33 ± 0.10 versus 1.13 ± 0.15, p < 0.02), bone (1.67 ± 0.45versus1.20 ± 0.40, p < 0.02), kidney (1.52 ± 0.25versus1.24 ± 0.26, p < 0.03), and gut (1.69 ± 0.20versus1.39 ± 0.34, p < 0.03). Albumin clearance was higher in most tissues but reached statistical significance only in skin (2135 ± 944versus775 ± 847 mL/g/min, p < 0.05) and bone (1012 ± 1107versus428 ±482 nL/g/min, p < 0.05). We conclude that overall vascular filtration is higher in the fetus than the adult. Infusion of ANP causes fetal hemoconcentration, decreases blood volume, and enhances vascular permeation of albumin in most tissues, particularly fetal skin. We speculate that the cardiac atria, by secreting ANP, participate in blood volume regulation by maintaining a critical balance between the intravascular and extravascular fluid compartments. Dysregulation of the ANP system might result in fetal hydrops.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We operated on 14 singleton fetal sheep at 126 ± 3 d gestation and produced nonimmune anemia in 12 of them to study the mechanisms responsible for hydrops. Two fetuses served as controls. Partial exchange transfusions were performed daily to lower the hematocrit while we measured arterial blood gas tensions; IIb concentration; oxygen saturation; arterial oxygen content; aortic, central venous, and umbilical venous pressures; heart rate; plasma protein concentration; and colloid osmotic pressure. Hydrops developed in six of the fetuses and did not develop in six others, although both groups were anemic to the same degree, had similar total amounts of blood withdrawn based on kilograms of dry weight, and had similar dry weights. The fetuses who had hydrops became anemic more rapidly than the nonhydropic fetus (5.2 ±1.9versus8.3 ± 2.7 d; p < 0.05) and had more blood exchanged each day (197 ± 56versus113 ± 28 mL/kg dry body wt/d; p = 0.008). Umbilical venous pressures increased in both hydropic and nonhydropic fetuses, but the central venous pressure became elevated only in the hydropic fetuses. Changes in heart rate, arterial pII and blood gas tensions, arterial oxygen content, plasma protein concentration, colloid osmotic pressure, and aortic pressure were similar in both groups. At autopsy the hydropic fetuses had 78 ± 47 mL of ascites and 20 ± 26 mL of pleural fluid. The water content of the hydropic fetuses and of the hydropic fetuses' placentas was greater than that of the nonhydropic fetuses. We conclude that a more rapid development of anemia is associated with hydrops in fetal sheep. The fetal sheep that became hydropic also had an elevated central venous pressure.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The prostaglandin H-synthase inhibitor in-domethacin decreases cerebral blood flow (CBF) in newborn pigs. The duration of this effect on CBF has not been established in piglets in the awake state. The purpose of the study was to determine in awake piglets the duration of cerebral vascular responses to a single dose of indo-methacin and the CBF responses to a second dose of indomethacin. Two groups of animals were studied. Newborn pigs 3–5 d old were instrumented the day before experiments. On the next day, sagittal sinus catheters were placed after the piglets were given local anesthesia. The experiments were performed on unanesthetized piglets that were put in a cloth sling and fed via an orogastric tube. In the first group of piglets (n = 8), the baseline CBF (microspheres) and cerebral metabolic rate for oxygen (CMRO2) measurements were made 30 min after sagittal sinus catheter placement. Indomethacin (5 mg/kg i.v.) was then given slowly over a 5-min period, and CBF and CMRO2measurements were made at 10, 60, 120, and 240 min. Total CBF (mean ± SEM) decreased significantly after indomethacin administration from 98 ± 12 mLmin−1100 g−1to 50 ± 3, 56 ± 7, and 70 ± 11 mLmin−1100 g−1at 10, 60, and 120 min, respectively. The total CBF returned to baseline levels at 240 min (101 ± 16 mL−1min−1100 g−1). After indomethacin administration, the CMRO2decreased significantly from the baseline level of 3.57 ± 0.52 mL O2/100 g−1min−1to 2.50 ± 0.39, 2.69 ± 0.52, and 2.41 ± 0.31 mL O2/100 g−1min−1at 10, 60, and 120 min, respectively. The CMRO2returned to baseline by 240 min (3.09 ±0.46 mL O2/100 g−1min−1). In the first group of piglets, we observed maximum CBF responses between 10–60 min of indomethacin administration and return of CBF to baseline values within 4 h. Therefore, in another group of piglets (n = 10) we determined the effect of a repeated dose of indomethacin on CBF. The first baseline CBF measurements were made, and then indomethacin (5 mg/kg i.v.) was given. The CBF measurements were repeated at 30 min. Four hours later, a second baseline CBF determination was made, and a second dose of indomethacin (5 mg/kg i.v.) was administered. Thirty minutes after the second dose of indomethacin, CBF was measured again. Total CBF decreased significantly (p < 0.05) 30 min after the first dose of indomethacin (91 ± 10 to 52 ± 5 mLmin−1100 g−1). By 4 h, total and regional CBF returned to baseline values (NS). With the second dose of indomethacin, total CBF again decreased significantly (p < 0.05) from baseline values (from 77 ± 4 to 55 ± 6 mLmin−1100 g−1). We conclude that i.v. administration of indomethacin at 5 mg/kg to unanesthetized piglets results in decreased CBF and CMRO2, which return to baseline levels by 4 h after treatment, and that a second dose of indomethacin also results in a decrease in CBF similar to that evoked by the first dose.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Early-onset neonatal group B β-hemolytic streptococcus (GBS) infection exhibits pathophysiologic characteristics of a toxic shock syndrome, in which a cascade of inflammatory mediators are involved. Thromboxane A2(TXA2) is thought to play an important role as a mediator of the pulmonary response to GBS toxin, because high lung lymph concentrations of a TXA2metabolite have been observed after GBS toxin injections in sheep. The aim of this study was to evaluate the effects of a selective antagonist of the TXA2-prostaglandin endoperoxide receptor (SQ 29,548). Six unanesthctized young lambs, each serving as its own control, were given SQ 29,548 or vehicle control followed by GBS toxin challenge. Hemodynamic and lung function (lung mechanics, lung volume, ventilation) responses were followed for 5 h. When compared with the control studies, treatment with SQ 29,548 significantly altered the response to GBS toxin. SQ 29,548 reduced the increase in pulmonary and systemic vascular resistance, improved cardiac output and stroke volume, improved dynamic lung compliance but not airway resistance, and improved oxygenation. The attenuating effect of SQ 29,548 was most pronounced during the first phase of toxin response (15–90 min after toxin infusion), but significant treatment effects were also seen during the second phase (120–300 min after toxin infusion). This study demonstrates that TXA2is an important mediator of the response to GBS toxin and is responsible for hemodynamic and lung function changes. Thromboxanc receptor blockade may offer a potential therapeutic approach to infants with severe early-onset GBS sepsis.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To better understand the impact of severe illness on the amino acid economy and nutritional needs of pediatric patients, we studied plasma phenylalanine and tyrosine kinetics in eleven critically ill patients (six full-term newborns and five young infants). Within 48 h of the diagnosis of sepsis they were given primed constant i.v. infusions of L-[1-13C]phenylalanine and L-[3,3,2H2]tyrosine for 4 h. Routine nutritional support continued during this period by parentcral administration of dextrose, lipid emulsion, and an amino acid mixture low in tyrosine. Phenylalanine and tyrosine fluxes and rate of phenylalanine hydroxylation did not differ significantly between the two age groups, and so the data were combined for evaluation. For the entire group, values (μmol-kg−1-h−1; mean ± SD) for phenylalanine and tyrosine fluxes and rate of phenylalanine hydroxylation were 132 ± 24, 66 ± 16, and 29 ± 12, respectively. Plasma phenylalanine to tyrosine concentration ratio was 1.67 ± 0.6. From a comparison of the rate of phenylalanine hydroxylation with measured phenylalanine intakes, it was concluded that their routine, clinical nutritional support was inadequate to achieve body phenylalanine balance. In comparison with published data, the relative rate of phenylalanine hydroxylation appears to be high. We speculate that tyrosine is a conditionally indispensable amino acid under these conditions; it would be desirable to establish the intake levels and ratio of phenylalanine to tyrosine that effectively support aromatic amino acid balance in these critically ill patients.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Using a sensitive technique measuring14CO2production from radiolabeled malate, we examined malic enzyme activity in both adult and newborn rat lung tissue and in L2 cells, a cell culture line of type II pneumocytes. Malic enzyme was present in both cytosolic and mitochondrial fractions. Time course experiments demonstrated a linear rate after the initial 10 min, up to 30 min. The optimal pH in the cytosolic fraction was 8.0, whereas maximal mitochondrial malic enzyme activity occurred at pII 7.0. The mitochondrial fraction exhibited biphasic kinetics over the 200-fold range of concentrations examined. The high-affinity Km was 0.16 mmol with Vmaxof 7.11 nmol/mg protein/min. The low-affinity Km was 6.95 mmol, with Vmaxof 31.82 nmol/mg protein/min. In the cytosol there was a single Km of 0.30 mmol and Vmaxof 5.95 nmol/mg protein/min. In paired experiments examining differences between 1-d-old and adult rat lung, significantly higher total and mitochondrial malic enzyme activity-occurred in the newborn as compared with the adult. Malic enzyme activity was also present in the L2 cells. The finding of malic enzyme activity in the lung suggests that cytosolic malic enzyme may play a role in generating NADPH needed in the lung for fatty acid synthesis. These findings of developmental differences in malic enzyme activity suggest that alternate substrates such as anaplerotic amino acids may be used in the young animal as energy substrates by way of the tricarboxylic acid cycle.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID