Protective effect of pentoxifylline on phorbol myristate acetate-induced acute lung injury in rats

The pathogenesis of adult respiratory distress syndrome (ARDS) is not clear, and its therapy is still a problem. Pentoxifylline, a methylxanthine derivative, can inhibit phosphodiesterase activity and thus increase the intracellular cAMP. There are also some hypotheses that pentoxifylline can attenuate pulmonary edema. In order to evaluate the protective effect of pentoxifylline in acute lung injury, we set up an isolated lung perfusion model in rats and induced experimental acute lung injury similar to ARDS by intravenously infused phorbol myristate acetate (PMA) 7.5 micrograms/300 g body weight. Four groups of experimental rats were studied: group 1, normal control group, neither PMA nor pentoxifylline was used in 6 rats; group 2 (acute lung injury group), only PMA was infused in 8 rats; group 3 (protective group), pentoxifylline 100 mg/300 g body weight was given intravenously before PMA infusion in 6 rats; group 4, only pentoxifylline was given in 6 rats. Pulmonary arterial pressure (PAP) as well as lung weight changes were recorded before and 5, 10, 15, 20 and 25 minutes after drug injection. Bronchial lavage fluids were then measured for albumin concentration. We found that PAP was strikingly increased in group 2 (54.0 +/- 8.8 mmHg), but the increase was significantly reduced in group 3 (29.8 +/- 5.8 mmHg, p less than 0.001). Similarly, the lung weight gain was markedly increased in group 2 (4.69 +/- 1.28 g), but was significantly attenuated in group 3 (1.25 +/- 1.60 g, p less than 0.001). There was no apparent change in PAP and lung weight gain throughout the entire procedure in groups 1 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchoalveolar lavage plus surfactant in a piglet model of meconium aspiration syndrome

INTRODUCTION: Meconium aspiration produces airway obstruction and surfactant inhibition. Bronchoalveolar lavage (BAL) and surfactant replacement have been proposed as treatments for the syndrome. OBJECTIVE: To evaluate the effect of BAL with normal saline followed by a supplementary dose of surfactant in a piglet model of meconium aspiration syndrome. METHODS: 15 newborn piglets were used in the study. The animals were ventilated with fixed settings. After inhalation of 4 ml/kg of diluted meconium, the piglets were randomized into three groups: group I (n = 5) - tracheal aspiration without BAL; group II (n = 5) - BAL with normal saline (15 ml/kg), and group III (n = 5) - BAL with normal saline (15 ml/kg) followed by a supplementary dose of surfactant (Curosurf(R) 100 mg/kg). Arterial blood gas samples were obtained 30 min and 6 h after the inhalation of meconium. RESULTS: A significant increase of PaO(2 )values at 6 h after treatment was only observed in group III (from 51 +/- 13 to 189 +/- 115 mm Hg; p = 0.04). At this time, PaO(2) in group III was significantly higher compared to group II (189 +/- 115 and 37 +/- 11 mm Hg, respectively; p = 0.023) and showed a borderline significance when compared to group I (p = 0.066). CONCLUSION: BAL with normal saline followed by a supplementary dose of surfactant may improve oxygenation in an experimental piglet model of meconium aspiration syndrome.     

Intratracheal albumin reduces interleukin-8 in tracheobronchial aspirates in piglets after meconium aspiration

Meconium aspiration induces pulmonary inflammation and reduces surfactant function. We hypothesized that albumin mixed with meconium attenuates pulmonary inflammation and improves surfactant function after meconium aspiration. We measured the concentration of free fatty acids (FFA) in the meconium (110 mg dry weight/mL) and added albumin to provide a molar FFA:albumin ratio of 1:1. Newborn piglets, 0-2 day of age, artificially ventilated and exposed to hypoxemia by ventilation with 8% O2, were randomized to group A receiving meconium (n = 12), or group B receiving meconium + albumin (n = 12), 3 ml/kg intratracheally. The animals were reoxygenated for 8 h. Reoxygenation was started when mean arterial blood pressure was < 20 mm Hg or base excess was < -20 mmol/L. During 8 h of reoxygenation the interleukin-8 concentrations in tracheobronchial aspirates increased 5-fold more in the meconium vs. the meconium + albumin groups (93 +/- 56 vs. 18 +/- 4 pg/mL, p < 0.005). There were no differences between the groups for tumor necrosis factor alpha in tracheobronchial aspirates, recruitment of inflammatory cells in the airspaces or surfactant function in bronchoalveolar lavage fluid. In conclusion, albumin significantly decreased interleukin-8 concentrations in tracheobronchial aspirates after meconium aspiration.     

Propranolol inhibits the maturational effect of adrenocorticotropin in the fetal sheep lung

We reported previously that metyrapone inhibited the maturational effect of adrenocorticotropin in the fetal sheep lung, even in the presence of exogenous glucocorticoids. To examine the role of beta-adrenergic input in this response we examined lung maturation in fetal sheep treated for 100 hours in vivo with adrenocorticotropin (66 ng/min for 15 minutes every 2 hours, n = 5); adrenocorticotropin plus propranolol (40 micrograms/min, n = 4), or saline solution (n = 8). Pulmonary maturation was assessed by pressure-volume curves, phospholipid content, and morphologic features. The basal cortisol level rose from less than 5 to 32.0 +/- 12.1 and 83.5 +/- 8.0 ng/ml in the adrenocorticotropin and adrenocorticotropin plus propranolol groups, respectively. The adrenal:body weight ratio (X 10(-4)) rose from 1.43 +/- 0.12 in the saline solution group to 2.90 +/- 0.16 and 2.51 +/- 0.14 in the adrenocorticotropin and adrenocorticotropin plus propranolol groups, respectively. Lung distensibility (milliliters of air per gram of lung) rose from 1.10 +/- 0.14 to 1.90 +/- 0.20 in the adrenocorticotropin group but was unchanged (0.98 +/- 0.24) in the adrenocorticotropin plus propranolol group. Phosphatidylcholine (milligrams per gram of lung) in the lung lavage rose from 0.07 +/- 0.02 to 0.23 +/- 0.11 in the adrenocorticotropin group but was not significantly changed (0.12 +/- 0.06) in the adrenocorticotropin plus propranolol group. We conclude that propranolol inhibits the maturational effects of adrenocorticotropin on the fetal lung, which implies that the mechanism of pulmonary maturation is not solely dependent on endogenous cortisol and must be mediated, at least in part, through adrenergic responses.     

Discordant accelerated pulmonary maturation after adrenocorticotropic hormone-induced labor in twin sheep fetuses

To examine the role of parturition on lung maturation in sheep, we studied parameters of lung development in singleton fetuses treated with pulsatile adrenocorticotropic hormone or saline solution from day 127 or twin pregnancies in which one fetus only received pulsatile adrenocorticotropic hormone from day 127 until labor occurred. These parameters were compared with those of term fetuses (145 days). Pulsatile adrenocorticotropic hormone provoked labor in a mean (+/- SEM) of 102.6 +/- 6.6 and 181.0 +/- 18.0 hours in single and twin pregnancies, respectively. Adrenal/body weight ratios increased similarly in adrenocorticotropic hormone-treated single and twin fetuses at delivery, and basal cortisol levels were two- to threefold higher prepartum in adrenocorticotropic hormone-treated fetuses. Little change in plasma cortisol levels occurred in singletons treated with saline solution or in twins not infused with adrenocorticotropic hormone. The lung weight/body weight was not altered in any group. Lung distensibility and stability were doubled to term values in fetuses treated with pulsatile adrenocorticotropic hormone compared with controls and untreated twins. Mean lavage phosphatidylcholine levels rose from 0.07 to 0.11 mg/gm in saline solution-treated or untreated fetuses to 0.20 to 0.23 mg/gm in pulsatile adrenocorticotropic hormone-treated singletons or twins, compared with 0.63 mg/gm at term. Phosphatidylcholine production increased from 0.51 dpm/gm/hr in saline solution-treated fetuses to 0.73 and 0.89 dpm/gm/hr in the single and twin pulsatile adrenocorticotropic hormone-infused fetuses, respectively; phosphatidylcholine production was 0.62 dpm/gm/hr in the noninfused twin. Lungs of twins treated with pulsatile adrenocorticotropic hormone were morphologically more mature than those of untreated twins. We conclude that fetal endocrine responses to exogenous adrenocorticotropic hormone, rather than the stimuli associated with labor per se, are responsible for lung maturation in the fetal sheep.     

Fetal monkey surfactants after intra-amniotic or maternal administration of betamethasone and thyroid hormone

OBJECTIVE: To compare direct intra-amniotic injection of betamethasone and thyroxine (T4) with maternal treatment and controls for accelerating pulmonary surfactant production. METHODS: Twelve pregnant monkeys (Macaca mulatta) on gestational day 125 (term 165 +/- 10 days) had surfactant protein A and B concentrations measured in amniotic fluid. In four controls, normal saline was injected into the amniotic fluid; four others (intra-amniotic) received intra-amniotic betamethasone (1 mg) and T4 (60 microg); and in four others (maternal), the dam was given betamethasone (12 mg) intramuscularly, repeated in 24 hours, plus TRH (400 microg) intravenously, repeated every 6 hours for 24 hours. Seventy-two hours after the initial amniocentesis, a hysterotomy was performed and fetal tissue and amniotic fluid harvested for determination of surfactant protein A and B concentrations and immunohistochemical staining for surfactant protein A. RESULTS: Amniotic fluid surfactant protein A was higher with intra-amniotic injection than with maternal treatment (P <.04) or controls (P =.07). Amniotic fluid surfactant protein B was higher in the intra-amniotic group than in controls (P =.06). Immunohistochemical staining for surfactant protein A in the lung tissue was increased in the intra-amniotic group compared with controls (0.145 +/- 0.01 versus 0.097 +/- 0.001, percent positive staining for surfactant protein A cells per lung tissue cells; P <.03). Birth weight was greater in the intra-amniotic group compared with the maternal group (P <.03) although not different from the controls. Finally, gut motility and the presence of formed meconium were increased in the intra-amniotic group compared with the other groups (P <.05). CONCLUSION: Intra-amniotic injection of betamethasone and T4 enhanced lung (and possibly intestinal) maturation of the preterm rhesus fetal monkey compared with maternal injections.     

Pulmonary function after surfactant lung lavage followed by surfactant administration in infants with severe meconium aspiration syndrome.

OBJECTIVE: The effect of surfactant lung lavage (SLL) on pulmonary function was examined in neonates with severe form of meconium aspiration syndrome (MAS) (mean +/- standard deviation: birth weight, 3178.1 +/- 237.6 g; gestational age, 37.7 +/- 1.8 weeks). METHODS: The infants were on mechanical ventilation and were subjected to SLL with Survanta. Dynamic compliance (Cdyn), airway resistance (Raw) and mean airway pressure (MAP) were obtained with use of the pneumotachometric method. Measurements of Cdyn, Raw, MAP and time constant (Tc) were compared in the study and control groups and between the groups before SLL and 24 and 48 h after SLL. RESULTS: A significant increase in Cdyn (from 1.06 +/- 0.23 to 2.12 +/- 0.99 (ml/cmH(2)O)/kg) (p < 0.05) and a drop in both Raw (from 264.7 +/- 41.5 to 146.6 +/- 39.4 (cmH(2)O/l)/s) and MAP (from 12.4 +/- 3.6 to 5.4 +/- 2.1 cmH(2)O) were observed 48 hours after SLL. CONCLUSIONS: These data suggest that SLL is associated with a rapid and significant improvement in pulmonary mechanics, together with an improvement in oxygenation, in newborns with severe MAS. We found that the beneficial effects of SLL on pulmonary mechanics persisted for at least 48 h after introduction of the procedure.     

Innovation in surfactant therapy I: surfactant lavage and surfactant administration by fluid bolus using minimally invasive techniques

Innovation in the field of exogenous surfactant therapy continues more than two decades after the drug became commercially available. One such innovation, lung lavage using dilute surfactant, has been investigated in both laboratory and clinical settings as a treatment for meconium aspiration syndrome (MAS). Studies in animal models of MAS have affirmed that dilute surfactant lavage can remove meconium from the lung, with resultant improvement in lung function. In human infants both non-randomised studies and two randomised controlled trials have demonstrated a potential benefit of dilute surfactant lavage over standard care. The largest clinical trial, performed by our research group in infants with severe MAS, found that lung lavage using two 15-ml/kg aliquots of dilute surfactant did not reduce the duration of respiratory support, but did appear to reduce the composite outcome of death or need for extracorporeal membrane oxygenation. A further trial of lavage therapy is planned to more precisely define the effect on survival. Innovative approaches to surfactant therapy have also extended to the preterm infant, for whom the more widespread use of continuous positive airway pressure (CPAP) has meant delaying or avoiding administration of surfactant. In an effort to circumvent this problem, less invasive techniques of bolus surfactant therapy have been trialled, including instillation directly into the pharynx, via laryngeal mask and via brief tracheal catheterisation. In a recent clinical trial, instillation of surfactant into the trachea using a flexible feeding tube was found to reduce the need for subsequent intubation. We have developed an alternative method of brief tracheal catheterisation in which surfactant is delivered via a semi-rigid vascular catheter inserted through the vocal cords under direct vision. In studies to date, this technique has been relatively easy to perform, and resulted in rapid improvement in lung function and reduced need for subsequent ventilation and duration of oxygen therapy. We are now commencing large-scale clinical trials of this method in preterm infants on CPAP.     

Effect of aminophylline on lung maturation in preterm rabbit fetuses

Pregnant rabbit does were treated intravenously with aminophylline (6 mg/kg/day) from the twenty-fifth day after the day of mating, and the fetuses were delivered by hysterotomy on the twenty-eighth day. One group of neonates was breathing air, and another group 100% oxygen. Lung mechanics were evaluated in the newborn animals during spontaneous or artificial ventilation, and the lungs were studied histologically with particular reference to the alveolar volume density. In one series of experiments, the lungs were washed and the lavage fluid was analyzed for phosphatidylcholine and phosphatidylglycerol. Aminophylline-treated litters had greater body weights, an improved survival rate, and an increased amount of phosphatidylglycerol in lung lavage fluid. Respiratory frequency was increased in aminophylline-treated animals breathing air, but data on lung compliance showed no significant difference between treated and control animals. In the present model, the beneficial effect of aminophylline can be attributed largely to a combination of accelerated fetal growth and improved postnatal regulation of breathing and less to a specific influence on the biochemical and functional maturation of the lung.     

Cerebral hemodynamics after exogenous surfactant administration for respiratory distress syndrome in piglet model

OBJECTIVE: The rapid improvement of lung function after exogenous surfactant treatment for respiratory distress syndrome (RDS) can affect the functions of several other systems, which includes cerebral blood flow volume (CBF). To evaluate the change in CBF after treatment with exogenous surfactant, we measured CBF in a newborn piglet model with RDS. METHOD: After the lung lavage with normal saline, ten animals under mechanical ventilation were administered either 120 mg/kg surfactant-TA (Surfacten) or air placebo. Heart rate, blood pressure, dynamic lung compliance (Cdyn), PaO2, PaCO2, and CBF were recorded before and every 15 min after surfactant treatment up to 120 min. RESULTS: Cdyn was improved significantly at 45 min and later after treatment; that of the control group remained unchanged. PaO2 increased and PaCO2 decreased significantly after surfactant treatment in both groups. However, the improvement was significantly less in the control group. CBF significantly decreased by about 30% in the control group, and by about 50% in the treated group at 120 min, with a significant difference between groups. Almost 70% of the changes in CBF were attributable to changes in PaCO2 by multivariate regression analysis. CONCLUSIONS: Treatment with exogenous surfactant improves lung compliance, and has little effect on CBF itself. The drop in levels of PaCO2 after treatment, however, had a strong relationship with decreases in CBF.     

Intra-amniotic corticosteroids for preterm lung maturation in sheep

OBJECTIVE: The purpose of this study was to compare efficacy on fetal lung maturation of intra-amniotic betamethasone or budesonide with the efficacy of maternal intramuscular betamethasone. STUDY DESIGN: Pregnant ewes received intra-amniotic betamethasone (0.5 mg/kg or 2 mg/kg fetal weight), intra-amniotic budesonide (0.5 mg/kg or 2 mg/kg), maternal intramuscular betamethasone (0.5 mg/kg maternal weight), intra-amniotic saline solution, or maternal saline solution. Lambs were delivered 2 or 7 days later, at 124 days of gestation for measurement of respiratory system compliance, ventilatory efficiency index, and surfactant levels. RESULTS: Lung function increased 2 days after maternal betamethasone, intra-amniotic betamethasone (2 mg/kg), and intra-amniotic budesonide (2 mg/kg) administration and 7 days after maternal betamethasone or intra-amniotic budesonide (2.0 mg/kg) administration. Lung function was not improved 7 days after intra-amniotic betamethasone (2.0 mg/kg) administration or 2 days after intra-amniotic betamethasone (0.5 mg/kg) or intra-amniotic budesonide (0.5 mg/kg) administration. Intra-amniotic corticosteroid administration increased fetal death and respiratory morbidity. CONCLUSION: Intra-amniotic corticosteroid administration improved preterm lung function, but the associated morbidity and mortality rates suggest that they are not suitable for clinical use.     

Treatment of severe meconium aspiration syndrome with dilute surfactant lavage.

BACKGROUND AND PURPOSE: Despite the development of new adjuvant therapies, meconium aspiration syndrome (MAS) remains a serious respiratory disorder in neonates. Surfactant inactivation by meconium can be overcome by use of exogenous surfactant. This study sought to assess the efficacy and safety of dilute surfactant lavage at 2 different concentrations to treat severe MAS. METHODS: We retrospectively reviewed the charts of all term infants with a diagnosis of MAS who had an oxygenation index (OI) > 20 during a 2-year period. Tracheobronchial lavage was performed with a dilute surfactant suspension (5 mg/mL or 10 mg/mL) to reach a total dose of 60 to 70 mg/kg of phospholipid, administered in aliquots of 2 mL. RESULTS: The records of 22 patients were reviewed, of whom 12 had undergone lavage. These patients were subdivided into low-concentration (surfactant concentration, 5 mg/mL; n = 6) and high-concentration (surfactant concentration, 10 mg/mL; n = 6) subgroups. There were no significant differences in demographic characteristics between these 2 subgroups. The lavaged infants had a significantly higher arterial partial pressure of oxygen (PaO(2)) 24 hours after lavage than the infants without lavage (178.3 mm Hg vs 80.6 mm Hg, p < 0.05). The incidence of pneumothorax (1/12 vs 7/10, p < 0.05) and requirement for inhaled nitric oxide (5/12 vs 9/10, p < 0.05) were significantly lower in the lavaged group. All infants tolerated the procedure well except for 2 with transient complications. There were no significant differences in duration of lavage, response and complications between subgroups lavaged at low and high surfactant concentration. CONCLUSIONS: Early lavage with dilute surfactant solution at a phospholipid concentration of either 5 mg/mL or 10 mg/mL is effective for the treatment of severe MAS. Further large-scale, prospective, randomized, controlled trials are necessary to establish the optimal dose, concentration, surfactant product, and instillation method of this treatment before it can be recommended for routine use.     

Effects of intrauterine growth restriction on lung liquid dynamics and lung development in fetal sheep

OBJECTIVE: The aim of this study was to determine the effects of intrauterine growth restriction on fetal lung liquid and lung development. STUDY DESIGN: Intrauterine growth restriction was induced in 7 fetal sheep from 120 to 140 days' gestation (term, approximately 147 days' gestation) by umbilicoplacental embolization. We used 6 control fetuses. Volumes and production rates of fetal lung liquid were measured, and lungs were removed post mortem (140 days' gestation) for analysis of concentrations of deoxyribonucleic acid, protein, and messenger ribonucleic acid for surfactant proteins A, B, and C. RESULTS: Umbilicoplacental embolization induced fetal hypoxemia, hypoglycemia, and intrauterine growth restriction. At 140 days' gestation lung weight was reduced by 34%, and the fetal lung liquid production rate (15.9 +/- 1.8 mL/h for intrauterine growth restriction vs 24.8 +/- 3.9 mL/h for control) and volume (110.9 +/- 16.3 mL for intrauterine growth restriction vs 178.1 +/- 11.9 mL for control) were reduced in the intrauterine growth restriction group. After adjustment for body weight, however, values were not different from those in the control group. Pulmonary deoxyribonucleic acid and plasma cortisol concentrations were elevated by intrauterine growth restriction, but levels of messenger ribonucleic acid for surfactant proteins were unchanged. CONCLUSION: In intrauterine growth restriction, lung liquid and lung growth were proportionate to body weight, and surfactant protein expression was unaffected. Alterations in lung deoxyribonucleic acid concentrations suggest that the lungs may be structurally immature.     

Exogenous surfactant for treatment of respiratory distress syndrome in premature infants

A prospective, randomized and controlled trial was conducted to evaluate the efficacy and safety of surfactant in the treatment of respiratory distress syndrome (RDS) in infants. Eighteen premature infants with RDS were studied. Group I consisted of 9 premature infants with a mean birth weight of 1,455 +/- 265.9 g and a mean gestational age of 31.4 +/- 1.3 weeks. Group II consisted of 9 premature infants with a mean birth weight of 1,411 +/- 379.0 g and a mean gestational age of 30.6 +/- 1.7 weeks. Reconstituted bovine surfactant (Surfactant TA, Tokyo Tanabe Co., Japan), 120 mg/kg body weight was suspended in 4 ml normal saline and delivered to the lungs of the patients in group I through an endotracheal tube via a catheter in five divided doses (mean age at this point was 5.7 +/- 4.5 hours). An air placebo (4 ml per kilogram) was given to the patients in group II. The results showed that significant improvement in oxygenation, characterized by (1) an increase in the ratio of arterial to alveolar oxygen tension; (2) a decrease in the fractional inspiratory oxygen concentration; and (3) changes in mean airway pressure and ventilatory index, were noted in the surfactant-treated group. Pneumothorax was found in one surfactant-treated infant and one control infant. Pulmonary interstitial emphysema was found in one control infant. One control infant later developed bronchopulmonary dysplasia. Four (44.4%) of the surfactant-treated infants and four (44.4%) of the control infants had evidence of patient ductus arteriosus. The mean duration from birth to extubation in the surfactant-treated infants was 121.9 +/- 1.9 hours.     

Epinephrine inhibits tracheal occlusion induced lung growth in fetal sheep

OBJECTIVE: Although the mechanisms responsible for lung growth following tracheal occlusion (TO) are not fully understood, lung fluid accumulation is a requirement for growth to occur. It is known that betamimetics such as epinephrine (Epi), terbutaline, and ritodrine inhibit fetal lung fluid production late in gestation. We hypothesized that continuous infusion of Epi would have a detrimental effect on lung growth following TO in the fetal sheep model. METHODS: Twenty fetal lambs were divided into four groups. Group 1: no TO without Epi (n = 4); group 2: TO without Epi (n = 4); group 3: no TO with Epi (n = 5), and group 4: TO with Epi (n = 7). TO was performed on days 130-134 of gestation (full term = 145 days). In groups 3 and 4, Epi was infused into the fetus at a rate of 2 microg/min using a miniosmotic pump implanted subcutaneously at the time of TO. The fetuses were sacrificed after 4 days, and lung volume (LV, ml/kg), drained lung fluid (LF, ml/kg), wet lung weight/body weight ratio (LW/BW, %), whole right-lung dry weight per body weight ratio (dRLW/BW, g/kg), volume density of lung parenchyma (v(Vp)), and right-lung DNA and protein contents were compared among the four groups by one-way Anova. RESULTS: LW/BW and dRLW/BW of group 4 (3.91 +/- 0.52 and 2.10 +/- 0.28, mean +/- SD) were significantly lower than those of group 2 (5.18 +/- 0.57 and 2.67 +/- 0.15) and were not statistically significantly different from those of group 1 or 3. LV, LF, V(Vp), and DNA and protein contents all showed a similar trend. CONCLUSIONS: Continuous infusion of Epi to the fetus results in less fluid accumulation within the TO lungs and abolishes significant lung growth after TO in the late-gestation fetal lamb. Drugs affecting lung fluid secretion may have a major impact on TO-induced lung growth.     

Magnesium sulfate effectively reduces blood pressure in an animal model of preeclampsia.

OBJECTIVE: We tested the ability of magnesium sulfate to reduce hypertension and neonatal growth retardation in an animal model of preeclampsia. STUDY DESIGN: On day 17 of pregnancy, osmotic minipumps were inserted subcutaneously to continuously deliver either vehicle (saline control group), or N-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day), or L-NAME (50 mg/kg/day) in combination with magnesium sulfate (60 mg/kg/day). Prior to insertion, blood pressure and heart rate were monitored with a pneumatic tail cuff device. Blood pressure measurements were repeated on days 18, 20, and 21 of pregnancy. Blood was obtained on days 17 and 21, along with urine, to assess magnesium levels and degree of proteinuria. Pups were weighed and measured at 48 hours postpartum. RESULTS: Rats receiving L-NAME developed hypertension within 24 hours of implantation (108 +/- 3.9 vs. 123 +/- 3.4 mmHg, p < 0.05). Magnesium sulfate, given along with L-NAME did not prevent mean blood pressure from increasing, but reduced it by day 21 compared to L-NAME given alone (107 +/- 3.4 vs. 122 +/- 8.7 mmHg, respectively, p < 0.05). Magnesium sulfate reduced neonatal growth retardation by improving the weight of the pups compared to pups from maternal rats given L-NAME alone (6.1 +/- 0.1 vs. 5.2 +/- 0.3 grams, respectively, p < 0.05). CONCLUSION: Maternal magnesium sulfate reduces blood pressure and increases neonatal size compared to L-NAME without magnesium. These findings support a beneficial effect of magnesium in preeclampsia.     

The effect of raloxifene on the uterine weight response in immature mice exposed to 17beta-estradiol, 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane, and methoxychlor

OBJECTIVE: The purpose of this study was to determine the effects of raloxifene on the uterine responses to both estradiol and the environmental estrogens 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane and methoxychlor in immature mice.Study Design: Immature female mice received the following compounds alone or in combination: sesame oil (control), 17beta-estradiol 1 mg/kg body weight, tamoxifen 1 mg/kg body weight, raloxifene 5 mg/kg body weight, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane 10 mg/kg body weight, and methoxychlor 10 mg/kg body weight. The animals were treated subcutaneously once a day for 5 consecutive days with the compound or compounds of interest in 0.1 mL sesame oil. Approximately 24 hours after the final treatment the animals were killed and the uteri were excised, stripped of remaining fat and mesentery, and weighed. Groups were analyzed with analysis of variance. RESULTS: Estradiol increased the mean (+/-SE) weight from 20 +/- 6.4 mg (as measured in the control group) to 77 +/- 6.2 mg. Tamoxifen increased uterine weight to 60 +/- 6.2 mg; however, raloxifene had no effect on uterine weight. Both 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane and methoxychlor increased uterine weight significantly, to 82 +/- 2.4 mg and 35 +/- 6.0 mg respectively. When raloxifene was coadministered with 17beta-estradiol it did not block the increase in uterine weight; however, when raloxifene was coadministered with 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane or methoxychlor, it completely blocked the uterine weight gain induced by either xenoestrogen. CONCLUSION: Raloxifene blocked the xenoestrogens 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane and methoxychlor but did not block 17beta-estradiol in the mouse model described. These results suggest that the xenoestrogens exert their estrogenic activities through a different site on the estrogen receptor or through a different mechanism than 17beta-estradiol.     

Ovine fetal lung fluid response to intravenous saline solution infusion: fetal atrial natriuretic factor effect

The fetal lung, a significant source of in utero fluid production, has been postulated to serve a regulatory role in maintenance of fetal body fluid homeostasis. Whereas the fetus responds to intravascular saline solution infusions with increased urine output, the fetal lung fluid response to this stimulus is unclear. Tracheal fluid output was measured in four chronically catheterized ovine fetuses (mean gestation, 129 +/- 1 days) subjected to successive 40-minute intravenous 0.9% saline solution infusions at rates of 0.5 and 1 ml/min/per kilogram of body weight. Tracheal fluid output decreased significantly (1.7 +/- 0.1 to 1.1 +/- 0.1 ml/10 min, p less than 0.01) during the infusion and returned to basal levels during the recovery period. Lung fluid osmolality and electrolyte concentration did not change. Fetal plasma atrial natriuretic factor increased significantly in response to the saline solution infusion (364 +/- 90 to 790 +/- 286 pg/ml, p less than 0.05) and returned to basal levels during the recovery period. There was a significant inverse correlation between plasma atrial natriuretic factor levels and tracheal fluid output. These results suggest that increased fetal plasma atrial natriuretic factor decreases lung fluid production. Lung fluid does not appear to compensate for fetal body water excess. Rather, lung fluid production appears to promote intrauterine pulmonary growth and to facilitate the transition to the extrauterine environment.     

Effects of saline instillation during tracheal suction on lung mechanics in newborn infants.

To evaluate the effect of saline instillation prior to tracheal suction on lung mechanics in mechanically ventilated newborn infants, we studied pulmonary mechanics in nine infants with respiratory distress syndrome (RDS) and nine infants with meconium-aspiration syndrome (MAS) at a mean postnatal age of 3 days. Pulmonary mechanics were measured at 10 minutes prior to, and at 10, 20, and 30 minutes after tracheal suction with saline instillation. Suction and study protocol were repeated within 12 hours without saline instillation. The sequence of the study with and without saline instillation was randomly assigned. In infants with RDS, tracheal suction had no effect on pulmonary compliance or airway resistance with and without saline instillation. In infants with MAS, there was no change in compliance after tracheal suction with and without saline instillation. Airway resistance decreased by 35% after tracheal suction with saline instillation in infants with MAS; tracheal suction without saline instillation had no effect on airway resistance. We conclude that saline instillation into trachea as commonly done during tracheal suction has no deleterious effects on lung mechanics in newborn infants.     

Preterm lung function after retreatment with antenatal betamethasone in preterm lambs

OBJECTIVE: We hypothesized that two doses of betamethasone administered 1 week apart would further enhance postnatal pulmonary function in preterm lambs (compared with a single dose).STUDY DESIGN: Fetal sheep (121 days' gestation) randomly received saline solution or betamethasone (0.5 mg/kg) as a single injection. Six days later fetal sheep were retreated with either saline solution or corticosteroid, and postnatal lung function was evaluated 1 day later.RESULTS: Betamethasone improved compliance and ventilation efficiency index nearly 50%, and total lung volume increased twofold. No effects of treatment-to-delivery interval (1 vs 7 days) or corticosteroid retreatment on pulmonary function were apparent. Although surfactant pool sizes increased as a function of duration of exposure, no additional effect of corticosteroid retreatment was noted. Antenatal betamethasone increased messenger ribonucleic acid levels for the surfactant proteins A and C, and retreatment augmented surfactant protein B messenger ribonucleic acid levels but suppressed surfactant protein A and C messenger ribonucleic acid.CONCLUSION: Improved postnatal lung function resulting from antenatal betamethasone was not augmented by retreatment. (Am J Obstet Gynecol 1997;176:308-15.)